CN102617558A - Preparation method of vilazodone - Google Patents

Abstract

The invention provides a preparation method of vilazodone, which comprises the following steps: reacting 5-cyanoindole, which is used as the initial raw material, with substituted phenylsulfonyl chloride under alkaline conditions, carrying out Friedel-Crafts reaction under the catalytic action of Lewis acid, reducing the product, and carrying out substitution reaction with 5-(1-piperazino)-benzofuryl-2-formamide to obtain the vilazodone. The invention also provides three intermediate compounds related to the vilazodone preparation method. The preparation method provided by the invention has the advantages of low cost, high yield and simple after-treatment, and is easy to operate and convenient for industrial production; and all the reagents are conventional reagents.

Description

A kind of preparation method of vilazodone

Technical field

The invention belongs to the medication preparation field, be specifically related to the improved preparation method of a kind of anti-depression drug vilazodone.

Background technology

Wella oxazolone (Vilazodone) is that a kind of selective serotonin absorbs and thrombotonin 1A acceptor inhibitor and partial agonist again.In January, 2011 U.S. food Drug Administration (FDA) approval listing is used for treatment adult major depressive disorder.

The chemistry of vilazodone is by name: 5-[4-[4-(5-cyanoindole base-3-yl) butyl] piperazinyl-1-yl] benzofuran-2-carboxamides (CAS NO:163521-12-8), and its chemical structural formula is following:

At present, the disclosed method for preparing vilazodone mainly contains following several kinds both at home and abroad:

1) so that 3-(4-hydroxybutyl) indoles-the 5-formonitrile HCN is an intermediates preparation

Publication number is that to disclose with 3-(4-oxo butyl) indoles-5-formonitrile HCN be the method for intermediate preparation vilazodone to the Chinese patent document of CN101163698A.This method is so that 3-(4-hydroxybutyl) indoles-the 5-formonitrile HCN is a raw material; Prepare 3-(4-oxo butyl) indoles-5-formonitrile HCN through oxidation; Again with 5-piperazinyl benzo furans-2-formamide; Get vilazodone through the sodium cyanoborohydride reduction amination, after acidifying salify and refining prepares the hydrochloric acid vilazodone.

This sodium cyanoborohydride that route employing toxicity is big, price is expensive is as the selective reduction agent; And midbody 3-(4-oxo butyl) indoles-5-formonitrile HCN prepares through oxidation; Need through column chromatography purification; The synthesis preparation method of key intermediate 3-(4-hydroxybutyl) indoles-5-formonitrile HCN is not seen bibliographical information, and this method is not suitable for being applied to a large amount of industrialization preparations of hydrochloric acid vilazodone.

2) be intermediates preparation with 3-(4-piperazine butyl) indoles-5-formonitrile HCN

Publication number is that disclosing with 3-(4-piperazine butyl) indoles-5-formonitrile HCN in the Chinese patent document of CN101163698A is the vilazodone preparation method of midbody.This method is a midbody with 3-(4-piperazine butyl) indoles-5-formonitrile HCN; At first under the catalysis of sodium tert-butoxide, three (dibenzalacetone)-two palladium and tri-butyl phosphine; Carry out linked reaction with 5-bromobenzene and furans-2-methane amide, again through acidifying salify and refining, preparation hydrochloric acid vilazodone.This method adopts expensive metal palladium catalyst and tri-butyl phosphine part; Not only preparation cost is high; And the preparation method of midbody 3-(4-piperazine butyl) indoles-5-formonitrile HCN also do not appear in the newspapers, and therefore is not suitable for a large amount of industrialization preparations of hydrochloric acid vilazodone.

3) so that 3-(4-chlorobutyl) indoles-the 5-formonitrile HCN is an intermediates preparation

Publication number is CN1106811, and number to be CN1056610C Chinese patent document be disclosed vilazodone compound patent the earliest to Granted publication, is that indoles-the 5-formonitrile HCN is the method for intermediate preparation vilazodone with 3-(4-chlorobutyl), and synthetic route is following:

3-(4-chlorobutyl) indoles-5-formonitrile HCN and 1-(2-carboxyl cumarone-5-yl) piperazine carry out condensation reaction; The 5-(coumarilic acid of 4-(4-(5-cyanoindole-3-yl) butyl) piperazine-1-); Then with 2-chloro-1-picoline mesylate reaction, after salify refining the hydrochloric acid vilazodone.

