CN103360373B - The synthetic method of vilazodone intermediate and salt thereof - Google Patents
The synthetic method of vilazodone intermediate and salt thereof Download PDFInfo
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Abstract
The present invention relates to a kind of vilazodone intermediate 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) synthetic method of benzofuran-2-carboxylic acid, ethyl ester and salt thereof, belong to technical field of medicine synthesis. Described synthetic method comprises the following steps: under nitrogen protection; 3-(4-chlorobutyl)-5-cyanoindole and catalyst are dissolved in anhydrous solvent; 5-(piperazine-1-base is added after being heated to reflux stirring) benzofuran-2-carboxylic acid, ethyl ester and alkali; react 4～6 hours when 80～110 DEG C; being stirred at room temperature down and be poured slowly into alkaline aqueous solution to precipitating out solid, post processing obtains 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester. The production cost of this synthetic method is low, environmental protection, and processing safety is high, and the yield of product and purity are high, and quality is good, are suitable for large-scale industrial production.
Description
Technical field
The present invention relates to the synthetic method of a kind of pharmaceutical intermediate, particularly relate to vilazodone intermediate 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) synthetic method of benzofuran-2-carboxylic acid, ethyl ester and salt thereof, belong to technical field of medicine synthesis.
Background technology
Vilazodone, is the new antidepressant developed by ClinicalData company, is used for treating major depressive disorder. Clinical testing data shows, vilazodone anti-strongly fragrant medicine existing with clinic compares, and has rapid-action, and patient is not had sexual dysfunction, the features such as untoward reaction is little by better tolerance. Its chemical name is 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochlorate, chemical formula is:
And 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester and salt thereof is the important intermediate of synthesis vilazodone, adopt 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester and salt synthesis vilazodone thereof have feature simple to operate, to be beneficial to industrialized production, and its synthetic route is as follows:
About synthesis 5-(4-[4-(5-cyano group-3-indyl)-butyl in prior art]-1-piperazinyl) document of benzofuran-2-carboxylic acid, ethyl ester has Heinrich, Timo; Boettcher, (the SynthesisandStructure-ActivityRelationshipinaClassofIndo lebutylpiperazinesasDual5-HT1AReceptorAgonistsandSeroton inReuptakeInhibitors of Henning et al., JournalofMedicinalChemistry47 (2004) 4684-4692), its concrete synthetic route is as follows:
Although prior art is by one-step synthesis method vilazodone intermediate 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester, but in this synthetic method, not only used poisonous acetonitrile and the acetone solvent that easily system is malicious, operator ' s health is caused high risks, is unfavorable for large-scale industrial production;And the response time of this synthetic method is long, post-reaction treatment needs just to obtain product, complex steps through extraction, column chromatography and three steps of recrystallization, causes that the cost of cost of material and post processing is high, and product yield is only about 32%. This external course of reaction is also easy to produce a large amount of three wastes, causes severe environmental pollution.
Summary of the invention
The present invention is directed to the defect of prior art, there is provided a kind of cost low, product yield is high, reactions steps and post processing are simple, the one-step synthesis method vilazodone intermediate 5-of environmental protection (4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) method of benzofuran-2-carboxylic acid, ethyl ester.
The above-mentioned purpose of the present invention can be realized by following technical proposal: one-step synthesis method 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) method of benzofuran-2-carboxylic acid, ethyl ester, described synthetic method comprises the steps: under nitrogen protection, 3-(4-chlorobutyl)-5-cyanoindole and catalyst are added to anhydrous solvent, forms reactant liquor, be heated to reflux stirring 2～4 hours; Then by 5-(piperazine-1-base) benzofuran-2-carboxylic acid, ethyl ester and alkali joins in reactant liquor, react when 80～110 DEG C 4～6 hours and react completely to TLC detection, then reactant liquor is cooled to room temperature, it is poured slowly into alkaline aqueous solution under stirring to precipitating out solid, sucking filtration, washing after stirring 0.5～2 hour, dries to obtain 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester.
