CN104098552A - Preparation method of vilazodone - Google Patents

Preparation method of vilazodone Download PDF

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Publication number
CN104098552A
CN104098552A CN201310113634.3A CN201310113634A CN104098552A CN 104098552 A CN104098552 A CN 104098552A CN 201310113634 A CN201310113634 A CN 201310113634A CN 104098552 A CN104098552 A CN 104098552A
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Prior art keywords
compound
add
alkoxide
carbon atom
organic solvent
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CN201310113634.3A
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Chinese (zh)
Inventor
李振伟
毕万福
单晓燕
陈旭东
时惠麟
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Priority to CN201310113634.3A priority Critical patent/CN104098552A/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to a preparation method of vilazodone, in particular to a preparation method of a compound shown as formula 1. The method includes reacting a compound shown as formula 2 with an amide compound in an organic solvent in the presence of alkoxide. (formula 1 and formula 2).

Description

The preparation method of vilazodone
Technical field
The present invention relates to chemical pharmacy field, relate in particular to a kind of preparation method of new vilazodone.
Background technology
Vilazodone (English name Vilazodone has another name called: EMD68843); Chemistry 5-{4-[4-(5-cyano group-3-indyl) butyl by name]-1-piperazinyl } benzofuran-2-carboxamides.It is the novel anti-depression drug of one of being developed by Merck KGaA company.GlaxoSmithKline PLC company of Britain has obtained the market sale power of this new drug, and has obtained approving of FDA in January, 2011.The structural formula of vilazodone is as follows:
Dysthymia disorders is a kind of common mental disorder, and that its cardinal symptom shows as is depressed, poor appetite, somnopathy, even suicide attempts etc., is clinically chronic, repeatability outbreak.In the annual report of announcing according to the World Health Organization 2009, show: dysthymia disorders has occupied the 4th in the large disease in the world ten at present, expects the year two thousand twenty, will jump to second.
Vilazodone, as anti-depression drug of new generation, is that one combines the novel anti-depression drug that 5-HT re-uptake suppresses (SSRI) and 5-HT1A receptor antagonist dual function.Be compared to existing anti-depression drug, vilazodone is considered to a kind of medicine of effective inhibition dysthymia disorders.
About the preparation method of vilazodone reports relatively less, the method of Merck & Co., Inc. (Merck) report is: adopting 5-nitro-cumarone-2-carboxylic acid, ethyl ester is raw material, pass through nitroreduction, two (2-chloroethyl) amine hydrochlorate cyclization, obtain J.Med.Chem.2004,47.4684-4692 with 5-cyano group-3-(4-chlorobutyl) indole reaction, hydrolysis, amidation.But the method total recovery is only 3.4%, is not suitable for suitability for industrialized production.
Document Journal of Medicinal Chemistry, 2004, the 47 volumes, the 19th phase, the method for 4690. reports comprises:
A. by 5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl } cumarone-2-carboxylic acid, ethyl ester and KOH, join containing in the reaction flask of methyl alcohol, reflux 3h, revolve steaming evaporate to dryness, residue is with after water dissolution, and with 1N HCl tune, pH is extremely neutral, filter, after gained solid drying, be 5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl } tetrahydrate of cumarone-2-carboxylic acid, yield 80%;
B. by 5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl } cumarone-2-carboxylic acid and the chloro-1-picoline of 2-iodide, after dissolving with NMP (N-Methyl pyrrolidone), pass into NH 3, dropwise drip N, N-diisopropyl ethyl amine, temperature is increased to 41 DEG C, after 15 minutes, is down to room temperature.Reaction solution is poured into water, after fully extracting by ethyl acetate, dry, obtain 5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl } benzofuran-2-carboxamides, be vilazodone, yield 72%.
The method of Chinese patent CN102180868 report comprises:
A. by 5-{4-[4-(the bromo-3-indyl of 5-) butyl]-1-piperazinyl } cumarone-2-carboxylic acid, ethyl ester, 80% hydrazine hydrate, Amberlyst A26 basic resin, ethylene glycol mix, vigorous stirring, reflux 2h, underpressure distillation is except desolventizing and remaining hydrazine hydrate.Again reaction flask is slowly warming up to 130 DEG C, continues reaction 2h, be cooled to room temperature.Add water and ethyl acetate washing.Remove by filter resin, organic layer is dry, filtration, underpressure distillation be except desolventizing.Crude product dehydrated alcohol recrystallization, obtains 5-{4-[4-(the bromo-3-indyl of 5-) butyl]-1-piperazinyl } cumarone-2-carboxylic acid, yield 72.1%;