This method reactions step is more relatively, and employing is not easy to obtain, expensive pyridinium salt compound carries out acylation reaction, is not suitable for a large amount of industrialization preparations.

Publication number is CN1330635A; Granted publication number is CN1140171 A for CN1155568C and publication number; Granted publication number is to be raw material with 3-(4-chloro butyl) indoles-5-formonitrile HCN for disclosed method in the Chinese patent document of CN1181067C; Carry out condensation reaction with 5-(1-piperazinyl)-benzofuran-2-carboxamides, salify gets the hydrochloric acid vilazodone again, and synthetic route is following:

But aforesaid method starting raw material 3-(4-chloro butyl) indoles-5-formonitrile HCN is difficult for making.

 

Document Synthesis and structure-Activity Relationship in a Class of Indolebutylpiperazines as Dual 5-HT1A Receptor Agonists and Serotonin Reuptake Inhibitors (Timo Heinrich; Etc; Journal of Medicinal Chemistry; 2004,47 (19): address the preparation method of 3-(4-chlorobutyl) indoles-5-formonitrile HCN 4684-4692), synthetic route is following:

This method is to be raw material with the 5-cyanoindole; Under the catalysis of isobutyl-al dichloride, carry out friedel-crafts acylation and get 3-(4-chlorobutyryl)-1H-indoles-5-formonitrile HCN; Through two (methoxy ethoxy) aluminum dihydride selective reduction ketone carbonyl, prepare midbody 3-(4-chlorobutyl) indoles-5-formonitrile HCN again.Used rare Lewis acid isobutyl-chlorination aluminium to be catalyzer in this route.Because this reagent is difficult to buy and preparation, and its unstable chemcial property, very easily combustion is not suitable for mass production in the air.In the reduction reaction step of this route; Adopt two (methoxy ethoxy) aluminum dihydride as the selective reduction agent, the yield of preparation 3-(4-chlorobutyl) indoles-5-formonitrile HCN is low, is merely 27%; And need through column chromatography purification, also be not suitable for being applied to a large amount of industrialization preparations.

Publication number is CN1330635A; Granted publication number is CN1140171 A for CN1155568C and publication number; Granted publication number under the catalysis of isobutyl-chlorination aluminium, carries out friedel-crafts acylation for the compound method of disclosed midbody 3-(4-chlorobutyl) indoles-5-formonitrile HCN in the Chinese patent document of CN1181067C is a raw material with the 5-cyanoindole all; Make 3-(4-chlorobutyryl) indoles-5-formonitrile HCN; Under the activation of isobutyl-chlorination aluminium, adopting Peng Qinghuana selective reduction ketone carbonyl is methylene radical again, preparation midbody 3-(4-chlorobutyl) indoles-5-formonitrile HCN.Synthetic route is following:

The major defect of this method also be isobutyl-chlorination aluminium be difficult to buy and preparation, and its unstable chemcial property, very easily combustion is not suitable for mass production in the air.

Document Allosteric IGF-1R Inhibitors (Timo Heinrich, etc, Med; Chem, Lett, 2010; 1, the 199-203) preparation method of report adopts aluminum chloride to replace isobutyl-al dichloride catalyzed reaction; Obtain midbody 3-(4-chlorobutyl) indoles-5-formonitrile HCN through two (methoxy ethoxy) aluminum dihydride as reductive agent then; Overall yield is lower, and product need be not suitable for being applied to a large amount of industrialization preparations of hydrochloric acid vilazodone through silica gel column chromatography separating purification.Synthetic route is following:

In sum, prior art is that the synthetic vilazodone of raw material exists defectives such as step is more, complex operation, yield is low, reagent is not easy to obtain with the 5-cyanoindole.

