CN102952121A - Improved preparation method for piperazine derivant - Google Patents
Improved preparation method for piperazine derivant Download PDFInfo
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- CN102952121A CN102952121A CN201210263029XA CN201210263029A CN102952121A CN 102952121 A CN102952121 A CN 102952121A CN 201210263029X A CN201210263029X A CN 201210263029XA CN 201210263029 A CN201210263029 A CN 201210263029A CN 102952121 A CN102952121 A CN 102952121A
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Abstract
The invention provides an improved preparation method for piperazine derivant. The improved preparation method comprises the following steps of: carrying out a reaction on halide and benzofuran derivant in the presence of inorganic alkali water solution. The preparation method is easy to operate, short in reaction time, simple in postprocessing method, high in yield, low in cost and suitable for industrial production.
Description
Technical field
The present invention relates to a kind of a kind of improved preparation method of bridged piperazine derivatives, particularly, the present invention relates to prepare a kind of Innovative method of formula I bridged piperazine derivatives
Wherein:
R
1For having alkyl, hydroxyalkyl or the COOR of 1 to 6 carbon atom
1a
R
1aFor having the alkyl of 1 to 6 carbon atom
R
2Be F, OH, OMe, COOH or CN
Background technology
2 kinds of methods that prepare the formula I bridged piperazine derivatives are disclosed in the prior art:
According to J.Med.Chem 2004,47 (19), the method that 4684-4692 describes, 5-(piperazine-1-yl) coumarilic acid carbethoxy hydrochloride and 3-(4-chlorobutyl)-5-methoxy-Indole at salt of wormwood under the condition that triethylamine exists, take acetonitrile as solvent, heating reflux reaction 12 hours, with the reaction solution cooling concentration, enriched material stirs in ethyl acetate and water, filtering and concentrating, obtain 5-[4-[4-(5-cyano group-3-indyl after the aftertreatment) butyl]-the 1-piperazinyl]-the coumarilic acid ethyl ester, yield is 32%.
According to the method that U.S. Patent No. 5532241 is described, 3-(4-chlorobutyl)-5-cyanoindole and 1-(2-methylol cumarone-5-yl) piperazine, take acetonitrile as reaction solvent, stirring at room reaction 10 hours.Obtain 1-[4-(5-methoxy indyl-3-yl behind the routine operation) butyl]-4-(2-methylol cumarone-5-yl) piperazine.
Aforesaid method can not be entirely satisfactory, because the post-reaction treatment complicated operation, concentrated solution need to be processed through silica gel column chromatography, is not suitable for suitability for industrialized production, and the yield of product is quite low.
Summary of the invention
In order to improve yield, reduce production costs, we have developed an easy handling, a kind of production technique of the improved preparation formula I bridged piperazine derivatives that the reaction times is short, post-treating method is easy, yield is high, cost is low, and this technique suitability for industrialized is produced.
Wherein:
R
1For having alkyl, hydroxyalkyl or the COOR of 1 to 6 carbon atom
1a
R
1aFor containing the alkyl of 1 to 6 carbon atom
R
2Be F, OH, OMe, COOH or CN
The method comprises the indole derivatives that makes logical formula II
Wherein X removes group for parent's ionization commonly used
X can be selected from Cl, Br, I ,-OSO
2CH
3Or p-toluenesulfonyl etc.
R
2Be F, OH, OMe, COOH or CN
Benzofuran derivative reaction with logical formula III
R wherein
1Be C
1-C
6Alkyl, hydroxyalkyl or COOR
1a
R
1aFor containing the alkyl of 1 to 6 carbon atom
Wherein, the indole derivatives of structure formula II can be with reference to J.Med.Chem 2004,47 (19), the method preparation for preparing 3-(4-chlorobutyl)-5-cyanoindole that 4684-4692 describes.Concrete preparation method is that 3-(4-chlorobutyl)-5-cyanoindole passes through F-K reaction with 5-cyanoindole and 4-chlorobutanoylchloride, obtains 3-(4-chlorobutyl)-5-cyanoindole through reduction reaction again.
