CN103755627A - Synthesis method for 2-amino-3-hydroxyl-5-chloropyridine - Google Patents
Synthesis method for 2-amino-3-hydroxyl-5-chloropyridine Download PDFInfo
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- CN103755627A CN103755627A CN201410009851.2A CN201410009851A CN103755627A CN 103755627 A CN103755627 A CN 103755627A CN 201410009851 A CN201410009851 A CN 201410009851A CN 103755627 A CN103755627 A CN 103755627A
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- 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
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- C07D213/73—Unsubstituted amino or imino radicals
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Abstract
The invention belongs to the field of organic synthesis and particularly relates to a synthesis method for 2-amino-3-hydroxyl-5-chloropyridine. The synthesis method for the 2-amino-3-hydroxyl-5-chloropyridine comprises the following steps: reacting oxazole[4,5-b]pyridine-2(3H)ketone and NCS (N-chlorosuccinimide) in a suitable solvent at a suitable temperature to generate 6-chlorooxazole[4,5-b]pyridine-2(3H)ketone; and then carrying out alkalization hydrolysis to generate the 2-amino-3-hydroxyl-5-chloropyridine. The synthesis method has the beneficial effects that the raw materials are easily available and are convenient to transport and store as being solids; meanwhile, in the reaction, heavy metal and corrosive gas are not used, the reaction is moderate, special requirements on reaction equipment do not exist and common corrosion-resisting equipment can be used for producing; furthermore, the reaction time is moderate, the reaction is easy to control, the post-treatment is simple, the product purity is high, the production cost is low and the synthesis method is easy to popularize and apply.
Description
Technical field
The invention belongs to organic synthesis field, particularly a kind of synthetic method of 2-amino-3-hydroxyl-5-chloropyridine.
Background technology
The derivative of pyridine is as chemical industry, and particularly the important source material of fine chemistry industry, is of wide application.Relate to new drug development, medicine intermediate, pharmaceutical products, agricultural chemicals research and development, pesticide intermediate, agricultural chemicals, feed and feedstuff raw material and other multinomial field.The pyridine derivate that polyfunctional group replaces has even more important using value.2-amino-3-hydroxyl-5-chloropyridine You Sige functional group for example, they are respectively-Cl ,-OH ,-NH
2with the nitrogen on pyridine ring.For example, 2-amino-3-hydroxyl-5-chloropyridine reacts with methylating reagent and generates 2-amino-3-methoxyl group-5-chloropyridine, then with the chloro-8-methoxyl group of corresponding alpha-bromo ketogenesis 6-imidazo [1,2-a] derivative of pyridine, the latter is used to research (the PCT Int. Appl. of kinases PIK3,2012007345,19 Jan 2012).The product that 2-amino-3-methoxyl group-5-chloropyridine reacts with oxine etc. has been used to the development research (U.S. Pat. Appl. Publ., 20110301193,08 Dec 2011) of medicine.2-amino-3-hydroxyl-5-chloropyridine reacts and generates 2-amino-3-phenyl-5-chloropyridine and 2-amino-3-benzyl-5-chloropyridine with corresponding halobenzene or cylite, and they have been respectively used to the activation of glucokinase and the research that selectivity is secreted plasma urokinase-type plasminogen activator.
Summary of the invention
The present invention, in order to make up the defect of prior art, provides a kind of synthetic method that is suitable for the synthetic 2-amino-3-hydroxyl-5-chloropyridine of industrialization
The present invention is achieved through the following technical solutions:
A synthetic method for 2-amino-3-hydroxyl-5-chloropyridine, is characterized in that, comprises the following steps:
(1). with oxazole [4,5-b] pyridine-2 (3H)-one and N-chlorosuccinimide be raw material, in solvent, in 10 ~ 120 ℃ of thermotonuses, within 1 ~ 36 hour, generates also [4,5-b] pyridin-2-ones of the chloro-3H-oxazole of 6-, after purifying, obtain also [4,5-b] pyridin-2-ones of the chloro-3H-oxazole of sterling 6-;
(2). ketone heating hydrolysis under suitable alkali effect in 6-chlorine oxazole [4,5-b] pyridine-2 (3H) generates 2-amino-3-hydroxyl-5-chloropyridine sodium salt, obtains product 2-amino-3-hydroxyl-5-chloropyridine after purifying.
In described step (1), solvent is methylene dichloride, the mixture of acetonitrile and Glacial acetic acid, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), N, any one material in N-dimethyl acetyl ammonia (DMA) or N-Methyl pyrrolidone (NMP).
