CN111087340B - Preparation method of vilazodone intermediate - Google Patents
Preparation method of vilazodone intermediate Download PDFInfo
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- CN111087340B CN111087340B CN201911206945.8A CN201911206945A CN111087340B CN 111087340 B CN111087340 B CN 111087340B CN 201911206945 A CN201911206945 A CN 201911206945A CN 111087340 B CN111087340 B CN 111087340B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
Abstract
The invention relates to a preparation method of a vilazodone intermediate, which is characterized in that a compound 1 raw material and 1-bromo-4-chlorobutane are subjected to an F-C alkylation reaction under the action of anhydrous zinc chloride, and a compound I, namely the vilazodone intermediate, is prepared through a one-step reaction. Compared with the prior art, the method has the advantages of short reaction route, easy post-treatment, high yield, cheap and easily-obtained reagents used in the F-C reaction, convenient operation, simple post-treatment, low cost and little environmental pollution, and is suitable for industrial production of the vilazodone intermediate I.
Description
Technical Field
The invention relates to the technical field of chemical pharmacy, in particular to a preparation method of a vilazodone intermediate.
Background
Vilazodone (Vilazodone) was approved by FDA for marketing in the united states on day 21/1/2011 and is the first 5-HT reuptake and 5-HT currently marketed1AA partially agonistic antidepressant drug. As a novel double-target antidepressant drug, vilazodone has the characteristics of quick response and asexual dysfunction. Experts in the industry all look at market prospects after the medicine is marketed, and development of the medicine on the market at home can provide good treatment options for a wide range of depression patients and create huge social and economic values. The chemical structure of vilazodone is shown below.
The preparation method of vilazodone has been reported in many documents (Journal of Medicinal Chemistry,2004,47(19): 4684-4692; Chinese patent CN1140171A), wherein the common synthetic method is as follows: the intermediate 3- (4-chlorobutyl) indole-5-formonitrile (I) and 5-piperazinyl benzofuran-2-formamide (II) are subjected to condensation reaction under the action of alkali to prepare vilazodone.
Wherein the compound I is a key intermediate of vilazodone.
The document Journal of Medicinal Chemistry,2004,47(19):4684-4692 reports that 5-cyanoindole (1) is used as a raw material, performing F-C acylation reaction under the catalysis of isobutyl aluminum dichloride to obtain 3- (4-chlorobutyryl) indole-5-formonitrile (2), selectively reducing carbonyl by using red aluminum (bis (methoxyethoxy) aluminum dihydride) to obtain an intermediate 3- (4-chlorobutyl) indole-5-formonitrile (I), in the F-C acylation reaction step of the route, rare Lewis acid isobutyl aluminum chloride is also used as a catalyst, in the reduction reaction step, the red aluminum is used as a selective reducing agent, but the weighing and charging of the red aluminum are not easy to operate in a workshop, the yield is low and is only 26%, and the red aluminum is required to be purified by column chromatography and is not suitable for industrial production.
Chinese patent CN1330635A also uses 5-cyanoindole (1) as raw material, and performs F-C acylation reaction under the catalysis of isobutylaluminum dichloride to obtain 3- (4-chlorobutyryl) indole-5-methyl cyanide (2), and then the 3- (4-chlorobutyl) indole-5-carbonitrile (I) is obtained by activating with isobutylaluminum chloride and selectively reducing ketocarbonyl with sodium borohydride to obtain methylene. The F-C acylation reaction and the reduction reaction of the method both adopt Lewis acid isobutyl aluminum chloride as a catalyst, the reagent is difficult to purchase and prepare, the chemical property of the reagent is unstable, the reagent is extremely flammable in the air, the pipeline type conveying is required, and the requirement on reaction equipment is high.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a preparation method of a vilazodone intermediate.
The purpose of the invention can be realized by the following technical scheme:
the invention provides a preparation method of a vilazodone intermediate, which comprises the steps of carrying out an F-C alkylation reaction on a compound 1 raw material and 1-bromo-4-chlorobutane (compound 3) under the action of anhydrous zinc chloride, and carrying out a one-step reaction to obtain a compound I, namely the vilazodone intermediate;
the chemical structures of compound 1 and compound I are shown below:
the reaction formula is as follows:
preferably, the reaction temperature is-10-30 ℃, and the reaction time is 1-3 h.
