CN100463907C - Preparing method of 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine} - Google Patents
Preparing method of 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)amino]-2-pyridine} Download PDFInfo
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- CN100463907C CN100463907C CNB2006100238299A CN200610023829A CN100463907C CN 100463907 C CN100463907 C CN 100463907C CN B2006100238299 A CNB2006100238299 A CN B2006100238299A CN 200610023829 A CN200610023829 A CN 200610023829A CN 100463907 C CN100463907 C CN 100463907C
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Abstract
The invention discloses a making method of 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methyl ethyl) amino]-2-pyridine} piperazine, which is reacted by 5-nitro-1H-indole-2-acylchlorine and 1-{3-[(1-methyl ethyl) amino]-2-pyridine} piperazine in the solvent.
Description
Technical field
The present invention relates to a kind of 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl) amino]-the 2-pyridine } preparation method of piperazine.
Background technology
Compound 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl) amino]-the 2-pyridine } piperazine is the important intermediate of non-nucleoside reverse transcriptase inhibitor anti-AIDS drug ground La Weiding (Delavirdine) important intermediate and non-nucleoside reverse transcriptase inhibitor piperazine derivative at present.
Patent WO9109849, WO9301181 and WO9726880, compound 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl is disclosed) amino]-the 2-pyridine } synthesis technique of piperazine, be with formula IV compound 5-nitro-1H-Indoline-2-carboxylic acid and formula III compound 1-{3-[(1-methylethyl) amino]-the 2-pyridine } piperazine is raw material, tetrahydrofuran (THF) is a solvent, at condensing agent 1-[3-(dimethylin) propyl group]-3-ethyl carbodiimide (be called for short EDC) effect reacts down, reaction is dissolved in chloroform after finishing, through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, drying obtains formula I compound 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl behind the purification by silica gel column chromatography) amino]-the 2-pyridine } piperazine.Its reaction formula is:
The shortcoming of this synthesis technique is:
With 5-nitro-1H-Indoline-2-carboxylic acid and 1-{3-[(1-methylethyl) amino]-the 2-pyridine } piperazine is raw material, both are in condensation reaction, condensing agent 1-[3-(dimethylin) propyl group of using]-3-ethyl carbodiimide (be called for short EDC) costs an arm and a leg, make and produce 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl) amino]-the 2-pyridine } cost of piperazine is higher relatively, and economic benefit is not good enough.Also use chloroform in the aftertreatment purification step as extracting reagent, and chloroform not only has harm to environment, can pollute water body, increase difficulty to the disposal of three wastes, and can act on people's nervus centralis, the heart, liver, kidney to the people have infringement, generally should not adopt chloroform as extracting reagent in the production process.In addition, purifying also needs to be unsuitable for plant-scale production by column chromatography.
Summary of the invention
The technical problem to be solved in the present invention is the defective that overcomes above-mentioned prior art, and a kind of low cost is provided, and is suitable for large-scale production 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl) amino]-the 2-pyridine } new preparation process of piperazine.
Concrete technical scheme of the present invention is: with 5-nitro-1H-indoles-2-acyl chlorides (II) and 1-{3-[(1-methylethyl) amino]-the 2-pyridine } piperazine (III) is raw material, reaction makes compound 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl in solvent) amino]-the 2-pyridine } piperazine (I), its reaction formula is as follows:
In a preferred embodiment of the present invention, this formula II compound places solvent, is added drop-wise in the mixed solution of being made up of formula III compound, solvent and weakly alkaline reagent.This alkaline reagents mainly plays katalysis, can adopt organic bases, as triethylamine, tripropyl amine, pyridine etc., or alkaline, inorganic salts such as yellow soda ash, salt of wormwood; The consumption of this weakly alkaline reagent, very little then oversize and reaction of reaction times not exclusively, otherwise too many, then increase cost and increase aftertreatment work, so the preferred molar ratio of the compound of minimum molar weight is 1:3～10 in itself and formula II or the formula III compound.
Wherein, above-mentioned solvent is selected from a kind of in methylene dichloride, dimethyl formamide (DMF), the dioxane or any two kinds.
The mole dosage ratio of two kinds of raw materials is formula II compound 5-nitro-1H-indoles-2-acyl chlorides: amino formula III compound 1-{3-[(1-methylethyl)]-the 2-pyridine } piperazine is 1:0.2～5.
