CN104592087B - A kind of vilazodone hydrochloride intermediate 3-(4-chlorobutyl) preparation method of-1H-5-cyanoindole - Google Patents
A kind of vilazodone hydrochloride intermediate 3-(4-chlorobutyl) preparation method of-1H-5-cyanoindole Download PDFInfo
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- 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
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- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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Abstract
The present invention relates to 3-(4-chlorobutyl) preparation method of-1H-5-cyanoindole; this compound is a kind of important intermediate preparing antidepressants Vilazodone Hydrochloride; including following reactions steps: sodium borohydride is disperseed in a solvent; it is subsequently adding trichloroacetic acid organic solution, then is dividedly in some parts 3-(4-chlorobutyryl)-1H-5-cyanoindole. The inventive method is preparing 3-(4-chlorobutyl in the middle of Vilazodone Hydrochloride) in-1H-5-cyanoindole process, simple to operate, the requirement of equipment is low, and also yield is high, and purity is good, is suitable for industrialized production, has significantly creativeness and actual application value. Its reaction equation is as follows:
Description
Invention field:
The present invention relates to medicinal chemistry art, the preparation method being specifically related to a kind of Vilazodone Hydrochloride key intermediate 3-(4-chlorobutyl)-1H-5-cyanoindole
Background technology:
FDA (Food and Drug Adminstration) (FDA) January 21 was ratified, and trade name Viibryd belongs to 5-HT1APartial agonist and selective serotonin reuptake inhibitor class medicine, be also first indolyl amine novel antidepressant. Its chemical formula structure is:
Wherein 3-(4-chlorobutyl)-1H-5-cyanoindole is the key intermediate preparing Vilazodone Hydrochloride, discloses following several preparation method at present both at home and abroad:
1) employing red aluminum as reducing agent in document JournalofMedicinalChemistry, 2004,47 (19): 4684-4692, obtain 3-(4-chlorobutyl)-1H-5-cyanoindole, its reaction equation is as follows:
The reducing agent that this reaction is used is red aluminum, and reaction temperature is 0 DEG C, and the method for its purification is column chromatography for separation, and last reaction yield is 26%.
There is problem and the defect of three below aspect in this reaction: one be reaction needed control temperature be 0 DEG C, this course of reaction is exothermic reaction, adds the difficulty of temperature control; Two is the method for the purification employing column chromatography for separation of product, is not suitable for industrialized production; Three is that yield is too low, and process costs is high, is also not suitable for industrialized production.
2) employing sodium borohydride in patent CN102659660A and trifluoroacetic acid prepares 3-(4-chlorobutyl)-1H-5-cyanoindole, its reaction equation is as follows:
Bibliographical information, the sodium borohydride that its operating process is dividedly in some parts, reaction temperature is less than 5 DEG C; And sodium borohydride and 3-(4-chlorobutyryl)-1H-5-cyanoindole mol ratio are greatly, the sodium borohydride amount that need to add is big.
In the industrial production, there is problem and the defect of two aspects in this reaction: one is that course of reaction needs to control relatively low temperature, can extend the response time, and exothermic heat of reaction is violent, should not control temperature; Two is that sodium borohydride reacts very exothermic with trifluoroacetic acid,Inflammable and explosiveIn order to control reaction temperature, the sodium borohydride amount every time added is limited, adds commercial production charging time and difficulty, and the cost of material of trifluoroacetic acid is far longer than the cost of material of trichloroacetic acid.
3) patent WO2000035872 reports the method with sodium borohydride and isobutyl aluminium dichloride synthesis 3-(4-chlorobutyl)-1H-5-cyanoindole, and reaction equation is as follows:
It is catalyst that this reaction have employed seldom used lewis acid isobutyl aluminium dichloride, this catalyst chemical character is unstable, very easily burn in atmosphere, pipeline transportation need to be adopted, the requirement of equipment is high, and this catalyst should not be bought, expensive, strongly limit the method and applying in industrialization.
Summary of the invention:
A kind of method that it is an object of the present invention to provide new preparation vilazodone hydrochloride intermediate 3-(4-chlorobutyl)-1H-5-cyanoindole, overcome existing method and technology cost high, synthesis yield is low, purification difficult, it is difficult in the technological deficiency of industrialization large-scale production.