The benzofuran derivative of structure formula III can be with reference to J.Med.Chem 2004,47 (19), and 4684-4692 describes prepares 5-(piperazine-1-yl) method of coumarilic acid ethyl ester prepares.The concrete preparation method of 5-(piperazine-1-yl) coumarilic acid ethyl ester reduces under Raney Nickel effect with 5-nitrobenzofuran-2-ethyl formate, reduzate obtains 5-(piperazine-1-yl with two (2-chloroethyl) ammonium chloride through ring-closure reaction under the effect of salt of wormwood) the coumarilic acid ethyl ester.
The technique of the indole derivatives of logical formula II of the present invention and the reaction of the benzofuran derivative of logical formula III can further specify by following reaction formula:
This reaction is carried out in polar organic solvent under the condition that inorganic base aqueous solution exists.
Mineral alkali can be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, yellow soda ash, sodium bicarbonate, salt of wormwood and saleratus etc.
Solvent is polar organic solvent, and polar organic solvent comprises protic polar organic solvent and non-proton property polar organic solvent.Wherein the protic polar organic solvent can be selected from C
1-C
5Organic Alcohol or its mixture; Non-proton property polar organic solvent can be selected from DMF, methyl-sulphoxide, acetonitrile or n-formyl sarcolysine base pyrrolidone.
The consumption of inorganic base aqueous solution water is 50%～500% of mineral alkali quality, more preferably 100%～300%.Temperature of reaction is 20～130 ℃, preferred 40 ℃～130 ℃ of temperature of reaction, further preferred 40 ℃～reaction solution reflux temperature.
The production technique of preparation formula I bridged piperazine derivatives of the present invention comprises the steps:
A. indole derivatives II, benzofuran derivative III and polar organic solvent are placed reaction vessel, stir, wherein the mol ratio of indole derivatives II and benzofuran derivative III is 1:1.
B. mineral alkali is dissolved with suitable quantity of water, obtain inorganic base aqueous solution.Wherein, the mol ratio of mineral alkali and indole derivatives II is 1:1, and the consumption of water is 50%～500% of mineral alkali quality.
C. the inorganic base aqueous solution for preparing in the B step is joined in the reaction solution of steps A, reaction solution is heated to 20～130 ℃.To the material reaction in the reaction vessel 6～8 hours, reaction was cooled to 10 ℃～30 ℃ with reaction system after finishing.
D. with reacting liquid filtering, filtrate concentrates and obtains enriched material.Add ethyl acetate and water in enriched material, the mixture that obtains is regulated pH value to 5～7 with the 1M aqueous hydrochloric acid, separates organic phase, with the organic phase anhydrous sodium sulfate drying, filter, mother liquor is concentrated into and muddiness occurs, concentrated solution leaves standstill to separating out solid, filters and obtains formula I compound.
Embodiment
The below is described in further detail the specific embodiment of the present invention.
Following examples are used for explanation the present invention, but are not used for limiting the scope of the invention.
Embodiment 1:5-[4-[4-(5-cyano group-3-indyl) butyl]-the 1-piperazinyl]-(preparation of formula I-A) of coumarilic acid ethyl ester
A. in reaction vessel, add successively 3-(4-chlorobutyl)-5-cyanoindole (52.4g, 0.225mol), 5-(piperazine-1-yl) coumarilic acid ethyl ester (61.7g, 0.225mol) and 1.6L acetonitrile, stir.
B. with salt of wormwood (31g, 0.225mol) 31g water dissolution, obtain wet chemical.
C. the wet chemical for preparing in the B step is joined in the reaction vessel of steps A, reaction solution is heated to backflow.Material in the reaction vessel is kept reflux state reaction 8 hours, then allow reaction system be cooled to 25 ℃.