The system of this reaction is alkaline, and reactant can be hydrolyzed in water, it is therefore desirable to carry out in anhydrous solvent. Alkali is used in neutralization system the acid produced. Catalyst plays catalytic action in the reaction, can promote the carrying out of substitution reaction. When substitution reaction temperature is 80～110 DEG C, response speed increases with reaction temperature and accelerates, if reaction temperature is more than 110 DEG C, reaction impurities becomes many, and yield reduces, if reaction temperature is below 80 DEG C, substitution reaction is then difficult to carry out. Therefore the reaction temperature in synthetic method is controlled at 80～110 DEG C by the present invention. The synthetic method of the present invention settles at one go, simple to operate, and condition is controlled.
Described raw material 5-(piperazine-1-base) benzofuran-2-carboxylic acid, ethyl ester can directly buy from the market, existing common technology can also be adopted to be synthetically derived, it is also possible to the 5-(piperazine-1-base with reference to disclosed in patent documentation (publication number: CN102964323A)) the relevant synthesis 5-(piperazine-1-base that discloses in the synthetic method process of benzofuran-2-carboxamides) method of benzofuran-2-carboxylic acid, ethyl ester is synthetically derived.
Raw material 3-(4-chlorobutyl)-5-cyanoindole directly can also buy or adopt existing common technology to be synthetically derived from the market, it is also possible to reference to patent documentation, (publication number is: the synthetic method of 3-(4-the chlorobutyl)-5-cyanoindole disclosed in CN102964287A) is synthetically derived.
At above-mentioned one-step synthesis method 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester method in, described 5-(piperazine-1-base) mol ratio of benzofuran-2-carboxylic acid, ethyl ester and 3-(4-chlorobutyl)-5-cyanoindole is (0.7～1.5): 1. The present invention is it have been investigated that 5-(piperazine-1-base) benzofuran-2-carboxylic acid, ethyl ester than 3-(4-chlorobutyl)-5-cyanoindole mole more time quaternary ammonium salt by-product can be avoided to generate.
At above-mentioned one-step synthesis method 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester method in, described catalyst is the one in iodide and bromide.
Wherein, described iodide are the one in lithium iodide, sodium iodide, potassium iodide, rubidium iodide, cesium iodide, Hydro-Giene (Water Science).. Described bromide is, one in lithium bromide, sodium bromide, potassium bromide, rubidium bromide, cesium bromide.
It is preferred that, described catalyst is the sodium iodide in iodide. The advantages such as compared with other catalyst, sodium iodide has cheap, and inventory is few.
Wherein, the mol ratio of described catalyst and 3-(4-chlorobutyl)-5-cyanoindole is (1～4): 1. First there is substitution reaction in catalyst and indole fragment in the present reaction, it is (1～4) by catalyst choice in the mol ratio of 3-(4-chlorobutyl)-5-cyanoindole: next step replacement activity of intermediate can be strengthened between 1, thus improving the yield of product.
At above-mentioned one-step synthesis method 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester method in, as preferably, described anhydrous solvent is one or more in DMF, oxolane, methanol, ethanol, isopropanol, n-butyl alcohol, chlorobenzene, dichloro-benzenes, ethyl acetate, isopropyl acetate, dimethyl sulfoxide, N-Methyl pyrrolidone, ethylene glycol, glycol dimethyl ether, ether, methyl tertiary butyl ether(MTBE), toluene, dimethylbenzene, dichloromethane, chloroform, acetonitrile. It is preferred that, described anhydrous solvent is DMF. Compared with its anhydrous solvent, DMF is cheap, and boiling point is high better to substrate dissolubility, and can dissolve each other with any ratio with water.
At above-mentioned one-step synthesis method 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester method in, as preferably, described alkali is potassium carbonate, triethylamine, N-methylmorpholine, pyridine, Feldalat NM, Sodium ethylate, sodium tert-butoxide, potassium tert-butoxide, methylamine, ethamine, dimethylamine, diethylamine, trimethylamine, tripropyl amine (TPA), tri-n-butylamine, triamylamine, tri-n-octyl amine, n-butylamine, TBAH, morpholine, N, N-diisopropylethylamine, DMAP, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, one in potassium hydroxide. it is preferred that, described alkali is potassium carbonate.
