CN104163790A - Preparation technique of 2-amino-4-methyl-5-bromopyridine - Google Patents
Preparation technique of 2-amino-4-methyl-5-bromopyridine Download PDFInfo
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- CN104163790A CN104163790A CN201410406851.6A CN201410406851A CN104163790A CN 104163790 A CN104163790 A CN 104163790A CN 201410406851 A CN201410406851 A CN 201410406851A CN 104163790 A CN104163790 A CN 104163790A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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Abstract
The invention discloses a preparation technique of 2-amino-4-methyl-5-bromopyridine. The technique comprises the following steps: dissolving 2-amino-4-methylpyridine using as a raw material in DMF (N,N-dimethylformamide) or acetonitrile in an ice bath, slowly adding NBS (N-bromosuccinimide) in batches or dropwisely adding an NBS solution, reacting at 0-50 DEG C for 8-10 hours, pouring the reaction solution into water, filtering, washing with water, filtering, drying, stirring and washing with acetonitrile, filtering and drying. The technique can selectively obtain the 2-amino-4-methyl-5-bromopyridine, has the advantages of wide controllable range of reaction temperature, simple and feasible after-treatment and high yield (up to 80%), and is an economical and efficient synthesis technique.
Description
Technical field
The present invention relates to the preparation technology of a kind of 2-amino-4-methyl-5 bromopyridine.
Background technology
Many bioactive moleculess comprise pyridine structure framework, many natural products also contain pyridine structure, 2-amino-4-methyl-5 bromopyridine is as a kind of pyridine derivate wherein, utilize the Br of 5, can synthesize numerous compounds by cross-coupling by reactions such as Stille/Suzuki, Heck, Sonogashira, at present, 2-amino-4-methyl-5 bromopyridine is synthetic for natural product and pharmaceutical intermediate mainly as intermediate, is also widely used in addition in novel material synthetic.
While preparing 2-amino-4-methyl-5 bromopyridine with 2-AMINO-4-PICOLINE at present, adopt Br
2, HBr or C5H6Br2N2O2 (DBDMH) etc. be as bromine source.
By bromine glacial acetic acid condition, after completion of the reaction, need distillation to remove most glacial acetic acid, in this process, because distillation temperature is higher, very easily produce 2-amino-4-methyl-2,5 dibromo pyridine by products, and yield is general; HBr is during as bromine source, and temperature of reaction is more than 70 DEG C, and yield only reaches 41%, has 2-amino-4-methyl-2 bromopyridine and 2-amino-4-methyl-2, and 5 dibromo pyridine by products generate, and need later separation; C5H6Br2N2O2 is during as bromine source, and temperature of reaction is-45 DEG C, and yield is 82%.This reaction is carried out at low temperatures, and energy consumption is high, and tests confirmation through us, and this condition mainly generates 2-amino-4-methyl-2, the two bromination products of 5 dibromo pyridines; With NaBr and NaBrO
3during for bromine source, temperature of reaction is 5-10 DEG C, and reaction is finished, and adjusts after reaction solution pH value, through extraction, dry, concentrating under reduced pressure and obtain product through column chromatography purification.Yield is 81%, and the method last handling process is loaded down with trivial details, and column chromatography method is applicable to the purifying of a small amount of product, belongs to the method for laboratory separation and purification.
Summary of the invention
The technical problem to be solved in the present invention is: the preparation technology that a kind of 2-amino-4-methyl-5 bromopyridine is provided, to solve prior art in the time preparing 2-amino-4-methyl-5 bromopyridine, the problems such as temperature of reaction condition is higher, and by product is many, yield is general, aftertreatment is loaded down with trivial details.
Technical scheme of the present invention: the preparation technology of a kind of 2-amino-4-methyl-5 bromopyridine, under ice bath, after 2-AMINO-4-PICOLINE is dissolved in DMF or acetonitrile, slowly add NBS in batches or drip NBS solution, control temperature of reaction 0-50 DEG C, reaction 8-10h, reaction solution is poured into water, filter, washing, filters, dry, stir and wash with acetonitrile, filter, be drying to obtain.
Crude product adds the acetonitrile of 4 times of amounts to pull an oar to be purified.
