CN103467422B - A kind of method preparing vilazodone intermediate 5-piperazinyl-2-acyl substituted cumarone - Google Patents
A kind of method preparing vilazodone intermediate 5-piperazinyl-2-acyl substituted cumarone Download PDFInfo
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- CN103467422B CN103467422B CN201310419251.9A CN201310419251A CN103467422B CN 103467422 B CN103467422 B CN 103467422B CN 201310419251 A CN201310419251 A CN 201310419251A CN 103467422 B CN103467422 B CN 103467422B
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Abstract
The invention discloses a kind of method preparing vilazodone intermediate 5-piperazinyl-2-acyl substituted cumarone.The method be 5-halogen substiuted-2-acyl substituted cumarone under copper-based catalysts, suitable solvent action, obtain corresponding 5-piperazinyl-2-acyl substituted cumarone to piperazine generation linked reaction.The invention provides a kind of novel method preparing vilazodone intermediate 5-piperazinyl-2-acyl substituted cumarone, have that route is short, synthesis is convenient, yield is high, low cost and other advantages, be applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to the preparation method of vilazodone intermediate 5-piperazinyl-2-acyl substituted cumarone.
Background technology
Hydrochloric acid vilazodone (Vilazodonehydrochloride), chemical name is 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride, is the new antidepressant developed by ClinicalData company.In January, 2011, through U.S. food Drug Administration (FDA) approval listing, be used for the treatment of major depressive disorder.Its chemical structure is as follows:
Vilazodone Hydrochloride is the novel antidepressant with the excitement of 5-HT1A acceptor portion and 5-HT re-uptake suppression dual function, compares, has rapid-action, patient is not had to the features such as sexual dysfunction side effect with clinical existing antidepressant drug.
At present, domestic and foreign literature openly adopts following several method to prepare Vilazodone Hydrochloride:
1) be the preparation method of intermediate with 3-(4-chlorobutyl) indoles-5-formonitrile HCN.Patent CN1056610C (WO2000/035872, EP0648767 are of the same clan) is disclosed vilazodone compound patent the earliest, be take 3-(4-chlorobutyl) indoles-5-formonitrile HCN as the method for Intermediate Preparation Vilazodone Hydrochloride, synthetic route is as follows:
First, 3-(4-chlorobutyl) indoles-5-formonitrile HCN and 1-(2-carboxybenzofuran-5-base) piperazine carry out condensation reaction, obtain 5-(4-(4-(5-cyanoindole-3-base) butyl) piperazine-1-) coumarilic acid, then chloro-1-picoline father-in-law mesylate reacts with 2-, finally by one-tenth salt refining, obtain Vilazodone Hydrochloride.
The method reactions steps is relatively many, and each step yield is not quite clear, and adopts pyridinium salt compound to carry out acylation reaction, and have certain toxicity, the industrialization being not suitable for being applied to Vilazodone Hydrochloride is prepared in a large number.
2) disclose the preparation method of intermediate 3-(4-chlorobutanol) indoles-5-first cyanogen in patent CN1155568C and CN1181067C, and it is preparing the application in Vilazodone Hydrochloride.Synthetic route is as follows:
With 3-(4-chlorobutanol) indoles-5-first cyanogen for raw material, carry out condensation reaction with 5-(1-piperazinyl)-benzofuran-2-carboxamides, then become salt refining, prepare the method for Vilazodone Hydrochloride.Do not provide concrete yield in patent CN1181067C, be difficult to the quality judging the method.Wherein, the syntheti c route of intermediate 3-(4-chlorobutanol) indoles-5-first cyanogen is as follows:
With 5-cyanoindole for raw material; under isobutyl-aluminum chloride-catalyzed; carry out F-K reaction; obtained 3-(4-chlorobutyryl) indoles-5-first cyanogen; again under the activation of isobutyl-aluminum chloride; adopt sodium borohydride selective reduction ketone carbonyl to be methylene radical, prepare intermediate 3-(4-chlorobutyl) indoles-5-formonitrile HCN.F-K reaction in this synthetic route and reduction reaction step, all have employed seldom used Lewis acid isobutyl-aluminum chloride is catalyzer, and this reagent is difficult to buy and preparation; and its unstable chemcial property; very easily fire in air, duct type need be adopted to carry, require high to conversion unit.In view of the preparation of isobutyl-aluminum chloride, storage and transportation cost are expensive, the method is not suitable for a large amount of industrialization preparations of Vilazodone Hydrochloride yet.
