CN102702066A - Novel method for preparing intermediate 6-chloro-5-fluoroindole used for synthesizing anticancer and weight-reducing medicine - Google Patents
Novel method for preparing intermediate 6-chloro-5-fluoroindole used for synthesizing anticancer and weight-reducing medicine Download PDFInfo
- Publication number
- CN102702066A CN102702066A CN2011100746704A CN201110074670A CN102702066A CN 102702066 A CN102702066 A CN 102702066A CN 2011100746704 A CN2011100746704 A CN 2011100746704A CN 201110074670 A CN201110074670 A CN 201110074670A CN 102702066 A CN102702066 A CN 102702066A
- Authority
- CN
- China
- Prior art keywords
- chloro
- midbody
- toluene
- fluoroindole
- anticancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Indole Compounds (AREA)
Abstract
The invention relates to a novel method for synthesizing an important intermediate 6-chloro-5-fluoroindole for anticancer and weight-reducing medicines. The method comprises the steps that: 3-chloro-4-fluoroaniline is reacted with boron trichloride in a toluene solution under the action of a Lewis acid aluminium trichloride to produce imine which is then hydrolyzed under the action of hydrochloric acid to get an intermediate, a target product is generated by the reduction of the intermediate by sodium borohydride in a dioxane/water system and then by reflux dewatering, and the 6-chloro-5-fluoroindole is produced by reduced pressure distillation of the initial product. The method has the advantages of readily available raw materials, short reaction steps and low costs, and is suitable for industrial production.
Description
Technical field
The invention belongs to medicine intermediate and contain the fluoro indole field, particularly relate to a kind of novel method anticancer and fat-reducing medicine intermediate 6-chloro-5-fluoro-indoles that is used for.
Background technology:
At present, 6-chloro-5-fluoro indole is a kind of novel 5-HT2C receptor stimulant-Ro 60-0715 (J.Med.Chem., 1997,40 (17), 2762-2769; Bioorganic & Medicinal Chemistry Letters, 2004,14 (9); Heterocyclic stem nucleus 2367-2370); The alternative 5-HT2C that suppresses of this compound has epoch making significance to reducing obesity, and then most important to reducing the disease that causes because of obesity; 6-chloro-5-fluoro indole also is glycogen biosynthesis synthase kinase 3 β (glycogen synthase kinase 3 β; GSK-3 β) important intermediate (J.Med.Chem.2009 of anticancer newtype drug such as suppressor factor; 52; 1853-1863), along with the research and development entering clinical stage of relevant with it antagonism colorectal carcinoma and carcinoma of the pancreas new drug, having than large economy of this midbody is worth and social value; In addition this midbody also be used for disease medicaments such as synthetic treatment dysmenorrhoea, hypertension, chronic arrhythmia, obsession (US2010256140A1, US5494928A).
But the nowadays known method that the many 6-of preparation chloro-5 fluoro indoles are arranged; Document 1: (Bioorganic & Medicinal Chemistry Letters, 2004,14 (9); 2367-2370) adopt the Leimgruber-Batcho reaction method totally 5 to go on foot total recovery 35% (scheme 2); Document 2: (J.Med.Chem.2009,52,1853-1863) also adopted identical compound method.This method route is longer, and by product 6-chloro-5-methoxyl group indoles is more, is difficult to purifying, and the three wastes are bigger simultaneously.
Though document 3: (Synthetic Communications; 2004; 34 (12); 2295-2300), the method for having improved document 1 and 2 has replaced DMF-DMA with DMF-DIPA in four-step reaction, and the amount of by product reduces to some extent, but synthesis technique still has pollution bigger, the shortcoming that cost is higher.The 6-chloro-5 fluoro indole verivates that also have first Synthetic 2-carboxylic acid-substituted in addition, high temperature decarboxylation then, this method yield is lower, and reaction conditions harshness is not suitable for industry and amplifies (like US5494928).
