CN100463907C - A kind of preparation method of 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine}piperazine - Google Patents

Abstract

The invention discloses a preparation method of 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine}piperazine , which is prepared by the reaction of 5-nitro-1H-indole-2-acyl chloride and 1-{3-[(1-methylethyl)amino]-2-pyridine}piperazine in a solvent. The preparation method of the invention has low cost, environmental protection and is suitable for industrial scale production.

Description

A kind of preparation method of 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine}piperazine

technical field

The invention relates to a preparation method of 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine}piperazine.

Background technique

The compound 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine}piperazine is currently a non-nucleoside reverse transcriptase inhibitor An important intermediate of anti-AIDS drug Delavirdine and an important intermediate of non-nucleoside reverse transcriptase inhibitor piperazine derivatives.

Patents WO9109849, WO9301181 and WO9726880 disclose compound 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine}piper The synthetic technique of oxazine is based on formula IV compound 5-nitro-1H-indole-2-carboxylic acid and formula III compound 1-{3-[(1-methylethyl)amino]-2-pyridine}piper Oxyzine is a raw material, tetrahydrofuran is a solvent, reacts under the action of condensing agent 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (abbreviated as EDC), dissolves in chloroform after the reaction, and passes through Saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution are washed, dried, obtain formula I compound 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[( 1-methylethyl)amino]-2-pyridine}piperazine. Its reaction formula is:

The disadvantages of this synthesis process are:

Using 5-nitro-1H-indole-2-carboxylic acid and 1-{3-[(1-methylethyl)amino]-2-pyridine}piperazine as raw materials, the two are used in the condensation reaction The condensing agent 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (abbreviated as EDC) is expensive and makes the production of 1-(5-nitro-1H-indole-2 The cost of -carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine}piperazine is relatively high, and the economic benefit is poor. Chloroform is also used as an extraction reagent in the post-treatment purification step, and chloroform is not only harmful to the environment, but also pollutes the water body, making it difficult to treat the three wastes, and can act on the central nervous system of the human body, causing damage to the human heart, liver, Kidneys are damaged, and chloroform is generally not suitable for use as an extraction reagent in the production process. In addition, purification requires column chromatography, which is not suitable for industrial scale production.

Contents of the invention

The technical problem to be solved in the present invention is to overcome the defects of the above-mentioned prior art and provide a low-cost, suitable for large-scale production of 1-(5-nitro-1H-indole-2-carbonyl)-4-{3 - Novel preparation of [(1-methylethyl)amino]-2-pyridine}piperazine.

The concrete technical scheme of the present invention is: with 5-nitro-1H-indole-2-acyl chloride (II) and 1-{3-[(1-methylethyl)amino]-2-pyridine}piperazine ( III) as a raw material, react in a solvent to obtain compound 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine } piperazine (I), its reaction formula is as follows:

In a preferred embodiment of the present invention, the compound of formula II is placed in a solvent, and added dropwise to a mixed solution composed of compound of formula III, solvent and weakly basic reagent. The alkaline reagent mainly plays a catalytic role, and organic bases such as triethylamine, tripropylamine, pyridine, etc., or basic inorganic salts such as sodium carbonate and potassium carbonate can be used; if the amount of the weakly alkaline reagent is too small, the reaction time will If it is too long and the reaction is not complete, otherwise too much will increase the cost and increase the post-treatment work, so the preferred molar ratio of the compound with the minimum molar amount of the compound of formula II or formula III is 1:3-10.

Wherein, the above-mentioned solvent is selected from one or any two of dichloromethane, dimethylformamide (DMF), and dioxane.

The molar dosage ratio of the two raw materials is formula II compound 5-nitro-1H-indole-2-acyl chloride: formula III compound 1-{3-[(1-methylethyl)amino]-2-pyridine}piper The ratio of azine is 1:0.2~5.

The reaction temperature of the present invention is 0-40° C., and the reaction time is 2-16 hours.

Preferably, the present invention adopts the following purification steps for environmental protection requirements and suitability for industrialized production: adding water and methylene chloride to the crude reactant, adjusting the reaction solution to a pH of 9-11 with 2N aqueous sodium hydroxide solution, and dividing The organic layer was taken out; the organic layer was adjusted to pH 2-4 with 2N hydrochloric acid, filtered, and the filtrate was separated from the organic layer, and the aqueous layer was extracted twice with dichloromethane, and the organic layers were combined, followed by saturated aqueous sodium bicarbonate solution, saturated Wash with aqueous sodium chloride; concentrate the organic phase under reduced pressure.

