CN103880729B - Vilazodone intermediate 5-cyano group-3(4-chlorobutyl)-indoles new technique for synthesizing - Google Patents
Vilazodone intermediate 5-cyano group-3(4-chlorobutyl)-indoles new technique for synthesizing Download PDFInfo
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- CN103880729B CN103880729B CN201410116115.7A CN201410116115A CN103880729B CN 103880729 B CN103880729 B CN 103880729B CN 201410116115 A CN201410116115 A CN 201410116115A CN 103880729 B CN103880729 B CN 103880729B
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- 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
- C07D209/12—Radicals substituted by oxygen atoms
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Abstract
The present invention is a kind of 5-cyano group-3(4-chlorobutyl)-indoles synthesis technique; to complete amido link dehydration under 3-position acylation reaction and catalyst action with 5-amino-formoxyl-indoles, 4-chlorobutanoylchloride to produce 5-position cyano group; under reducing agent effect, de-carbonyl reaction generates product again, and last refining methanol obtains high-purity, high-load 5-cyano group-3(4-chlorobutyl)-indoles. The method technique is succinct, simple to operate, is applicable to industrialized production.
Description
Technical field
The present invention relates to a kind of novel treatment severe depression disease drug vilazodone intermediate-5-cyano group-3(4-chlorobutyl)-indoles synthetic; being specifically related to synthesis material is that 5-amino-formoxyl-indoles, 4-chlorobutanoylchloride complete amido link dehydration production 5-position cyano group under 3-position acylation reaction and catalyst action; under reducing agent effect, de-carbonyl reaction generates product again, and last separation and purification obtains high-purity, high-load 5-cyano group-3(4-chlorobutyl)-indoles.
Background technology
Vilazodone is as a kind of novel antidepressant drug, and its effect has double mechanism, is the partial agonist of selective serotonin reuptaking inhibitor and serotonin 1A acceptor. This medicine can improve fast again 5-hydroxyl look ammonia and be subject to extracellular concentration in exciting 5-hydroxyl look ammonia acceptor, is the antidepressant drug of at present quick acting. FDA's approval on January 21st, 2011 Vilazodone Hydrochloride sheet is used for the treatment of adult's major depressive disorder, is first indolyl amine novel antidepressant.
The synthetic route of vilazodone has 5, has been mainly concerned with two important fragments, i.e. cyanoindole parent nucleus and benzofuran parent nucleus, and these two parent nucleus connections obtain final vilazodone product. Wherein most important intermediate is cyanoindole parent nucleus fragment-5-cyano group-3(4-chlorobutyl)-indoles.
Bibliographical information, 5-cyano group-3(4-chlorobutyl)-indoles is taking 5-cyano group-indoles as raw material, be Butyrylation, then catalytic reduction decarbonylation base obtains through 3-. Although this route route is short, technique is relatively simple, and 5-cyanoindole price is high, and synthetic final intermediate cost is too high. Meanwhile, 5-cyano group-indoles derives from indoles, and its preparation process complexity uses the great acetic anhydride of excitant, bromine, has used the extremely strong metal cyanides of toxicity, and its environmental protection cost of preparing is too high, causes final price expensive. Meanwhile, environment and production operator health are had to larger harm. So this route must improve.
Sum up above vilazodone intermediate-5-cyano group-3(4-chlorobutyl of preparing) method of-indoles is mainly present in following shortcomings: (1) cost of material is expensive, causes the high system of final product price. (2) there is the dual harm to environment and production operator in the production of raw material 5-cyano group-indoles, unsuitable industrialization. (3) supply of raw material 5-cyano group-indoles is unstable, intermediate is produced and be vulnerable to impact.
