CN113336758B - Novel synthesis method of compound 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine - Google Patents

Abstract

The invention provides a method for preparing a triazine compound shown as a formula (I). The invention uses pyruvic acid andusing formamidine as a starting material to synthesize an intermediate

The compound shown in the formula (I) can be obtained through two steps of reaction. The method provided by the invention has mild conditions, is simple and convenient to operate, greatly reduces the cost, and is suitable for industrial mass production.

Description

Novel synthesis method of compound 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

Technical Field

The invention relates to a new synthesis and purification method of a compound 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazine-4-amine, belonging to the fields of chemistry and medicine.

Background

7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine (CAS number 1770840-43-1) is an important intermediate, the structure of which is a key starting material for Reidesciclovir and has the formula:

redysivir was used initially for the treatment of ebola virus disease and marburg virus infection and was later found to exhibit reasonable antiviral activity against more distantly related viruses such as respiratory syncytial virus, hunin virus, lassa fever virus and MERS. Therefore, the synthesis of the precursor fragment 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine is key for further reducing the cost and improving the productivity.

At present, the synthesis method of 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazine-4-amine is mainly a small-amount synthesis route reported by a patent (WO2007064931), wherein a compound 01 and Boc hydrazine are used as starting materials, ring closure is carried out to obtain an intermediate 02, further sulfonyl chloride isocyanate is used for cyano group on pyrrole 2 position to obtain a compound 03, further Boc protecting group is removed under acidic condition to obtain a compound 04, and ring closure is carried out with methyl ether and iodine on NIS is used for obtaining a product compound 06 (7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazine-4-amine). The detailed reaction route is shown as the following formula.

As can be seen from the above routes, the ring closing step 1 has a yield of less than 60%, and chlorosulfonic acid isocyanate used in step 2 is highly toxic and requires column chromatography for purification, so the routes are not suitable for industrial scale-up. From the viewpoint of cost, due to the compound 01 and BocN ₂ H ₄ The cost is large and the yield of step 1 is low, resulting in high overall route cost. Furthermore, we have developed the compound 7-iodopyrrolo [2, 1-f][1，2，4]The new route for triazin-4-amines is of the formula:

we used pyruvic acid and formamidine hydrochloride as starting materials, and hydrazine hydrate in ethanol under reflux to obtain triazine fragment (compound 03), and then further with bromo diethyl acetal to obtain compound 04, completing the construction of main ring. Further conversion of the hydroxyl group to chlorine using phosphorus oxychloride gives the key intermediate compound 05. Subsequently, preferential ammonolysis using compound 05 as starting material affords compound 06 with further iodination to afford product 07 (scheme A). At the same time, starting from compound 05, it is also possible to obtain compound 08 by preferential iodination and subsequent ammonolysis to obtain compound 07 (scheme B).

The method has the advantages that the yield of each step is high, the intermediate is easy to recrystallize and purify, isomers can be avoided, and accordingly, the yield and the purification difficulty are improved, and the method is favorable for industrial production. In addition, the raw materials of the route are basic chemicals, so that the price is low and easy to obtain, and the production cost of the product 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazine-4-amine is greatly reduced.

Disclosure of Invention

The invention aims to develop a novel method for preparing 7-iodopyrrolo- [2, 1-f ] [1, 2, 4] triazin-4-amine, and the method can improve the yield and reduce the production cost, so that the method is suitable for industrial mass production.

The invention provides a novel method for preparing 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine. The method comprises the following steps:

1) the intermediate shown in (II) is formed by the ring closure of pyruvic acid and formamidine under the participation of hydrazine:

2) reacting the intermediate obtained in the step 1) as shown in the formula (II) with halogenated acetaldehyde or halogenated acetal to obtain an intermediate as shown in the formula (III):

3) carrying out dehydroxylation and chlorination on the intermediate obtained in the step 2) as shown in the formula (III) to obtain an intermediate as shown in the formula (IV):

4) converting the intermediate obtained in the step 3) as shown in the formula (IV) to obtain a target compound as shown in the formula (I):

in the step 1), formamidine hydrochloride or formamidine acetate can be used.

The solubility of hydrazine hydrate used in the step 1) may be 40% to 80%, or a salt of hydrazine such as hydrazine acetate, hydrazine hydrochloride, hydrazine sulfate, or the like may be used.

In the step 1), an alcohol solvent such as ethanol, isopropanol or tert-butanol is preferably used.

The reaction temperature of the step 1) is-20 ℃ to 100 ℃.

The step 2) uses halogenated acetaldehyde or halogenated acetal.

Further, chloroacetaldehyde or bromoacetaldehyde is preferably selected.

If halogenated acetal is used in the step 2), a catalytic amount of acid is added into the reaction system.

Further, the acid may be selected from hydrochloric acid, sulfuric acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, or the like.

Further, the amount of the acid is 1 to 50% by mass of the halogenated acetal.

The dehydroxylation and chlorination reagent used in the step 3) is phosphorus oxychloride or thionyl chloride.

Further, phosphorus oxychloride is preferably used.