To achieve these goals, technical scheme is as follows:
The preparation method of 3-(4-chlorobutyl)-1H-5-cyanoindole comprises the steps: to disperse in a solvent sodium borohydride; dropping solution of trichloroacetic acid; it is dividedly in some parts 3-(4-chlorobutyryl)-1H-5-cyanoindole (Formulas I) again; react 1～15 hour at 5 DEG C～45 DEG C; after completion of the reaction; process reactant liquor and obtain product, products obtained therefrom recrystallization. Its reaction equation is as follows:
Wherein organic solvent is 20～60mL/g with the volume mass ratio of formula I compound, it is preferred to 25～40mL/g; The mol ratio of formula I compound and sodium borohydride is 1:3～15, it is preferred to 1:4～10; The amount of substance mol ratio of formula I formula compound and trichloroacetic acid is 1:3～15, it is preferred to 1:4～10.
Wherein reaction temperature preferably 15 DEG C～35 DEG C; Preferably 3～10 hours response time.
Described solvent is chloroform, dichloromethane, one in 1,2-dichloroethanes or mixed solvent, it is preferable that dichloromethane.
In the present invention, term " process ", refers to and is separated from solvent by target product, it is possible to adopt the conventional treatment method that this area is current, it would however also be possible to employ the processing method of other uniquenesses. The processing method of current this area routine is for extracting, and alkali cleaning, brine wash, vacuum concentrates, recrystallization etc.
The invention has the advantages that: 1. the raw material used in the present invention is the cheap raw material of routine; 2. product is when ensureing that purity is more than 98%, it is to avoid adopt column chromatography for separation, and yield can reach 92%; 3. reaction condition of the present invention is gentle, and post-processing operation is simple, and combined coefficient is high, is suitable to industrialized production, has significant creative and actual application value.
In order to technical scheme is explained further, below in conjunction with drawings and Examples, the present invention is described in further detail.
Accompanying drawing illustrates:
Fig. 1 is the nuclear magnetic spectrum of Vilazodone Hydrochloride
Fig. 2 is the analysis collection of illustrative plates preparing 3-(4-chlorobutyl)-1H-5-cyanoindole HPLC in embodiment 1;
Fig. 3 is the analysis collection of illustrative plates preparing 3-(4-chlorobutyl)-1H-5-cyanoindole HPLC in embodiment 3;
Fig. 4 is the analysis collection of illustrative plates preparing 3-(4-chlorobutyl)-1H-5-cyanoindole HPLC in embodiment 5;
Fig. 5 is the analysis collection of illustrative plates preparing 3-(4-chlorobutyl)-1H-5-cyanoindole HPLC in embodiment 8;
Fig. 6 is the analysis collection of illustrative plates preparing 3-(4-chlorobutyl)-1H-5-cyanoindole HPLC in embodiment 10;
Fig. 7 is the analysis collection of illustrative plates preparing 3-(4-chlorobutyl)-1H-5-cyanoindole HPLC in embodiment 11.
Detailed description of the invention:
The preparation method one of embodiment 1:3-(4-chlorobutyl)-1H-5-cyanoindole:
The sodium borohydrides of 18 grams are dispersed in the dichloromethane of 200mL; it is slowly added into 200mL dissolved with trichloroacetic acid (80 grams) dichloromethane solution; being dividedly in some parts 3-(4-chlorobutyryl)-1H-5-cyanoindole (20 grams), 30 DEG C are stirred 6 hours. Reactant liquor is poured into water, branch vibration layer. Adding 1N sodium hydrate aqueous solution in organic facies, regulate pH value to 7～9, organic facies saturated sodium-chloride water solution washs, and decompression removes organic solvent. Crude product recrystallizing methanol, obtains 15.5 grams of off-white color products.Yield is 82%, and HPLC shows purity: 99.06%.
The preparation method two of embodiment 2:3-(4-chlorobutyl)-1H-5-cyanoindole:
The sodium borohydrides of 18 grams are dispersed in the dichloromethane of 600mL; it is slowly added into 600mL dissolved with trichloroacetic acid (80 grams) dichloromethane solution; being dividedly in some parts 3-(4-chlorobutyryl)-1H-5-cyanoindole (20 grams), 30 DEG C are stirred 6 hours. Reactant liquor is poured into water, branch vibration layer. Adding 1N sodium hydrate aqueous solution in organic facies, regulate pH value to 7～9, organic facies saturated sodium-chloride water solution washs, and decompression removes organic solvent. Crude product recrystallizing methanol, obtains 16.8 grams of off-white color products, and yield is 88.9%.
The preparation method three of embodiment 3:3-(4-chlorobutyl)-1H-5-cyanoindole:
The sodium borohydrides of 18 grams are dispersed in the dichloromethane of 400mL; it is slowly added into 300mL dissolved with trichloroacetic acid (50 grams) dichloromethane solution; being dividedly in some parts 3-(4-chlorobutyryl)-1H-5-cyanoindole (20 grams), 30 DEG C are stirred 6 hours. Reactant liquor is poured into water, branch vibration layer. Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent. Crude product recrystallizing methanol, obtains 16.1 grams of off-white color products. Yield is 85.2%, and HPLC shows purity: 98.1%.