Summary of the invention:
Technical problem to be solved by this invention provides a kind of novel method of synthetic important anticancer and fat-reducing medicine intermediate 5-fluoro-6-chloro-indoles, and preparation technology of the present invention has raw material and is easy to get, and reactions step is short, and is simple to operate, environmentally friendly, low cost and other advantages; The pure article 6-of the target compound that this method obtains chloro-5 fluoro indole purity reach more than 97%, and total recovery is more than 55%.
Reaction equation of the present invention is following:
The novel method of a kind of synthetic important anticancer and fat-reducing medicine intermediate 5-fluoro-6-chloro-indoles of the present invention; Comprise: (1) drips in the toluene solution of 3-chloro-4-fluoroaniline under ice-water bath in the toluene solution of boron trichloride; In mixing solutions, add chloromethyl cyanide and aluminum trichloride (anhydrous) subsequently successively, reaction solution was nitrogen protection refluxed 6-8 hour.Reaction system cooling back has a large amount of depositions to separate out to the hydrochloric acid that wherein adds 2N.Under agitation condition, be heated to 80 degrees centigrade, dissolve up to solid.Use dichloromethane extraction after the reaction solution cooling.Water is used dichloromethane extraction after being neutralized to neutrality with the 2N aqueous sodium hydroxide solution.Merge organic phase,, obtain the midbody bullion after the pressure solvent evaporated through dry.This midbody need not be further purified and directly be used for next step reaction.
(2) midbody is dissolved in the system of dioxane/water, adds Peng Qinghuana, reaction system reflux 8-10 hour, after reaction substrate disappeared, decompression steamed solvent, added dichloromethane extraction.Organic phase is told after after the drying, distillation obtains out product after removing and desolvating.With after underpressure distillation obtains product.
3-chloro-4-fluoroaniline in the said step (1): boron trichloride: chloromethyl cyanide: the amount of substance ratio of aluminum trichloride (anhydrous) is 1: 1.1: 1.2: 1.1; The ratio of 3-chloro-4-fluoroaniline and toluene is 80g: 600Ml; The midbody that obtains directly is used for next step without purifying; Toluene is used the 4A molecular sieve drying.
The amount of substance ratio of the Peng Qinghuana/midbody in the said step (2) is 1.1: 1; The volume ratio of solvent dioxane/water is 10: 1.
Anticancer and the fat-reducing of the present invention's preparation can be used for field of biological pharmacy with medicine intermediate 6-chloro-5-fluoro indole, is mainly used in synthetic anticancer kind new medicine.
3 maos of yields of the first step reaction intermediate of the present invention are greater than 90%, and purity is more than 90%, and outward appearance is a light yellow solid; The second step product 6-chloro-5-fluoro indole reaction yield is greater than 70%, and product purity is greater than 97%, and outward appearance is a white solid.
Beneficial effect
(1) preparation technology of the present invention has raw material and is easy to get (4-fluoro-3-chloroaniline is the important intermediate of synthetic Norxin, and other raw materials are the basic chemical industry raw material), and reactions step is short, and is simple to operate, environmentally friendly, low cost and other advantages;
(2) the pure article 6-of the target compound chloro-5 fluoro indole purity that obtain of this method reach more than 97%, and total recovery is more than 55%.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit to scope of the present invention.Should be understood that in addition those skilled in the art can do various changes and modification to the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1
The first step reaction: preparation midbody 3
Under ice-water bath to boron chloride (6.45g; Drip 4-fluoro-3-chloroaniline (7.28g in toluene 55mmol) (60mL) solution; Toluene 5mmol) (60mL) solution, in mixing solutions, successively add subsequently chloromethyl cyanide (3.8mL, 60mmol) and aluminum trichloride (anhydrous) (7.34g; 55mmol), reaction solution was nitrogen protection refluxed 6-8 hour.Reaction system cooling back has a large amount of depositions to separate out to the hydrochloric acid that wherein adds 2N.Under agitation condition, be heated to 80 degrees centigrade, dissolve up to solid.Reaction solution cooling back is with dichloromethane extraction three times.Water is neutralized to neutral back with dichloromethane extraction three times with the 2N aqueous sodium hydroxide solution.Merge organic phase,, obtain midbody 3 (bullion 10g, hair yield 90%, purity 90%) after the pressure solvent evaporated through dry.
