CN103896939A - 6-chloro-8-hydroxy-imidazo (1, 2a) pyridine hydrochloride and synthesis method thereof - Google Patents
6-chloro-8-hydroxy-imidazo (1, 2a) pyridine hydrochloride and synthesis method thereof Download PDFInfo
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- CN103896939A CN103896939A CN201410089106.3A CN201410089106A CN103896939A CN 103896939 A CN103896939 A CN 103896939A CN 201410089106 A CN201410089106 A CN 201410089106A CN 103896939 A CN103896939 A CN 103896939A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a 6-chloro-8-hydroxy-imidazo (1, 2a) pyridine hydrochloride and a synthesis method thereof. The synthesis method comprises the following steps: with 2-amino-3-hydroxy-5-bromopyridine and chloroacetaldehyde as raw materials, reacting at proper temperature in a proper solvent to generate 6-chloro-8-hydroxy-imidazo (1, 2a) pyridine hydrochloride, and then purifying to obtain a pure 6-chloro-8-hydroxy-imidazo (1, 2a) pyridine hydrochloride product. The 6-chloro-8-hydroxy-imidazo (1, 2a) pyridine hydrochloride has the beneficial effects that the 6-chloro-8-hydroxy-imidazo (1, 2a) pyridine hydrochloride is easily available in raw materials, reasonable in price, and mild in reaction, no heavy metal or a corrosive gas is not used in preparation reaction, and the 6-chloro-8-hydroxy-imidazo (1, 2a) pyridine hydrochloride has no special requirements on reaction equipment, and can be produced by common corrosion resistant equipment. In addition, the 6-chloro-8-hydroxy-imidazo (1, 2a) pyridine hydrochloride is proper in reaction condition, easy to control reaction, simple in post treatment, high in product purity and easy to popularize.
Description
Technical field
The invention belongs to organic synthesis field, particularly chloro-8-hydroxyl-imidazo (1, the 2a) pyridine hydrochloride of a kind of 6-and synthetic method thereof.
Background technology
The chloro-8-hydroxyl-imidazo of 6-(1,2a) pyridine hydrochloride is a kind of new, important organic synthesis intermediate, and particularly, in pharmaceutical chemical research and application, its more function group or potential more function group are its key points that is used to organic synthesis.Therefore, develop a kind of raw material cheap and easy to get, easy and simple to handle, reaction conditions gentleness, production cost is low, and productive rate is high, is applicable to scale operation, and the method for storage, production process safety is completely necessary.
Summary of the invention
The present invention, in order to make up the defect of prior art, provides a kind of and can be applied to laboratory and synthetic chloro-8-hydroxyl-imidazo (1, the 2a) pyridine hydrochloride of 6-and the synthetic method thereof of industrialization.
The present invention is achieved through the following technical solutions:
A kind of chloro-8-hydroxyl-imidazo of 6-(1,2a) pyridine hydrochloride, is characterized in that, its chemical structural formula is:
The synthetic method of the chloro-8-hydroxyl-imidazo of 6-of the present invention (1,2a) pyridine hydrochloride, is characterized in that, comprises the following steps:
Take 2-amino-3-hydroxyl-5-chloropyridine and monochloroacetaldehyde as raw material, in solvent, temperature rise rate with 1.25 ℃/min rises to 100 ℃ by 0 ℃, and at 100 ℃ successive reaction 0 ~ 24 hour, generate the chloro-8-hydroxyl-imidazo (1 of 6-, 2a) pyridine hydrochloride crude product obtains the chloro-8-hydroxyl-imidazo of product 6-(1,2a) pyridine hydrochloride after purifying.
Described reactant charging capacity is: 2-amino-3-hydroxyl-5-chloropyridine: monochloroacetaldehyde=1:0.4 ~ 5.2 are more than mol ratio.
Described solvent is the trimethyl carbinol and ethanol, methyl alcohol, ethyl acetate, propyl alcohol, Virahol, one or both in methylene dichloride.
The charging capacity of described reactant and solvent is: hydroxyl-5,2-amino-3 chloropyridine: solvent=1:0.5 ~ 6 are more than weight ratio.
Described reaction conditions is for to rise to 50 ℃ with the temperature rise rate of 1.25 ℃/min by 30 ℃, and at 50 ℃ successive reaction 0 ~ 24 hour.
Described purification step comprises extraction agent extraction, evaporation concentration, recrystallization etc. successively.
The solvent of described recrystallization is ethyl acetate, ethanol, methylene dichloride, one or both materials in normal hexane.
The invention has the beneficial effects as follows: raw material of the present invention is easy to get, reasonable price, in preparation feedback, do not use heavy metal and corrosive gases simultaneously, reaction temperature and, reflection equipment is not had to special requirement, and common corrosion resistant apparatus can be produced, and reaction conditions of the present invention is moderate in addition, reaction is easy to control, aftertreatment is simple, and product purity is high, is easy to promote.
Embodiment
Embodiment 1:
In the round bottom single port flask of a 100ml, add methylene dichloride 50ml, insert thermometer and start magnetic stirring apparatus, and add 2-amino-3-hydroxyl-5-chloropyridine of 14.4g, add monochloroacetaldehyde 9.4g, under 25 ℃ of stirrings, react 8 hours.TLC and GC are definite to have reacted.Be extracted with ethyl acetate, revolve to steam and remove extraction agent, obtain thick product, obtain the chloro-8-hydroxyl-imidazo of straight product 6-(1,2a) pyridine hydrochloride with ethanol and normal hexane recrystallization, after being dried, calculated yield 45%, purity 97.5%.Nuclear magnetic resonance spectroscopy: 1HNMR (DMSO-d6) 400MHz: δ 8.658PPM(S, 1H); δ 8.252 (d, J=2.0Hz, 1H); δ 8.055 (d, J=2.0,1H); δ 7.303(S, 1H); δ 5.305(S, 2H).
