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Method for preparing 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine

A technology for the preparation of imidazole bromide, applied in the field of drug synthesis, can solve the problems of low yield, incapable of large-scale production, and many intermediate by-products, and achieve the effects of high yield, high yield and simple operation

Active Publication Date: 2014-10-08
PHARMABLOCK SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves technical problems such as low yield, many intermediate by-products, and inability to mass-produce existing synthetic methods.

Method used

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  • Method for preparing 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine
  • Method for preparing 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine
  • Method for preparing 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Synthesis of Compound XI

[0026]

[0027] In a 10L four-neck flask, add compound IX (179.7g, 1.93mol, 1.0eq.), dissolve THF (3L), cool down to about 0°C in an ice-water bath, and add potassium tert-butoxide (1083.3g, 9.65mol, 5.0eq.), the reaction was heated up, stirred at room temperature for 1h, added 1.5L THF, added compound X (351.4g, 1.93mol, 1.0eq.), stirred at room temperature for 1h, added acetic acid (35g, 0.13mol, 0.3eq.) to quench Reaction, stirring for 10 min, filtration and vacuum distillation to remove the solvent, and vacuum distillation to obtain 189.0 g of compound XI, yield: 90.6%. MS(ES+APCI)M+1=109.

[0028] Synthesis of Compound XII

[0029]

[0030] In a 10L four-neck flask, add compound XI (162.2g, 1.5mol, 1.0eq.), 3.5L of ethanol, add formamidine acetate (234.2g, 2.25mol, 1.5eq.), heat up to 85°C for 16h, compound The XI reaction is complete. Cool down, remove ethanol by distillation under reduced pressure, add 1.5L of water, adjust th...

Embodiment 2

[0035] Synthesis of Compound XI

[0036]

[0037] In a 10L four-necked flask, add compound IX (179.7g, 1.93mol, 1.0eq.), dissolve 1,4-dioxane (2.5L), cool down to about 0°C in an ice-water bath, and add NaH (154.4 g, 3.86mol, 2.0eq.), the reaction was heated up, stirred at room temperature for 1h, added 1.5L 1,4-dioxane, added compound X (702.8g, 3.86mol, 2.0eq.), stirred at room temperature for 1h, GC showed the raw material Compound IX is almost completely reacted. Stir for 10 min, filter and distill under reduced pressure to remove the solvent, and then distill under reduced pressure to obtain 193.0 g of compound XI, yield: 92.5%. MS(ES+APCI)M+1=109. GC:t R =4.848 (column model: Agilent HP-50.32mm*30m0.25um, initial temperature of 80 degrees, keep for 2 minutes, increase the temperature by 40 degrees per minute, rise to the highest temperature of 300 degrees, and keep for 4 minutes).

[0038] Synthesis of Compound XII

[0039]

[0040]In a 10L four-necked flask, ...

Embodiment 3

[0045] Synthesis of Compound XI

[0046]

[0047] In a 10L four-neck flask, add compound IX (179.7g, 1.93mol, 1.0eq.), dissolve N-methylpyrrolidone (2.5L), cool down to about 0°C in an ice-water bath, add NaH (231.6g, 5.79 mol, 3.0eq.), the reaction was heated up, stirred at room temperature for 1h, added 1.5L tetrahydrofuran, added compound X (421.68g, 2.316mol, 1.2eq.), stirred at room temperature for 1h, stirred for 10min, filtered and distilled under reduced pressure to remove the solvent, and then Compound XI was obtained by distillation under reduced pressure and directly proceeded to the next reaction.

[0048] Synthesis of Compound XII

[0049]

[0050] In a 10L four-neck flask, add compound XI (208.63g, 1.93mol, 1.0eq.), 2L of N,N-dimethylformamide, add formamidine acetate (468.5g, 4.5mol, 3.0eq.), and heat up React at 110°C for 8h, and the reaction of compound XI is complete. Cool down, add 3L of water, adjust the pH to about 10 with 10N NaOH, solids precipi...

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Abstract

The invention discloses a method for preparing 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine. According to the invention, a compound IX is adopted as a a raw material, and is subjected to a reaction with a compound X under the effect of alkali, such that a compound XI is obtained; the compound XI is subjected to a ring-closing reaction with formamidine acetate, such that a compound XII is obtained; and the compound XII is subjected to a reaction with a bromination reagent, such that the compound 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine is obtained. The compound IX can be obtained through the following reactions: a compound XIII is subjected to a reaction with RCl under an alkali condition, such that a compound XIV is obtained; the compound XIV is subjected to a reaction with n-butyllithium, N,N-dimethylformamide, ammonia water and iodine, such that a compound XV is obtained; and deprotection is carried out under an acidic condition, such that the compound IX is obtained. The preparation method provided by the invention has the advantages of less reaction steps, simple operation, high yield, and mild reaction conditions. A total yield can reach 84.2%. The process route of the method is suitable for large-scale preparations.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a synthesis method of 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine. Background technique [0002] 7-Bromoimidazo[2,1-f][1,2,4]triazin-4-amine is an important intermediate in the synthesis of inhibitors of adenosine deaminase, a process in purine metabolism An important enzyme that catalyzes the irreversible deamination of adenosine and deoxyadenosine into inosine and deoxyinosine, respectively. Adenosine deaminase inhibitors are a class of compounds that can inhibit the reaction of adenosine deamination, which can regulate the level of intracellular adenosine and deoxyadenosine, affect the growth and function of lymphocytes, and can improve the chemotherapy effect of adenosine analogues. Effect. So 7-bromoimidazo[2,1-f][1,2,4]triazin-4-amine will have a good market prospect. [0003] ACS Med.Chem.Lett.2010,1,287 reported a synthesis method of 7-bromoimidazo[2,1-f][1,2,4]triazin-4-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 毛俊朱经伟舒庆宁赵树海杨民民吴希罕
Owner PHARMABLOCK SCIENCES (NANJING) INC
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