For overcoming above vilazodone intermediate-5-cyano group-3(4-chlorobutyl of preparing) shortcoming of-indoles; the present invention adopts new synthetic route; complete amido link dehydration under 3-position acylation reaction and catalyst action with 5-amino-formoxyl-indoles, 4-chlorobutanoylchloride and produce 5-position cyano group, then de-carbonyl reaction generates product under reducing agent effect. The present invention is with the different characteristic part of said method: (1) is reacted base stock low price, is easy to get, and production cost can reduce greatly. (2) in synthetic intermediate and raw material process, do not relate to hazardous chemical and the large chemicals of toxicity. (3) technique is simple, and reaction controllability is strong, less demanding to producers. (4) producing in the reaction of cyano group, do not use the extremely strong metal cyanides of toxicity, greatly reduce the harmfulness to environment and personnel health. In sum, vilazodone intermediate-5-cyano group-3(4-chlorobutyl of the present invention)-indoles new preparation process has that productive rate is high, flow process simple and the advantage such as health, environmental protection, has extraordinary industrialization prospect.
Summary of the invention
The key problem that the present invention need to solve is to overcome existing vilazodone intermediate-5-cyano group-3(4-chlorobutyl)-indoles preparation technology's shortcoming, set up that environmental protection, Atom economy are high, more low cost, 5-cyano group-3(4-chlorobutyl of good quality more)-indoles industrialized producing technology.
Object of the present invention is achieved through the following technical solutions, and concrete route is shown in Figure of description:
Vilazodone intermediate-5-cyano group-3(4-chlorobutyl)-indoles synthesis route is to complete under 3-position acylation reaction and catalyst action amido link dehydration with 5-amino-formoxyl-indoles, 4-chlorobutanoylchloride to produce 5-position cyano group; under reducing agent effect, de-carbonyl reaction generates product again, and last separation and purification obtains high-purity, high-load 5-cyano group-3(4-chlorobutyl)-indoles. Concrete steps are as follows:
1, in enamel reaction still, add methylene chloride, then cryosel bathe 5 DEG C of left and right add the chloro-butyl chloride of reactant 4-, then add aluminum trichloride (anhydrous) in batches, and at this temperature stirring reaction 1-2h, form complex compound. Continue again to drop into reactant 5-amino-formoxyl-indoles, be slowly warming up to room temperature, stirring reaction 3-4h. Thin-layer chromatography monitoring 5-amino-formoxyl-indoles spot disappears, and is considered as acylation reaction and completes. Then add 5% sodium hydrate aqueous solution adjust pH 10 left and right, continue stirring reaction 0.5h, stratification; separate after organic phase, then add dichloromethane extraction once, merge organic phase; anhydrous sodium sulfate drying, reduced pressure concentration, obtains the chloro-bytyry of 5-amino-formoxyl-3(4-)-indoles.
2, in enamel reaction still, add methylene chloride and the chloro-bytyry of raw material 5-amino-formoxyl-3(4-)-indoles, cryosel is bathed control temperature and is added below POCl3 at 10 DEG C, and about 0.5h adds. Slowly temperature rising reflux reacts 4-6h again, the chloro-bytyry of thin-layer chromatography monitoring intermediate 5-amino-formoxyl-3(4-) disappearance of-indoles spot, be considered as dehydration and complete. Lower the temperature below 10 DEG C, 5% sodium hydrate aqueous solution adjust pH 8 left and right add again. Stratification, separates after carrene, then with dichloromethane extraction once, merge organic phase, dry, reduced pressure concentration, obtains the chloro-bytyry of 5-cyano group-3(4-)-indoles intermediate.
3, in enamel reaction still, add methylene chloride and the chloro-bytyry of raw material 5-cyano group-3(4-)-indoles; after stirring and dissolving; under room temperature, pass into diborane; approximately continue 1h; slowly rise to again back flow reaction 3h; chloro-bytyry-the indoles of thin-layer chromatography monitoring intermediate 5-cyano group-3(4-) spot disappearance, be considered as reduction reaction and complete. Reduced pressure concentration obtains solid 5-cyano group-3(4-chlorobutyl-indoles) crude product, then with methyl alcohol heat of solution, filter, concentrated, crystallization, obtains 5-cyano group-3(4-chlorobutyl)-indoles fine work.
