CN103044370A - Preparation method of 5-(piperazinyl-1-yl) benzofuranyl-2-carboxamide - Google Patents
Preparation method of 5-(piperazinyl-1-yl) benzofuranyl-2-carboxamide Download PDFInfo
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- CN103044370A CN103044370A CN2012105822588A CN201210582258A CN103044370A CN 103044370 A CN103044370 A CN 103044370A CN 2012105822588 A CN2012105822588 A CN 2012105822588A CN 201210582258 A CN201210582258 A CN 201210582258A CN 103044370 A CN103044370 A CN 103044370A
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Abstract
The invention relates to a preparation method of 5-(piperazinyl-1-yl) benzofuranyl-2-carboxamide. The 5-(piperazinyl-1-yl) benzofuranyl-2-carboxamide is an important intermediate for synthesizing vilazodone hydrochloride. The preparation method comprises the following steps of: reacting 5-aminobenzofuranyl-2-ethyl carboxylate and N, N-bis(2-chloroethyl) amine hydrochloride in a proper solvent, without alkaline catalysis in a reaction process, to obtain 5-(piperazinyl-1-yl) benzofuranyl-2-ethyl carboxylate; and directly performing aminolysis to obtain the 5-(piperazinyl-1-yl) benzofuranyl-2-carboxamide. By the preparation method, reaction steps are reduced, and the yield and product purity are improved; and the preparation method is simple, reliable, and low in production cost, and has relatively high implementation value and social and economic benefits.
Description
Technical field
The present invention relates to a kind of 5-(piperazine-1-yl) preparation method of benzofuran-2-carboxamides, this compound is a kind of important intermediate of synthetic hydrochloric acid vilazodone.
Background technology
Vilazodone Hydrochloride is used for the treatment of the middle major depressive disorder of growing up by FDA's approval in January, 2011.Clinical testing data shows that its curative effect obviously is better than placebo, better tolerance, and untoward reaction is little.
5-(piperazine-1-yl) benzofuran-2-carboxamides is the key intermediate of synthetic hydrochloric acid vilazodone, has announced a kind of its synthetic method in the US Patent No. 5723614:
The method is take the amino cumarone of 5--2-carboxylic acid, ethyl ester as raw material and N; two (2-chloroethyl) amine reactions of N-make 5-(piperazine-1-yl) cumarone-2-carboxylic acid, ethyl ester; make 5-(piperazine-1-yl by BOC protection amino, amidation, deprotection again) benzofuran-2-carboxamides; reactions steps is more, and complex operation is not suitable for suitability for industrialized production.
Chinese patent CN00816701.X has reported another kind of synthetic method:
The method take the 5-bromosalicylaldehyde as raw material and ethyl bromoacetate reaction make 5-bromobenzene and furans-2-carboxylic acid, ethyl ester, then in the presence of sodium methylate, make 5-bromobenzene and furans-2-methane amide with formamide, at last at transition-metal catalyst Pd(OAc)
2/ P(t-Bu)
3Make 5-(piperazine-1-yl with the piperazine reaction under the catalysis) benzofuran-2-carboxamides, wherein expensive being difficult to of catalyst system therefor bought, and be dangerous high, is not suitable for suitability for industrialized production.
Summary of the invention
It is simple and reliable to the purpose of this invention is to provide a kind of step, and production cost is low, the vilazodone key intermediate 5-(piperazine that yield is good, purity is high-1-yl) preparation method of benzofuran-2-carboxamides.
The synthetic route that the present invention adopts is as follows:
5-(piperazine of the present invention-1-yl) preparation method of benzofuran-2-carboxamides, step is as follows:
(1) with the amino cumarone of 5--2-carboxylic acid, ethyl ester and N, two (2-chloroethyl) amine hydrochlorates of N-react in solvent, reaction times is 8-20 hour, temperature of reaction be room temperature to the reflux temperature of solvent, make 5-(piperazine-1-yl) cumarone-2-carboxylic acid, ethyl ester; Described solvent is one or more of diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, DMF, ethylene glycol, N-Methyl pyrrolidone etc.;
(2) with 5-(piperazine-1-yl) cumarone-2-carboxylic acid, ethyl ester ammonia solution in solvent makes 5-(piperazine-1-yl) benzofuran-2-carboxamides; Described solvent is alcoholic solvent; Ammonia solution temperature is 0-100 ℃, ammonia solution time 6-24 hour.
Temperature of reaction described in the step (1) is 100-170 ℃.
Solvent described in the step (1) is one or both of diethylene glycol monomethyl ether, N-Methyl pyrrolidone.
Ammonia solution temperature described in the step (2) is 20-80 ℃.
Alcoholic solvent described in the step (2) is one or more in methyl alcohol, ethanol, the Virahol.
The invention has the beneficial effects as follows: the present invention is take the amino cumarone of 5--2-carboxylic acid, ethyl ester as raw material and N, the reaction in suitable solvent of two (2-chloroethyl) amine hydrochlorates of N-makes 5-(piperazine-1-yl) cumarone-2-carboxylic acid, ethyl ester, reaction process does not need the catalysis of alkali, avoided the decomposition of raw material rotten, yield is higher; 5-(piperazine-1-yl) the direct ammonia solution of cumarone-2-carboxylic acid, ethyl ester makes 5-(piperazine-1-yl) benzofuran-2-carboxamides, saved the amino step of protection, simplified operation.5-(piperazine of the present invention-1-yl) benzofuran-2-carboxamides yield 70%-74%, the purity 98%-98.8% of the product that obtains.