Summary of the invention

The present invention proposes a kind of preparation method of vilazodone, may further comprise the steps:

(1) the 5-cyanoindole takes place suc as formula reaction shown in (I) with the substituted benzene SULPHURYL CHLORIDE under alkaline condition;

Formula (I)

(2) the step 1 products therefrom is carried out under Louis acid catalysis suc as formula (II) Fu-Ke reaction;

Formula (II)

(3) the step 2 products therefrom is carried out suc as formula reduction reaction shown in (III) with reductive agent;

Formula (III)

(4) step 3 products therefrom and 5-(1-piperazinyl)-benzofuran-2-carboxamides are carried out substitution reaction shown in formula IV;

Formula IV

Wherein, R1 and R2 can be hydrogen, methyl, methoxyl group, bromine, chlorine, nitro.

Among the preparation method of the present invention; In the step (1) used alkali be sodium salt or the sylvite of triethylamine, diisopropyl ethyl amine, yellow soda ash, salt of wormwood, cesium carbonate, C1～6 alcohol, any one or a few the combination in the sodium hydrogen; Reaction solvent is methylene dichloride, toluene, THF, N; The combination of any one or a few in dinethylformamide, DMAC N,N, N-Methyl pyrrolidone, the methyl-sulphoxide.

Among the preparation method of the present invention, used lewis acid catalyst is any one or a few the combination in aluminum chloride, tin tetrachloride, iron trichloride, zinc chloride, the boron trifluoride in the step (2).

Among the preparation method of the present invention, used reductive agent is the (combination of any one or a few in (two (2-methoxy ethoxy) sodium aluminates of dihydro), tetrahydrochysene lithium aluminium, borane complex, triethyl silicane, the trifluoroacetic acid of red aluminium in the step (3).

Among the preparation method of the present invention, used reaction solvent is N in the step (4), the combination of any one or a few in dinethylformamide, DMAC N,N, N-Methyl pyrrolidone, methyl-sulphoxide, acetonitrile, the butanone.

The invention still further relates to a kind of midbody for preparing vilazodone, have following structure:

R ₁Be in hydrogen, methyl, methoxyl group, bromine, chlorine, the nitro any one, R ₂Be in hydrogen, methyl, methoxyl group, bromine, chlorine, the nitro any one.

The invention still further relates to a kind of midbody for preparing vilazodone, have following structure:

R ₁Be in hydrogen, methyl, methoxyl group, bromine, chlorine, the nitro any one, R ₂Be in hydrogen, methyl, methoxyl group, bromine, chlorine, the nitro any one.

The invention still further relates to a kind of midbody for preparing vilazodone, have following structure:

R ₁Be in hydrogen, methyl, methoxyl group, bromine, chlorine, the nitro any one, R ₂Be in hydrogen, methyl, methoxyl group, bromine, chlorine, the nitro any one.

Each step reaction according to the invention is all carried out under normal condition, and pressure is normal pressure, and TR is-10 ℃ ~ 150 ℃, easy handling.

Preparing method's of the present invention cost is low, and yield is high, and easy handling, agents useful for same are conventional reagent, and aftertreatment is simple, is convenient to suitability for industrialized production.

Embodiment

In conjunction with following specific embodiment and accompanying drawing, the present invention is done further detailed description, protection content of the present invention is not limited to following examples.Under spirit that does not deviate from inventive concept and scope, variation and advantage that those skilled in the art can expect all are included among the present invention, and are protection domain with the appending claims.

Below with R ₁And R ₂Being Wasserstoffatoms illustrates.

The preparation of embodiment 1 compound 1-benzenesulfonyl-1H-indoles-5-formonitrile HCN

(5.6g 0.14mol) and THF (200ml), is cooled to below 0 ℃ then to add 60% sodium hydrogen in three mouthfuls of reaction flasks of 500mL.(20g 0.14moL), treats that venting finishes, and stirs 20 minutes slowly to add the 5-cyanoindole.(49.5g 0.28mol), after finishing, slowly rises to 40 ℃ of reactions, and TLC monitoring raw material reaction is intact slowly to add benzene sulfonyl chloride.Reaction solution goes out with ammonium chloride saturated solution collection, and water merges organic phase with ethyl acetate extraction twice, washing, dried overnight.Filter, filtrate decompression concentrate dried obtain compound 1-benzenesulfonyl-1H-indoles-5-formonitrile HCN (39g, 0.14moL).