Wherein, the mol ratio of described alkali and 3-(4-chlorobutyl)-5-cyanoindole is (1～3): 1. The alkali number of vast scale can improve response speed.
At above-mentioned one-step synthesis method 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester method in, as preferably, described alkaline aqueous solution is the one in sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.
At above-mentioned one-step synthesis method 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester method in, as preferably, described reaction temperature is 90～100 DEG C, and the response time is 4～6 hours.
Another object of the present invention also resides in provides a kind of 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) synthetic method of benzofuran-2-carboxylic acid, ethyl ester salt, this synthetic method comprises the steps: to choose 5-that above-mentioned synthetic method prepares (4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester is dissolved in alcoholic solution, heating is to all dissolving, add acid fully reaction to precipitating out solid, the lower cooling of stirring, sucking filtration, washing dry 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester salt.
Acid is as a kind of part in the present reaction, makes vilazodone become salt with acid. Because salt is inorganic matter, it is dissolved in alcohol and can precipitate out. First reactant liquor heating can be made 5-(4-[4-(5-cyano group-3-indyl)-butyl to 70～90 DEG C]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester fully dissolves, precipitate out and freezing under cryosel is bathed after solid precipitation within 0.5～1 hour, can be made more thorough, thus improving 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) yield of benzofuran-2-carboxylic acid, ethyl ester salt. Additionally, should also be noted that during acid adding that the amount adding acid is not easily too much, hyper acid that the solid of precipitation can be made to dissolve in addition, reduction product yield.
At above-mentioned 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester salt synthetic method in, as preferably, described alcoholic solution is straight-chain alkyl alcohol, one or more in a kind of and methyl tertiary butyl ether(MTBE) in cycloalkanyl alcohol, aromatic alcohol, normal heptane, petroleum ether, normal hexane, ether, hexamethylene, ethyl acetate, Isosorbide-5-Nitrae-dioxane, oxolane, glycol dimethyl ether. It is preferred that, described alcoholic solution is the isopropanol in straight-chain alkyl alcohol. Because isopropanol is cheap, viscosity is big, and product, between methanol and ethyl acetate, is had good dissolubility by polarity.
At above-mentioned 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester salt synthetic method in, as preferably, the acid of described addition is the one in hydrochloric acid, sulphuric acid, hydrobromic acid, acetic acid, tartaric acid, maleic acid, fumaric acid, oxalic acid, citric acid, phosphoric acid, trifluoroacetic acid, formic acid, succinic acid, mandelic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, benzoic acid, Nitrodracylic acid, P-hydroxybenzoic acid. It is preferred that, the acid of described addition is hydrochloric acid.
As preferably, 5-that the present invention prepares (4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester salt is 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylate hydrochloride.
5-of the present invention (4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) chemical equation of synthetic method of benzofuran-2-carboxylic acid, ethyl ester salt is as follows:
Wherein, HX takes from acid for the one in hydrochloric acid, sulphuric acid, hydrobromic acid, acetic acid, tartaric acid, maleic acid, fumaric acid, oxalic acid, citric acid, phosphoric acid, trifluoroacetic acid, formic acid, succinic acid, mandelic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, benzoic acid, Nitrodracylic acid, P-hydroxybenzoic acid.
In sum, the invention have the advantages that
1, the synthetic method of the present invention is with 3-(4-chlorobutyl)-5-cyanoindole and 5-(piperazine-1-base) benzofuran-2-carboxylic acid, ethyl ester is for raw material, raw materials used and reagent is cheap and easy to get and does not use the poisonous reagent that operator and environment have harm, while reducing cost, course of reaction environmental protection, achieve cleaning to produce, there is the better market competitiveness.
2, all reagent and the solvent that use in the synthetic method of the present invention are regular industrial specification, and environmental pollution is minimum, and processing safety is high, and post-reaction treatment is simple, are suitable for large-scale industrial production.