The preparation method four of embodiment 4:3-(4-chlorobutyl)-1H-5-cyanoindole:
The sodium borohydrides of 18 grams are dispersed in the dichloromethane of 400mL; it is slowly added into 300mL dissolved with trichloroacetic acid (120 grams) dichloromethane solution; being dividedly in some parts 3-(4-chlorobutyryl)-1H-5-cyanoindole (20 grams), 30 DEG C are stirred 6 hours. Reactant liquor is poured into water, branch vibration layer. Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent. Crude product recrystallizing methanol, obtains 17 grams of off-white color products, and yield is 89.9%.
The preparation method five of embodiment 5:3-(4-chlorobutyl)-1H-5-cyanoindole:
The sodium borohydrides of 10 grams are dispersed in the dichloromethane of 400mL; it is slowly added into 300mL dissolved with trichloroacetic acid (80 grams) dichloromethane solution; being dividedly in some parts 3-(4-chlorobutyryl)-1H-5-cyanoindole (20 grams), 30 DEG C are stirred 6 hours. Reactant liquor is poured into water, branch vibration layer. Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent. Crude product recrystallizing methanol, obtains 13.3 grams of off-white color products. Yield is 70.3%, and HPLC shows purity: 98.22%.
The preparation method six of embodiment 6:3-(4-chlorobutyl)-1H-5-cyanoindole:
The sodium borohydrides of 36 grams are dispersed in the dichloromethane of 400mL; it is slowly added into 300mL dissolved with trichloroacetic acid (80 grams) dichloromethane solution; being dividedly in some parts 3-(4-chlorobutyryl)-1H-5-cyanoindole (20 grams), 30 DEG C are stirred 6 hours. Reactant liquor is poured into water, branch vibration layer. Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent. Crude product recrystallizing methanol, obtains 17.1 grams of off-white color products, and yield is 90.5%.
The preparation method seven of embodiment 7:3-(4-chlorobutyl)-1H-5-cyanoindole:
The sodium borohydrides of 18 grams are dispersed in the dichloromethane of 400mL; it is slowly added into 300mL dissolved with trichloroacetic acid (80 grams) dichloromethane solution; being dividedly in some parts 3-(4-chlorobutyryl)-1H-5-cyanoindole (20 grams), 10 DEG C are stirred 18 hours.Reactant liquor is poured into water, branch vibration layer. Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent. Crude product recrystallizing methanol, obtains 14.3 grams of off-white color products, and yield is 75.7%.
The preparation method eight of embodiment 8:3-(4-chlorobutyl)-1H-5-cyanoindole:
The sodium borohydrides of 18 grams are dispersed in the dichloromethane of 400mL; it is slowly added into 300mL dissolved with trichloroacetic acid (80 grams) dichloromethane solution; being dividedly in some parts 3-(4-chlorobutyryl)-1H-5-cyanoindole (20 grams), 30 DEG C are stirred 7 hours. Reactant liquor is poured into water, branch vibration layer. Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent. Crude product recrystallizing methanol, obtains 17.2 grams of off-white color products. Yield is 91%, and HPLC shows purity: 99.38%.
The preparation method nine of embodiment 9:3-(4-chlorobutyl)-1H-5-cyanoindole:
The sodium borohydrides of 18 grams are dispersed in the dichloromethane of 400mL; it is slowly added into 300mL dissolved with trichloroacetic acid (80 grams) dichloromethane solution; being dividedly in some parts 3-(4-chlorobutyryl)-1H-5-cyanoindole (20 grams), 35 DEG C are stirred 5 hours. Reactant liquor is poured into water, branch vibration layer. Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent. Crude product recrystallizing methanol, obtains 17.5 grams of off-white color products, and yield is 92.6%.
The preparation method ten of embodiment 10:3-(4-chlorobutyl)-1H-5-cyanoindole:
The sodium borohydrides of 18 grams are dispersed in the dichloromethane of 400mL; it is slowly added into 300mL dissolved with trichloroacetic acid (80 grams) dichloromethane solution; being dividedly in some parts 3-(4-chlorobutyryl)-1H-5-cyanoindole (20 grams), 20 DEG C are stirred 10 hours. Reactant liquor is poured into water, branch vibration layer. Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent. Crude product recrystallizing methanol, obtains 17 grams of off-white color products. Yield is 89.9%, and HPLC shows purity: 99.3%.