3) disclosing in patent WO2006/114202 and CN101163698A with 3-(4-hydroxybutyl) indoles-5-formonitrile HCN and 3-(4-oxo butyl) indoles-5-formonitrile HCN is the method for Intermediate Preparation vilazodone.Synthetic route is as follows:
The method is for raw material with 3-(4-hydroxybutyl) indoles-5-formonitrile HCN, through oxidation preparation 3-(4-oxo butyl)-indoles-5-formonitrile HCN, again with 5-piperazinyl cumarone-2-formamide, through sodium cyanoborohydride reduction amination, obtain vilazodone, finally by acidifying salify and refining, prepare Vilazodone Hydrochloride.
It is not quite clear that this route respectively walks reaction yield, and employ that toxicity is large, price sodium cyanoborohydride is costly as selective reduction agent.Intermediate 3-(4-oxo butyl) indoles-5-formonitrile HCN, need through column chromatography purification through oxidation preparation, and the production cycle is long, and inefficiency, therefore the method is also not suitable for the large production of industryization being applied to Vilazodone Hydrochloride.Further, the synthesis preparation method of key intermediate 3-(4-hydroxybutyl) indoles-5-formonitrile HCN has no bibliographical information.
4) also disclosing in patent WO2006/114202 and CN101163698A with 3-(4-piperazine butyl) indoles-5-formonitrile HCN is the vilazodone preparation method of intermediate, and synthetic route is as follows:
The method with 3-(4-piperazine butyl) indoles-5-formonitrile HCN for intermediate, first sodium tert-butoxide, three (dibenzalacetone)-two palladium and tri-tert phosphorus catalysis under, linked reaction is carried out with 5-bromobenzofuran-2-methane amide, again through acidifying salify and refining, prepare Vilazodone Hydrochloride.The method adopts expensive palladium metal complex catalyst and tri-tert phosphorus part, not only preparation cost is high, and the preparation method of intermediate 3-(4-piperazine butyl) indoles-5-formonitrile HCN has no report, therefore the method is not also suitable for a large amount of industrialization preparations of Vilazodone Hydrochloride.
In these synthetic routes above-mentioned, all using the important intermediate of 5-piperazinyl-2-acyl substituted cumarone (I) as vilazodone.
But the synthetic method of the compound (I) of report is little at present, commonly completed by a kind of very loaded down with trivial details route, comprising a series of process such as nitrated, metal catalytic reduction, nucleophilic substitution, not only route is long, yield is low, and seriously polluted.As US Patent No. 5723614 describe compound (I partial synthesis a):
Then and two (2-chloroethyl) amine reaction of N, N-it is raw material that this route uses 5-nitro to replace cumarone-2-carboxylic acid, ethyl ester, first hydro-reduction nitro under metal catalyst effect, obtains compound (I).There is a lot of shortcoming in this method, and first to replace the preparation of cumarone-2-carboxylic acid, ethyl ester not only loaded down with trivial details for raw material 5-nitro, and owing to using nitrifying process, not only has larger danger but also seriously polluted.In addition, also need to use two (2-chloroethyl) amine of expensive N, N-, this all significantly limit its suitability for industrialized production.
Chinese invention patent application 201110401159.0 provides a kind of novel method preparing vilazodone intermediate 5-piperazinyl-2-acyl substituted cumarone.The method specifically comprises the steps: that 5-halogen substiuted-2-acyl substituted cumarone is under metal palladium catalyst, suitable part, solvent and alkali acting in conjunction, obtains corresponding 5-piperazinyl-2-acyl substituted cumarone to diethylenediamine compound generation linked reaction.