In a word, preparation method's step of the present invention is simple and reliable, and production cost is low, has improved yield and product purity, has larger implementary value and economic results in society.
Embodiment
Below by specific embodiment technical scheme of the present invention is described in detail, following embodiment is to describe in detail technical scheme of the present invention, and unrestricted the present invention.
Embodiment 1
Add the amino cumarone of 5--2-carboxylic acid, ethyl ester 50g in the 1L reaction flask, N, two (2-chloroethyl) the amine hydrochlorate 50g of N-, diethylene glycol monomethyl ether 500ml, be warming up to 130 ℃ of reactions 12 hours, suction filtration, filter cake add in the 200ml water, regulate pH to 9-10 with saturated sodium carbonate solution, ethyl acetate (500ml * 2) extraction, anhydrous sodium sulfate drying, solvent evaporated gets little yellow solid, the gained solid adds the saturated methanol solution 600ml of ammonia, be warming up to 70 ℃, confined reaction 10 hours, suction filtration gets light yellow solid 45g, yield 72.3%, HPLC purity 98.8%.
Embodiment 2
Add the amino cumarone of 5--2-carboxylic acid, ethyl ester 50g in the 1L reaction flask, N, two (2-chloroethyl) the amine hydrochlorate 50g of N-, N-Methyl pyrrolidone 300ml and diethylene glycol monomethyl ether 200ml, be warming up to 100 ℃ of reactions 20 hours, suction filtration, filter cake add in the 200ml water, regulate pH to 9-10 with saturated sodium carbonate solution, ethyl acetate (500ml * 2) extraction, anhydrous sodium sulfate drying, solvent evaporated gets little yellow solid, the gained solid adds the saturated ethanolic soln 600ml of ammonia, be warming up to 90-100 ℃, confined reaction 6 hours, suction filtration gets light yellow solid 41.8g, yield 70%, HPLC purity 98.4%.
Embodiment 3
Add the amino cumarone of 5--2-carboxylic acid, ethyl ester 50g in the 1L reaction flask, N, two (2-chloroethyl) the amine hydrochlorate 50g of N-, diethylene glycol monomethyl ether 500ml, be warming up to 170 ℃ of reactions 8 hours, suction filtration, filter cake add in the 200ml water, regulate pH to 9-10 with saturated sodium carbonate solution, ethyl acetate (500ml * 2) extraction, anhydrous sodium sulfate drying, solvent evaporated gets little yellow solid, the gained solid adds the saturated aqueous isopropanol 600ml of ammonia, be incubated 20-30 ℃, confined reaction 24 hours, suction filtration gets light yellow solid 44.2g, yield 74%, HPLC purity 98.2%.
Claims (5)
1. the 5-(piperazine-1-yl) preparation method of benzofuran-2-carboxamides, step is as follows:
(1) with the amino cumarone of 5--2-carboxylic acid, ethyl ester and N, two (2-chloroethyl) amine hydrochlorates of N-react in solvent, reaction times is 8-20 hour, temperature of reaction be room temperature to the reflux temperature of solvent, make 5-(piperazine-1-yl) cumarone-2-carboxylic acid, ethyl ester; Described solvent is one or more of diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, DMF, ethylene glycol, N-Methyl pyrrolidone etc.;
(2) with 5-(piperazine-1-yl) cumarone-2-carboxylic acid, ethyl ester ammonia solution in solvent makes 5-(piperazine-1-yl) benzofuran-2-carboxamides; Described solvent is alcoholic solvent; Ammonia solution temperature is 0-100 ℃, ammonia solution time 6-24 hour.
2. preparation method according to claim 1 is characterized in that, the solvent described in the step (1) is one or both of diethylene glycol monomethyl ether, N-Methyl pyrrolidone.
3. preparation method according to claim 1 is characterized in that, the ammonia solution temperature described in the step (2) is 20-80 ℃.
4. preparation method according to claim 1 is characterized in that, the alcoholic solvent described in the step (2) is one or more in methyl alcohol, ethanol, the Virahol.
5. preparation method according to claim 1 is characterized in that, the temperature of reaction described in the step (1) is 100-170 ℃.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012105822588A CN103044370A (en) | 2012-12-28 | 2012-12-28 | Preparation method of 5-(piperazinyl-1-yl) benzofuranyl-2-carboxamide |
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| CN2012105822588A CN103044370A (en) | 2012-12-28 | 2012-12-28 | Preparation method of 5-(piperazinyl-1-yl) benzofuranyl-2-carboxamide |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1140171A (en) * | 1995-04-20 | 1997-01-15 | 默克专利股份有限公司 | Benzofurans |
| WO2009086264A1 (en) * | 2007-12-21 | 2009-07-09 | Exelixis, Inc. | Benzofuropyrimidinones as protein kinase inhibitors |
-
2012
- 2012-12-28 CN CN2012105822588A patent/CN103044370A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1140171A (en) * | 1995-04-20 | 1997-01-15 | 默克专利股份有限公司 | Benzofurans |
| WO2009086264A1 (en) * | 2007-12-21 | 2009-07-09 | Exelixis, Inc. | Benzofuropyrimidinones as protein kinase inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| ROY A. JOHNSON等: "Thromboxane A2 Synthase Inhibitors. 5-(3-Pyridylmethyl)benzofuran-2-carboxylic Acids", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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Application publication date: 20130417 |