B. by 5-{4-[4-(the bromo-3-indyl of 5-) butyl]-1-piperazinyl } mixture of cumarone-2-carboxylic acid, cuprous cyanide, N-Methyl pyrrolidone is placed in the microwave reaction kettle of 200W reaction 40 minutes, then reactant is cooled to room temperature, the dilution of employing frozen water, filter, gained solid ammonia scrubbing, gained solid chloroform extraction, obtain 5-{4-[4-(5-cyano group-3-indyl) butyl with Virahol recrystallization again]-1-piperazinyl } cumarone-2-carboxylic acid, yield 71.4%;
C. by 5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl } cumarone-2-carboxylic acid, the chloro-1-picoline of 2-iodide, N-Methyl pyrrolidone mixture be placed in a sealed tube.Pass into ammonia, by N, N-diisopropyl ethyl amine is slowly added dropwise in reaction solution, temperature is slowly down to room temperature after being increased to 50 DEG C, after reaction solution is poured into water, extract, remove ethyl acetate with anhydrous sodium sulfate drying, underpressure distillation by ethyl acetate, obtain 5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl } free state of benzofuran-2-carboxamides, yield 62.4%.
Above-mentioned two kinds of methods mentioned prepare 5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl in the method for benzofuran-2-carboxamides, all want two steps or above operation, and complex operation, yield is low.
This area needs less, easy and simple to handle and yield is higher and prepared by applicable mass-producing business 5-{4-[4-(5-cyano group-3-indyl) butyl of a kind of step]-1-piperazinyl } preparation method of benzofuran-2-carboxamides.
Summary of the invention
The present invention aims to provide a kind of preparation method of new vilazodone.
In a first aspect of the present invention, the object of the present invention is to provide the 5-{4-[4-that a kind of step is less, easy and simple to handle and yield is higher and prepared by applicable mass-producing business (5-cyano group-3-indyl) butyl]-1-piperazinyl } preparation method of benzofuran-2-carboxamides.
The reaction formula of the inventive method is as follows
Specifically, the method for preparation formula 1 compound of the present invention comprises the following steps: under the existence of alkoxide, formula 2 compounds are reacted with amide compound in organic solvent:
Wherein, R is the alkyl with 1-6 carbon atom.
In some embodiments, R is the alkyl with 1-4 carbon atom.
In some embodiments, described alkoxide is lithium salts, sodium salt or the sylvite of 1-4 carbon atom alcohol.
In some embodiments, described amide compound is methane amide or ethanamide.
In some embodiments, described organic solvent is DMF.
In some embodiments, described reaction is carried out at 0-25 DEG C.Some preferred embodiment in, described reaction is carried out in room temperature.
In some embodiments, said method comprising the steps of:
(1) by structural formula compound dissolution as shown in Equation 2 in organic solvent;
(2) add amide compound, then add alkoxide, obtain reaction solution 1;
(3) reaction solution 1 is poured into water, the solid of separating out after filtration, washing, ether wash, obtain compound as shown in Equation 1 after dry.Some preferred embodiment in, described alkoxide is lithium salts, sodium salt or the sylvite of 1-4 carbon atom alcohol.Some preferred embodiment in, described organic solvent is DMF; Described amide compound is methane amide or ethanamide.
Embodiment
Contriver, through extensive and deep research, is surprised to find that under the existence of alkoxide, obtains structural formula compound as shown in Equation 1 after structural formula compound as shown in Equation 2 can react with amide compound.
The structural formula of compound the present invention relates to is as follows:
In formula, R is the alkyl of 1-6 carbon atom.
In a preferred embodiment, R is the alkyl of 1-4 carbon atom.Or in some embodiments, R is the alkyl of 1-2 carbon atom.
Particularly, the preparation method of structural formula provided by the invention compound be as shown in Equation 1 by structural formula compound dissolution as shown in Equation 2 in organic solvent, add amide compound, after stirring, ice-water bath, adds alkoxide, room temperature reaction, obtains product through aftertreatment.Described organic solvent is DMF.Described alkoxide is lithium salts, sodium salt, the sylvite of 1-4 carbon atom alcohol.For example, alkoxide can be sodium methylate, sodium ethylate, potassium tert.-butoxide, lithium methoxide, sodium isopropylate etc.Described amide compound can be methane amide or ethanamide.Described aftertreatment can comprise step: a, reaction solution is poured into water, and separates out solid; With b, to the solid filtering of separating out, washing, ether obtain final product after washing, being dried.
In one embodiment of the invention, the compound of formula 1 is prepared by following method: by 5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl } cumarone-2-carboxylic acid, ethyl ester is dissolved in DMF, add amide compound, after stirring, ice-water bath, add alkoxide, room temperature reaction.Then, reaction solution is poured into water, separates out solid.Continue to stir, filter, washing, ether is washed, and after being dried, obtains product.
