CN103755627B - The synthetic method of 2-amino-3-hydroxyl-5-chloropyridine - Google Patents
The synthetic method of 2-amino-3-hydroxyl-5-chloropyridine Download PDFInfo
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- CN103755627B CN103755627B CN201410009851.2A CN201410009851A CN103755627B CN 103755627 B CN103755627 B CN 103755627B CN 201410009851 A CN201410009851 A CN 201410009851A CN 103755627 B CN103755627 B CN 103755627B
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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 organic synthesis field, particularly a kind of synthetic method of 2-amino-3-hydroxyl-5-chloropyridine.The synthetic method of this 2-amino-3-hydroxyl-5-chloropyridine, comprise the following steps: Yi oxazole [4,5-b] pyridine-2 (3H) ketone and NCS (N-chlorosuccinimide) reaction in appropriate solvent and under proper temperature generates 6-chlorine oxazole [4,5-b] pyridine-2 (3H) ketone, then generate 2-amino-3-hydroxyl-5-chloropyridine through alkalization hydrolysis.The invention has the beneficial effects as follows: raw material of the present invention is easy to get, and is solid, transport, it is convenient to store; Do not use heavy metal and corrosive gases in simultaneous reactions, reaction temperature and, do not have particular requirement to conversion unit, common erosion resistance equipment can be produced; Reaction times of the present invention is moderate in addition, and reaction is easy to control, and aftertreatment is simple, and product purity is high, and production cost is low, is easy to 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, the research and development of medicine intermediate, pharmaceutical products, agricultural chemicals, 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.Such as 2-amino-3-hydroxyl-5-chloropyridine has four functional groups, and they are-Cl ,-OH ,-NH respectively
2with the nitrogen on pyridine ring.Such as, 2-amino-3-hydroxyl-5-chloropyridine and methylating reagent react and generate 2-amino-3-methoxyl group-5-chloropyridine, then with corresponding alpha-bromo ketogenesis 6-chloro-8-methoxyl group imidazo [1,2-a] derivative of pyridine, the latter is used to the research (PCTInt.Appl. of kinases PIK3,2012007345,19Jan2012).The product that 2-amino-3-methoxyl group-5-chloropyridine and oxine etc. react has been used to the development research (U.S.Pat.Appl.Publ., 20110301193,08Dec2011) of medicine.2-amino-3-hydroxyl-5-chloropyridine and corresponding halobenzene or cylite react and generate 2-amino-3-phenyl-5-chloropyridine and 2-amino-3-benzyl-5-chloropyridine, and they have been respectively used to the research that the activation of glucokinase and selectivity secrete 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 being suitable for the 2-amino-3-hydroxyl-5-chloropyridine of industrialization synthesis
The present invention is achieved through the following technical solutions:
A synthetic method for 2-amino-3-hydroxyl-5-chloropyridine, is characterized in that, comprise the following steps:
(1). with oxazole [4,5-b] pyridine-2 (3H)-one and N-chlorosuccinimide be raw material, the chloro-3H-oxazole of 6-also [4 is generated in a solvent in 10 ~ 120 DEG C of thermotonuses 1 ~ 36 hour, 5-b] pyridin-2-ones, the chloro-3H-oxazole of sterling 6-also [4,5-b] pyridin-2-ones is obtained after purifying;
(2) .6-Lv oxazole [4,5-b] pyridine-2 (3H) ketone heating hydrolysis under suitable alkali effect generates 2-amino-3-hydroxyl-5-chloropyridine sodium salt, after purifying, obtain product 2-amino-3-hydroxyl-5-chloropyridine.
In described step (1), solvent is the mixture of methylene dichloride, acetonitrile and Glacial acetic acid, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), any one material in N, N-dimethylacetamide 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, is more than weight ratio.
In described step (1), reaction conditions is react 6 ~ 24 hours at 20 ~ 90 DEG C.
In described step (1), purification step comprises the separatory that adds water successively, filters, washing, desiccant dryness, evaporation concentration, solvent recrystallization.
In described step (1), recrystallization solvent is ethyl acetate, ethanol, methylene dichloride, chloroform, any one or two kinds of materials in normal hexane.
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 DEG C ~ 100 DEG C.
In described step (2), purification step comprises acidifying, filters, and washing is dry.