1H?NMR(400MHz，CDCl
3)：δ7.40(d，J＝10.0Hz，1H)，6.75(d，J＝10.0Hz，1H)，6.19(s，br，2H)，4.70(s，2H)。
Second step reaction: 6-chloro-5-fluoro indole
3 bullion 10g are dissolved in the system of dioxane/water (250/25mL) with midbody, and the adding Peng Qinghuana (1.9g, 49.5mmol), reaction system reflux 8-10 hour, decompression steams solvent, adds dichloromethane extraction three times.Organic phase is told after after the drying, distillation obtains out product after removing and desolvating.With after underpressure distillation obtain 6-chloro-5-fluoro indole (4.6g, two the step total recoverys 55%, purity 97%).
1H?NMR(400MHz，CDCl
3)：δ8.10(s，br，1H)，7.39(d，J＝6.0Hz，1H)，7.35(d，J＝9.6Hz，1H)，7.23(t，J＝6.0Hz，1H)，6.50(m，1H)。
Claims (2)
1. one kind is used for novel preparation method synthetic anticancer and slimming medicine midbody 6-chloro-5-fluoro indole, comprising:
(1) under ice-water bath, in the toluene solution of boron chloride, drip the toluene solution of 4-fluoro-3-chloroaniline, in mixing solutions, successively add chloromethyl cyanide and aluminum trichloride (anhydrous) subsequently, reaction solution was nitrogen protection refluxed 6-8 hour.Reaction system cooling back has a large amount of depositions to separate out to the hydrochloric acid that wherein adds 2N.Under agitation condition, be heated to 80 degrees centigrade, dissolve up to solid.Use dichloromethane extraction after the reaction solution cooling.Water is used dichloromethane extraction after being neutralized to neutrality with the 2N aqueous sodium hydroxide solution.Merge organic phase,, obtain the midbody bullion after the pressure solvent evaporated through dry.
(2) midbody is dissolved in the system of dioxane/water, adds Peng Qinghuana, reaction system reflux 8-10 hour, decompression steams solvent, adds dichloromethane extraction three times.Organic phase is told after after the drying, distillation obtains out product after removing and desolvating.With after underpressure distillation obtains pure article.
2. a kind of novel preparation method synthetic anticancer and slimming medicine midbody 6-chloro-5-fluoro indole that is used for according to claim 1, it is characterized in that: the 3-chloro-4-fluoroaniline in the said step (1): boron trichloride: chloromethyl cyanide: the amount of substance ratio of aluminum trichloride (anhydrous) is 1: 1.1: 1.2: 1.1; The ratio of 3-chloro-4-fluoroaniline and toluene is 80g: 600Ml; The midbody that obtains directly is used for next step without purifying; Toluene is used the 4A molecular sieve drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100746704A CN102702066A (en) | 2011-03-28 | 2011-03-28 | Novel method for preparing intermediate 6-chloro-5-fluoroindole used for synthesizing anticancer and weight-reducing medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100746704A CN102702066A (en) | 2011-03-28 | 2011-03-28 | Novel method for preparing intermediate 6-chloro-5-fluoroindole used for synthesizing anticancer and weight-reducing medicine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102702066A true CN102702066A (en) | 2012-10-03 |
Family
ID=46895179
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100746704A Pending CN102702066A (en) | 2011-03-28 | 2011-03-28 | Novel method for preparing intermediate 6-chloro-5-fluoroindole used for synthesizing anticancer and weight-reducing medicine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102702066A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104151226A (en) * | 2014-08-26 | 2014-11-19 | 江苏万年长药业有限公司 | Extracting recycle method of indole from indole synthesis waste water |
| CN111233707A (en) * | 2020-04-27 | 2020-06-05 | 南京远淑医药科技有限公司 | Synthesis and refining method of 4-fluorobenzoylacetonitrile |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1105988A (en) * | 1993-10-22 | 1995-08-02 | 弗·哈夫曼-拉罗切有限公司 | 1-amino-ethylindole-derivatives |