The above-mentioned feature that the present invention mentions, or the feature that embodiment mentions can arbitrary combination.All features that this case specification sheets discloses can with any composition forms use, each feature disclosing in specification sheets, can anyly provide the alternative characteristics of identical, impartial or similar object to replace.Therefore apart from special instruction, the feature disclosing is only the general example of equalization or similar features.
Major advantage of the present invention is:
1, preparation method's step provided by the invention is less, easy and simple to handle.
2, preparation method's productive rate provided by the invention is high.
3, preparation method provided by the invention is suitable for large-scale industrial production.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, the condition of conventionally advising according to normal condition or according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio, ratio, ratio or umber by weight.
Unit in percent weight in volume in the present invention is well-known to those skilled in the art, for example, refer to the weight of solute in the solution of 100 milliliters.
Unless otherwise defined, the same meaning that all specialties that use in literary composition and scientific words and one skilled in the art are familiar.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
The reagent using in following embodiment and comparative example and raw material are commercially available technical grade Chemicals.
Embodiment 1
In 10ml eggplant-shape bottle, add 0.2g5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl } cumarone-2-carboxylic acid, ethyl ester, 3ml DMF, after dissolving, add 0.2g methane amide, stir after 10min, ice-water bath, adds 0.05g sodium methylate, room temperature reaction, reaction solution is poured in 12ml water, separates out solid, stirs 1h, filter, wash twice with 6ml washing twice, 6ml methyl tertiary butyl ether, dry to obtain product 0.14g(78%).MS:441.22。
Embodiment 2
In 10ml eggplant-shape bottle, add 0.2g5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl } cumarone-2-carboxylic acid, ethyl ester, 3mlDMF, after dissolving, add 0.2g methane amide, stir after 10min ice-water bath, add 0.06g sodium ethylate, room temperature reaction, obtains target compound.MS:441.22。
Embodiment 3
In 10ml eggplant-shape bottle, add 0.2g5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl } cumarone-2-carboxylic acid, ethyl ester, 3mlDMF, after dissolving, add 0.2g methane amide, stir after 10min, ice-water bath, add 0.1g potassium tert.-butoxide, room temperature reaction, obtains target compound.MS:441.22。
Embodiment 4
In 10ml eggplant-shape bottle, add 0.2g5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl } cumarone-2-carboxylic acid, ethyl ester, 3mlDMF, after dissolving, add 0.2g methane amide, stir after 10min ice-water bath, add 0.04g lithium methoxide, room temperature reaction, obtains target compound.MS:441.22。
Embodiment 5
In 10ml eggplant-shape bottle, add 0.2g5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl } cumarone-2-carboxylic acid, ethyl ester, 3mlDMF, after dissolving, add 0.2g methane amide, stir after 10min, ice-water bath, add 0.08g sodium isopropylate, room temperature reaction, obtains target compound.MS:441.22。
Embodiment 6
In 10ml eggplant-shape bottle, add 0.2g5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl } cumarone-2-carboxylate methyl ester, 3mlDMF, after dissolving, add 0.2g methane amide, stir after 10min ice-water bath, add 0.05g sodium methylate, room temperature reaction, obtains target compound.MS:441.22。
Embodiment 7
In 10ml eggplant-shape bottle, add 0.2g5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl } cumarone-2-carboxylic acid, ethyl ester, 3mlDMF, after dissolving, add 0.26g ethanamide, stir after 10min, ice-water bath, add 0.05g sodium methylate, room temperature reaction, obtains target compound.MS:441.22。
Embodiment 8
In 10ml eggplant-shape bottle, add 0.2g5-{4-[4-(5-cyano group-3-indyl) butyl]-1-piperazinyl } cumarone-2-carboxylic acid, ethyl ester, 3mlDMF, after dissolving, add 0.26g ethanamide, stir after 10min, ice-water bath, add 0.06g sodium ethylate, room temperature reaction, obtains target compound.MS:441.22。
The foregoing is only preferred embodiment of the present invention, not in order to limit essence technology contents scope of the present invention, essence technology contents of the present invention is to be broadly defined in the claim scope of application, any technology entity or method that other people complete, if defined identical with the claim scope of application, also or a kind of change of equivalence, be all covered by among this claim scope being regarded as.