3, the present invention synthesizes vilazodone intermediate 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) reactions steps of benzofuran-2-carboxylic acid, ethyl ester and salt thereof is few, and yield is high, and quality is good, is suitable for large-scale industrial production.
Accompanying drawing explanation
Fig. 1 is 5-(4-[4-(5-cyano group-3-the indyl)-butyl adopting synthetic method of the present invention synthesis]-1-piperazinyl) liquid chromatogram of benzofuran-2-carboxylate hydrochloride.
Detailed description of the invention
The following is specific embodiments of the invention and in conjunction with accompanying drawing, technical scheme is further described, but the present invention is not limited to these embodiments.
Embodiment 1
Under room temperature condition, under nitrogen protection 2.4g1.1-dimethoxy-6-chlorohexane is dissolved in the mixed solution of 24mL ethanol and 12mL water, is warming up to 68 DEG C and makes whole dissolving. Under room temperature condition, the mixed solvent of 1.9g4-cyanophenylhydrazine hydrochlorate, 19mL ethanol and 9.5mL pure water is slowly added dropwise in 1.9g1.1-dimethoxy-6-chlorohexane reactant liquor, it is incubated 0.8 hour when 70 DEG C, question response liquid is down to room temperature, precipitate out a large amount of solid, sucking filtration, filter cake, with 50% ethanol water recrystallization, obtains 0.7g3-(4-chlorobutyl)-5-cyanoindole.
Under room temperature, reaction bulb adds 15mL anhydrous acetonitrile under the protection of nitrogen, adds 3.26g4-piperazine-1-base-phenol, 2.35gMgCl2With 6.0mL triethylamine, 1.9g paraformaldehyde, temperature rising reflux reacts 5 hours, and question response liquid is cooled to room temperature, reactant liquor is poured slowly in the 0.1L hydrochloric acid that concentration is 5%, mixed liquid 0.2L dichloromethane extraction twice, aqueous phase concentration is the NaOH aqueous solution adjustment pH to 8 of 10%, precipitates out a large amount of solid, sucking filtration, filter cake removes inorganic salt twice with a small amount of washing, and during filter cake 60 DEG C, air blast is dried, and obtains 4.25g4-(piperazine-1-base) salicylide. under room temperature, reaction bulb adds 50mL toluene, stirring is lower adds the 4.25g4-(piperazine-1-base prepared) salicylide, 3.25g potassium carbonate, 4.0g potassium iodide and 2.85g ethyl chloroacetate, temperature rising reflux reacts 8 hours, question response liquid is cooled to room temperature, reactant liquor is poured slowly in the 100mL hydrochloric acid that concentration is 10% to being completely dissolved, mixed liquid 200mL dichloromethane extraction twice, being adjusted to pH with the NaOH aqueous solution that concentration is 10% again is 10, precipitate out a large amount of solid, sucking filtration, filter cake is washed twice and is removed inorganic salt, filter cake air blast when 60 DEG C is dried, obtain the 5-(piperazine-1-base of 3.02g) benzofuran-2-carboxylic acid, ethyl ester.
Under nitrogen protection, above-mentioned prepared 0.70g3-(4-chlorobutyl)-5-cyanoindole and 0.65g sodium iodide are dissolved in the DMF of 15mL and form reactant liquor, be heated to reflux stirring 3 hours. Then above-mentioned prepared 1.0g5-piperazine-benzofuran 2-carboxylic acid, ethyl ester and 0.63g potassium carbonate are joined in the reactant liquor under stirring, reactant liquor is reacted at 95 DEG C 5 hours and react completely to TLC detection. The reactant liquor reacted completely is cooled to room temperature, it is poured slowly in 5% sodium bicarbonate aqueous solution of 200mL of stirring, precipitate out a large amount of yellow solid, the reactant liquor precipitating out solid being stirred sucking filtration after 1 hour and obtains filter cake, filter cake 50mL water is washed three post-dryings respectively and is obtained 1.25g5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester.