In described step (1), the charging capacity of reactant and solvent is oxazole [4,5-b] pyridine-2 (3H)-one: N-chlorosuccinimide: solvent=5:6 ~ 6.3:30 ~ 34 are more than weight ratio.
In described step (1), reaction conditions is at 20 ~ 90 ℃, to react 6 ~ 24 hours.
In described step (1), purification step comprises successively and adds moisture liquid, filters washing, desiccant dryness, evaporation concentration, solvent recrystallization.
In described step (1), recrystallization solvent is ethyl acetate, ethanol, methylene dichloride, chloroform, any one in normal hexane or two kinds of materials.
In described step (2), alkali is lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, any one material in magnesium hydroxide.
In described step (2), heating hydrolysis temperature of reaction is 25 ℃ ~ 100 ℃.
In described step (2), purification step comprises acidifying, filter, and washing, dry.
In described step (2), the acid that acidifying is used refers to hydrochloric acid, sulfuric acid, phosphoric acid.
The invention has the beneficial effects as follows: raw material of the present invention is easy to get, and be solid, transportation, it is convenient to store; In simultaneous reactions, do not use heavy metal and corrosive gases, reaction temperature and, conversion unit is not had to particular requirement, common erosion resistance equipment can be produced; In addition the reaction times of the present invention moderate, reaction is easy to control, aftertreatment is simple, product purity is high, and production cost is low, is easy to apply.
Embodiment
Embodiment 1:
In three mouthfuls of round-bottomed flasks of one 250 mL, add methylene dichloride (200 mL).On there-necked flask, add a reflux condensing tube, start magnetic stirring apparatus and add oxazole [4,5-b] pyridine-2 (3H)-one (4.1 g).After oxazole [4,5-b] pyridine-2 (3H)-one is all dissolved, will add in batches N-chlorosuccinimide (4.7 g).10 ℃ of stirring reactions 4 hours, then heating reflux reaction was 12 hours.TLC and GC are definite to have reacted.Revolve and steam except desolventizing.Thick product obtains straight product 6-chlorinated oxazoline [4,5-b] pyridine-2 (3H)-one (3.14 g), productive rate 61%, purity 97.3%(GC from methylene dichloride and re-crystallizing in ethyl acetate).182 ℃ ~ 185 ℃ of fusing points (183 ℃ ~ 186 ℃, document).Nuclear magnetic resonance spectroscopy, 1H NMR (DMSO-d6) 300 MHz: δ 8.107ppm (d, J=4Hz, 1H); 7.815ppm (d, J=4Hz, 1H).
In the single necked round bottom flask of one 50 mL, add sodium hydroxide (1.68 grams, 0.042 mole) and water (20 mL).Starting magnetic stirring apparatus all dissolves sodium hydroxide.Above-mentioned gained 6-chlorinated oxazoline [4,5-b] pyridine-2 (3H)-one (3.14 grams, 0.018 mole) is joined and in reaction flask and on reaction flask, adds a reflux condensing tube.Reaction mixture is heated and refluxes 8 hours.TLC and gas chromatographic analysis show to react completely.With 12 mol/L hydrochloric acid, regulate the pH value of reaction mixture to have a large amount of precipitations to generate to 8().Filter, filter cake washes (5 milliliters) with water.Dry to obtain 1.99 grams of product 2-amino-3-hydroxyl-5-chloropyridines, productive rate 74.8%, purity 99.9% (GC).197 ℃ ~ 200 ℃ of fusing points (198 ℃ ~ 201 ℃, document).
Embodiment 2:
In three mouthfuls of round-bottomed flasks of one 10 L, add DMF(2000 mL).On there-necked flask, add a reflux condensing tube.Start mechanical stirrer and add oxazole [4,5-b] pyridine-2 (3H)-one (497g).Stirring is all dissolved oxazole [4,5-b] pyridine-2 (3H)-one.N-chlorosuccinimide (608 g) is dissolved in DMF(2500 mL) in.Then be transferred to a constant pressure funnel, slowly drip N-chlorosuccinimide in reaction flask, control temperature of reaction and be no more than 40 ℃ (use if desired frozen water cooling).After dripping, remove ice-water bath, under room temperature, stir and spend the night.With TLC and GC, follow the tracks of reaction.After question response completes, under frozen water is cooling, slowly add water 4000 mL.Stirred reaction mixture 30 minutes, filters.Filter cake washes twice with water, and vacuum-drying obtains crude product 530 g.Thick product obtains straight product 6-chlorinated oxazoline [4,5-b] pyridine-2 (3H)-one (505 g), productive rate 81%, purity 99.1%(GC from methylene dichloride and re-crystallizing in ethyl acetate).184 ℃ ~ 187 ℃ of fusing points (183 ℃ ~ 186 ℃, document).