Prepared by the Chinese style of embodiment 11:3-(4-chlorobutyl)-1H-5-cyanoindole:
The sodium borohydrides of 1.8 kilograms are dispersed in the dichloromethane of 40L; it is slowly added into 30L dissolved with trichloroacetic acid (8 kilograms) dichloromethane solution; being dividedly in some parts 3-(4-chlorobutyryl)-1H-5-cyanoindole (2 kilograms), 35 DEG C are stirred 5 hours. Reactant liquor is poured into water, branch vibration layer. Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent. Crude product recrystallizing methanol, obtains 1.73 kilograms of off-white color products. Yield is 91.5%, and HPLC shows purity: 99.67%.
Claims (15)
1. the preparation method of vilazodone intermediate 3-(4-chlorobutyl)-1H-5-cyanoindole, it comprises the steps: to be dispersed in organic solvent dichloromethane by sodium borohydride, dropping trichloroacetic acid organic solution, it is dividedly in some parts formula (I) compound and 3-(4-chlorobutyryl)-1H-5-cyanoindole again, control temperature 15 DEG C～35 DEG C and 3～10 hours response time, after completion of the reaction, process reactant liquor and obtain formula II compound: 3-(4-chlorobutyl)-1H-5-cyanoindole;
Reaction equation is as follows:
;
The mol ratio of described formula I compound and sodium borohydride is 1:3～15, and the mol ratio of formula I compound and trichloroacetic acid is 1:3～15.
2. preparation method according to claim 1, the volume mass ratio of organic solvent dichloromethane and formula I compound is 20～60mL/g.
3. preparation method according to claim 1, the volume mass ratio of organic solvent dichloromethane and formula I compound is 25～40mL/g.
4. the mol ratio of preparation method according to claim 1, formula I compound and sodium borohydride is 1:4～10.
5. the mol ratio of preparation method according to claim 1, formula I compound and trichloroacetic acid is 1:4～10.
6. preparation method according to claim 1, it comprises the following steps: be dispersed in the dichloromethane of 200mL by the sodium borohydrides of 18 grams, it is slowly added into the 200mL dichloromethane solution dissolved with 80 grams of trichloroacetic acids, being dividedly in some parts 20 grams of 3-(4-chlorobutyryl)-1H-5-cyanoindole, 30 DEG C are stirred 6 hours; Reactant liquor is poured into water, branch vibration layer; Adding 1N sodium hydrate aqueous solution in organic facies, regulate pH value to 7～9, organic facies saturated sodium-chloride water solution washs, and decompression removes organic solvent; Crude product recrystallizing methanol, obtains 15.5 grams of off-white color products.
7. preparation method according to claim 1, it comprises the following steps: be dispersed in the dichloromethane of 600mL by the sodium borohydrides of 18 grams, it is slowly added into the 600mL dichloromethane solution dissolved with 80 grams of trichloroacetic acids, being dividedly in some parts 20 grams of 3-(4-chlorobutyryl)-1H-5-cyanoindole, 30 DEG C are stirred 6 hours; Reactant liquor is poured into water, branch vibration layer; Adding 1N sodium hydrate aqueous solution in organic facies, regulate pH value to 7～9, organic facies saturated sodium-chloride water solution washs, and decompression removes organic solvent; Crude product recrystallizing methanol, obtains 16.8 grams of off-white color products.
8. preparation method according to claim 1, it comprises the following steps: be dispersed in the dichloromethane of 400mL by the sodium borohydrides of 18 grams, it is slowly added into the 300mL dichloromethane solution dissolved with 50 grams of trichloroacetic acids, adding 20 grams in batches and enter 3-(4-chlorobutyryl)-1H-5-cyanoindole, 30 DEG C are stirred 6 hours; Reactant liquor is poured into water, branch vibration layer; Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent; Crude product recrystallizing methanol, obtains 16.1 grams of off-white color products.
9. preparation method according to claim 1, it comprises the following steps: be dispersed in the dichloromethane of 400mL by the sodium borohydrides of 18 grams, it is slowly added into the 300mL dichloromethane solution dissolved with 120 grams of trichloroacetic acids, being dividedly in some parts 20 grams of 3-(4-chlorobutyryl)-1H-5-cyanoindole, 30 DEG C are stirred 6 hours; Reactant liquor is poured into water, branch vibration layer; Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent; Crude product recrystallizing methanol, obtains 17 grams of off-white color products.