Further preferably, the reaction temperature is 0 ℃ and the reaction time is 2 h.
Preferably, the molar ratio of 1-bromo-4-chlorobutane (compound 3) to compound 1 is 1.5-1: 1.
Further preferably, the molar ratio of 1-bromo-4-chlorobutane (compound 3) to compound 1 is 1.1: 1.
Preferably, the molar ratio of anhydrous zinc chloride to compound 1 is 1.5-1: 1.
Further preferably, the molar ratio of anhydrous zinc chloride to compound 1 is 1.1: 1.
Preferably, the method further comprises the steps of quenching, extracting, separating, concentrating, purifying and drying after the F-C alkylation reaction.
Compared with the prior art, the invention has the following beneficial effects:
(1) the raw material of the compound 1 is reacted with 1-bromo-4-chlorobutane (compound 3) in 1 step under the action of anhydrous zinc chloride to directly produce the vilazodone intermediate (compound I), and compared with the prior art, the method has the advantages of short reaction route, easy post-treatment and high yield.
(2) The reagent used in the F-C reaction is cheap and easy to obtain, and the method has the advantages of convenient operation, simple post-treatment, low cost and small environmental pollution, and is suitable for industrial production.
The invention has high yield, stable product quality, low cost and simple operation, is suitable for the industrial preparation of the vilazodone key intermediate (compound I), and the synthetic route and the preparation method thereof have novel, creative, practical and scientific progress.
Detailed Description
A preparation method of vilazodone intermediate is characterized in that compound 1 raw material and 1-bromo-4-chlorobutane (compound 3) are subjected to F-C alkylation reaction under the action of anhydrous zinc chloride, and compound I, namely the vilazodone intermediate, is prepared through one-step reaction;
the chemical structures of compound 1 and compound I are shown below:
the reaction formula is as follows:
preferably, the reaction temperature is-10-30 ℃, and the reaction time is 1-3 h. Further preferably, the reaction temperature is 0 ℃ and the reaction time is 2 h.
Preferably, the molar ratio of 1-bromo-4-chlorobutane (compound 3) to compound 1 is 1.5-1: 1. Further preferably, the molar ratio of 1-bromo-4-chlorobutane (compound 3) to compound 1 is 1.1: 1.
Preferably, the molar ratio of anhydrous zinc chloride to compound 1 is 1.5-1: 1. Further preferably, the molar ratio of anhydrous zinc chloride to compound 1 is 1.1: 1.
Preferably, the method further comprises the steps of quenching, extracting, separating, concentrating, purifying and drying after the F-C alkylation reaction.
The present invention will be described in detail with reference to specific examples.
Example 1
Preparation of 3- (4-chlorobutyl) indole-5-carbonitrile (compound I) having the following reaction formula:
compound 1(142.2g, 1.0mol) was dissolved in dichloromethane (1.5L), and anhydrous zinc chloride (150g, 1.1mol) was added thereto while controlling the internal temperature at 0 to 5 ℃. After the addition, the temperature is reduced to about-10 ℃ of the internal temperature, 1-bromo-4-chlorobutane (compound 3) (188.6g, 1.1mol) is started to be dripped, the internal temperature is controlled to be lower than-5 ℃ in the dripping process, and after the dripping is finished, the temperature is increased to 0 ℃ of the reaction temperature for reaction for 2 hours. After completion of the reaction, dichloromethane (0.5L) was diluted, ice water (1L) was broken, and then 1N sodium hydroxide solution was added thereto to adjust pH to about 7, followed by extraction and liquid separation. The organic phase was washed with saturated brine (0.5L) and separated. After the organic phase was concentrated to dryness, the residue was recrystallized from isopropyl acetate (0.5L) to give 205g of product (I) in 88% yield and 99.62% purity by HPLC.
mp.99～100℃；m/z：233(M+H)；1H NMR(DMSO-d6，ppm)：δ＝11.27 (br，1H)，8.06(s，1H)，7.39(d，J＝8.4Hz,1H)，7.23(m，2H)，3.65(m， 2H)，2.69(m，2H)，1.88(m，4H)。
Examples 2 to 4
The intermediate I was prepared by the above method, and the reaction conditions and results are shown in table 1.