By above-mentioned prepared 1.25g5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester is dissolved in the isopropanol of 50mL, heat and to 80 DEG C, filter cake is dissolved, 5mL concentrated hydrochloric acid it is slowly added dropwise to precipitating out a large amount of solid under stirring, it is cooled under stirring after room temperature with sucking filtration after freezing 0.5 hour of cryosel bath, and filter cake dry 1.35g5-after washing with 20mL cold isopropanol (4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylate hydrochloride.Final products purity is 99.0%, and yield is 95.7%.
Embodiment 2
Under room temperature condition, under nitrogen protection 5.2g1.1-dimethoxy-6-chlorohexane is dissolved in the mixed solution of 52mL methanol and 26mL water, is warming up to 72 DEG C and makes whole dissolving. Under room temperature condition, the mixed solvent of 4.8g4-cyanophenylhydrazine hydrochlorate, 48mL methanol and 24mL pure water is slowly added dropwise in 4.6g1.1-dimethoxy-6-chlorohexane reactant liquor, it is incubated 1.0 hours when 72 DEG C, question response liquid is down to room temperature, precipitate out a large amount of solid, sucking filtration, filter cake, with 53% ethanol water recrystallization, obtains 9.5g3-(4-chlorobutyl)-5-cyanoindole.
Under room temperature, reaction bulb adds 50mL oxolane under the protection of nitrogen, adds 3.5g4-piperazine-1-base-phenol, 2.4gMgCl2With 2.0mL triethylamine, 3.6g paraformaldehyde, temperature rising reflux reacts 4 hours, and question response liquid is cooled to room temperature, reactant liquor is poured slowly in the 0.1L hydrochloric acid that concentration is 5%, mixed liquid 0.1L dichloromethane extraction twice, aqueous phase concentration is the NaOH aqueous solution adjustment pH to 8 of 10%, precipitates out a large amount of solid, sucking filtration, filter cake removes inorganic salt twice with a small amount of washing, and during filter cake 55 DEG C, air blast is dried, and obtains 3.8g4-(piperazine-1-base) salicylide. under room temperature, reaction bulb adds 38mLDMF, stirring is lower adds the 4.3g4-(piperazine-1-base prepared) salicylide, 4.5g sodium carbonate, 3.7g sodium iodide and 1.9g ethyl chloroacetate, temperature rising reflux reacts 4 hours, question response liquid is cooled to room temperature, reactant liquor is poured slowly in the 100mL hydrochloric acid that concentration is 10% to being completely dissolved, mixed liquid 200mL dichloromethane extraction twice, being adjusted to pH with the NaOH aqueous solution that concentration is 10% again is 10, precipitate out a large amount of solid, sucking filtration, filter cake is washed twice and is removed inorganic salt, filter cake air blast when 55 DEG C is dried, obtain the 5-(piperazine-1-base of 3.1g) benzofuran-2-carboxylic acid, ethyl ester.
Under nitrogen protection, above-mentioned prepared 3.1g3-(4-chlorobutyl)-5-cyanoindole and 2.4g potassium iodide are dissolved in the oxolane of 35mL and form reactant liquor, be heated to reflux stirring 2 hours. Then above-mentioned prepared 2.9g5-piperazine-benzofuran 2-carboxylic acid, ethyl ester and 1.4g triethylamine are joined in the reactant liquor under stirring, reactant liquor is reacted at 80 DEG C 4 hours and react completely to TLC detection. The reactant liquor reacted completely is cooled to room temperature, it is poured slowly in the potassium bicarbonate aqueous solution of 100mL of stirring, precipitate out a large amount of yellow solid, the reactant liquor precipitating out solid being stirred sucking filtration after 0.5 hour and obtains filter cake, filter cake 100mL water is washed three post-dryings respectively and is obtained 5.6g5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester.
By above-mentioned prepared 5.6g5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester is dissolved in the methanol of 60mL, heat and to 70 DEG C, filter cake is dissolved, 5mL sulphuric acid it is slowly added dropwise to precipitating out a large amount of solid under stirring, it is cooled under stirring after room temperature with sucking filtration after freezing 0.6 hour of cryosel bath, and filter cake dry 6.0g5-after washing with 50mL cold methanol (4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester sulfate. Final products purity is 99.6%, and yield is 92.3%.