This invention used catalyst is metal palladium catalyst, be selected from: triphenylphosphine palladium, palladium, palladium chloride, dual-triphenylphosphine palladium chloride, three (dibenzalacetone) two palladium or two (dibenzalacetone) palladium, these metal palladium catalyst market value are higher, are not suitable for suitability for industrialized production.
Therefore, not yet there is the preparation method of relatively perfectly vilazodone intermediate 5-piperazinyl-2-acyl substituted cumarone at present, need to continue to explore screening.
Summary of the invention
Instant invention overcomes the defect of above-mentioned prior art, provide the novel method that one prepares vilazodone intermediate 5-piperazinyl-2-acyl substituted cumarone (I).Present method has that route is short, synthesis is convenient, yield is high, low cost and other advantages, is applicable to suitability for industrialized production.
The present invention specifically comprises the steps: that 5-halogen substiuted-2-acyl substituted cumarone (II) is under the effect of copper-based catalysts; in suitable solvent, there is linked reaction with piperazine (III) and obtain corresponding 5-piperazinyl-2-acyl substituted cumarone (I).
Involved in the present invention to reaction can represent with following reaction formula:
In formula, X is chlorine or bromine, and R is amino or hydroxyl.
The reaction needed that-2-acyl substituted cumarone (II) from 5-halogen substiuted of the present invention and piperazine (III) prepare corresponding 5-piperazinyl-2-acyl substituted cumarone (I) uses copper-based catalysts; selected copper-based catalysts is the one in copper halide, cupric cyanide and cupric nitrate, the wherein preferred cupric chloride of copper halide.
The reaction that-2-acyl substituted cumarone (II) from 5-halogen substiuted of the present invention and piperazine (III) prepare corresponding 5-piperazinyl-2-acyl substituted cumarone (I) is carried out in a suitable solvent, and selected solvent is the one in dimethyl sulfoxide (DMSO), dimethyl formamide, toluene, tetrahydrofuran (THF), methylene dichloride.
-2-acyl substituted cumarone (II) from 5-halogen substiuted of the present invention and piperazine (III) prepare the reaction of corresponding 5-piperazinyl-2-acyl substituted cumarone (I); the amount of substance mol ratio of compound (II) and compound (III) is 1:2 ~ 3; temperature of reaction is 150 DEG C, and the amount of substance mol ratio of copper-based catalysts and compound (II) is 1:10.
The concrete reaction process of preparation method of the present invention is as follows:
In there-necked flask, add 5-halogen substiuted-2-acyl substituted cumarone (II), piperazine (III), copper-based catalysts and solvent, react at 150 DEG C.After reaction terminates, except desolventizing, add ether, vigorous stirring in system, solid is separated out.Solid is carried out recrystallization in ethyl acetate, obtains highly purified 5-piperazinyl-2-acyl substituted cumarone (I).
Specific embodiment
Below the specific embodiment of content of the present invention, for set forth in present specification want the concrete technical scheme of technical solution problem, but realization of the present invention is not limited to these embodiments, and these embodiments not limit scope of the present invention.The experimental technique of not marked actual conditions in the following example, conventionally and condition, the reaction raw materials in unreceipted source and reagent are commercially available.
In following embodiment:
The structure of compound is determined by nucleus magnetic resonance (NMR) or mass spectrum (MS).NMR displacement (δ) provides with the unit of 1,000,000/(ppm).The mensuration of NMR is that measuring solvent is deuterochloroform (CDC by Varian-Inova-400 type nuclear magnetic resonance analyser
l3), be inside designated as trimethyl silane (TMS), chemical shift is with 10
-6(ppm) provide as unit.The mensuration MAT212 magnetic-type mass spectrograph of MS.
Embodiment 1 adds 5-chloro-2-amide group cumarone (3.91g in 100ml there-necked flask, 0.02mol), piperazine (3.44g, 0.04mol), cupric chloride (0.27g, 0.002mol), and dimethyl sulfoxide (DMSO) (50ml), heated and stirred reaction at 150 DEG C.With thin-layer chromatography monitoring reaction, after question response terminates, except desolventizing, add 10ml ether, vigorous stirring in system, solid is separated out.Solid is carried out recrystallization in ethyl acetate, and obtain 5-piperazinyl-2-amide group cumarone 3.52g, yield is 72%.