D. with reacting liquid filtering, the filtrate concentrating under reduced pressure obtains enriched material.In enriched material, add 500ml ethyl acetate and 500ml water, stir, the mixture that obtains is regulated pH value to 6 with the 1M aqueous hydrochloric acid, separates organic phase, with the organic phase anhydrous sodium sulfate drying, filter, filtrate is evaporated to solution and muddiness occurs, and concentrated solution leaves standstill to separating out solid, filters, obtain formula I-A compound (89g, yield 85%).
Embodiment 2:5-[4-[4-(5-cyano group-3-indyl) butyl]-the 1-piperazinyl]-(preparation of formula I-B) of coumarilic acid butyl ester
A. in reaction vessel, add successively 3-(4-chlorobutyl)-5-cyanoindole (52.4g, 0.225mol), 5-(piperazine-1-yl) coumarilic acid butyl ester (68g, 0.225mol) and 1.6L acetonitrile, stir.
B. with salt of wormwood (31g, 0.225mol) 77g water dissolution, obtain wet chemical.
C. the wet chemical for preparing in the B step is joined in the reaction vessel of steps A, be heated to 60 ℃.Material in the reaction vessel is kept 60 ℃ of reactions 6 hours, then allow reaction system be cooled to 10 ℃.
D. with reacting liquid filtering, the filtrate concentrating under reduced pressure obtains enriched material.Add 500ml ethyl acetate and 500ml water in the enriched material, stir, the mixture that obtains is regulated pH value to 7 with the 1M aqueous hydrochloric acid, separates organic phase, with the organic phase anhydrous sodium sulfate drying, filter, filtrate is evaporated to solution and muddiness occurs, and concentrated solution leaves standstill to separating out solid, filters, obtain formula I-B compound (93g, yield 83%).
Embodiment 3:1-[4-(5-methoxy-Indole base-3-yl) butyl]-4-(2-methylol cumarone-5-yl) piperazine (preparation of formula I-C)
A. in reaction vessel, add successively 3-(4-brombutyl)-5-methoxy-Indole (60.3g, 0.225mol), 2-methylol-5-(piperazine-1-yl) cumarone (52.3g, 0.225mol) and 1.6L Virahol, stir.
B. with yellow soda ash (24g, 0.225mol) 72g water dissolution, obtain aqueous sodium carbonate.
C. the aqueous sodium carbonate for preparing in the B step is joined in the reaction vessel of steps A, be heated to backflow.Material in the reaction vessel is kept reflux state reaction 10 hours, then allow reaction system be cooled to 20 ℃.
D. with reacting liquid filtering, the filtrate concentrating under reduced pressure obtains enriched material.Add 500ml ethyl acetate and 500ml water in the enriched material, stir, the mixture that obtains is regulated pH value to 6 with the 1M aqueous hydrochloric acid, separates organic phase, with the organic phase anhydrous sodium sulfate drying, filter, filtrate is evaporated to solution and muddiness occurs, and concentrated solution leaves standstill to separating out solid, filters, obtain formula I-C compound (80g, yield 82%).
Embodiment 4:1-[4-(5-methoxy indyl-3-yl) butyl]-4-(2-methyl cumarone-5-yl) piperazine (preparation of formula I-D)
A. add successively 3-(4-brombutyl)-5-methoxy-Indole (60.3g, 0.225mol), 2-methyl-5-(piperazine-1-yl) cumarone (48.7g, 0.225mol) and 1.6LN in reaction vessel, dinethylformamide stirs.
B. with sodium hydroxide (9g, 0.225mol) 45g water dissolution, obtain aqueous sodium hydroxide solution.
C. the aqueous sodium hydroxide solution for preparing in the B step is joined in the reaction vessel of steps A, be heated to backflow.Material in the reaction vessel is kept reflux state reaction 6 hours, then allow reaction system be cooled to 20 ℃.