The invention solves the disadvantages of high cost and unsuitable for large-scale production in the prior art, has the advantages of low cost, suitable for large-scale production, and is environmentally friendly.

Detailed ways

The present invention will be further illustrated below by way of examples, but the present invention is not limited thereto.

Wherein, formula II compound 5-nitro-1H-indole-2-acyl chloride in the following examples can be synthesized according to the literature [Khim.-Farm.Zh., 19 (9), 1075-8 (Russia) 1985], specifically Formula IV compound 5-nitro-1H-indole-2-carboxylic acid reacts with thionyl chloride to generate formula II compound 5-nitro-1H-indole-2-acyl chloride

Wherein formula IV compound 5-nitro-1H-indole-2-carboxylic acid is according to literature (Parmerter, S.M.; Cook, G.; Dixon, W.B.J.Am.Chem Soc.1958,80,4621-4622; Rydon, H.N. ; Siddappa, S..J.Chem.Soc., 1951,2462-2467) method synthesis, specifically p-nitroaniline and sodium nitrite and hydrochloric acid, to obtain p-nitrobenzene diazonium salt (b), Compound b and ethyl α-methyl acetoacetate generate hydrazone (c), compound c is cyclized in polyphosphoric acid to obtain ethyl 5-nitro-1H-indole-2-carboxylate (d), compound d is hydrolyzed It is the compound of formula IV 5-nitro-1H-indole-2-carboxylic acid (the reaction formula is as follows).

Compound 1-{3-[(1-methylethyl)amino]-2-pyridine}piperazine in the above-mentioned examples is synthesized according to the method in the literature (WO9109849 and WO8808424A1), specifically 2-chloro-3-nitro Base pyridine and anhydrous piperazine generate 2-(1-piperazine)-3-nitropyridine (e) under the catalysis of potassium carbonate, and compound e is hydrogenated and reduced to obtain 3-amino-2-(1-piperazine) pyridine (f), compound f reacts with di-tert-butyl dicarbonate ((Boc) ₂ O) to generate 1-[1,1-dimethylethoxycarbonyl]-4-[3-amino-2-pyridine]piperazine (g), compound g was dissolved in methanol, added acetone, cooled to zero, adjusted to pH 4.0 with acetic acid, added cyanide sodium borohydride to obtain 1-[1,1-dimethylethoxycarbonyl]-4-[ 3-(1-methylethyl)amino]-2-pyridine)piperazine (h), then use trifluoroacetic acid deprotection group to obtain formula III compound 1-{3-[(1-methylethyl) Amino]-2-pyridine}piperazine (the reaction formula is as follows).

Reagents not specified are all commercially available chemically pure.

Example 1:

4 g (0.018 mol) of 1-{3-[(1-methylethyl)amino]-2-pyridine}piperazine was added to 100 ml of dichloromethane, and 20 ml of triethylamine was added. 0～5℃, add dropwise the dichloromethane/DMF solution of 5-nitro-1H-indole-2-acyl chloride [5.5 g (0.025mol) of 5-nitro-1H-indole-2-acyl chloride + dichloro Methane 50ml+DMF 10ml]. 3～7℃, react for 2～6 hours. 100 ml of water and 50 ml of dichloromethane were added, the reaction solution was adjusted to pH 9-10 with 2N aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was adjusted to pH 2-4 with 2N hydrochloric acid. After filtration, the filtrate was separated into an organic layer, and the aqueous layer was extracted with dichloromethane (100 ml×2). The combined organic layers were washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic phase was concentrated under reduced pressure to obtain 4.2 g of 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine}piperazine , Yield: 57%.

Example 2:

4 g (0.018 mol) of 1-{3-[(1-methylethyl)amino]-2-pyridine}piperazine was added to 100 ml of dichloromethane, and 7 g of potassium carbonate was added. 0～5℃, add dropwise the dichloromethane/DMF solution of 5-nitro-1H-indole-2-acyl chloride [5.5 g (0.025mol) of 5-nitro-1H-indole-2-acyl chloride + dichloro Methane 50ml+DMF 10ml]. 20～25℃, react for 12～16 hours. 100 ml of water and 50 ml of dichloromethane were added, the reaction solution was adjusted to pH 10-11 with 2N aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was adjusted to pH 2-4 with 2N hydrochloric acid. After filtration, the filtrate was separated into an organic layer, and the aqueous layer was extracted with dichloromethane (100 ml×2). The combined organic layers were washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic phase was concentrated under reduced pressure to obtain 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine}piperazine.