Present embodiment gained compound structure is

, and productive rate is: 98%.

ESI-MS m/z:283.3?(M+1)。

The preparation of embodiment 2 compound 3-(4-chlorobutyryl)-1-(benzenesulfonyl)-1H-indoles-5-formonitrile HCN

(56.7g, 0.43mol) and methylene dichloride (800ml), (61.2g 0.43moL), stirred 20 minutes slowly to add the 4-chlorobutanoylchloride under the room temperature to add aluminum chloride in three mouthfuls of reaction flasks of 1L.(40g, methylene dichloride 0.14mol) (200ml) solution after finishing, continue stirring reaction, and TLC monitoring raw material reaction is intact slowly to add 1-benzenesulfonyl-1H-indoles-5-formonitrile HCN.Reaction solution goes out with the frozen water collection, and water merges organic phase with dichloromethane extraction twice, washing, dried overnight.Filter, filtrate decompression concentrate dried obtain compound 3-(4-chlorobutyryl)-1-(benzenesulfonyl)-1H-indoles-5-formonitrile HCN (39.8g, 0.1moL).

Present embodiment gained compound structure is

, and productive rate is: 73%.

¹ H?NMR?(CDCl3)δ8.73?(dd,?1H),?8.37?(s,?1H),?8.07(d,?1H),?7.99?(m,?2H),?7.68(m,2H),?7.59(m,2H),?3.70(t,2H),?3.14(t,2H),?2.27(m,2H)。

The preparation of embodiment 3 compound 3-(4-chlorobutyl)-1-(benzenesulfonyl)-1H-indoles-5-formonitrile HCN

(1g, 2.6mmol), (0.9g 7.8mmol) and trifluoroacetic acid (20ml), is warming up to 50 ℃, stirring reaction to triethyl silicane to add 3-(4-chlorobutyryl)-1-(benzenesulfonyl)-1H-indoles-5-formonitrile HCN in three mouthfuls of reaction flasks of 100ml.TLC monitoring raw material reaction is intact.Reaction solution goes out with 2N hydrochloric acid soln collection.Water is with twice of ethyl acetate extraction.Merge organic phase, washing adds anhydrous sodium sulfate drying and spends the night.Filter, filtrate decompression has been concentrated into solid and has separated out, and stirs 0.5 hour, filters and obtains compound 3-(4-chlorobutyl)-1-(benzenesulfonyl)-1H-indoles-5-formonitrile HCN(0.9g, 2.4mmol).

Present embodiment gained compound structure is

, and productive rate is: 93%.

¹ H?NMR?(CDCl3)δ8.4(d,?1H),?7.9(d,?2H),?7.8?(s,?1H),?7.6(m,2H),?7.5(m,3H),?3.6(t,2H),?2.7(t,2H),?1.86(m,4H)。

Synthesizing of embodiment 4 compound vilazodones

Add in three mouthfuls of reaction flasks of 50ml 3-(4-chlorobutyl)-1-(benzenesulfonyl)-1H-indoles-5-formonitrile HCN (0.3g, 0.8mmol), 5-piperazinyl benzo furans-2-methane amide (0.2g; 0.8mmol), yellow soda ash (0.2g, 2.03mmol) and N; Dinethylformamide (20ml); Stir, be warming up to 120 ℃ of reactions, the TLC monitoring reacts completely.Reaction solution is reduced to room temperature, adds entry and stirs 30 minutes, filters, and filter cake is used water washing, drain solid.

The gained solid is added in 75% methanol aqueous solution (20ml), and (0.3g 2.4mmol) refluxes, and the TLC monitoring reacts completely to add salt of wormwood.Reduce to room temperature, concentrating under reduced pressure methyl alcohol, residuum add ETHYLE ACETATE (20ml) and water (15ml) stirred 30 minutes.Ethyl acetate layer water, saturated brine successively washs once.Concentrating under reduced pressure is dried obtain resistates with recrystallizing methanol obtain vilazodone (0.2g, 0.48mmol).

Present embodiment gained compound structure is

, and productive rate is: 60%.