In the step 4), the compound (IV) can be iodo to obtain a compound (I):

or the compound (IV) is iodo firstly and then is ammonolyzed to obtain the compound (I):

further, the iodinating agent may be selected from iodine, N-iodosuccinimide, or iodine chloride.

Further, the amination reaction may use aqueous ammonia or an alcoholic solution of ammonia, preferably an alcoholic solution of ammonia.

The invention provides a method for preparing triazine compounds. The preparation method is simple and convenient, has low cost and is suitable for industrial production. Obviously, many modifications, substitutions, and alterations are possible in light of the above teachings of the invention, without departing from the basic technical ideas of the invention, as defined by the following general technical knowledge and conventional practices of the art.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Detailed Description

The starting materials and equipment used in the embodiment of the present invention are known products and are obtained by purchasing commercially available products.

Example 1: synthesis of compound 6-methyl-1, 2, 4-triazin-5 (4H) -one.

Adding an ethanol solution of formamidine hydrochloride (compound 02) and hydrazine hydrate into a reaction bottle, cooling the system to-10 ℃, then adding the compound 01 into the reaction system, and adding a trace amount of acetic acid for catalysis. And heating and refluxing the system for 5 hours, cooling and filtering after the reaction is finished, and concentrating the filtrate to be dry to obtain a crude product of the compound 03, wherein the crude product is directly used for the next reaction without purification.

Example 2: synthesis of the compound pyrrolo [2, 1-f ] [1, 2, 4] triazin-4 (3H) -one.

Adding the crude product of the compound 03 into water, then adding 2-bromo-diglycal into the system, adding trace hydrochloric acid into the system, then heating to 90 ℃ to react for 3 hours, cooling the system to room temperature after the raw materials disappear, filtering, and washing a filter cake with cold water to obtain a compound 04 (the yield of the two steps is 65%).

Example 3: synthesis of 4-chloropyrrolo [2, 1-f ] [1, 2, 4] triazine.

DIPEA and phosphorus oxychloride are added into a toluene solution of a compound 04, a system is heated to 120 ℃ to react for 24 hours, after raw materials disappear, the reaction liquid is added into ice water to be quenched, then sodium bicarbonate is added to adjust the pH value to be neutral, the system is subjected to liquid separation, an aqueous phase is extracted for 2 times by toluene, organic phases are combined, dried, filtered and concentrated to obtain the compound 05 (the yield is 93%).

Example 4: synthesis of compound 4-aminopyrrolo [2, 1-f ] [1, 2, 4] triazine

Compound 05 was dissolved in tetrahydrofuran, and then, an amine methanol solution was added to the system, the system was stirred at room temperature for 0.5 hour, then, at 50 ℃ overnight, after TLC showed disappearance of the starting material, water was added to quench the reaction, the mixture was stirred at room temperature for 2 hours, and filtered, and the cake was collected to give compound 06 (yield: 82%).

Example 5: synthesis of compound 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

Dissolving the compound 06 in dimethyl sulfoxide, adding NIS in batches, stirring the system at room temperature for 16 hours, adding water into the system to quench the reaction after TLC identification of the disappearance of the raw materials, continuing stirring for 2 hours, filtering the system, and collecting a filter cake to obtain a compound 07 (yield: 75%)

Example 6: synthesis of compound 4-chloro-7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazine

Dissolving Compound 05 in anhydrous dichloromethane, adding NIS, stirring at room temperature for 16 hr, TLC monitoring for disappearance of raw material, filtering, collecting filtrate, washing filtrate with sodium sulfite aqueous solution twice, collecting organic phase, drying organic phase, filtering, collecting filtrate, and concentrating to obtain Compound 06 (yield: 75%)

Example 7: synthesis of compound 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine

Dissolving the compound 05 in tetrahydrofuran, adding an amine methanol solution, stirring the reaction at room temperature for 2 hours after the addition is finished, heating to 55 ℃ for reaction for 16 hours, adding water to quench the reaction after TLC (thin layer chromatography) monitors that raw materials disappear, removing an organic phase by concentrating the mixture under reduced pressure, adding ethanol into the system, pulping for 2 hours, filtering, and collecting a filter cake to obtain the compound 07 (yield: 81%).

Claims (2)

1. A preparation method of triazine compounds shown in formula (I),

the method is characterized by comprising the following steps:

1) the intermediate shown in (II) is formed by the ring closure of pyruvic acid and formamidine under the participation of hydrazine:

2) reacting the intermediate obtained in the step 1) and shown in the formula (II) with halogenated acetaldehyde or halogenated acetal to obtain an intermediate shown in the formula (III):

3) carrying out dehydroxylation and chlorination on the intermediate obtained in the step 2) as shown in the formula (III) to obtain an intermediate as shown in the formula (IV):

4) converting the intermediate obtained in the step 3) as shown in the formula (IV) to obtain a target compound as shown in the formula (I):

in the step 4), the compound (IV) can be converted into an amino intermediate and then iodo to obtain a compound (I):

or the compound (IV) is iodo firstly and then is ammonolyzed to obtain the compound (I):

2. the method as set forth in claim 1, wherein the dehydroxychlorination reagent used in step 3) is phosphorus oxychloride or thionyl chloride.