Preparation method of 7-bromopyrrolo [2, 1-f][1, 2, 4] thiazine-4-amine

A technology of bromopyrrole and thiazide, which is applied in the field of chemical synthesis of drugs, can solve the problems of harsh reaction conditions, expensive raw materials, and high prices, and achieve the effects of mild reaction conditions, high yield and purity, and reduced prices

Inactive Publication Date: 2020-02-28
CHENGDU AF BIOCHEM
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

GS-441524 is a nucleoside drug in the experimental stage. It has inhibitory effect on a variety of RNA viruses. Its synthesis is as difficult as GC376, but its dosage is much lower than GC376. What is even more surprising is that this compound can pass through the blood The brain barrier, that is to say, also has a control effect on cases of neurological symptoms. In the future, 3C protease inhibitors, nucleosides, and MS-02 (to prevent the virus from adsorbing target cells) will be used at the same time. Compounds with different mechanisms will be used at the same time. Will overcome FIP
[0003] And 7-bromopyrrolo[2,1-f][1,2,4]thiazin-4-amine is an important intermediate for the synthesis of GS441524. ][1,2,4]The preparation method of thiazin-4-amine has relatively expensive raw materials, more intermediate by-products, and extremely high yield of finished products, and the reaction conditions are relatively harsh, so large-scale production cannot be realized, resulting in GS- The high price of 441524 seriously restricts the research process of FIP

Method used

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  • Preparation method of 7-bromopyrrolo [2, 1-f][1, 2, 4] thiazine-4-amine
  • Preparation method of 7-bromopyrrolo [2, 1-f][1, 2, 4] thiazine-4-amine
  • Preparation method of 7-bromopyrrolo [2, 1-f][1, 2, 4] thiazine-4-amine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] In this example, intermediate I, namely 1-Boc-1-aminopyrrole, was synthesized from tert-butyl carbazate and 2,5-dimethoxytetrahydrofuran as raw materials.

[0019] Concrete synthetic route is as follows:

[0020]

[0021] The specific synthesis method is:

[0022] Add 1000g of tert-butyl carbazate (7.6mol, 1.0eq), 1100g of 2,5-dimethoxytetrahydrofuran (8.3nol, 1.09eq), and 8L of solvent into a 20L three-necked flask. After stirring evenly, slowly add an equivalent With 100 mL of 2N hydrochloric acid, the temperature was slowly raised to 90°C for 10 h. The reaction was monitored, and when the reaction of the raw materials was completed, the heating was stopped, the temperature was lowered to 20° C., and 16 L of water was added and stirred to precipitate a solid. Suction filtration, the filter cake was washed with water and dissolved with dichloromethane; the dichloromethane phase was washed with saturated brine and then filtered through a silica gel column, the filt...

Embodiment 2

[0029] In this example, intermediate I prepared in the above example was reacted with isocyanate methanesulfonate to synthesize intermediate II, namely 1-Boc-1-amino-(9ci)-1H-pyrrole-2-carbonitrile.

[0030] Concrete synthetic route is as follows:

[0031]

[0032] The specific synthesis method is as follows:

[0033] Under the protection of an inert gas, add 1000g of intermediate I (5.49mol, 1.0eq) and 10L of anhydrous acetonitrile into a 20L three-necked flask, stir well and cool down to 0°C, slowly add 500ml of chlorosulfonyl isocyanate dropwise (5.77mol, 1.05eq). Keep the internal temperature below 5°C, and a white suspension can be observed in about 20 minutes. After 30 min, 1 L of anhydrous DMF was added, and the reaction solution became clear. Keep the reaction at 0°C for 30min. After the reaction, the reaction solution was poured into a mixture of ice water and ethyl acetate, stirred and separated; the organic phase was sequentially washed with saturated sodium b...

Embodiment 3

[0039] In this example, the intermediate II prepared in the above example was deaminated and protected under acidic conditions to obtain intermediate III, namely 1-amino-(9ci)-1H-pyrrole-2-carbonitrile hydrochloride.

[0040] Concrete reaction route is as follows:

[0041]

[0042] The specific preparation method is:

[0043] Add 1000g of compound II (4.83mol, 1.0eq) and 3L of anhydrous ethyl acetate into a 20L three-necked flask, stir to dissolve, and cool down to 0°C to obtain a reaction solution for later use; use acid as the solute and ethyl acetate as the solvent to prepare 5 L of ethyl acetate solution with a concentration of 1 mol / l was completely added to the prepared reaction solution. The reaction was kept at 0°C, and a large amount of white solid was observed to be produced after 30 minutes. After the reaction was monitored by TLC, it was suction filtered, and the residue was washed with anhydrous ethyl acetate and dried in vacuo to obtain 680 g of a white soli...

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Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of 7-bromopyrrolo [2, 1-f][1, 2, 4] thiazine-4-amine, which comprises the followingsteps: 1) synthesizing an intermediate I, namely 1-Boc-1-aminopyrrole, by taking tert-Butyl carbazate and 2, 5-dimethoxytetrahydrofuran as raw materials; 2) enabling the intermediate I to react withan isocyanate methanesulfonate to synthesize an intermediate II, namely 1-Boc-1-amino-(9ci)-1H-pyrrole-2-carbonitrile; 3) performing deamination protection on the intermediate II under an acidic condition to obtain an intermediate III, namely 1-amino-(9ci)-1H-pyrrole-2-carbonitrile hydrochloride; 4) performing a ring closing reaction on the intermediate III and formamidine acetate to obtain an intermediate IV, namely 4-aminopyrrolo [2, 1-f] [1, 2, 4] triazine; and 5) reacting the intermediate IV with a bromination reagent to obtain a final product, namely 7-bromopyrrolo [2, 1-f] [1, 2, 4] thiazine-4-amine. The preparation method disclosed by the invention has the advantages of cheap and easily available raw materials, few reaction steps, high yield, mild reaction conditions and capabilityof realizing large-scale production.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis of drugs, in particular to a preparation method of 7-bromopyrrolo[2,1-f][1,2,4]thiazin-4-amine. Background technique [0002] Feline infectious peritonitis (FIP) is one of the chronic viral infections in cats, and GS-441524 is the second targeted antiviral drug for the treatment of FIP after GC376. Experiments have shown that GS-441524 is more potent than GC376 against naturally occurring FIP. GS-441524 is a nucleoside drug in the experimental stage. It has inhibitory effect on a variety of RNA viruses. Its synthesis is as difficult as GC376, but its dosage is much lower than GC376. What is even more surprising is that this compound can pass through the blood The brain barrier, that is to say, also has a control effect on cases of neurological symptoms. In the future, 3C protease inhibitors, nucleosides, and MS-02 (to prevent the virus from adsorbing target cells) will be used at the s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 张卓申茂赵林吉
Owner CHENGDU AF BIOCHEM
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