In described step (2), the acid that acidifying uses 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 is solid, transport, it is convenient to store; Do not use heavy metal and corrosive gases in simultaneous reactions, reaction temperature and, do not have particular requirement to conversion unit, common erosion resistance equipment can be produced; Reaction times of the present invention is moderate in addition, and reaction is easy to control, and aftertreatment is simple, and product purity is high, and production cost is low, is easy to apply.
Embodiment
Embodiment 1:
Methylene dichloride (200mL) is added in three mouthfuls of round-bottomed flasks of a 250mL.There-necked flask adds a reflux condensing tube, starts magnetic stirring apparatus and Jia Ru oxazole [4,5-b] pyridine-2 (3H)-one (4.1g).After Dang oxazole [4,5-b] pyridine-2 (3H)-one is all dissolved, N-chlorosuccinimide (4.7g) will be added in batches.10 DEG C of stirring reactions 4 hours, then heating reflux reaction 12 hours.TLC and GC determines that reaction completes.Revolve and steam except desolventizing.Thick product obtains straight product 6-Lv oxazole [4,5-b] pyridine-2 (3H)-one (3.14g) from methylene dichloride and re-crystallizing in ethyl acetate, productive rate 61%, purity 97.3%(GC).Fusing point 182 DEG C ~ 185 DEG C (183 DEG C ~ 186 DEG C, document).Nuclear magnetic resonance spectroscopy, 1HNMR (DMSO-d6) 300MHz: δ 8.107ppm (d, J=4Hz, 1H); 7.815ppm (d, J=4Hz, 1H).
Sodium hydroxide (1.68 grams, 0.042 mole) and water (20mL) is added in the single necked round bottom flask of a 50mL.Starting magnetic stirring apparatus makes sodium hydroxide all dissolve.Above-mentioned gained 6-Lv oxazole [4,5-b] pyridine-2 (3H)-one (3.14 grams, 0.018 mole) to be joined in reaction flask and on reaction flask, to add a reflux condensing tube.Reaction mixture was by reflux 8 hours.TLC and gas chromatographic analysis show to react completely.Regulate the pH value of reaction mixture to have to 8(with 12mol/L hydrochloric acid and precipitate generation in a large number).Filter, filter cake washes with water (5 milliliters).Dry to obtain product 2-amino-3-hydroxyl-5-chloropyridine 1.99 grams, productive rate 74.8%, purity 99.9%(GC).Fusing point 197 DEG C ~ 200 DEG C (198 DEG C ~ 201 DEG C, document).
Embodiment 2:
DMF(2000mL is added) in three mouthfuls of round-bottomed flasks of a 10L.There-necked flask adds a reflux condensing tube.Start mechanical stirrer and Jia Ru oxazole [4,5-b] pyridine-2 (3H)-one (497g).Jiao Ban Shi oxazole [4,5-b] pyridine-2 (3H)-one is all dissolved.N-chlorosuccinimide (608g) is dissolved in DMF(2500mL) 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 DEG C (cooling with frozen water if desired).After dripping, remove ice-water bath, room temperature for overnight.Reaction is followed the tracks of with TLC and GC.After question response completes, under frozen water cooling, slowly add water 4000mL.Stirred reaction mixture 30 minutes, filters.Filter cake washes twice with water, and vacuum-drying obtains crude product 530g.Thick product obtains straight product 6-Lv oxazole [4,5-b] pyridine-2 (3H)-one (505g) from methylene dichloride and re-crystallizing in ethyl acetate, productive rate 81%, purity 99.1%(GC).Fusing point 184 DEG C ~ 187 DEG C (183 DEG C ~ 186 DEG C, document).
Sodium hydroxide (355 grams, 8.883 moles) and water (3.5L) is added in the single necked round bottom flask of a 5L.Starting magnetic stirring apparatus makes sodium hydroxide all dissolve.Above-mentioned gained 6-Lv oxazole [4,5-b] pyridine-2 (3H)-one (505 grams, 2.961 moles) to be joined in reaction flask and on reaction flask, to add a reflux condensing tube.Reaction mixture was by reflux 10 hours.Follow the tracks of reaction with TLC and GC to show to react completely.Regulate the pH value of reaction mixture to have to 8(with 12mol/L hydrochloric acid and precipitate generation in a large number).Filter, filter cake washes with water (400 milliliters).Dry to obtain product 2-amino-3-hydroxyl-5-chloropyridine 420 grams, productive rate 98%, purity 97.9%(GC).Fusing point 197 DEG C ~ 202 DEG C (198 DEG C ~ 201 DEG C, document).