In the single necked round bottom flask of one 5 L, add sodium hydroxide (355 grams, 8.883 moles) and water (3.5 L).Starting magnetic stirring apparatus all dissolves sodium hydroxide.Above-mentioned gained 6-chlorinated oxazoline [4,5-b] pyridine-2 (3H)-one (505 grams, 2.961 moles) is joined and in reaction flask and on reaction flask, adds a reflux condensing tube.Reaction mixture is heated and refluxes 10 hours.With TLC and GC, following the tracks of reaction shows to react completely.With 12 mol/L hydrochloric acid, regulate the pH value of reaction mixture to have a large amount of precipitations to generate to 8().Filter, filter cake washes (400 milliliters) with water.Dry to obtain 420 grams of product 2-amino-3-hydroxyl-5-chloropyridines, productive rate 98%, purity 97.9% (GC).197 ℃ ~ 202 ℃ of fusing points (198 ℃ ~ 201 ℃, document).
Embodiment 3:
In the reactor of one 50 L, add DMF(4 L).Start mechanical stirrer and add oxazole [4,5-b] pyridine-2 (3H)-one (4.97 kg).Stirring is all dissolved oxazole [4,5-b] pyridine-2 (3H)-one.N-chlorosuccinimide (6.08 kg) is dissolved in DMF(25 L) in.Then slowly drip N-chlorosuccinimide in reactor, control temperature of reaction and be no more than 40 ℃ (use if desired circulating condensing pump cooling).After dripping, under room temperature, stir and spend the night.With TLC and GC, follow the tracks of reaction.After question response completes, reaction solution is shifted in the reactor of one 100 L, under cooling, slowly add water 35 L.Stirred reaction mixture 60 minutes, filters.Filter cake washes twice with water, and vacuum-drying obtains crude product 4.95 kg.Thick product recrystallization from methylene dichloride and ethyl acetate obtains straight product 6-chlorinated oxazoline [4,5-b] pyridine-2 (3H)-one (4.76 kg), productive rate 76%, purity 99.4%(GC).183 ℃ ~ 185 ℃ of fusing points (183 ℃ ~ 186 ℃, document).
In the reactor of one 50 L, add sodium hydroxide (3.348 kilograms, 83.7 moles) and water (35 L).Starting magnetic stirring apparatus all dissolves sodium hydroxide.Above-mentioned gained 6-chlorinated oxazoline [4,5-b] pyridine-2 (3H)-one (4.76 kilograms, 27.9 moles) is joined and in reaction flask and on reaction flask, adds a reflux condensing tube.Reaction mixture is heated and refluxes 12 hours.With TLC and GC, following the tracks of reaction shows to react completely.With 12 mol/L hydrochloric acid, regulate the pH value of reaction mixture to have a large amount of precipitations to generate to 8().Filter, filter cake washes (10 liters) with water.Dry to obtain 3.90 kilograms of product 2-amino-3-hydroxyl-5-chloropyridines, productive rate 96%, purity 98.6% (GC).199 ℃ ~ 202 ℃ of fusing points (198 ℃ ~ 201 ℃, document).
Claims (10)
1. a synthetic method for 2-amino-3-hydroxyl-5-chloropyridine, is characterized in that, comprises the following steps:
With oxazole [4,5-b] pyridine-2 (3H)-one and N-chlorosuccinimide be raw material, in solvent, in 10 ~ 120 ℃ of thermotonuses, within 1 ~ 36 hour, generates also [4,5-b] pyridin-2-ones of the chloro-3H-oxazole of 6-, after purifying, obtain also [4,5-b] pyridin-2-ones of the chloro-3H-oxazole of sterling 6-;
Ketone heating hydrolysis under suitable alkali effect in 6-Lv oxazole [4,5-b] pyridine-2 (3H) generates 2-amino-3-hydroxyl-5-chloropyridine sodium salt, obtains product 2-amino-3-hydroxyl-5-chloropyridine after purifying.
2. the synthetic method of 2-amino-3-hydroxyl-5-chloropyridine according to claim 1, it is characterized in that: in described step (1), solvent is methylene dichloride, the mixture of acetonitrile and Glacial acetic acid, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), N, any one material in N-dimethyl acetyl ammonia (DMA) or N-Methyl pyrrolidone (NMP).