D. with reacting liquid filtering, the filtrate concentrating under reduced pressure obtains enriched material.Add 500ml ethyl acetate and 500ml water in the enriched material, stir, the mixture that obtains is regulated pH value to 6 with the 1M aqueous hydrochloric acid, separates organic phase, with the organic phase anhydrous sodium sulfate drying, filter, filtrate is evaporated to solution and muddiness occurs, and concentrated solution leaves standstill to separating out solid, filters, obtain formula I-D compound (74g, yield 76%).
Embodiment 5:5-[4-[4-(5-cyano group-3-indyl) butyl]-the 1-piperazinyl]-(preparation of I-A) of coumarilic acid ethyl ester
A. in reaction vessel, add successively 3-(4-chlorobutyl)-5-cyanoindole (52.4g, 0.225mol), 5-(piperazine-1-yl) coumarilic acid ethyl ester (61.7g, 0.225mol) and 1.6L acetonitrile, stir.
B. with salt of wormwood (31g, 0.225mol) 16g water dissolution, obtain wet chemical.
C. the wet chemical for preparing in the B step is joined in the reaction vessel of steps A, be heated to 40 ℃, and under 40 ℃ of conditions, reacted 8 hours, then allow reaction system be cooled to 20 ℃.
D. with reacting liquid filtering, the filtrate concentrating under reduced pressure obtains enriched material.Add 500ml ethyl acetate and 500ml water in the enriched material, stir, the mixture that obtains is regulated pH value to 6 with the 1M aqueous hydrochloric acid, separates organic phase, with the organic phase anhydrous sodium sulfate drying, filter, filtrate is evaporated to solution and muddiness occurs, and concentrated solution leaves standstill to separating out solid, filters, obtain formula I-A compound (75g, yield 72%).
Embodiment 6:5-[4-[4-(5-cyano group-3-indyl) butyl]-the 1-piperazinyl]-(preparation of formula I-B) of coumarilic acid butyl ester
A. in reaction vessel, add successively 3-(4-chlorobutyl)-5-cyanoindole (52.4g, 0.225mol), 5-(piperazine-1-yl) coumarilic acid butyl ester (68g, 0.225mol) and 1.6L acetonitrile, stir.
B. with potassium hydroxide (12.6g, 0.225mol) 50g water dissolution, obtain potassium hydroxide aqueous solution.
C. the potassium hydroxide aqueous solution for preparing in the B step is joined in the reaction vessel of steps A, be heated to backflow.Material in the reaction vessel was kept back flow reaction 6 hours, then allow reaction system be cooled to 10 ℃.
D. with reacting liquid filtering, the filtrate concentrating under reduced pressure obtains enriched material.Add 500ml ethyl acetate and 500ml water in the enriched material, stir, the mixture that obtains is regulated pH value to 6 with the 1M aqueous hydrochloric acid, separates organic phase, with the organic phase anhydrous sodium sulfate drying, filter, filtrate is evaporated to solution and muddiness occurs, and concentrated solution leaves standstill to separating out solid, filters, obtain formula I-B compound (93g, yield 83%).
Embodiment 7:5-[4-[4-(5-cyano group-3-indyl) butyl]-the 1-piperazinyl]-(preparation of formula I-A) of coumarilic acid ethyl ester
A. in reaction vessel, add successively 3-(4-chlorobutyl)-5-cyanoindole (52.4g, 0.225mol), 5-(piperazine-1-yl) coumarilic acid ethyl ester (61.7g, 0.225mol) and 1.6LN, dinethylformamide stirs.
B. with salt of wormwood (31g, 0.225mol) 31g water dissolution, obtain wet chemical.
C. the wet chemical for preparing in the B step is joined in the reaction vessel of steps A, reaction solution is heated to 130 ℃.Material in the reaction vessel is kept 130 ℃ of reactions 8 hours, then allow reaction system be cooled to 25 ℃.