The invention provides vilazodone intermediate 5-cyano group-3(4-chlorobutyl)-Indomethacin technique; complete amido link dehydration under 3-position acylation reaction and catalyst action with 5-amino-formoxyl-indoles, 4-chlorobutanoylchloride and produce 5-position cyano group, then de-carbonyl reaction generates product under reducing agent effect. Aspect reaction use reagent, supplementary material, all considering with environmental protection, efficiency. This method has that atom economy type, equipment are simple, production routine environmental protection, has very large economic and social benefit.
Brief description of the drawings:
5-cyano group-3(4-chlorobutyl)-indoles synthetic route is shown in accompanying drawing.
Detailed description of the invention:
Further illustrate in the following embodiments the present invention, this does not limit the scope of the invention.
The chloro-bytyry of embodiment 15-amino-formoxyl-3(4-)-indoles synthetic
In enamel reaction still, add methylene chloride 500L, cryosel bathe 5 DEG C of left and right of temperature control add the chloro-butyl chloride 56.0kg of reactant 4-, then add aluminum trichloride (anhydrous) 45.0kg in batches, and at this temperature stirring reaction 1h, form complex compound. Continue again to drop into reactant 5-amino-formoxyl-indoles 50.0kg, be slowly warming up to room temperature, stirring reaction 3-4h. Thin-layer chromatography monitoring 5-amino-formoxyl-indoles spot disappears, and is considered as acylation reaction and completes. Then add 5% sodium hydrate aqueous solution adjust pH 10 left and right; continue stirring reaction 0.5h; stratification; separate after organic phase; add again 300L dichloromethane extraction once, merge organic phase, anhydrous sodium sulfate drying; reduced pressure concentration, obtains the chloro-bytyry of 5-amino-formoxyl-3(4-)-indoles crude product 65.4kg.
The chloro-bytyry of embodiment 25-cyano group-3(4-)-indoles synthetic
In enamel reaction still, add methylene chloride 400L and the chloro-bytyry of raw material 5-amino-formoxyl-3(4-)-indoles 60.0kg, cryosel is bathed control temperature and is added below POCl3 30.0kg at 10 DEG C, and about 0.5h adds. Slowly temperature rising reflux reacts 4-6h again, the chloro-bytyry of thin-layer chromatography monitoring intermediate 5-amino-formoxyl-3(4-) disappearance of-indoles spot, be considered as dehydration and complete. Lower the temperature below 10 DEG C, 5% sodium hydrate aqueous solution adjust pH 8 left and right add again. Stratification, separates after carrene, then extracts once with carrene 200L, merges organic phase, and dry, reduced pressure concentration, obtains the chloro-bytyry of 5-cyano group-3(4-)-indoles intermediate crude product 51.0kg.
Embodiment 35-cyano group-3(4-chlorobutyl)-indoles synthetic
In enamel reaction still, add methylene chloride 400L and the chloro-bytyry of raw material 5-cyano group-3(4-)-indoles 50.0kg; after stirring and dissolving; under room temperature, pass into diborane 5.1kg; approximately continue 1h; slowly rise to again back flow reaction 3h; chloro-bytyry-the indoles of thin-layer chromatography monitoring intermediate 5-cyano group-3(4-) spot disappearance, be considered as reduction reaction and complete. Reduced pressure concentration obtains solid 5-cyano group-3(4-chlorobutyl-indoles) crude product 45.6kg. Crude product, again with methyl alcohol 200L heat of solution, filters, concentrated, and decrease temperature crystalline filters, and dries, and obtains 5-cyano group-3(4-chlorobutyl)-indoles fine work 41.2kg.