Beneficial effect of the present invention: the present invention is brominated reagent by using NBS, can optionally obtain the single bromination product in 5-position, temperature of reaction is 0-50 DEG C, and yield can reach 80%, without 2-amino-4-methyl-3 bromopyridine and 2-amino-4-methyl-3,5 dibromo pyridines generate.The present invention is ensureing in high yield, solved that existing method by product is many, the problem of temperature of reaction condition harshness and aftertreatment complexity.Because temperature of reaction is at 0-50 DEG C, temperature range is large, simple and easy to do, and preparation cost is low.Product yield and the highest method of existing yield maintain an equal level.
This technique under high reaction temperature, obtain a large amount of 3, two bromination product 2-amino-4-methyl-3,5-position, 5 dibromo pyridines, so the temperature of reaction in this technique plays key effect to the acquisition of product.
Embodiment
Embodiment 1
Under condition of ice bath, 2-AMINO-4-PICOLINE (30g, 277.8mmol) is dissolved in to DMF(150ml) in, slowly add NBS(49.44g, 277.8mmol in batches), 0 DEG C of reaction 8-10h.TLC detects, and reacts completely.Reaction solution is poured into water, has brown solid to separate out, filtration, washing, filters, dry, stirs and washes with acetonitrile (148ml), filters, and is dried to obtain brown solid (37g, 70%).
Product mass spectrometric detection result: 1HNMR:(400Hz, CDCl3 δ 2.277 (S, 3H); 4.481 (S, 2H); 6.406 (S, 1H); 8.078 (S, 1H); Mass Spec 188 (m+1).
Embodiment 2
Under condition of ice bath, 2-AMINO-4-PICOLINE (30g, 277.8mmol) is dissolved in to DMF(150ml) in, slowly add NBS(49.44g, 277.8mmol in batches), 10 DEG C of reaction 8-10h.TLC detects, and reacts completely.Reaction solution is poured into water, has brown solid to separate out, filtration, washing, filters, dry, stirs and washes with acetonitrile (154ml), filters, and is dried to obtain brown solid (39g, 74.6%).
Product mass spectrometric detection result: 1HNMR:(400Hz, CDCl3) δ 2.277 (S, 3H); 4.481 (S, 2H); 6.406 (S, 1H); 8.078 (S, 1H); Mass Spec 188 (m+1).
Embodiment 3
Under condition of ice bath, 2-AMINO-4-PICOLINE (30g, 277.8mmol) is dissolved in to DMF(150ml) in, slowly add NBS(49.44g, 277.8mmol in batches), 20 DEG C of reaction overnight.TLC detects, and reacts completely.Reaction solution is poured into water, has brown solid to separate out, filtration, washing, filters, dry, stirs and washes with acetonitrile (161ml), filters, and is dried to obtain brown solid (41g, 78%).
Product mass spectrometric detection result: 1HNMR:(400Hz, CDCl3) δ 2.277 (S, 3H); 4.481 (S, 2H); 6.406 (S, 1H); 8.078 (S, 1H); Mass Spec 188 (m+1).
Embodiment 4
Under condition of ice bath, 2-AMINO-4-PICOLINE (30g, 277.8mmol) is dissolved in to DMF(150ml) in, slowly add NBS(49.44g, 277.8mmol in batches), 30 DEG C of reaction 8-10h.TLC detects, and reacts completely.Reaction solution is poured into water, has brown solid to separate out, filtration, washing, filters, dry, stirs and washes with acetonitrile (164ml), filters, and is dried to obtain brown solid (42g, 80%).
Product mass spectrometric detection result: 1HNMR:(400Hz, CDCl3) δ 2.277 (S, 3H); 4.481 (S, 2H); 6.406 (S, 1H); 8.078 (S, 1H); Mass Spec 188 (m+1).
Embodiment 5
Under condition of ice bath, 2-AMINO-4-PICOLINE (30g, 277.8mmol) is dissolved in to DMF(150ml) in, slowly add NBS(49.44g, 277.8mmol in batches), 50 DEG C of reaction 8-10h.TLC detects, and reacts completely.Reaction solution is poured into water, has brown solid to separate out, filtration, washing, filters, dry, stirs and washes with acetonitrile (155ml), filters, and is dried to obtain brown solid (39g, 75%).