Embodiment 3
Under room temperature condition, under nitrogen protection 3.6g1.1-dimethoxy-6-chlorohexane is dissolved in the mixed solution of 36mL ethanol and 18mL water, is warming up to 72 DEG C and makes whole dissolving.Under room temperature condition, the mixed solvent of 2.4g4-cyanophenylhydrazine hydrochlorate, 24mL methanol and 12mL pure water is slowly added dropwise in 4.0g1.1-dimethoxy-6-chlorohexane reactant liquor, it is incubated 1.1 hours when 72 DEG C, question response liquid is down to room temperature, precipitate out a large amount of solid, sucking filtration, filter cake, with 55% ethanol water recrystallization, obtains 4.5g3-(4-chlorobutyl)-5-cyanoindole.
Under room temperature, reaction bulb adds 50mL toluene under the protection of nitrogen, adds 6.0g4-piperazine-1-base-phenol, 3.2gMgCl2With 2.1mL diisopropylethylamine, 3.6g paraformaldehyde, temperature rising reflux reacts 7 hours, and question response liquid is cooled to room temperature, reactant liquor is poured slowly in the 0.1L hydrochloric acid that concentration is 5%, mixed liquid 0.2L dichloromethane extraction twice, aqueous phase concentration is the NaOH aqueous solution adjustment pH to 8 of 10%, precipitates out a large amount of solid, sucking filtration, filter cake removes inorganic salt twice with a small amount of washing, and during filter cake 65 DEG C, air blast is dried, and obtains 5.3g4-(piperazine-1-base) salicylide. under room temperature, reaction bulb adds 55mLDMF, stirring is lower adds the 5.3g4-(piperazine-1-base prepared) salicylide, 3.8g potassium carbonate, 3.6g sodium iodide and 1.9g ethyl chloroacetate, temperature rising reflux reacts 5 hours, question response liquid is cooled to room temperature, reactant liquor is poured slowly in the 100mL hydrochloric acid that concentration is 10% to being completely dissolved, mixed liquid 200mL dichloromethane extraction twice, being adjusted to pH with the NaOH aqueous solution that concentration is 10% again is 10, precipitate out a large amount of solid, sucking filtration, filter cake is washed twice and is removed inorganic salt, filter cake air blast when 55 DEG C is dried, obtain the 5-(piperazine-1-base of 3.9g) benzofuran-2-carboxylic acid, ethyl ester.
Under nitrogen protection, above-mentioned prepared 3.0g3-(4-chlorobutyl)-5-cyanoindole and 3.6g potassium bromide are dissolved in the dichloromethane alkanamine of 40mL and form reactant liquor, be heated to reflux stirring 4 hours. Then above-mentioned prepared 3.9g5-piperazine-benzofuran 2-carboxylic acid, ethyl ester and 3.0gN-methyl morpholine are joined in the reactant liquor under stirring, reactant liquor is reacted at 85 DEG C 6 hours and react completely to TLC detection. The reactant liquor reacted completely is cooled to room temperature, it is poured slowly in the aqueous sodium carbonate of 200mL of stirring, precipitate out a large amount of yellow solid, the reactant liquor precipitating out solid being stirred sucking filtration after 2 hours and obtains filter cake, filter cake 100mL water is washed three post-dryings respectively and is obtained 5.2g5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester.
By above-mentioned prepared 5.2g5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester is dissolved in the normal heptane of 52mL, heat and to 90 DEG C, filter cake is dissolved, 2.0mL trifluoroacetic acid it is slowly added dropwise to precipitating out a large amount of solid under stirring, it is cooled under stirring after room temperature with sucking filtration after freezing 0.4 hour of cryosel bath, and dry 5.9g5-after filter cake 50mL cold normal heptane washing (4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester trifluoroacetate. Final products purity is 99.0%, and yield is 98.7%.