Claims (2)
1. synthesizing of a vilazodone intermediate---5-cyano group-3 (4-chlorobutyl)-indolesMethod, is characterized in that, completes 3-position acyl with 5-amino-formoxyl-indoles, 4-chlorobutanoylchlorideChange amido link dehydration under reaction and catalyst action and generate 5-position cyano group, then under reducing agent effectDe-carbonyl reaction generates product, and last separation and purification obtains 5-cyano group-3 of high-purity, high-load(4-chlorobutyl)-indoles;
Concrete steps are as follows: 1), in enamel reaction still, add methylene chloride,Cryosel is bathed 5 DEG C and is added the chloro-butyl chloride of reactant 4-, then adds aluminum trichloride (anhydrous) in batches,And at this temperature stirring reaction 1-2h, form complex compound; Continue again to drop into reactant 5-ammoniaBase-formoxyl-indoles, is slowly warming up to room temperature, stirring reaction 3-4h; Thin-layer chromatography monitoring5-amino-formoxyl-indoles spot disappears, and is considered as acylation reaction and completes; Then add 5% hydrogenAqueous solution of sodium oxide adjust pH 10, continues stirring reaction 0.5h, and stratification, has separatedMachine mutually after, then add dichloromethane extraction once, merge organic phase, anhydrous sodium sulfate drying,Reduced pressure concentration, obtains 5-amino-formoxyl-3 (the chloro-bytyry of 4-)-indoles;
2), in enamel reaction still, add methylene chloride and raw material 5-amino-formoxyl-3(the chloro-bytyry of 4-)-indoles, cryosel is bathed control temperature and is added below POCl3 at 10 DEG C,0.5h adds; Slowly temperature rising reflux reacts 4-6h again, thin-layer chromatography monitoring intermediate 5-amino-formoxyl-3 (the chloro-bytyry of 4-)-indoles spot disappears, and is considered as dehydration and completes; Fall againTemperature, below 10 DEG C, adds 5% sodium hydrate aqueous solution adjust pH 8; Stratification, pointGo out after carrene, then with dichloromethane extraction once, merge organic phase, dry, reduce pressure denseContracting, obtains 5-cyano group-3 (the chloro-bytyry of 4-)-indoles intermediate;
3) (4-is chloro-, in enamel reaction still, to add methylene chloride and raw material 5-cyano group-3Bytyry)-indoles, after stirring and dissolving, under room temperature, pass into diborane, continue 1h, slowerRise to back flow reaction 3h, thin-layer chromatography monitoring intermediate 5-cyano group-3 (the chloro-bytyry-indoles of 4-)Spot disappears, and is considered as reduction reaction and completes; Reduced pressure concentration obtains solid 5-cyano group-3 (4-neopreneBase-indoles) crude product, then with methyl alcohol heat of solution, filter, concentrated, crystallization, obtains 5-cyano group-3 (4-chlorobutyl)-indoles fine work.
2. synthetic method according to claim 1, is characterized in that, described step 1)For: in enamel reaction still, add methylene chloride 500L, cryosel is bathed 5 DEG C of temperature controls and is addedEnter the chloro-butyl chloride 56.0kg of reactant 4-, then add aluminum trichloride (anhydrous) 45.0kg in batches,And at this temperature stirring reaction 1h, form complex compound; The reactant of continuation input again 5-amino-Formoxyl-indoles 50.0kg, is slowly warming up to room temperature, stirring reaction 3-4h; Thin-layer chromatography prisonSurvey 5-amino-formoxyl-indoles spot and disappear, be considered as acylation reaction and complete; Then add 5%Sodium hydrate aqueous solution adjust pH 10, continue stirring reaction 0.5h, stratification, pointGo out after organic phase, then add 300L dichloromethane extraction once, merge organic phase, anhydrous sulphurAcid sodium is dry, and reduced pressure concentration, obtains 5-amino-formoxyl-3 (the chloro-bytyry of 4-)-indoles thickProduct 65.4kg;