MS(ESI
+，m/e)：246.12[M+H]
+
1H-NMR(400MHz,CDCl
3)δ(ppm):1.91(m,1H),2.78(m,4H),3.46(m,4H),6.52(s,1H),7.78(s,1H),7.48(s,1H),7.59(s,1H),7.85(s,2H)
Embodiment 2 adds 5-chloro-2-amide group cumarone (3.91g in 100ml there-necked flask, 0.02mol), piperazine (4.30g, 0.05mol), cupric bromide (0.45g, 0.002mol), and methylene dichloride (50ml), heated and stirred reaction at 150 DEG C.With thin-layer chromatography monitoring reaction, after question response terminates, except desolventizing, add 10ml ether, vigorous stirring in system, solid is separated out.Solid is carried out recrystallization in ethyl acetate, and obtain 5-piperazinyl-2-amide group cumarone 3.33g, yield is 68%.
Embodiment 3 adds 5-bromo-2-amide group cumarone (4.80g in 100ml there-necked flask, 0.02mol), piperazine (5.16g, 0.06mol), cupric cyanide (0.23g, 0.002mol), and dimethyl formamide (50ml), heated and stirred reaction at 150 DEG C.With thin-layer chromatography monitoring reaction, after question response terminates, except desolventizing, add 10ml ether, vigorous stirring in system, solid is separated out.Solid is carried out recrystallization in ethyl acetate, and obtain 5-piperazinyl-2-amide group cumarone 3.43g, yield is 70%.
Embodiment 4 adds 5-chloro-2-amide group cumarone (3.91g, 0.02mol), piperazine (3.44g, 0.04mol), cupric nitrate (0.37g, 0.002mol) in 100ml there-necked flask, and toluene (50ml), heated and stirred reaction at 150 DEG C.With thin-layer chromatography monitoring reaction, after question response terminates, except desolventizing, add 10ml ether, vigorous stirring in system, solid is separated out.Solid is carried out recrystallization in ethyl acetate, and obtain 5-piperazinyl-2-amide group cumarone 3.28g, yield is 67%.
Embodiment 5 adds 5-bromo-2-amide group cumarone (4.80g in 100ml there-necked flask, 0.02mol), piperazine (3.44g, 0.04mol), cupric chloride (0.27g, 0.002mol), and tetrahydrofuran (THF) (50ml), heated and stirred reaction at 150 DEG C.With thin-layer chromatography monitoring reaction, after question response terminates, except desolventizing, add 10ml ether, vigorous stirring in system, solid is separated out.Solid is carried out recrystallization in ethyl acetate, and obtain 5-piperazinyl-2-amide group cumarone 3.43g, yield is 70%.
Embodiment 6 adds 5-chloro-2-carboxybenzofuran (3.93g in 100ml there-necked flask, 0.02mol), piperazine (3.44g, 0.04mol), cupric chloride (0.27g, 0.002mol), and dimethyl sulfoxide (DMSO) (50ml), heated and stirred reaction at 150 DEG C.With thin-layer chromatography monitoring reaction, after question response terminates, except desolventizing, add 10ml ether, vigorous stirring in system, solid is separated out.Solid is carried out recrystallization in ethyl acetate, and obtain 5-piperazinyl-2-carboxybenzofuran 3.44g, yield is 70%.
MS(ESI
+，m/e)：247.10[M+H]
+
1H-NMR(400MHz,CDCl
3)δ(ppm):1.91(m,1H),2.78(m,4H),3.46(m,4H),6.52(s,1H),7.78(s,1H),7.48(s,1H),7.60(s,1H),11.0(s,1H)
Embodiment 7 adds 5-chloro-2-carboxybenzofuran (3.93g, 0.02mol), piperazine (4.30g, 0.05mol), cupric bromide (0.45g, 0.002mol) in 100ml there-necked flask, and methylene dichloride (50ml), heated and stirred reaction at 150 DEG C.With thin-layer chromatography monitoring reaction, after question response terminates, except desolventizing, add 10ml ether, vigorous stirring in system, solid is separated out.Solid is carried out recrystallization in ethyl acetate, and obtain 5-piperazinyl-2-carboxybenzofuran 3.39g, yield is 69%.