Temperature of reaction of the present invention is 0～40 ℃, and the reaction times is 2～16 hours.
Preferably, more adapt to suitability for industrialized production for environmental requirement reaches, the present invention adopts following purification step: add entry and methylene dichloride in the crude reaction thing, with the 2N aqueous sodium hydroxide solution reaction solution being transferred to pH is 9～11, tells organic layer; It is 2～4 that organic layer transfers to pH with 2N hydrochloric acid, filters, and after filtrate was told organic layer, its water layer merged organic layer with dichloromethane extraction twice, uses saturated sodium bicarbonate aqueous solution successively, the saturated sodium-chloride water solution washing; The concentrating under reduced pressure organic phase.
The invention solves prior art cost height, the shortcoming of unsuitable scale production has low cost, is suitable for the advantage of large-scale production, and environmental protection.
Embodiment
Further specify the present invention below by embodiment, but the present invention is not limited.
Wherein, nitro-1H-indoles-2-acyl chlorides can be according to document [Khim.-Farm.Zh. for the following example Chinese style II compound 5-, 19 (9), 1075-8 (Russia) 1985] synthetic, be specially the reaction of formula IV compound 5-nitro-1H-Indoline-2-carboxylic acid and thionyl chloride, production II compound 5-nitro-1H-indoles-2-acyl chlorides
Its Chinese style IV compound 5-nitro-the 1H-Indoline-2-carboxylic acid is according to document (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, method 2462-2467) is synthetic, be specially p-Nitroaniline and Sodium Nitrite and hydrochloric acid effect, obtain p-nitrophenyl diazonium salt (b), compound b and Alpha-Methyl methyl aceto acetate generate hydrazone (c), compound c cyclization in polyphosphoric acid obtains 5-nitro-1H-Ethyl indole-2-carboxylate (d), and compound d is through being hydrolyzed to formula IV compound 5-nitro-1H-Indoline-2-carboxylic acid (reaction formula is as follows).
Formula III compound 1-{3-[(1-methylethyl in the foregoing description) amino]-the 2-pyridine } piperazine is synthetic according to the method in the document (WO9109849 and WO8808424A1), be specially 2-chloro-3-nitropyridine and Piperazine anhydrous and under the catalysis of salt of wormwood, generate 2-(1-piperazine)-3-nitropyridine (e), the Verbindung hydro-reduction gets 3-amino-2-(1-piperazine) pyridine (f), compound f and two dimethyl dicarbonate fourth fat ((Boc)
2O) reaction generates 1-[1; the 1-dimethyl ethoxycarbonyl]-4-[3-amino-2-pyridine] piperazine (g); compound g is dissolved in methyl alcohol; add acetone; be chilled to zero degree, acetate transfers to pH4.0, adds the reduction of cyano group sodium borohydride and obtains 1-[1; the 1-dimethyl ethoxycarbonyl]-4-[3-(1-methylethyl) amino]-the 2-pyridine) piperazine (h), obtain formula III compound 1-{3-[(1-methylethyl with trifluoroacetic acid deprotection group again) amino]-the 2-pyridine } piperazine (reaction formula is as follows).
The reagent of specified otherwise is not conventional commercially available chemical pure.
Embodiment 1:
The 1-{3-[(1-methylethyl) amino]-the 2-pyridine } piperazine 4 gram (0.018mol) joins in 100 milliliters of the methylene dichloride, adds 20 milliliters of triethylamines.0～5 ℃, the methylene dichloride/DMF liquid of Dropwise 5-nitro-1H-indoles-2-acyl chlorides [5-nitro-1H-indoles-2-acyl chlorides 5.5 restrains 10 milliliters of 50 milliliters+DMF of (0.025mol)+methylene dichloride].3～7 ℃, reacted 2～6 hours.Add 50 milliliters of 100 milliliters of entry and methylene dichloride, reaction solution is transferred to pH9～10, tell organic layer with the 2N aqueous sodium hydroxide solution.It is 2～4 that organic layer transfers to pH with 2N hydrochloric acid.Filter, after filtrate was told organic layer, its water layer merged organic layer with dichloromethane extraction (100 milliliters * 2), uses saturated sodium bicarbonate aqueous solution successively, the saturated sodium-chloride water solution washing.The organic phase concentrating under reduced pressure gets 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl) amino]-the 2-pyridine } piperazine 4.2 grams, productive rate: 57%.