ESI-MS m/z:442.2?(M+1)。

¹ H?NMR?(DMSO-d6)δ11.35?(s,?1H),?8.05?(s,?1H),?8.00(brs,?1H),?7.59?(brs,?1H),?7.45?(m,?4H),?7.32(s,1H),?7.10?(m,?2H),?3.05?(m,?4H),?2.75?(t,?2H),?2.49(m,?4H),?2.32(m,2H),?1.67?(m,2H),?1.50(m,2H)。

R ₁Be Wasserstoffatoms, R ₂Be exemplified below during for nitro, other substituting group situation response class seemingly.

The preparation of embodiment 5 compound 1-p-nitrophenyl alkylsulfonyl-1H-indoles-5-formonitrile HCNs

(5.6g 0.14mol) and THF (200ml), is cooled to below 0 ℃ then to add 60% sodium hydrogen in three mouthfuls of reaction flasks of 500mL.(20g 0.14moL), treats that venting finishes, and stirs 20 minutes slowly to add the 5-cyanoindole.(62g 0.28mol), after finishing, slowly rises to 40 ℃ of reactions, and TLC monitoring raw material reaction is intact slowly to add the 4-nitrobenzene sulfonyl chloride.Reaction solution goes out with ammonium chloride saturated solution collection, and water merges organic phase with ethyl acetate extraction twice, washing, dried overnight.Filter, filtrate decompression concentrate dried obtain compound 1-p-nitrophenyl alkylsulfonyl-1H-indoles-5-formonitrile HCN (42.2g, 0.14moL).

Present embodiment gained compound structure is

, and productive rate is: 92%.

ESI-MS?m/z:328.3?(M+1)。

The preparation of embodiment 6 compound 3-(4-chlorobutyryl)-1-(p-nitrophenyl alkylsulfonyl)-1H-indoles-5-formonitrile HCN

(56.7g, 0.43mol) and methylene dichloride (800ml), (61.2g 0.43moL), stirred 20 minutes slowly to add the 4-chlorobutanoylchloride under the room temperature to add aluminum chloride in three mouthfuls of reaction flasks of 1L.(45.8g, methylene dichloride 0.14mol) (200ml) solution after finishing, continue stirring reaction, and TLC monitoring raw material reaction is intact slowly to add 1-p-nitrophenyl alkylsulfonyl-1H-indoles-5-formonitrile HCN.Reaction solution goes out with the frozen water collection, and water merges organic phase with dichloromethane extraction twice, washing, dried overnight.Filter, filtrate decompression concentrate dried obtain compound 3-(4-chlorobutyryl)-1-(p-nitrophenyl alkylsulfonyl)-1H-indoles-5-formonitrile HCN (41.3g, 0.1moL).

Present embodiment gained compound structure is

, and productive rate is: 71%.

ESI-MS?m/z:432.3?(M+1)。

The preparation of embodiment 7 compound 3-(4-chlorobutyl)-1-(p-nitrophenyl alkylsulfonyl)-1H-indoles-5-formonitrile HCN

(1.1g, 2.6mmol), (0.9g 7.8mmol) and trifluoroacetic acid (20ml), is warming up to 50 ℃, stirring reaction to triethyl silicane to add 3-(4-chlorobutyryl)-1-(p-nitrophenyl alkylsulfonyl)-1H-indoles-5-formonitrile HCN in three mouthfuls of reaction flasks of 100ml.TLC monitoring raw material reaction is intact.Reaction solution goes out with 2N hydrochloric acid soln collection.Water is with twice of ethyl acetate extraction.Merge organic phase, washing adds anhydrous sodium sulfate drying and spends the night.Filter, filtrate decompression has been concentrated into solid and has separated out, and stirs 0.5 hour, filters and obtains compound 3-(4-chlorobutyl)-1-(p-nitrophenyl alkylsulfonyl)-1H-indoles-5-formonitrile HCN(0.8g, 1.9mmol).

Present embodiment gained compound structure is

, and productive rate is: 73%.

