CN102702196A - Method for synthesizing 3-methyl-7-diazaindene - Google Patents
Method for synthesizing 3-methyl-7-diazaindene Download PDFInfo
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- CN102702196A CN102702196A CN2012101940513A CN201210194051A CN102702196A CN 102702196 A CN102702196 A CN 102702196A CN 2012101940513 A CN2012101940513 A CN 2012101940513A CN 201210194051 A CN201210194051 A CN 201210194051A CN 102702196 A CN102702196 A CN 102702196A
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- FSWWVCUJRHZKEU-UHFFFAOYSA-N CC(C)(C)OC(Nc1nc(C)ccc1C)=O Chemical compound CC(C)(C)OC(Nc1nc(C)ccc1C)=O FSWWVCUJRHZKEU-UHFFFAOYSA-N 0.000 description 1
- 0 CCc1c(N=C(O[*+])OC(C)(C)C)nccc1 Chemical compound CCc1c(N=C(O[*+])OC(C)(C)C)nccc1 0.000 description 1
- PKZDPOGLGBWEGP-UHFFFAOYSA-N Cc1c[nH]c2ncccc12 Chemical compound Cc1c[nH]c2ncccc12 PKZDPOGLGBWEGP-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to the field of synthesis of medicinal intermediates, in particular to a method for synthesizing 3-methyl-7-diazaindene. The method is characterized by comprising the following steps of: making 7-diazaindene and methenamine serving as raw materials react with each other to obtain a compound VIII; and reacting the compound VIII under the action of a reducing agent. Due to the adoption of the synthesizing method, the total yield can be up to 81.6 percent. The reaction conditions are mild, post-treatment is easy, and a pure product is obtained. Compared with literatures, the yield is low, and is about 45 percent. Moreover, steps are long. The method is more suitable for large-scale preparation.
Description
Technical field
The present invention relates to the synthetic field of pharmaceutical intermediate, be specifically related to the compound method of 3-methyl-7-azaindole (I).
Background technology
3-methyl-7-azaindole is a kind of very useful as intermediates.The indoles parent nucleus is the important structure of the natural compounds and the synthetic medicine of many biologically actives.3 substituted compounds of carbon of indoles are one type of very important cns class medicines, especially for the treatment of nervous system disease.Though the report of the compound method of existing a lot of relevant indoles, these methods lack practicality usually.
For the preparation of 3-methyl-7-azaindole, the bibliographical information related methods of synthesis is following:
Method is by Synthesis, (7), 877-882; 1996 reports, as follows:
Reagent and condition: (a) tert-Butyl dicarbonate, ETHYLE ACETATE (EA)/normal hexane, yield: 84%; (b) n-BuLi, THF (THF); (c) CH3I, two step yields: 73%; (d) n-BuLi, N, dinethylformamide (DMF), yield: 74%.
Not enough below this compound method exists: step is long, and total recovery is low: 45.3%; Be not easy purifying, need column chromatography in the d step after, recrystallization just can obtain pure article again; There were two steps to relate to the low-temp reaction of the anhydrous and oxygen-free of butyllithium in addition in the synthesis step; Therefore this method does not possess the feasibility of mass preparation.
Method is by J.Phys.Chem., and 106 (35), 8006-8012; Report in 2002 and J.Am.Chem.Soc.77,457 (1955), as follows:
Reagent and condition: (e) (CH
2O) x, Me
2NH.HCl; (f) (CH
2)
6N
4(g) sodium acetate (AcONa); (h) Na, (HOCH
2CH
2)
2O, yield: 55%.
Not enough below this compound method exists: route is long, and total recovery is low, needs column chromatography during purifying, does not possess the feasibility of mass preparation.
Method is by Angewandte Chemie, International Edition, 47 (5), 888-890; 2008 reports, as follows:
Reagent and condition: (i) three (dibenzalacetone) two palladium (Pd
2Dba
3), 1,1 '-two (diphenylphosphine) ferrocene (dppf), NaOtBu, toluene, yield: 37%.
Not enough below this compound method exists: catalyzer is relatively more expensive, and yield is low, needs column chromatography to carry out purifying, does not possess the feasibility of mass preparation.
Summary of the invention
The purpose of this invention is to provide a kind of efficient, compound method of possessing 3-methyl-7-azaindole that mass preparation is worth.Mainly solve existing 3-methyl-7-azaindole prepare that yield is low in the route, reagent is expensive, be difficult to purifying, can't scale operation etc. technical problem.
Preparing method of the present invention is a raw material reaction with 7-azaindole and urotropine, reduces again, obtains compound I.
Reaction formula is following:
When preparing compound VIII by compound VI and urotropine, reaction is preferably carried out under acidic conditions.