Embodiment 8 adds 5-bromo-2-carboxybenzofuran (4.82g in 100ml there-necked flask, 0.02mol), piperazine (5.16g, 0.06mol), cupric cyanide (0.23g, 0.002mol), and dimethyl formamide (50ml), heated and stirred reaction at 150 DEG C.With thin-layer chromatography monitoring reaction, after question response terminates, except desolventizing, add 10ml ether, vigorous stirring in system, solid is separated out.Solid is carried out recrystallization in ethyl acetate, and obtain 5-piperazinyl-2-carboxybenzofuran 3.30g, yield is 67%.
Embodiment 9 adds 5-chloro-2-carboxybenzofuran (3.93g, 0.02mol), piperazine (3.44g, 0.04mol), cupric nitrate (0.37g, 0.002mol) in 100ml there-necked flask, and toluene (50ml), heated and stirred reaction at 150 DEG C.With thin-layer chromatography monitoring reaction, after question response terminates, except desolventizing, add 10ml ether, vigorous stirring in system, solid is separated out.Solid is carried out recrystallization in ethyl acetate, and obtain 5-piperazinyl-2-carboxybenzofuran 3.49g, yield is 71%.
Embodiment 10 adds 5-bromo-2-carboxybenzofuran (4.82g, 0.02mol), piperazine (3.44g, 0.04mol), cupric chloride (0.27g, 0.002mol) in 100ml there-necked flask, and tetrahydrofuran (THF) (50ml), heated and stirred reaction at 150 DEG C.With thin-layer chromatography monitoring reaction, after question response terminates, except desolventizing, add 10ml ether, vigorous stirring in system, solid is separated out.Solid is carried out recrystallization in ethyl acetate, and obtain 5-piperazinyl-2-amide group cumarone 3.34g, yield is 68%.
Claims (7)
1. prepare the method for vilazodone intermediate 5-piperazinyl-2-acyl substituted cumarone (I) for one kind; under it is characterized in that comprising the steps: the katalysis of a kind of catalyzer of 5-halogen substiuted-2-acyl substituted cumarone (II) in copper halide, cupric cyanide and cupric nitrate, reacting by heating in a solvent, there is linked reaction with piperazine (III) and obtain corresponding 5-piperazinyl-2-acyl substituted cumarone (I):
Wherein, X is chlorine or bromine, and R is amino or hydroxyl.
2. method according to claim 1, is characterized in that described copper halide is cupric chloride.
3. method according to claim 1, is characterized in that described solvent is selected from the one in dimethyl sulfoxide (DMSO), dimethyl formamide, toluene, tetrahydrofuran (THF), methylene dichloride.
4. method according to claim 1, is characterized in that described Heating temperature is 150 DEG C.
5. method according to claim 1, is characterized in that 5-halogen substiuted-2-acyl substituted cumarone (II) and piperazine (III) amount of substance mol ratio are 1:2 ~ 3.
6. method according to claim 1, is characterized in that the amount of substance mol ratio of catalyzer and 5-halogen substiuted-2-acyl substituted cumarone (II) is 1:10.
7. method according to claim 1, it is characterized in that it comprises the steps: in 100mL there-necked flask, add 3.93g5-chloro-2-carboxybenzofuran, 3.44g piperazine, 0.27g cupric chloride, and 50mL dimethyl sulfoxide (DMSO), heated and stirred reaction at 150 DEG C, with thin-layer chromatography monitoring reaction, after question response terminates, except desolventizing, 10mL ether is added in system, vigorous stirring, solid is separated out, and solid is carried out recrystallization in ethyl acetate, obtains 5-piperazinyl-2-carboxybenzofuran.
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