Embodiment 4
Under nitrogen protection, 3.4g3-(4-the chlorobutyl)-5-cyanoindole being purchased and 4.5g sodium bromide are dissolved in the ethyl acetate of 40mL and form reactant liquor, be heated to reflux stirring 2.5 hours. Then the 4.2g5-being purchased piperazine-benzofuran 2-carboxylic acid, ethyl ester and 1.9g pyridine are joined in the reactant liquor under stirring, reactant liquor is reacted at 100 DEG C 4.5 hours and react completely to TLC detection.The reactant liquor reacted completely is cooled to room temperature, it is poured slowly in the wet chemical of 100mL of stirring, precipitate out a large amount of yellow solid, the reactant liquor precipitating out solid being stirred sucking filtration after 1.5 hours and obtains filter cake, filter cake 50mL water is washed three post-dryings respectively and is obtained 4.2g5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester.
By above-mentioned prepared 4.0g5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester is dissolved in the ether of 40mL, heat and to 45 DEG C, filter cake is dissolved, 100mL concentrated hydrochloric acid it is slowly added dropwise to precipitating out a large amount of solid under stirring, it is cooled under stirring after room temperature with sucking filtration after freezing 0.5 hour of cryosel bath, filter cake 4.7g5-dry after 50mL cold ether (4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylate hydrochloride. Final products purity is 99.2%, and yield is 92.0%.
Embodiment 5
Under nitrogen protection, 6.8g3-(4-the chlorobutyl)-5-cyanoindole being purchased and 8.9g Hydro-Giene (Water Science). are dissolved in the ether of 70mL and form reactant liquor, be heated to reflux stirring 3.5 hours. Then the 5.9g5-being purchased piperazine-benzofuran 2-carboxylic acid, ethyl ester and 60g Feldalat NM are joined in the reactant liquor under stirring, reactant liquor is reacted at 90 DEG C 5.5 hours and react completely to TLC detection. The reactant liquor reacted completely is cooled to room temperature, it is poured slowly in the potassium hydroxide aqueous solution of 100mL of stirring, precipitate out a large amount of yellow solid, the reactant liquor precipitating out solid being stirred sucking filtration after 1 hour and obtains filter cake, filter cake 50mL water is washed three post-dryings respectively and is obtained 8.9g5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester.
By above-mentioned prepared 8.9g5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester is dissolved in the oxolane of 90mL, heat and to 60 DEG C, filter cake is dissolved, 12mL trifluoroacetic acid it is slowly added dropwise to precipitating out a large amount of solid under stirring, it is cooled under stirring after room temperature with sucking filtration after freezing 0.5 hour of cryosel bath, and dry 9.5g5-after filter cake 50mL cold oxolane washing (4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester trifluoroacetate. Final products purity is 99.3%, and yield is 95.0%.
Extract vilazodone intermediate 5-(4-[4-(5-cyano group-3-the indyl)-butyl adopting synthetic method of the present invention synthesis immediately]-1-piperazinyl) benzofuran-2-carboxylate hydrochloride's sample detected by liquid chromatograph.
Testing conditions: instrument: Agilent 1100 high performance liquid chromatograph;
Chromatographic column: LunaC18,4.6mm × 250mm, 5 μm;
Column temperature: 25 DEG C;
Flow velocity: 1.0mL/min;
Detection wavelength: 240nm;
Sampling volume: 5 μ L;
Mobile phase: acetonitrile: 0.1% phosphate aqueous solution=60:40 (v/v);
Operation time: 30min.
After detection, the liquid chromatogram of sample is as shown in Figure 1; Analysis result is as shown in table 1.
Table 1: adopt 5-that synthetic method of the present invention synthesizes (4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylate hydrochloride's sample liquid analysis of hplc result
From Fig. 1 and Biao 1 it can be seen that adopt 5-(4-[4-(5-cyano group-3-the indyl)-butyl of synthetic method of the present invention synthesis]-1-piperazinyl) benzofuran-2-carboxylate hydrochloride's purity is higher, reaches 99.0309%.
Specific embodiment described herein is only to present invention spirit explanation for example. Described specific embodiment can be made various amendment or supplements or adopt similar mode to substitute by those skilled in the art, but without departing from the spirit of the present invention or surmount the scope that appended claims is defined.