3. the synthetic method of 2-amino-3-hydroxyl-5-chloropyridine according to claim 1, it is characterized in that: in described step (1), the charging capacity of reactant and solvent is oxazole [4,5-b] pyridine-2 (3H)-one: N-chlorosuccinimide: solvent=5:6 ~ 6.3:30 ~ 34 are more than weight ratio.
4. the synthetic method of 2-amino-3-hydroxyl-5-chloropyridine according to claim 1, is characterized in that: in described step (1), reaction conditions is at 20 ~ 90 ℃, to react 6 ~ 24 hours.
5. the synthetic method of 2-amino-3-hydroxyl-5-chloropyridine according to claim 1, is characterized in that: in described step (1), purification step comprises successively and adds moisture liquid, filters washing, desiccant dryness, evaporation concentration, solvent recrystallization.
6. the synthetic method of 2-amino-3-hydroxyl-5-chloropyridine according to claim 5, is characterized in that: in described step (1), recrystallization solvent is ethyl acetate ethanol, methylene dichloride, chloroform, any one in normal hexane or two kinds of materials.
7. the synthetic method of 2-amino-3-hydroxyl-5-chloropyridine according to claim 1, is characterized in that: in described step (2), alkali is lithium hydroxide sodium hydroxide, potassium hydroxide, calcium hydroxide, any one material in magnesium hydroxide.
8. the synthetic method of 2-amino-3-hydroxyl-5-chloropyridine according to claim 1, is characterized in that: in described step (2), heating hydrolysis temperature of reaction is 25 ℃ ~ 100 ℃.
9. the synthetic method of 2-amino-3-hydroxyl-5-chloropyridine according to claim 1, is characterized in that: in described step (2), purification step comprises acidifying, filter, and washing, dry.
10. the synthetic method of 2-amino-3-hydroxyl-5-chloropyridine according to claim 9, is characterized in that: in described step (2), the acid that acidifying is used refers to hydrochloric acid, sulfuric acid, phosphoric acid.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110950888A (en) * | 2019-11-11 | 2020-04-03 | 山东省科学院菏泽分院 | Preparation method of chlorooxanone with Vilsmeier reagent |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006021884A2 (en) * | 2004-08-26 | 2006-03-02 | Pfizer Inc. | Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors |
| CN103242345A (en) * | 2012-09-14 | 2013-08-14 | 日出实业集团有限公司 | Synthetic method of picoline phosphate intermediate 6-chloxazole [4,5-b] pyridine-2(3H) acetone |
| CN103265477A (en) * | 2003-02-26 | 2013-08-28 | 苏根公司 | Aminoheteroaryl compounds as protein kinase inhibitors |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103265477A (en) * | 2003-02-26 | 2013-08-28 | 苏根公司 | Aminoheteroaryl compounds as protein kinase inhibitors |
| WO2006021884A2 (en) * | 2004-08-26 | 2006-03-02 | Pfizer Inc. | Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors |
| CN103242345A (en) * | 2012-09-14 | 2013-08-14 | 日出实业集团有限公司 | Synthetic method of picoline phosphate intermediate 6-chloxazole [4,5-b] pyridine-2(3H) acetone |
Non-Patent Citations (1)
| Title |
|---|
| MAREK MAC，等: "Fluorescence properties of the derivatives of oxazolo[4,5-b]pyridyne", 《JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY, A: CHEMISTRY》, vol. 192, no. 23, 25 May 2007 (2007-05-25), pages 189 - 1 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110950888A (en) * | 2019-11-11 | 2020-04-03 | 山东省科学院菏泽分院 | Preparation method of chlorooxanone with Vilsmeier reagent |
| CN110950888B (en) * | 2019-11-11 | 2022-05-20 | 山东省科学院菏泽分院 | Preparation method of chlorooxanone with Vilsmeier reagent |
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Address after: 274100 Shandong city of Heze province Dingtao County Economic Development Zone, Fang Shan (Tianyuan West) Patentee after: Shandong You Bang biochemical technology company limited Address before: 274100 Shandong city of Heze province Dingtao County Economic Development Zone, Fang Shan (Tianyuan West) Patentee before: Dingyao County You Bang Chemical Co., Ltd. |
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Effective date of registration: 20210413 Address after: Chenzhuang Town, Pucheng County, Weinan City, Shaanxi Province (high tech Industrial Development Zone) Patentee after: Shaanxi Youbang Biomedical Technology Co.,Ltd. Address before: 274100 Fangshan Economic Development Zone, Dingtao County, Heze City, Shandong Province (West of Tianyuan company) Patentee before: SHANDONG YOUBANG BIOCHEMICAL TECHNOLOGY Co.,Ltd. |