Described step 2) be: in enamel reaction still, add methylene chloride 400L and formerMaterial 5-amino-formoxyl-3 (the chloro-bytyry of 4-)-indoles 60.0kg, cryosel is bathed control temperature and is existed10 DEG C add POCl3 30.0kg below, and 0.5h adds; Slowly temperature rising reflux reaction again4-6h, thin-layer chromatography monitoring intermediate 5-amino-formoxyl-3 (the chloro-bytyry of 4-)-indoles spotPoint disappears, and is considered as dehydration to complete; Lower the temperature again below 10 DEG C, add 5% NaOHAqueous solution adjust pH 8; Stratification, separates after carrene, then uses carrene 200LExtraction once, merges organic phase, and dry, reduced pressure concentration, obtains 5-cyano group-3 (the chloro-butyryl of 4-Base)-indoles intermediate crude product 51.0kg;
Described step 3) be: in enamel reaction still, add methylene chloride 400L and formerMaterial 5-cyano group-3 (the chloro-bytyry of 4-)-indoles 50.0kg, after stirring and dissolving, passes under room temperatureDiborane 5.1kg, continues 1h, more slowly rises to back flow reaction 3h, in thin-layer chromatography monitoringMesosome 5-cyano group-3 (the chloro-bytyry-indoles of 4-) spot disappears, and is considered as reduction reaction and completes;Reduced pressure concentration obtains solid 5-cyano group-3 (4-chlorobutyl-indoles) crude product 45.6kg; Crude product againWith methyl alcohol 200L heat of solution, filter, concentrated, decrease temperature crystalline, filters, and dries, and obtains 5-Cyano group-3 (4-chlorobutyl)-indoles fine work 41.2kg.
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| CN107501159B (en) * | 2017-08-14 | 2020-11-24 | 连云港恒运药业有限公司 | Synthesis method of vilazodone intermediate 3- (4-chlorobutyl) -5-cyanoindole |
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| CN102875440A (en) * | 2012-10-30 | 2013-01-16 | 江西隆莱生物制药有限公司 | Preparation method of 3-(4-chlorobutyl)-5-cyanoindole |
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| CN102875440A (en) * | 2012-10-30 | 2013-01-16 | 江西隆莱生物制药有限公司 | Preparation method of 3-(4-chlorobutyl)-5-cyanoindole |
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| "Reactions of Vilsmeier-Haack reagent with aromatic and heterocyclic aldoximes";Kusurkar, Radhika等;《 Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry》;20031231;第42B卷(第12期);第3148页scheme1,第3150页右栏最后1段 * |
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Denomination of invention: A new synthetic process of verazolone intermediate 5-cyano-3 (4-chlorobutyl) - indole Effective date of registration: 20210930 Granted publication date: 20160511 Pledgee: Agricultural Bank of China Limited Zhangjiagang branch Pledgor: ZHANG JIA GANG VINSCE BIO-PHARM Co.,Ltd. Registration number: Y2021320010400 |
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Address after: No. 2, Nanjing Middle Road, Jiangsu Yangzijiang Chemical Industrial Park, Zhangjiagang Free Trade Zone, Suzhou City, Jiangsu Province, 215634 Patentee after: Wison Biomedical (Suzhou) Co.,Ltd. Address before: 215634 No. 2 Nanjing Middle Road, Yangtze River Chemical Industrial Park, Zhangjiagang Free Trade Zone, Suzhou City, Jiangsu Province Patentee before: Weisheng Biomedical (Suzhou) Co.,Ltd. Address after: 215634 No. 2 Nanjing Middle Road, Yangtze River Chemical Industrial Park, Zhangjiagang Free Trade Zone, Suzhou City, Jiangsu Province Patentee after: Weisheng Biomedical (Suzhou) Co.,Ltd. Address before: 215634 Building D, No. 7 Guangdong Road, Zhangjiagang Free Trade Zone, Suzhou City, Jiangsu Province (Weisheng) Patentee before: ZHANG JIA GANG VINSCE BIO-PHARM Co.,Ltd. |
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Date of cancellation: 20221031 Granted publication date: 20160511 Pledgee: Agricultural Bank of China Limited Zhangjiagang branch Pledgor: ZHANG JIA GANG VINSCE BIO-PHARM Co.,Ltd. Registration number: Y2021320010400 |