Although the present invention has made a detailed description and has quoted as proof some specific embodiments, but to those skilled in the art, as long as it is obvious for can making various changes without departing from the spirit and scope of the present invention or revise.
Claims (8)
1. the method for one-step synthesis method 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester, it is characterized in that, described synthetic method comprises the steps: under nitrogen protection, 3-(4-chlorobutyl)-5-cyanoindole and catalyst are added to anhydrous solvent, forms reactant liquor, be heated to reflux stirring; Then 5-(piperazine-1-base) benzofuran-2-carboxylic acid, ethyl ester and alkali are joined in reactant liquor, 4～6 hours are reacted to reacting completely when 80～110 DEG C, then reactant liquor is cooled to room temperature, it is poured slowly into alkaline aqueous solution under stirring to precipitating out solid, sucking filtration, washing after being again stirring for 0.5～2 hour, dries to obtain 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester; The mol ratio of described catalyst and 3-(4-chlorobutyl)-5-cyanoindole is (1～4): 1, and described catalyst is the one in lithium iodide, sodium iodide, potassium iodide, Hydro-Giene (Water Science)., lithium bromide, sodium bromide, potassium bromide; The mol ratio of described alkali and 3-(4-chlorobutyl)-5-cyanoindole is (1～3): 1, and described alkali is the one in potassium carbonate, triethylamine, N-methylmorpholine, pyridine, Feldalat NM, Sodium ethylate.
2. the method for one-step synthesis method 5-according to claim 1 (4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester, it is characterized in that, the mol ratio of described 5-(piperazine-1-base) benzofuran-2-carboxylic acid, ethyl ester and 3-(4-chlorobutyl)-5-cyanoindole is (0.7～1.5): 1.
3. the method for one-step synthesis method 5-according to claim 1 (4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester, it is characterized in that, described anhydrous solvent is N, dinethylformamide, oxolane, methanol, ethanol, isopropanol, n-butyl alcohol, chlorobenzene, dichloro-benzenes, ethyl acetate, isopropyl acetate, dimethyl sulfoxide, N-Methyl pyrrolidone, ethylene glycol, glycol dimethyl ether, ether, methyl tertiary butyl ether(MTBE), toluene, dimethylbenzene, dichloromethane, chloroform, one or more in acetonitrile.
4. the method for one-step synthesis method 5-according to claim 1 (4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester, it is characterized in that, described alkaline aqueous solution is the one in sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.
5. the method for one-step synthesis method 5-according to claim 1 (4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester, it is characterized in that, described reaction temperature is 90～100 DEG C, and the response time is 4～6 hours.
6. the synthetic method of 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester salt, it is characterized in that, this synthetic method comprises the steps: that 5-(4-[4-(5-cyano group-3-indyl)-the butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester choosing method as claimed in any one of claims 1 to 5, wherein prepared is dissolved in alcoholic solution, heating is to all dissolving, add acid fully reaction to precipitating out solid, stirring cooling, sucking filtration, washing dries to obtain 5-(4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester salt.
7. the synthetic method of 5-according to claim 6 (4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester salt, it is characterized in that, described alcoholic solution is straight-chain alkyl alcohol, one or more in a kind of and methyl tertiary butyl ether(MTBE) in cycloalkanyl alcohol, aromatic alcohol, normal heptane, petroleum ether, normal hexane, ether, hexamethylene, ethyl acetate, Isosorbide-5-Nitrae-dioxane, oxolane, glycol dimethyl ether.
8. the synthetic method of 5-(4-[4-(5-cyano group-3-indyl)-the butyl]-1-piperazinyl) benzofuran-2-carboxylic acid, ethyl ester salt according to claim 6 or 7, it is characterized in that, the acid of described addition is the one in hydrochloric acid, sulphuric acid, hydrobromic acid, acetic acid, tartaric acid, maleic acid, fumaric acid, oxalic acid, citric acid, phosphoric acid, trifluoroacetic acid, formic acid, succinic acid, mandelic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, benzoic acid, Nitrodracylic acid, P-hydroxybenzoic acid.
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