Preferred acetic acid of acid or hydrochloric acid.The concentration of acid can be 12%～40%.
Reductive agent is preferably lithium aluminum hydride or Peng Qinghuana-trifluoroacetic acid.
Preparing in the compound I step by compound VIII, the mol ratio of compound VIII and reductive agent is preferably 1.0: 0.25～and 1.0: 3.0.
Prepare in the compound I step preferred THF of reaction solvent or ether by compound VIII.Reaction finishes the back and carries out cancellation with the NaOH aqueous solution.
Total recovery can reach 81.6% among the present invention.The starting material and the reagent cost that use are cheap, and reaction conditions is gentle, and aftertreatment is simple, is very easy to obtain pure article.And yield is not high in the documents, about 45%, and also step is long.So present method is more suitable for mass preparation.
Embodiment
Embodiment 1
Synthesizing of compound VIII:
Add in the 2L four-hole bottle compound VI (118.14g, 1.0mol, 1.0eq.), urotropine (HMTA) (196.27g, 1.4mol, 1.4eq.), 300mL AcOH, 600mL H
2O is heated to backflow, and reaction is spent the night.Question response liquid is cooled to room temperature, has a large amount of solids to separate out, suction filtration, and the filter cake washing gets white solid 123.3g, yield: 85% after the oven dry.
1H?NMR(400MHz，DMSO-d
6)δ(ppm)12.68（s，1H），9.92(s，1H)，8.47(s，1H)，8.39(dd，J＝1.6，7.8Hz,1H)，8.37(dd，J＝1.6，4.7Hz,1H)，7.26-7.29(dd，J＝4.7，7.8Hz,1H)。
Synthesizing of compound I
In the 3L four-hole bottle, (115.9g, 0.79mol 1.0eq.) are dissolved in 2LTHF, slowly add LiAlH under the room temperature in batches with compound VIII
4(15.0g, 0.395mol 0.5eq.), have great amount of bubbles to produce, and control reaction temperature finishes less than 50 ℃, and back flow reaction is spent the night.Question response is cooled to room temperature, in reaction solution, adds 15mL H successively
2O, 15mL 15% NaOH solution, 30mL H
2O, filtrating use anhydrous sodium sulfate drying, and revolving behind the dried solvent must faint yellow solid 99.6g, yield 96%, purity: 99%.
1H?NMR(400MHz，CDCl
3)δ(ppm)9.86(bs，1H)，8.31(dd，J＝1.6，4.8Hz，1H)，7.94(dd，J＝1.4，7.6Hz，1H)，7.13(s，1H)，7.12(dd，J＝4.4，8.0Hz，1H)，2.35(s,3H)。
Embodiment 2
Synthesizing of compound VIII:
Add in the 1L four-hole bottle compound VI (59.07g, 0.5mol, 1.0eq.), urotropine (HMTA) (105.1g, 0.75mol, 1.5eq.), 100mL hydrochloric acid, 200mL H
2O is heated to backflow, and reaction is spent the night.Question response liquid is cooled to room temperature, regulates the pH value to alkalescence with saturated aqueous sodium carbonate, has a large amount of solids to separate out, suction filtration, and the filter cake washing gets white solid 56.5g, yield: 78% after the oven dry.
1H?NMR(400MHz，DMSO-d
6)δ(ppm)12.68（s，1H），9.92(s，1H)，8.47(s，1H)，8.39(dd，J＝1.6，7.8Hz,1H)，8.37(dd，J＝1.6，4.7Hz,1H)，7.26-7.29(dd，J＝4.7，7.8Hz,1H)。
Synthesizing of compound I
In the 1L four-hole bottle, (29.3g, 0.2mol 1.0eq.) are dissolved in the 500mL ether, slowly add NaBH under the room temperature in batches with compound VIII
4(30.2g, 0.8mol 4.0eq.), add the back and stir 2h; Again trifluoroacetic acid (TFA) (50mL) is dripped in reaction solution, reaction 2h, raw material reaction finishes, and in reaction solution, slowly adds 50mL25%NaOH solution; Use ethyl acetate extraction, organic phase is used brine wash, uses anhydrous sodium sulfate drying; Get faint yellow solid 23.4g, yield after revolving dried solvent: 89.9%, purity: 99%.
1H?NMR(400MHz，CDCl
3)δ(ppm)9.86(bs，1H)，8.31(dd，J＝1.6，4.8Hz，1H)，7.94(dd，J＝1.4，7.6Hz，1H)，7.13(s，1H)，7.12(dd，J＝4.4，8.0Hz，1H)，2.35(s,3H)。
Claims (6)
1. the preparation method of a compound I comprises:
2. the preparation method of claim 1 when preparing compound VIII by compound VI and urotropine, is reflected under the acidic conditions and carries out.