D. with reacting liquid filtering, the filtrate concentrating under reduced pressure obtains enriched material.In enriched material, add 500ml ethyl acetate and 500ml water, stir, the mixture that obtains is regulated pH value to 6 with the 1M aqueous hydrochloric acid, separates organic phase, with the organic phase anhydrous sodium sulfate drying, filter, filtrate is evaporated to solution and muddiness occurs, and concentrated solution leaves standstill to separating out solid, filters, obtain formula I-A compound (89g, yield 85%).
Claims (4)
1. a kind of Innovative method for preparing a kind of bridged piperazine derivatives of formula I
Wherein:
R
1For having alkyl, hydroxyalkyl or the COOR of 1 to 6 carbon atom
1a
R
1aFor containing the alkyl of 1 to 6 carbon atom
R
2Be F, OH, OMe, COOH or CN
This improved preparation method comprises:
Under the condition that inorganic base aqueous solution exists, the halides of logical formula II and the benzofuran derivative of logical formula III are reacted in polar organic solvent:
Wherein X is Cl, Br, I, methylsulfonyl or p-toluenesulfonyl
R
2Such as above-mentioned definition
R wherein
1Such as above-mentioned definition
It is characterized in that mineral alkali is selected from salt of wormwood, yellow soda ash, sodium hydroxide or potassium hydroxide.
2. method according to claim 1, the consumption that it is characterized in that water is 50%～500% of mineral alkali quality.
3. method according to claim 2 is characterized in that the consumption of water is preferably 100%～300% of mineral alkali quality.
4. method according to claim 1 is characterized in that the temperature of the benzofuran derivative reaction of the halides of formula II and formula III is 40～130 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103360373A (en) * | 2013-07-12 | 2013-10-23 | 苏州永健生物医药有限公司 | Synthesis method of vilazodone intermediate and salt thereof |
| US9533949B2 (en) | 2012-09-12 | 2017-01-03 | Apotex Pharmachem Inc. | Processes for the preparation of 3-alkyl indoles |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1983004254A1 (en) * | 1982-05-28 | 1983-12-08 | Sandoz Ag | Piperazine derivative compounds, production method thereof and drugs containing them |
| CN101735201A (en) * | 2009-12-17 | 2010-06-16 | 宁夏康亚药业有限公司 | Preparation method of piribedil |
| CN101830891A (en) * | 2010-05-18 | 2010-09-15 | 沈阳药科大学 | Synthesizing method of piribedil |
| CN102267932A (en) * | 2011-06-15 | 2011-12-07 | 上海医药工业研究院 | 4-(5-cyano-1H-indole-3-yl) butyl substituted sulphonate compounds and use thereof |
-
2012
- 2012-07-27 CN CN201210263029XA patent/CN102952121A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1983004254A1 (en) * | 1982-05-28 | 1983-12-08 | Sandoz Ag | Piperazine derivative compounds, production method thereof and drugs containing them |
| CN101735201A (en) * | 2009-12-17 | 2010-06-16 | 宁夏康亚药业有限公司 | Preparation method of piribedil |
| CN101830891A (en) * | 2010-05-18 | 2010-09-15 | 沈阳药科大学 | Synthesizing method of piribedil |
| CN102267932A (en) * | 2011-06-15 | 2011-12-07 | 上海医药工业研究院 | 4-(5-cyano-1H-indole-3-yl) butyl substituted sulphonate compounds and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| TIMO HEINRICH,等: "Synthesis and Structure Activity Relationship in a Class of Indolebutylpiperazines as Dual 5-HT1A Receptor Agonists and Serotonin Reuptake Inhibitors", 《J. MED. CHEM.》, vol. 47, 8 October 2004 (2004-10-08), pages 4684 - 4692 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9533949B2 (en) | 2012-09-12 | 2017-01-03 | Apotex Pharmachem Inc. | Processes for the preparation of 3-alkyl indoles |
| CN103360373A (en) * | 2013-07-12 | 2013-10-23 | 苏州永健生物医药有限公司 | Synthesis method of vilazodone intermediate and salt thereof |
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Application publication date: 20130306 |