Embodiment 2:
The 1-{3-[(1-methylethyl) amino]-the 2-pyridine } piperazine 4 gram (0.018mol) joins in 100 milliliters of the methylene dichloride, adds salt of wormwood 7 grams.0～5 ℃, the methylene dichloride/DMF liquid of Dropwise 5-nitro-1H-indoles-2-acyl chlorides [5-nitro-1H-indoles-2-acyl chlorides 5.5 restrains 10 milliliters of 50 milliliters+DMF of (0.025mol)+methylene dichloride].20～25 ℃, reacted 12～16 hours.Add 50 milliliters of 100 milliliters of entry and methylene dichloride, reaction solution is transferred to pH10～11, tell organic layer with the 2N aqueous sodium hydroxide solution.Organic layer transfers to pH2～4 with 2N hydrochloric acid.Filter, after filtrate was told organic layer, its water layer merged organic layer with dichloromethane extraction (100 milliliters * 2), uses saturated sodium bicarbonate aqueous solution successively, the saturated sodium-chloride water solution washing.The organic phase concentrating under reduced pressure gets 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl) amino]-the 2-pyridine } piperazine.
Embodiment 3:
The 1-{3-[(1-methylethyl) amino]-the 2-pyridine } piperazine 5.5 gram (0.025mol) joins among 20 milliliters of the DMF, adds 7 milliliters of triethylamines.0～5 ℃, the DMF liquid of Dropwise 5-nitro-1H-indoles-2-acyl chlorides [5-nitro-1H-indoles-2-acyl chlorides 2.25 restrains 15 milliliters of (0.010mol)+DMF].35～40 ℃, reacted 3～6 hours.Add 200 milliliters of 100 milliliters of entry and methylene dichloride, reaction solution is transferred to pH9～10, tell organic layer with the 2N aqueous sodium hydroxide solution.Organic layer transfers to pH2～4 with 2N hydrochloric acid.Filter, after filtrate was told organic layer, its water layer merged organic layer with dichloromethane extraction (100 milliliters * 2), uses saturated sodium bicarbonate aqueous solution successively, the saturated sodium-chloride water solution washing.The organic phase concentrating under reduced pressure gets 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl) amino]-the 2-pyridine } piperazine.
Embodiment 4:
The 1-{3-[(1-methylethyl) amino]-the 2-pyridine } piperazine 11 gram (0.050mol) joins in the mixing solutions of being made up of 90 milliliters of methylene dichloride and DMF10 milliliter 5 milliliters of adding pyridines.0～5 ℃, the methylene dichloride/DMF liquid of Dropwise 5-nitro-1H-indoles-2-acyl chlorides [5-nitro-1H-indoles-20 milliliters+DMF5 of 2-acyl chlorides 2.25 gram (0.010mol)+methylene dichloride milliliter].0～5 ℃, reacted 4～8 hours.Add 50 milliliters of 100 milliliters of entry and methylene dichloride, reaction solution is transferred to pH9～10, tell organic layer with the 2N aqueous sodium hydroxide solution.Organic layer transfers to pH2～4 with 2N hydrochloric acid.Filter, after filtrate was told organic layer, its water layer merged organic layer with dichloromethane extraction (100 milliliters * 2), uses saturated sodium bicarbonate aqueous solution successively, the saturated sodium-chloride water solution washing.The organic phase concentrating under reduced pressure gets 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl) amino]-the 2-pyridine } piperazine.
Embodiment 5:
The 1-{3-[(1-methylethyl) amino]-the 2-pyridine } piperazine 1.1 gram (0.005mol) joins in 30 milliliters of the dioxane, adds 10 milliliters of tripropyl amines.0～5 ℃, the dioxane/DMF liquid of Dropwise 5-nitro-1H-indoles-2-acyl chlorides [5-nitro-1H-indoles-2-acyl chlorides 5.5 restrains 10 milliliters of 20 milliliters+DMF of (0.025mol)+dioxane].20～25 ℃, reacted 6～10 hours.Add 200 milliliters of 100 milliliters of entry and methylene dichloride, reaction solution is transferred to pH9～10, tell organic layer with the 2N aqueous sodium hydroxide solution.Organic layer transfers to pH2～4 with 2N hydrochloric acid.Filter, after filtrate was told organic layer, its water layer merged organic layer with dichloromethane extraction (100 milliliters * 2), uses saturated sodium bicarbonate aqueous solution successively, the saturated sodium-chloride water solution washing.The organic phase concentrating under reduced pressure gets 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl) amino]-the 2-pyridine } piperazine.