3. the preparation method of claim 2, wherein acid is acetic acid or hydrochloric acid.
4. the preparation method of claim 1, wherein reductive agent is lithium aluminum hydride or Peng Qinghuana-trifluoroacetic acid.
5. the preparation method of claim 1 is prepared in the compound I step by compound VIII, and the mol ratio of compound VIII and reductive agent is 1.0: 0.25～1.0: 3.0.
6. the preparation method of claim 1 is prepared in the compound I step by compound VIII, and reaction solvent is THF or ether.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279154A (en) * | 2016-08-02 | 2017-01-04 | 叶芳 | A kind of preparation method of 7 azaindole 3 formaldehyde |
| CN112409353A (en) * | 2020-11-27 | 2021-02-26 | 苏州艾缇克药物化学有限公司 | Preparation method of 7-azaindole derivative |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100378097C (en) * | 2003-05-09 | 2008-04-02 | 弗·哈夫曼-拉罗切有限公司 | Methyl indoles and methyl pyrrolopyridines as alph-1 adrenergic agonists |
| US20100061982A1 (en) * | 2008-09-10 | 2010-03-11 | Wyeth | 3-substituted-1h-indole, 3-substituted-1h-pyrrolo[2,3-b]pyridine and 3-substituted-1h-pyrrolo[3,2-b]pyridine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their syntheses |
| CN102171210A (en) * | 2008-08-05 | 2011-08-31 | 第一三共株式会社 | Imidazopyridin-2-on derivative |
-
2012
- 2012-06-13 CN CN201210194051.3A patent/CN102702196B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100378097C (en) * | 2003-05-09 | 2008-04-02 | 弗·哈夫曼-拉罗切有限公司 | Methyl indoles and methyl pyrrolopyridines as alph-1 adrenergic agonists |
| CN102171210A (en) * | 2008-08-05 | 2011-08-31 | 第一三共株式会社 | Imidazopyridin-2-on derivative |
| US20100061982A1 (en) * | 2008-09-10 | 2010-03-11 | Wyeth | 3-substituted-1h-indole, 3-substituted-1h-pyrrolo[2,3-b]pyridine and 3-substituted-1h-pyrrolo[3,2-b]pyridine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their syntheses |
Non-Patent Citations (6)
| Title |
|---|
| 《Angew. Chem. Int. Ed.》 20081231 Thomas Jensen,et al. "Palladium-Catalyzed Aryl Amination-Heck Cyclization Cascade: A One-Flask Approach to 3-Substituted Indoles" 第888-890页 1-6 第47卷, * |
| 《J. Phys. Chem. A》 20060407 Javier Catalan，et al. "Excited State Proton Transfer in 3-Methyl-7-Azaindole Dimer. Symmetry Control" 第9116-9122页 1-6 第110卷, 第29期 * |
| 《Journal of the American Chemical Society》 19550120 Robison, Michael M. et al. "7-Azaindole. I. Synthesis and Conversion to 7-Azatryptophan and Other Derivatives" 第457-460页 1-6 第77卷, * |
| JAVIER CATALAN，ET AL.: ""Excited State Proton Transfer in 3-Methyl-7-Azaindole Dimer. Symmetry Control"", 《J. PHYS. CHEM. A》, vol. 110, no. 29, 7 April 2006 (2006-04-07), pages 9116 - 9122 * |
| ROBISON, MICHAEL M. ET AL.: ""7-Azaindole. I. Synthesis and Conversion to 7-Azatryptophan and Other Derivatives"", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》, vol. 77, 20 January 1955 (1955-01-20), pages 457 - 460 * |
| THOMAS JENSEN,ET AL.: ""Palladium-Catalyzed Aryl Amination–Heck Cyclization Cascade: A One-Flask Approach to 3-Substituted Indoles"", 《ANGEW. CHEM. INT. ED.》, vol. 47, 31 December 2008 (2008-12-31), pages 888 - 890 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279154A (en) * | 2016-08-02 | 2017-01-04 | 叶芳 | A kind of preparation method of 7 azaindole 3 formaldehyde |
| CN112409353A (en) * | 2020-11-27 | 2021-02-26 | 苏州艾缇克药物化学有限公司 | Preparation method of 7-azaindole derivative |
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Address after: 210061 Nanjing high tech Industrial Development Zone, Jiangsu Province Road, No. 10 Patentee after: PHARMABLOCK (NANJING) R&D CO., LTD. Address before: 210061 Nanjing high tech Industrial Development Zone, Jiangsu Province Road, No. 10 Patentee before: Nanjing Medical Stone and Medicine Research and Development Co., Ltd. |