CN102659675A - Synthetic method for 6- bromo-2-methyl sulfonyl-1,2,3,4,-tetrahydroisoquinoline - Google Patents
Synthetic method for 6- bromo-2-methyl sulfonyl-1,2,3,4,-tetrahydroisoquinoline Download PDFInfo
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- CN102659675A CN102659675A CN2011104434913A CN201110443491A CN102659675A CN 102659675 A CN102659675 A CN 102659675A CN 2011104434913 A CN2011104434913 A CN 2011104434913A CN 201110443491 A CN201110443491 A CN 201110443491A CN 102659675 A CN102659675 A CN 102659675A
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- bromo
- tetrahydroisoquinoline
- reaction
- methyl sulphonyl
- methyl sulfonyl
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Abstract
The invention discloses a synthetic method for 6- bromo -2-methyl sulfonyl-1,2,3,4,-tetrahydroisoquinoline. The present method mainly adopts 3- bromo-phenylethylamine as a raw material, after a reaction with methane sulfonyl chloride, N-(3 bromophenethyl) methylsulfonamide is obtained. N-(3 bromophenethyl) methylsulfonamide reacts with paraformaldehyde and 6- bromo-2-methyl sulfonyl-1,2,3,4,-tetrahydroisoquinoline is obtained. But the reaction time of N-(3 bromophenethyl) methylsulfonamide and formagene is as long as 72 h, and the reaction yield is as low as 2 to 30% because of the incomplete depolymerization of formagene. The method adopts formalin to replace formagene, making the reaction time as short as 10 to 30 min and the reaction yield as high as more than 80%.
Description
Technical field
The present invention relates to 6-bromo-2-methyl sulphonyl-1,2,3,4, a kind of synthesis technology of-tetrahydroisoquinoline improves, and belongs to medicine, chemical technology field.
Background technology
6-bromo-2-methyl sulphonyl-1,2,3,4 ,-tetrahydroisoquinoline are a kind of medicine intermediates of great use.Bromine can connect the new compound of formation through various types of linked reactions with other compound; Amino protection base methylsulfonyl also is good leavings group, can generate amino or amide compound with chemical compound lot; Or both connect different groups respectively and can form various compounds especially.
Existing method mainly is to be raw material with 3-bromo-phenylethylamine, and obtains obtaining 6-bromo-2-methyl sulphonyl-1,2,3,4 ,-tetrahydroisoquinoline with polyformaldehyde reaction behind N-(the 3 bromobenzene ethyl) Toluidrin after the methylsulfonyl chloride reaction.But in the time of this method N-(3 bromobenzene ethyl) Toluidrin and polyformaldehyde reaction, time long (72 hours), reaction yield low (20-30% yield), aftertreatment trouble (needing column chromatography).Given this, be necessary prior art is improved, to overcome the deficiency that it exists.
Summary of the invention
Not enough to prior art, the inventive method replaces Paraformaldehyde 96 with formaldehyde solution, solved the incomplete drawback of Paraformaldehyde 96 depolymerization after, reaction times short (5-10 minute), reaction yield high (more than 80%), aftertreatment simple (recrystallization gets final product).
6-bromo-2-methyl sulphonyl-1,2,3,4 according to the invention, the compound method of-tetrahydroisoquinoline like chemical formula (1), begins from facile 3-bromo-phenylethylamine.In methylene dichloride, do alkali with triethylamine, obtain N-(3 bromobenzene ethyl) Toluidrin with the Methanesulfonyl chloride reaction; In the mixing solutions of N-(3 bromobenzene ethyl) Toluidrin vitriolization and acetic acid; Low temperature obtains the 6-bromo-2-methyl sulphonyl-1,2 of high yield, 3 down with the formalin reaction; 4 ,-tetrahydroisoquinoline.
Chemical formula (1)
The practical implementation instance:
Like chemical formula (1), compound 2 synthetic
(30.5g 152mmol) is dissolved in methylene dichloride (400ml) to the 3-Bretylium Tosylate, is cooled to 0 ℃; Add 46.5ml triethylamine (2.2 equivalent), drip 13.1ml methylsulfonyl chloride (1.1 equivalent) then, add and slowly be raised to room temperature; React adding 200ml methylene dichloride after 3 hours, use saturated ammonium chloride solution (200ml) successively, anhydrous magnesium sulfate drying is used in saturated nacl aqueous solution (200ml) washing back; Filtration obtains 43 gram N-(3 bromobenzene ethyl) Toluidrins, yield 100% after revolving and steaming methylene dichloride.Directly be used for next step reaction.
Like chemical formula (1), 6-bromo-2-methyl sulphonyl-1,2,3,4 ,-tetrahydroisoquinoline synthetic
The mixing solutions of sulfuric acid (150ml) and acetic acid (100ml) is cooled to 0 ℃, and (10 grams 36mmol), drip 40% formalin (6ml after stirring to add N-(3 bromobenzene ethyl) Toluidrin; 2 equivalents), add and remove ice-water bath, be raised to room temperature; Silica-gel plate chromatography detection reaction raw material is carefully poured in the frozen water after finishing, and filters and collects precipitate, and washing (20ml) obtains white solid one time; Obtain white solid product 6-bromo-2-methyl sulphonyl-1,2,3 with re-crystallizing in ethyl acetate after the vacuum-drying; 4 ,-tetrahydroisoquinoline 8.2 grams, yield 80%.