Product mass spectrometric detection result: 1HNMR:(400Hz, CDCl3) δ 2.277 (S, 3H); 4.481 (S, 2H); 6.406 (S, 1H); 8.078 (S, 1H); Mass Spec 188 (m+1).
Embodiment 6
Under condition of ice bath, 2-AMINO-4-PICOLINE (30g, 277.8mmol) is dissolved in acetonitrile (150ml), slowly adds NBS(49.44g, 277.8mmol in batches), 20 DEG C of reaction overnight.TLC detects, and reacts completely.There is solid to separate out, filtration, washing, filters, dry, stirs and washes with acetonitrile (158ml), filters, and is dried to obtain brown solid (40g, 77%).
Product mass spectrometric detection result: 1HNMR:(400Hz, CDCl3) δ 2.277 (S, 3H); 4.481 (S, 2H); 6.406 (S, 1H); 8.078 (S, 1H); Mass Spec 188 (m+1).
Embodiment 7
Under condition of ice bath, 2-AMINO-4-PICOLINE (30g, 277.8mmol) is dissolved in to DMF(150ml) in, drip NBS solution (49.44g, 277.8mmol), 20 DEG C of reaction 8-10h.TLC detects, and reacts completely.Reaction solution is poured into water, has brown solid to separate out, filtration, washing, filters, dry, stirs and washes with acetonitrile (164ml), filters, and is dried to obtain brown solid (42g, 80%).
Product mass spectrometric detection result: 1HNMR:(400Hz, CDCl3) δ 2.277 (S, 3H); 4.481 (S, 2H); 6.406 (S, 1H); 8.078 (S, 1H); Mass Spec 188 (m+1).
Claims (2)
1. a preparation technology for 2-amino-4-methyl-5 bromopyridine, is characterized in that: under ice bath, after 2-AMINO-4-PICOLINE is dissolved in DMF or acetonitrile, slowly add NBS in batches or drip NBS solution, control temperature of reaction 0-50 DEG C, reaction 8-10h, reaction solution is poured into water, filter, washing, filters, dry, stir and wash with acetonitrile, filter, be drying to obtain.
2. the preparation technology of a kind of 2-amino-4-according to claim 1 methyl-5 bromopyridine, is characterized in that: crude product adds the acetonitrile of 4 times of amounts to pull an oar to be purified.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101128461A (en) * | 2005-02-24 | 2008-02-20 | 伊莱利利公司 | Imidazo (1, 2-a) pyridine compounds as VEGF-R2 inhibitors |
| CN101863830A (en) * | 2010-06-22 | 2010-10-20 | 浙江科源化工有限公司 | Synthesis method of 2-amino-5-bromine isonicotinic acid |
| CN102898358A (en) * | 2012-10-24 | 2013-01-30 | 上海泰坦科技有限公司 | Preparation method of fluoropyridine compounds |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101128461A (en) * | 2005-02-24 | 2008-02-20 | 伊莱利利公司 | Imidazo (1, 2-a) pyridine compounds as VEGF-R2 inhibitors |
| CN101863830A (en) * | 2010-06-22 | 2010-10-20 | 浙江科源化工有限公司 | Synthesis method of 2-amino-5-bromine isonicotinic acid |
| CN102898358A (en) * | 2012-10-24 | 2013-01-30 | 上海泰坦科技有限公司 | Preparation method of fluoropyridine compounds |
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Denomination of invention: Preparation process of 2-amino-4-methyl-5-bromopyridine Effective date of registration: 20211103 Granted publication date: 20160210 Pledgee: Guiyang Jinyang sub branch of China Construction Bank Co.,Ltd. Pledgor: GUIZHOU WYLTON JINGLIN ELECTRONIC MATERIAL CO.,LTD. Registration number: Y2021520000016 |
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Date of cancellation: 20230704 Granted publication date: 20160210 Pledgee: Guiyang Jinyang sub branch of China Construction Bank Co.,Ltd. Pledgor: GUIZHOU WYLTON JINGLIN ELECTRONIC MATERIAL CO.,LTD. Registration number: Y2021520000016 |
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