The appraising datum of the compound that makes in the foregoing description: mp:152-154 ℃, m/z=408, consistent with the disclosed relevant data of document.
Claims (8)
1. an amino formula I compound 1-(5-nitro-1H-indole-2-carbonyl)-4-{3-[(1-methylethyl)]-the 2-pyridine } preparation method of piperazine, it is anti-in solvent by formula II compound and formula III compound
Should make.
2. preparation method as claimed in claim 1 is characterized in that this formula II compound places solvent, is added drop-wise in the mixed solution of being made up of formula III compound, solvent and weakly alkaline reagent.
3. preparation method as claimed in claim 2 is characterized in that this alkaline reagents is organic bases or alkaline, inorganic salts.
4. preparation method as claimed in claim 3 is characterized in that this organic bases is selected from triethylamine, tripropyl amine and pyridine; This alkaline, inorganic salts is selected from yellow soda ash and salt of wormwood.
5. preparation method as claimed in claim 1 is characterized in that this solvent is selected from a kind of in methylene dichloride, dimethyl formamide, the dioxane or any two kinds.
6. preparation method as claimed in claim 1, it is characterized in that this formula II compound: the mol ratio of formula III compound is 1:0.2～5.
7. preparation method as claimed in claim 1 is characterized in that described temperature of reaction is 0～40 ℃, and the reaction times is 2～16 hours.
8. as each described preparation method of claim 1～7, it also comprises purification step: add entry and methylene dichloride in crude reaction product, with the 2N aqueous sodium hydroxide solution reaction solution being transferred to pH is 9～11, tells organic layer; It is 2～4 that organic layer transfers to pH with 2N hydrochloric acid, filters, and after filtrate was told organic layer, its water layer dichloromethane extraction merged organic layer, uses saturated sodium bicarbonate aqueous solution successively, the saturated sodium-chloride water solution washing; The concentrating under reduced pressure organic phase.
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| CN100500661C (en) * | 2006-02-21 | 2009-06-17 | 上海医药工业研究院 | Method for purifying 1-(5-nitro-III-indole-2-carbonyl)-4 {3-[(1-methyl-ethyl)-amino]-2-pyridine} ethylene imine |
| CN102358944A (en) * | 2011-08-23 | 2012-02-22 | 哈尔滨理工大学 | Preparation method of aminopyridine chloride |
| CN102675284A (en) * | 2012-05-25 | 2012-09-19 | 王恩思 | Synthesis method of delavirdine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991009849A1 (en) * | 1989-12-28 | 1991-07-11 | The Upjohn Company | Diaromatic substituted anti-aids compounds |
| WO1993001181A1 (en) * | 1991-07-03 | 1993-01-21 | The Upjohn Company | Substituted indoles as anti-aids pharmaceuticals |
| WO1997026880A2 (en) * | 1996-01-26 | 1997-07-31 | Pharmacia & Upjohn Company | Use of a combination of delavirdine and one or more protease inhibitors in hiv-1 infected patients |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991009849A1 (en) * | 1989-12-28 | 1991-07-11 | The Upjohn Company | Diaromatic substituted anti-aids compounds |
| WO1993001181A1 (en) * | 1991-07-03 | 1993-01-21 | The Upjohn Company | Substituted indoles as anti-aids pharmaceuticals |
| WO1997026880A2 (en) * | 1996-01-26 | 1997-07-31 | Pharmacia & Upjohn Company | Use of a combination of delavirdine and one or more protease inhibitors in hiv-1 infected patients |
Non-Patent Citations (2)
| Title |
|---|
| 5-Nitroindole-2-carboxylic acid derivatioves. Shengeliya, M. S. et al.Khim.-Farm. Zh.,,Vol.19 No.9. 1985 |
| 5-Nitroindole-2-carboxylic acid derivatioves. Shengeliya, M. S. et al.Khim.-Farm. Zh.,,Vol.19 No.9. 1985 * |
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