10. preparation method according to claim 1, it comprises the following steps: be dispersed in the dichloromethane of 400mL by the sodium borohydrides of 10 grams, it is slowly added into the 300mL dichloromethane solution dissolved with 80 grams of trichloroacetic acids, being dividedly in some parts 20 grams of 3-(4-chlorobutyryl)-1H-5-cyanoindole, 30 DEG C are stirred 6 hours; Reactant liquor is poured into water, branch vibration layer; Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent;Crude product recrystallizing methanol, obtains 13.3 grams of off-white color products.
11. preparation method according to claim 1, it comprises the following steps: be dispersed in the dichloromethane of 400mL by the sodium borohydrides of 36 grams, it is slowly added into the 300mL dichloromethane solution dissolved with 80 grams of trichloroacetic acids, being dividedly in some parts 20 grams of 3-(4-chlorobutyryl)-1H-5-cyanoindole, 30 DEG C are stirred 6 hours; Reactant liquor is poured into water, branch vibration layer; Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent; Crude product recrystallizing methanol, obtains 17.1 grams of off-white color products.
12. preparation method according to claim 1, it comprises the following steps: be dispersed in the dichloromethane of 400mL by the sodium borohydrides of 18 grams, it is slowly added into the 300mL dichloromethane solution dissolved with 80 grams of trichloroacetic acids, being dividedly in some parts 20 grams of 3-(4-chlorobutyryl)-1H-5-cyanoindole, 30 DEG C are stirred 7 hours; Reactant liquor is poured into water, branch vibration layer; Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent; Crude product recrystallizing methanol, obtains 17.2 grams of off-white color products.
13. preparation method according to claim 1, it comprises the following steps: be dispersed in the dichloromethane of 400mL by the sodium borohydrides of 18 grams, it is slowly added into the 300mL dichloromethane solution dissolved with 80 grams of trichloroacetic acids, being dividedly in some parts 20 grams of 3-(4-chlorobutyryl)-1H-5-cyanoindole, 35 DEG C are stirred 5 hours; Reactant liquor is poured into water, branch vibration layer; Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent; Crude product recrystallizing methanol, obtains 17.5 grams of off-white color products.
14. preparation method according to claim 1, it comprises the following steps: be dispersed in the dichloromethane of 400mL by the sodium borohydrides of 18 grams, it is slowly added into the 300mL dichloromethane solution dissolved with 80 grams of trichloroacetic acids, being dividedly in some parts 20 grams of 3-(4-chlorobutyryl)-1H-5-cyanoindole, 20 DEG C are stirred 10 hours; Reactant liquor is poured into water, branch vibration layer; Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent; Crude product recrystallizing methanol, obtains 17 grams of off-white color products.
15. preparation method according to claim 1, it comprises the following steps: be dispersed in the dichloromethane of 40L by the sodium borohydrides of 1.8 kilograms, it is slowly added into the 30L dichloromethane solution dissolved with 8 kilograms of trichloroacetic acids, being dividedly in some parts 2 kilograms of 3-(4-chlorobutyryl)-1H-5-cyanoindole, 35 DEG C are stirred 5 hours; Reactant liquor is poured into water, branch vibration layer; Organic facies 1N sodium hydrate aqueous solution, regulates pH value to 7～9, then washs with saturated sodium-chloride water solution, and decompression removes organic solvent; Crude product recrystallizing methanol, obtains 1.73 kilograms of off-white color products.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1330635A (en) * | 1998-12-17 | 2002-01-09 | 默克专利股份公司 | Method for producing 3-alkanoylindoles and 3-alkylindoles |
| CN102617558A (en) * | 2012-03-26 | 2012-08-01 | 上海泛凯生物医药科技有限公司 | Preparation method of vilazodone |
| CN102659660A (en) * | 2012-05-11 | 2012-09-12 | 杭州和泽医药科技有限公司 | Preparation method and application of 3-(4-chlorobutyl)-5-cyano-1H-indole |
| CN103058912A (en) * | 2012-12-28 | 2013-04-24 | 山东邹平大展新材料有限公司 | Preparation method of 3-(4-chlorobutyl)indole-5-formonitrile |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1330635A (en) * | 1998-12-17 | 2002-01-09 | 默克专利股份公司 | Method for producing 3-alkanoylindoles and 3-alkylindoles |
| CN102617558A (en) * | 2012-03-26 | 2012-08-01 | 上海泛凯生物医药科技有限公司 | Preparation method of vilazodone |
| CN102659660A (en) * | 2012-05-11 | 2012-09-12 | 杭州和泽医药科技有限公司 | Preparation method and application of 3-(4-chlorobutyl)-5-cyano-1H-indole |
| CN103058912A (en) * | 2012-12-28 | 2013-04-24 | 山东邹平大展新材料有限公司 | Preparation method of 3-(4-chlorobutyl)indole-5-formonitrile |
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