Claims (10)

1. for the preparation of a method for formula 1 compound, it is characterized in that, under the existence of alkoxide, formula 2 compounds reacted with amide compound in organic solvent:
Wherein, R is the alkyl with 1-6 carbon atom.
2. the method for claim 1, is characterized in that, R is the alkyl with 1-4 carbon atom.
3. the method for claim 1, is characterized in that, described alkoxide is lithium salts, sodium salt or the sylvite of 1-4 carbon atom alcohol.
4. the method for claim 1, is characterized in that, described amide compound is methane amide or ethanamide.
5. the method for claim 1, is characterized in that, described organic solvent is DMF.
6. the method for claim 1, is characterized in that, described reaction is carried out at 0-25 DEG C.
7. the method for claim 1, is characterized in that, described reaction is carried out in room temperature.
8. the method for claim 1, is characterized in that, said method comprising the steps of:
(1) by structural formula compound dissolution as shown in Equation 2 in organic solvent;
(2) add amide compound, then add alkoxide, obtain reaction solution 1;
(3) reaction solution 1 is poured into water, the solid of separating out after filtration, washing, ether wash, obtain compound as shown in Equation 1 after dry.
9. method as claimed in claim 8, is characterized in that, described alkoxide is lithium salts, sodium salt or the sylvite of 1-4 carbon atom alcohol.
10. method as claimed in claim 8, is characterized in that, described organic solvent is DMF; Described amide compound is methane amide or ethanamide.
CN201310113634.3A 2013-04-02 2013-04-02 Preparation method of vilazodone Pending CN104098552A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104513233A (en) * 2013-10-08 2015-04-15 无锡万全医药技术有限公司 Novel method for preparing 5-(4-(4-(5-cyano-1H-indole-3-yl)butyl)piperazine-1-yl)coumarone-2-methanamide
CN110092778A (en) * 2019-05-14 2019-08-06 浙江工业大学 A method of using cheap metal copper for vilazodone intermediate and vilazodone drug

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1106811A (en) * 1993-09-30 1995-08-16 默克专利股份有限公司 Piperidines and piperazines

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
CN1106811A (en) * 1993-09-30 1995-08-16 默克专利股份有限公司 Piperidines and piperazines

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANTONIO RAMIREZ,等: "A Mechanistic Study on the Amidation of Esters Mediated by Sodium Formamide", 《J. ORG. CHEM.》 *
EVAN L. ALLRED,等: "Amidation of Esters with Amides in the Presence of Methoxide Ion", 《J. ORG. CHEM.》 *
王启发,等: "盐酸维拉唑酮的合成", 《中国医药工业杂志》 *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104513233A (en) * 2013-10-08 2015-04-15 无锡万全医药技术有限公司 Novel method for preparing 5-(4-(4-(5-cyano-1H-indole-3-yl)butyl)piperazine-1-yl)coumarone-2-methanamide
CN110092778A (en) * 2019-05-14 2019-08-06 浙江工业大学 A method of using cheap metal copper for vilazodone intermediate and vilazodone drug

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Application publication date: 20141015