CN111909153B

CN111909153B - Synthesis process of 7-iodopyrrolo [2,1-F ] [1,2,4] triazin-4-amine

Info

Publication number: CN111909153B
Application number: CN202010299569.8A
Authority: CN
Inventors: 李伟; 李光跃; 薛建军; 翟鑫; 李国侯; 刘少杰; 韩帅
Original assignee: Weihai Zhongteng Pharmaceutical Technology Co ltd; Shandong Luxi Pharmaceutical Co ltd
Current assignee: Weihai Zhongteng Pharmaceutical Technology Co ltd; Shandong Luxi Pharmaceutical Co ltd
Priority date: 2020-04-16
Filing date: 2020-04-16
Publication date: 2021-11-19
Anticipated expiration: 2040-04-16
Also published as: CN111909153A

Abstract

The invention belongs to the technical field of chemical synthesis of medicines, and relates to a synthesis process of 7-iodopyrrolo [2,1-F ] [1,2,4] triazine-4-amine. The invention takes 2, 5-dimethoxy tetrahydrofuran and acethydrazide as initial raw materials and is obtained by substitution, cyanation, deacetylation, cyclization and iodination. The preparation method is simple, the starting raw materials are 2, 5-dimethoxy tetrahydrofuran and acethydrazide, the price is low, the raw materials are easy to obtain, the yield of the four steps of reaction reaches more than 85%, the productivity is greatly improved, the total yield of the product is more than 50%, and the purity can reach more than 99%. Meanwhile, the intermediate product has good quality, so that the dosage of formamidine acetate is reduced when the intermediate IV is prepared. Compared with the traditional process route, the route has obvious advantages through experimental comparison.

Description

Synthesis process of 7-iodopyrrolo [2,1-F ] [1,2,4] triazin-4-amine

Technical Field

The invention belongs to the technical field of chemical synthesis of medicines, and relates to a synthesis process of 7-iodopyrrolo [2,1-F ] [1,2,4] triazine-4-amine.

Background

The 7-iodopyrrolo [2,1-F ] [1,2,4] triazine-4-amine is an amine organic matter and can be used as an intermediate of various raw material medicaments. Has wide application. The traditional synthetic route of 7-iodopyrrolo [2,1-F ] [1,2,4] triazine-4-amine mainly adopts 2-pyrrole formaldehyde and hydroxylamine sulfonic acid as starting materials, a large amount of excessive hydroxylamine sulfonic acid is used in the reaction process, the 2-pyrrole formaldehyde is not completely reacted, and a large amount of impurities are generated in the reaction process. In the post-reaction treatment process, the extraction and secondary filtration are carried out for 4-5 times, the operation is very complicated, and the working hours are very long. The obtained product has poor state, is a black oily substance, wraps more impurities, and has low yield and high cost. The content of the reaction liquid needs to be measured before the feeding of the second step reaction every time, and the operation steps are increased. In the second reaction step, the excess of formamidine acetate added is large, generally about 3eq, which further increases the cost.

Therefore, various factors which are unfavorable for production exist in the existing synthetic method, and a synthetic method of 7-iodopyrrolo [2,1-F ] [1,2,4] triazin-4-amine which is environment-friendly, low in cost and high in yield is to be developed to replace the traditional synthetic method.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention designs a new synthetic route of 7-iodopyrrolo [2,1-F ] [1,2,4] triazin-4-amine (compound I), the route completely abandons the dependence on hydroxylamine oxysulfonic acid, and the environmental protection property is greatly improved.

The invention is realized by the following technical scheme:

the compound is prepared by using 2, 5-dimethoxy tetrahydrofuran and acethydrazide as starting materials and performing substitution, cyanation, deacetylation, cyclization and iodination reactions.

Specifically, the method comprises the following steps:

(1) carrying out substitution reaction on 2, 5-dimethoxy tetrahydrofuran and acethydrazide to obtain an intermediate I;

(2) subjecting the intermediate I to cyanation to obtain an intermediate II;

(3) deacetylating the intermediate II to obtain an intermediate III;

(4) cyclizing the intermediate III and formamidine acetate to obtain an intermediate IV;

(5) and iodinating the intermediate IV to obtain the compound I.

In the step (1), the selected solvent is one of DMF, tetrahydrofuran and dioxane;

the mass ratio of the 2, 5-dimethoxy tetrahydrofuran to the acethydrazide is 1:1, and the reaction temperature is 100-.

In the step (2), the selected solvent is DMF, and the selected reagents are oxalyl chloride and hydroxylamine;

the temperature of the oxalyl chloride is controlled to be 20-25 ℃, and the reaction temperature is 80-100 ℃.

In the step (3), concentrated hydrochloric acid or 40% sodium hydroxide solution or 40% potassium hydroxide solution is selected, and the reaction temperature is 90-100 ℃.

In the step (4), the selected reagent is one of methanol, ethanol and butanol;

the mass ratio of the intermediate III to the formamidine acetate is 1:2.8-2.9, and the reaction temperature is 75-80 ℃.

In step (5), DMF is used as solvent, and N-iodosuccinimide (NIS) is added at a temperature below 8 deg.C, preferably 3-8 deg.C.

The preparation method is simple, the starting raw materials are 2, 5-dimethoxy tetrahydrofuran and acethydrazide, the price is low, the raw materials are easy to obtain, the yield of the four steps of reaction reaches more than 85%, the productivity is greatly improved, the total yield of the product is more than 50%, and the purity can reach more than 99%. Meanwhile, the intermediate product has good quality, so that the dosage of formamidine acetate is reduced when the intermediate IV is prepared. Compared with the traditional process route, the route has obvious advantages through experimental comparison.