TABLE 1 EXAMPLES 2-4 reaction conditions and results
The embodiments described above are intended to facilitate the understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (2)
1. A preparation method of a vilazodone intermediate is characterized in that a compound 1 raw material and 1-bromo-4-chlorobutane are subjected to an F-C alkylation reaction under the action of anhydrous zinc chloride, and a compound I, namely the vilazodone intermediate, is prepared through a one-step reaction;
the chemical structures of compound 1 and compound I are shown below:
the reaction temperature is 0 ℃, and the reaction time is 2 hours;
the molar ratio of 1-bromo-4-chlorobutane to compound 1 is 1.1: 1;
the molar ratio of anhydrous zinc chloride to compound 1 was 1.1: 1.
2. The method for preparing vilazodone intermediate according to claim 1, characterized in that the method further comprises steps of quenching, extraction, concentration and drying after the F-C alkylation reaction.
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| JP2002201176A (en) * | 2000-12-29 | 2002-07-16 | Japan Science & Technology Corp | Method for synthesizing aromatic adduct |
| CN1155568C (en) * | 1998-12-17 | 2004-06-30 | 默克专利股份公司 | Method for producing 3-alkanoylindoles and 3-alkylindoles |
| MXPA06006669A (en) * | 2003-12-16 | 2006-08-11 | Wyeth Corp | A synthetic methodology for the reductive alkylation at the c-3 position of indoles. |
| CN103304466A (en) * | 2013-05-18 | 2013-09-18 | 嘉兴中科化学有限公司 | Synthetic method of 3-alkyl-substituted indole compound |
| CN103709089A (en) * | 2013-12-31 | 2014-04-09 | 南通恒盛精细化工有限公司 | Method for preparing 3-(4'-chlorobutyl)-5-cyanoindole |
| CN105753762A (en) * | 2016-04-21 | 2016-07-13 | 南京工业大学 | Indole-C3 derivative and preparation method thereof |
| CN107501159A (en) * | 2017-08-14 | 2017-12-22 | 连云港恒运药业有限公司 | The cyanoindole synthetic method of vilazodone intermediate 3 (4 chlorobutyl) 5 |
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- 2019-11-29 CN CN201911206945.8A patent/CN111087340B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1155568C (en) * | 1998-12-17 | 2004-06-30 | 默克专利股份公司 | Method for producing 3-alkanoylindoles and 3-alkylindoles |
| JP2002201176A (en) * | 2000-12-29 | 2002-07-16 | Japan Science & Technology Corp | Method for synthesizing aromatic adduct |
| MXPA06006669A (en) * | 2003-12-16 | 2006-08-11 | Wyeth Corp | A synthetic methodology for the reductive alkylation at the c-3 position of indoles. |
| CN103304466A (en) * | 2013-05-18 | 2013-09-18 | 嘉兴中科化学有限公司 | Synthetic method of 3-alkyl-substituted indole compound |
| CN103709089A (en) * | 2013-12-31 | 2014-04-09 | 南通恒盛精细化工有限公司 | Method for preparing 3-(4'-chlorobutyl)-5-cyanoindole |
| CN105753762A (en) * | 2016-04-21 | 2016-07-13 | 南京工业大学 | Indole-C3 derivative and preparation method thereof |
| CN107501159A (en) * | 2017-08-14 | 2017-12-22 | 连云港恒运药业有限公司 | The cyanoindole synthetic method of vilazodone intermediate 3 (4 chlorobutyl) 5 |
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| SYNTHESIS OF 1,2,3,4-TE’IRAHYDROQUINOLINES AND 1,2,3,4-TETRAIIYDRO-1,6-NAPHTHYRIDINES BY A DIRECTED LITIIIATION REACTION;J. Norman Reed et al.;《Tetrahedron Letters》;19881231;第29卷(第45期);第5725-5728页 * |
| 酸催化合成双吲哚烷基化合物的方法研究进展;李宁东 等;《广州化工》;20130228;第41卷(第4期);第35-37页 * |
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