ESI-MS?m/z:418.3?(M+1)。

Synthesizing of embodiment 8 compound vilazodones

Add in three mouthfuls of reaction flasks of 50ml 3-(4-chlorobutyl)-1-(p-nitrophenyl alkylsulfonyl)-1H-indoles-5-formonitrile HCN (0.5g, 1.2mmol), 5-piperazinyl benzo furans-2-methane amide (0.3g; 1.2mmol), yellow soda ash (0.35g, 2.5mmol) and N; Dinethylformamide (20ml); Stir, be warming up to 120 ℃ of reactions, the TLC monitoring reacts completely.Reaction solution is reduced to room temperature, adds entry and stirs 30 minutes, filters, and filter cake is used water washing, drain solid.

The gained solid is added in 75% methanol aqueous solution (20ml), and (0.3g 2.4mmol) refluxes, and the TLC monitoring reacts completely to add salt of wormwood.Reduce to room temperature, concentrating under reduced pressure methyl alcohol, residuum add ETHYLE ACETATE (20ml) and water (15ml) stirred 30 minutes.Ethyl acetate layer water, saturated brine successively washs once.Concentrating under reduced pressure is dried obtain resistates with recrystallizing methanol obtain vilazodone (0.3g, 0.78mmol).

The present embodiment productive rate is: 65%.

Claims (8)

1. the preparation method of a vilazodone is characterized in that, said method comprising the steps of:

(1) the 5-cyanoindole takes place suc as formula reaction shown in (I) with the substituted benzene SULPHURYL CHLORIDE under alkaline condition;

formula (I)

(2) step (1) products therefrom is carried out under Louis acid catalysis suc as formula (II) Fu-Ke reaction;

formula (II)

(3) step (2) products therefrom is carried out suc as formula reduction reaction shown in (III) with reductive agent;

formula (III)

(4) step (3) products therefrom and 5-(1-piperazinyl)-benzofuran-2-carboxamides are carried out substitution reaction shown in formula IV;

formula IV

Wherein, R ₁Be in hydrogen, methyl, methoxyl group, bromine, chlorine, the nitro any one, R ₂Be in hydrogen, methyl, methoxyl group, bromine, chlorine, the nitro any one.

2. preparation method as claimed in claim 1; It is characterized in that; In the step (1) used alkali be sodium salt or the sylvite of triethylamine, diisopropyl ethyl amine, yellow soda ash, salt of wormwood, cesium carbonate, C1～6 alcohol, any one or a few the combination in the sodium hydrogen; Reaction solvent is methylene dichloride, toluene, THF, N, the combination of any one or a few in dinethylformamide, DMAC N,N, N-Methyl pyrrolidone, the methyl-sulphoxide.

3. preparation method as claimed in claim 1 is characterized in that, used Lewis acid is any one or a few the combination in aluminum chloride, tin tetrachloride, iron trichloride, zinc chloride, the boron trifluoride in the step (2).

4. preparation method as claimed in claim 1; It is characterized in that used reductive agent is any one or a few combination of red aluminium ((dihydro two (2-methoxy ethoxy) sodium aluminates), tetrahydrochysene lithium aluminium, borane complex, triethyl silicane, trifluoroacetic acid in the step (3).

5. preparation method as claimed in claim 1; It is characterized in that; Used reaction solvent is N in the step (4), the combination of any one or a few in dinethylformamide, DMAC N,N, N-Methyl pyrrolidone, methyl-sulphoxide, acetonitrile, the butanone.

6. midbody for preparing vilazodone is characterized in that having following structure:

R ₁Be in hydrogen, methyl, methoxyl group, bromine, chlorine, the nitro any one, R ₂Be in hydrogen, methyl, methoxyl group, bromine, chlorine, the nitro any one.

7. midbody for preparing vilazodone is characterized in that having following structure:

R ₁Be in hydrogen, methyl, methoxyl group, bromine, chlorine, the nitro any one, R ₂Be in hydrogen, methyl, methoxyl group, bromine, chlorine, the nitro any one.

8. midbody for preparing vilazodone is characterized in that having following structure:

R ₁Be in hydrogen, methyl, methoxyl group, bromine, chlorine, the nitro any one, R ₂Be in hydrogen, methyl, methoxyl group, bromine, chlorine, the nitro any one.