Embodiment 3:
DMF(4L is added) in the reactor of a 50L.Start mechanical stirrer and Jia Ru oxazole [4,5-b] pyridine-2 (3H)-one (4.97kg).Jiao Ban Shi oxazole [4,5-b] pyridine-2 (3H)-one is all dissolved.N-chlorosuccinimide (6.08kg) is dissolved in DMF(25L) in.Then slowly drip N-chlorosuccinimide in reactor, control temperature of reaction and be no more than 40 DEG C (if desired with the cooling of circulating condensing pump).After dripping, room temperature for overnight.Reaction is followed the tracks of with TLC and GC.After question response completes, reaction solution is shifted in the reactor of a 100L, under cooling, slowly add water 35L.Stirred reaction mixture 60 minutes, filters.Filter cake washes twice with water, and vacuum-drying obtains crude product 4.95kg.Thick product recrystallization from methylene dichloride and ethyl acetate obtains straight product 6-Lv oxazole [4,5-b] pyridine-2 (3H)-one (4.76kg), productive rate 76%, purity 99.4%(GC).Fusing point 183 DEG C ~ 185 DEG C (183 DEG C ~ 186 DEG C, document).
Sodium hydroxide (3.348 kilograms, 83.7 moles) and water (35L) is added in the reactor of a 50L.Starting magnetic stirring apparatus makes sodium hydroxide all dissolve.Above-mentioned gained 6-Lv oxazole [4,5-b] pyridine-2 (3H)-one (4.76 kilograms, 27.9 moles) to be joined in reaction flask and on reaction flask, to add a reflux condensing tube.Reaction mixture was by reflux 12 hours.Follow the tracks of reaction with TLC and GC to show to react completely.Regulate the pH value of reaction mixture to have to 8(with 12mol/L hydrochloric acid and precipitate generation in a large number).Filter, filter cake washes with water (10 liters).Dry to obtain product 2-amino-3-hydroxyl-5-chloropyridine 3.90 kilograms, productive rate 96%, purity 98.6%(GC).Fusing point 199 DEG C ~ 202 DEG C (198 DEG C ~ 201 DEG C, document).
Claims (1)
1. the synthetic method of a 2-amino-3-hydroxyl-5-chloropyridine, it is characterized in that, comprise the following steps: in three mouthfuls of round-bottomed flasks of a 10L, add 2000mLDMF, there-necked flask adds a reflux condensing tube, start mechanical stirrer and add 497g oxazole [4,5-b] pyridine-2 (3H)-one, Jiao Ban Shi oxazole [4,5-b] pyridine-2 (3H)-one is all dissolved; 608gN-chlorosuccinimide is dissolved in 2500mLDMF and is then transferred to a constant pressure funnel, slowly drip N-chlorosuccinimide in reaction flask, control temperature of reaction and be no more than 40 DEG C, after dripping, remove ice-water bath, room temperature for overnight, follow the tracks of reaction with TLC and GC; After question response completes, under frozen water cooling, slowly add water 4000mL, stirred reaction mixture 30 minutes, filter; Filter cake washes twice with water, and vacuum-drying obtains crude product 530g, and thick product obtains straight product 505g6-Lv oxazole [4 from methylene dichloride and re-crystallizing in ethyl acetate, 5-b] pyridine-2 (3H)-one, productive rate 81%, gas chromatographic purity 99.1%, fusing point 184 DEG C ~ 187 DEG C;
355 grams of sodium hydroxide and 3.5L water is added in the single necked round bottom flask of a 5L, starting magnetic stirring apparatus makes sodium hydroxide all dissolve, by above-mentioned gained 505 grams of 6-Lv oxazoles [4,5-b] pyridine-2 (3H)-one to join in reaction flask and on reaction flask, to add a reflux condensing tube, reaction mixture was by reflux 10 hours, follow the tracks of reaction with TLC and GC to show to react completely, regulate the pH value of reaction mixture to 8 with 12mol/L hydrochloric acid, now have and precipitate generation in a large number; Filter, filter cake 400 ml waters wash, and dry to obtain product 2-amino-3-hydroxyl-5-chloropyridine 420 grams, productive rate 98%, purity 97.9%, fusing point 197 DEG C ~ 202 DEG C.
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| 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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| 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 |
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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. |
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