Detailed Description

Example 1

Preparation of intermediate I

Adding 13.2Kg of 2, 5-dimethoxy tetrahydrofuran and 7.4Kg of acethydrazide into a reaction kettle while stirring, adding 50Kg of dioxane, heating to 100-105 ℃, keeping the temperature for reaction for 4h, slowly cooling to 10-15 ℃, separating out solids, carrying out suction filtration after keeping the temperature for 1h, washing a filter cake with 5Kg of water, carrying out forced air drying on the filter cake at 50 ℃ for 8h, weighing 11.8Kg, and obtaining the yield of 95.2%.

Example 2

Preparation of intermediate II

Adding 50Kg of DMF into a reaction kettle, sequentially adding 12.4Kg of intermediate 3.6Kg of hydroxylamine under stirring, dropwise adding 13.9Kg of oxalyl chloride at 20-25 ℃, heating to 80 ℃, keeping the temperature for reaction for 3h, closing, heating and cooling to 30 ℃, quickly dropwise adding 100Kg of water into the reaction kettle, continuously stirring for 1h, centrifuging, washing a filter cake with 10Kg of water, drying the filter cake by blowing at 80 ℃ for 12h to obtain a light yellow solid, weighing 13.5Kg of the light yellow solid, and obtaining the yield of 90.6%.

Example 3

Preparation of intermediate III

Weighing 100Kg of concentrated hydrochloric acid, adding into a reaction kettle, adding 14.3Kg of intermediate II under stirring, heating to reflux, stirring for 3h, cooling and stirring to 5-10 ℃, keeping the temperature and stirring for 1h, centrifuging, washing the filter cake with 10Kg of water, and drying at 80 ℃ for 10h to obtain light yellow solid, weighing 12.8Kg, with the yield of 95.5%.

Example 4

Preparation of intermediate IV

6 liters of absolute ethyl alcohol is added into a reaction kettle, 1.43Kg of intermediate III and 3.0Kg of formamidine acetate are added, the reaction system is heated to reflux, and the reflux is kept for 10-15 hours. After the reaction is finished, the temperature is controlled below 50 ℃, and the distillation is carried out under reduced pressure until the liquid does not flow basically. Adding 4 liters of water, stirring, cooling to 20-25 ℃, filtering, and leaching a filter cake once by using 0.9 liter of water. Vacuum drying at 50 deg.c to obtain yellow solid 1.20Kg in 90.0% yield.

Example 5

Preparation of Compound 1

And adding 0.8kg of intermediate IV and 4.8 liters of DMF into the reaction kettle, and stirring at 20-25 ℃ for clarification. The temperature of the reaction system is reduced to 3-8 ℃, and then 1.343kg of NIS is added. Stirring for 4 h. The reactor was added to an aqueous solution of sodium hydroxide (sodium hydroxide 1.2k g, water 20 liters) at 20-25 degrees. The resulting suspension is stirred at 20 to 25 ℃ for about 1 hour. Filtration and the filter cake washed twice with 2 liters of water. The obtained wet product is dried by blowing air at the temperature of not higher than 55 ℃ for 8 hours to obtain 1.24kg of product. 1.24k of the dried filter cake was added to 6 liters of MTBE and stirred at 20-25 ℃ for 1 h. Filtration and the filter cake rinsed once with 1 liter of MTBE. The obtained filter cake is dried for 8 hours under vacuum at the temperature of not higher than 55 ℃, and a white-like product of 1.18kg is obtained. The yield was 76.1% and the purity was 99.5%.

Claims

The synthesis process of 1.7-iodopyrrolo [2,1-F ] [1,2,4] triazin-4-amine is characterized in that 2, 5-dimethoxytetrahydrofuran and acethydrazide are used as starting materials and are obtained through substitution, cyanation, deacetylation, cyclization and iodination reactions, and the specific steps are as follows:

(1) carrying out substitution reaction on 2, 5-dimethoxy tetrahydrofuran and acethydrazide to obtain an intermediate I;

(2) subjecting the intermediate I to cyanation to obtain an intermediate II;

(3) deacetylating the intermediate II to obtain an intermediate III;

(4) the intermediate III is cyclized to obtain an intermediate IV;

(5) iodinating the intermediate IV to obtain a compound 7-iodopyrrolo [2,1-F ] [1,2,4] triazine-4-amine (I);

in the step (1), the selected solvent is dioxane; the mass ratio of the 2, 5-dimethoxy tetrahydrofuran to the acethydrazide is 1: 1;

in the step (2), the selected reagents are oxalyl chloride and hydroxylamine; the selected solvent is DMF; the temperature of oxalyl chloride is controlled to be 20-25 ℃, and the reaction temperature is 80-100 ℃;

in the step (3), the selected reagent is concentrated hydrochloric acid;

in the step (4), the mass ratio of the intermediate III to the formamidine acetate substance is 1: 2.8-2.9;

in the step (5), the selected solvent is DMF, NIS is added, and the temperature is controlled to be below 8 ℃;

。
2. the synthetic process of claim 1 wherein the reaction scheme is:

intermediate I intermediate II

Intermediate III intermediate IV compound I.
3. The process as claimed in claim 1, wherein in step (1), the reaction temperature is 100-105 ℃.
4. The process of claim 1, wherein in step (3), the reaction temperature is 90-100 ℃.
5. The process of claim 1, wherein in step (4), the selected reagent is one of methanol, ethanol and butanol.
6. The process of claim 1, wherein in step (4), the reaction temperature is 75-80 ℃.
7. The process of claim 1, wherein in step (5), the temperature is 3-8 ℃.