Claims (3)
1. it mainly is from the synthetic 6-bromo-2-methyl sulphonyl-1,2,3,4 of N-(3 bromobenzene ethyl) Toluidrin, this step of-tetrahydroisoquinoline that 6-bromo-2-methyl sulphonyl-1,2,3,4 according to the invention, the compound method of-tetrahydroisoquinoline improve.It is characterized in that N-(3 bromobenzene ethyl) Toluidrin is dissolved in a kind of nitration mixture, be cooled to certain temperature after, drip the aqueous solution of formaldehyde; Add and be warmed up to room temperature, the reaction certain hour after again aftertreatment obtain 6-bromo-2-methyl sulphonyl-1,2; 3,4 ,-tetrahydroisoquinoline.Wherein, nitration mixture can be sulfuric acid/acetate, phosphoric acid/acetate etc., but not only refer to these two kinds.
2. certain temperature is meant that-30 spend between 50 degree.
3. formalin can be the formalin of any concentration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104434913A CN102659675A (en) | 2011-12-27 | 2011-12-27 | Synthetic method for 6- bromo-2-methyl sulfonyl-1,2,3,4,-tetrahydroisoquinoline |
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| CN2011104434913A CN102659675A (en) | 2011-12-27 | 2011-12-27 | Synthetic method for 6- bromo-2-methyl sulfonyl-1,2,3,4,-tetrahydroisoquinoline |
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| CN102659675A true CN102659675A (en) | 2012-09-12 |
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| CN2011104434913A Pending CN102659675A (en) | 2011-12-27 | 2011-12-27 | Synthetic method for 6- bromo-2-methyl sulfonyl-1,2,3,4,-tetrahydroisoquinoline |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103102304A (en) * | 2013-01-19 | 2013-05-15 | 安徽师范大学 | Preparation method of N-sulfonyl substituted tetrahydroisoquinoline derivatives |
| CN103694170A (en) * | 2013-04-01 | 2014-04-02 | 常州夏青化工有限公司 | Synthetic method of 6,7-difluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride |
| CN106957255A (en) * | 2017-03-28 | 2017-07-18 | 上海馨远医药科技有限公司 | Methylisoindoline of 5 bromines of one kind (R) N Boc 1 and its preparation method and application |
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| CN1768041A (en) * | 2003-04-04 | 2006-05-03 | 麦克公司 | Acylated spiropiperidine derivatives as the melanocortin-4 receptor agonist |
| WO2006108709A1 (en) * | 2005-04-11 | 2006-10-19 | Glaxo Group Limited | 3-sulfonylamino-pyrrolidine-2-one derivatives as factor xa inhibitors |
| CN101663278A (en) * | 2007-02-02 | 2010-03-03 | Irm责任有限公司 | It is used as the compound and composition of GPR119 activity regulation agent |
Non-Patent Citations (6)
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| 《Tetrahedron Letters》 20010903 Su-Dong Cho,等 Regioselectivity of Pictet-Spengler cyclization: synthesis of halotetrahydroisoquinolines 第6251-6253页 1-3 第42卷, 第36期 * |
| 《Tetrahedron Letters》 20060717 Jian Liu,等 Preparation of 2,3-dihydro-1H-spiro[isoquinoline-4,4"-piperidine] via an N-sulfonyl Pictet-Spengler reaction 第5115-5117页 1-3 第47卷, 第29期 * |
| JIAN LIU,等: "Preparation of 2,3-dihydro-1H-spiro[isoquinoline-4,4"-piperidine] via an N-sulfonyl Pictet–Spengler reaction", 《TETRAHEDRON LETTERS》 * |
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| 倪峰,等: "用N-磺酰基Pictet-Spengler反应合成1,2,3,4-四氢异喹啉", 《合成化学》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103102304A (en) * | 2013-01-19 | 2013-05-15 | 安徽师范大学 | Preparation method of N-sulfonyl substituted tetrahydroisoquinoline derivatives |
| CN103102304B (en) * | 2013-01-19 | 2015-03-11 | 安徽师范大学 | Preparation method of N-sulfonyl substituted tetrahydroisoquinoline derivatives |
| CN103694170A (en) * | 2013-04-01 | 2014-04-02 | 常州夏青化工有限公司 | Synthetic method of 6,7-difluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride |
| CN103694170B (en) * | 2013-04-01 | 2016-04-06 | 常州夏青化工有限公司 | The fluoro-1-methyl isophthalic acid of 6,7-bis-, the synthetic method of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt |
| CN106957255A (en) * | 2017-03-28 | 2017-07-18 | 上海馨远医药科技有限公司 | Methylisoindoline of 5 bromines of one kind (R) N Boc 1 and its preparation method and application |
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Application publication date: 20120912 |