Example 3:

5.5 g (0.025 mol) of 1-{3-[(1-methylethyl)amino]-2-pyridine}piperazine was added to 20 ml of DMF, and 7 ml of triethylamine was added. 0～5℃, add dropwise the DMF solution of 5-nitro-1H-indole-2-acyl chloride [5-nitro-1H-indole-2-acyl chloride 2.25 g (0.010 mol) + DMF 15 ml]. 35～40℃, react for 3～6 hours. 100 ml of water and 200 ml of dichloromethane were added, the reaction solution was adjusted to pH 9-10 with 2N aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was adjusted to pH 2-4 with 2N hydrochloric acid. After filtration, the filtrate was separated into an organic layer, and the aqueous layer was extracted with dichloromethane (100 ml×2). The combined organic layers were washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic phase was concentrated under reduced pressure to obtain 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine}piperazine.

Example 4:

11 g (0.050 mol) of 1-{3-[(1-methylethyl) amino]-2-pyridine}piperazine was added to a mixed solution consisting of 90 ml of dichloromethane and 10 ml of DMF, and 5 ml of pyridine was added . 0～5℃, add dropwise the dichloromethane/DMF solution of 5-nitro-1H-indole-2-acyl chloride [5-nitro-1H-indole-2-acyl chloride 2.25 g (0.010mol) + dichloro Methane 20 ml + DMF 5 ml]. 0～5℃, react for 4～8 hours. 100 ml of water and 50 ml of dichloromethane were added, the reaction solution was adjusted to pH 9-10 with 2N aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was adjusted to pH 2-4 with 2N hydrochloric acid. After filtration, the filtrate was separated into an organic layer, and the aqueous layer was extracted with dichloromethane (100 ml×2). The combined organic layers were washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic phase was concentrated under reduced pressure to obtain 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine}piperazine.

Example 5:

1.1 g (0.005 mol) of 1-{3-[(1-methylethyl)amino]-2-pyridine}piperazine was added to 30 ml of dioxane, and 10 ml of tripropylamine was added. 0～5℃, add dropwise the dioxane/DMF solution of 5-nitro-1H-indole-2-acyl chloride [5.5 g (0.025mol) of 5-nitro-1H-indole-2-acyl chloride + di Oxycycline 20ml+DMF 10ml]. 20～25℃, react for 6～10 hours. 100 ml of water and 200 ml of dichloromethane were added, the reaction solution was adjusted to pH 9-10 with 2N aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was adjusted to pH 2-4 with 2N hydrochloric acid. After filtration, the filtrate was separated into an organic layer, and the aqueous layer was extracted with dichloromethane (100 ml×2). The combined organic layers were washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic phase was concentrated under reduced pressure to obtain 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine}piperazine.

The identification data of the compound prepared in the above examples: mp: 152-154°C, m/z=408, consistent with the relevant data published in the literature.

Claims (8)

1. A preparation of formula I compound 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine}piperazine Method, it is reacted in solvent by formula II compound and formula III compound should be made. 2. The preparation method according to claim 1, characterized in that the compound of formula II is placed in a solvent and added dropwise to the mixed solution composed of compound of formula III, solvent and weakly alkaline reagent. 3. The preparation method according to claim 2, characterized in that the alkaline reagent is an organic base or a basic inorganic salt. 4. preparation method as claimed in claim 3 is characterized in that this organic base is selected from triethylamine, tripropylamine and pyridine; This basic inorganic salt is selected from sodium carbonate and potassium carbonate. 5. The preparation method according to claim 1, characterized in that the solvent is selected from one or any two of dichloromethane, dimethylformamide, and dioxane. 6. The preparation method according to claim 1, characterized in that the molar ratio of the compound of formula II: the compound of formula III is 1:0.2-5. 7. The preparation method according to claim 1, characterized in that the reaction temperature is 0-40°C, and the reaction time is 2-16 hours. 8. The preparation method according to any one of claims 1 to 7, further comprising a purification step: adding water and methylene chloride to the crude reaction product, and adjusting the reaction solution to a pH of 9 to 9 with 2N aqueous sodium hydroxide solution 11. Separate the organic layer; adjust the organic layer to pH 2-4 with 2N hydrochloric acid, filter, separate the organic layer from the filtrate, extract the aqueous layer with dichloromethane, combine the organic layers, and sequentially wash with saturated aqueous sodium bicarbonate solution, Wash with saturated aqueous sodium chloride; concentrate the organic phase under reduced pressure.