| WO2008119741A2 (en) * | 2007-03-29 | 2008-10-09 | Novartis Ag | 3-imidazolyl-indoles for the treatment of proliferative diseases |
-
2011
- 2011-03-28 CN CN2011100746704A patent/CN102702066A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1105988A (en) * | 1993-10-22 | 1995-08-02 | 弗·哈夫曼-拉罗切有限公司 | 1-amino-ethylindole-derivatives |
| WO2008119741A2 (en) * | 2007-03-29 | 2008-10-09 | Novartis Ag | 3-imidazolyl-indoles for the treatment of proliferative diseases |
Non-Patent Citations (2)
| Title |
|---|
| BIAO JIANG等: "Total Synthesis of （±）-Dragmacidin：A cytotoxic bis(indole)alkaloid of marine origin", 《J. ORG. CHEM.》, vol. 59, no. 22, 30 November 1994 (1994-11-30) * |
| DAVID R. ADAMS等: "Preparation of 6-chloro-5-fluoroindole via the use of palladium and copper-mediated heterocyclisations", 《TETRAHEDRON LETTERS》, vol. 43, no. 42, 14 October 2002 (2002-10-14), XP004383424, DOI: doi:10.1016/S0040-4039(02)01758-6 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104151226A (en) * | 2014-08-26 | 2014-11-19 | 江苏万年长药业有限公司 | Extracting recycle method of indole from indole synthesis waste water |
| CN111233707A (en) * | 2020-04-27 | 2020-06-05 | 南京远淑医药科技有限公司 | Synthesis and refining method of 4-fluorobenzoylacetonitrile |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110015985B (en) | 2- (alpha-deuterium-alpha-hydroxy-alpha-aryl/alkyl) aza-aromatic hydrocarbon compound and preparation method and application thereof | |
| CN103204819B (en) | Deuterated diazepam and preparation method thereof | |
| WO2017096996A1 (en) | Preparation method for cobimetinib | |
| CN103880744A (en) | Preparation method for 5'-methoxylaudanosine | |
| CN106117216B (en) | A kind of method of atmospheric synthesis 6H- iso-indoles [2,1-a] indoles -6- ketone compounds | |
| CN102603718B (en) | Synthesis method of cediranib | |
| CN102702066A (en) | Novel method for preparing intermediate 6-chloro-5-fluoroindole used for synthesizing anticancer and weight-reducing medicine | |
| CN103896858B (en) | The preparation technology of cytosine | |
| CN105820174B (en) | A kind of preparation method of polysubstituted thiophene diindyl derivative | |
| CN101723870B (en) | Production method of thiophanate methyl | |
| CN103880745A (en) | Chemical synthesis method of 6-bromo-1,2,3,4-tetrahydroisoquinolyl-1-formic acid | |
| CN103102306A (en) | Preparation method for celecoxib | |
| CN104193643B (en) | For the synthesis of the intermediate of anti-AIDS drug toughener cobicistat | |
| CN106279236B (en) | Method for synthesizing 2-triisopropyl silicon-based acetylene indole compound | |
| CN113861103B (en) | Method for synthesizing pyridine, bipyridine and terpyridine ligand | |
| CN105949176B (en) | A kind of purification process of linatinib | |
| CN103204856B (en) | Deuterated alprazolam and preparation method thereof | |
| CN104945434B (en) | (2 ﹣ bis- substitution phosphines phenyl) -1- alkyl-indols Phosphine ligands and its synthetic method and application | |
| CN103724357A (en) | Synthetic method of 3, 4-dihydropyran [3, 2-b] indole-2-ketones compound | |
| CN103570781B (en) | A kind of industrialized process for preparing of capecitabine | |
| CN104356133A (en) | Method for preparing antidepressant mirtazapine | |
| CN111484460A (en) | Synthetic method of olanzapine related substance compound I and compound II | |
| CN107235886B (en) | Synthesis method of 2, 3-dihydropyrrole ring | |
| CN103254108B (en) | Preparation method of multifunctional pyrrole and pyrrolo [3,4-C ] quinoline | |
| CN108101838A (en) | A kind of synthetic method of Du Lutewei intermediates and its related substance detecting method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20121003 |