Embodiment 2:
In the round bottom single port flask of a 2L, add methylene dichloride 550ml, insert thermometer and start magnetic stirring apparatus, and add 2-amino-3-hydroxyl-5-chloropyridine of 269.5g, add monochloroacetaldehyde 263.3g, under 40 ℃ of stirrings, react 6 hours.TLC and GC are definite to have reacted.Be extracted with ethyl acetate, revolve to steam and remove extraction agent, obtain thick product, obtain the chloro-8-hydroxyl-imidazo of straight product 6-(1,2a) pyridine hydrochloride with ethanol and normal hexane recrystallization, after being dried, calculated yield 60%, purity 98.5%.Nuclear magnetic resonance spectroscopy: 1HNMR (DMSO-d6) 400MHz: δ 8.658PPM(S, 1H); δ 8.252 (d, J=2.0Hz, 1H); δ 8.055 (d, J=2.0,1H); δ 7.303(S, 1H); δ 5.305(S, 2H).
Embodiment 3:
In the flask with three necks,round bottom of a 10L, add methylene dichloride 4950ml, insert thermometer and condensation reflux unit is installed, and adding 2-amino-3-hydroxyl-5-bromopyridine of 2060g, adding monochloroacetaldehyde 3915.2g, start magnetic stirring apparatus, stir under condensing reflux and react 5.5 hours at 78 ℃.TLC and GC are definite to have reacted.Be extracted with ethyl acetate, revolve to steam and remove extraction agent, obtain thick product, obtain the bromo-8-hydroxyl-imidazo of straight product 6-(1,2a) pyridine hydrochloride with ethanol and normal hexane recrystallization, after being dried, calculated yield 71.5%, purity 97.6%.Nuclear magnetic resonance spectroscopy: 1HNMR (DMSO-d6) 400MHz: δ 8.658PPM(S, 1H); δ 8.252 (d, J=2.0Hz, 1H); δ 8.055 (d, J=2.0,1H); δ 7.303(S, 1H); δ 5.305(S, 2H).
Embodiment 4:
In the flask with three necks,round bottom of a 50L, add methylene dichloride 15L, insert thermometer and condensation reflux unit be installed and added 2-amino-3-hydroxyl-5-chloropyridine of 6650.5g, add monochloroacetaldehyde 9046.3g, start magnetic stirring apparatus, condensing reflux reaction 3.5 hours under 80 ℃ of stirrings.TLC and GC are definite to have reacted.Be extracted with ethyl acetate, revolve to steam and remove extraction agent, obtain thick product, obtain the chloro-8-hydroxyl-imidazo of straight product 6-(1,2a) pyridine hydrochloride with ethanol and normal hexane recrystallization, after being dried, calculated yield 74.6%, purity 99.2%.Nuclear magnetic resonance spectroscopy: 1HNMR (DMSO-d6) 400MHz: δ 8.658PPM(S, 1H); δ 8.252 (d, J=2.0Hz, 1H); δ 8.055 (d, J=2.0,1H); δ 7.303(S, 1H); δ 5.305(S, 2H).
Claims (8)
1. the chloro-8-hydroxyl-imidazo of 6-(1,2a) pyridine hydrochloride, is characterized in that, its chemical structural formula is:
2. the synthetic method of the chloro-8-hydroxyl-imidazo of 6-according to claim 1 (1,2a) pyridine hydrochloride, is characterized in that, comprises the following steps:
Take 2-amino-3-hydroxyl-5-chloropyridine and monochloroacetaldehyde as raw material, in solvent, temperature rise rate with 1.25 ℃/min rises to 100 ℃ by 0 ℃, and at 100 ℃ successive reaction 0 ~ 24 hour, generate the chloro-8-hydroxyl-imidazo (1 of 6-, 2a) pyridine hydrochloride crude product obtains the chloro-8-hydroxyl-imidazo of product 6-(1,2a) pyridine hydrochloride after purifying.
3. the synthetic method of the chloro-8-hydroxyl-imidazo of 6-according to claim 2 (1,2a) pyridine hydrochloride, is characterized in that: described reactant charging capacity is: 2-amino-3-hydroxyl-5-chloropyridine: monochloroacetaldehyde=1:0.4 ~ 5.2 are more than mol ratio.
4. the synthetic method of the chloro-8-hydroxyl-imidazo of 6-according to claim 2 (1,2a) pyridine hydrochloride, is characterized in that: described solvent is the trimethyl carbinol and ethanol, methyl alcohol, ethyl acetate, propyl alcohol, Virahol, one or both in methylene dichloride.
5. chloro-8-hydroxyl-imidazo (1, the 2a) pyridine hydrochloride of 6-according to claim 2 and synthetic method thereof, is characterized in that: the charging capacity of described reactant and solvent is: hydroxyl-5,2-amino-3 chloropyridine: solvent=1:0.5 ~ 6 are more than weight ratio.
6. the chloro-8-hydroxyl-imidazo (1 of 6-according to claim 2,2a) the synthetic method of pyridine hydrochloride, it is characterized in that: described reaction conditions is for to rise to 50 ℃ with the temperature rise rate of 1.25 ℃/min by 30 ℃, and at 50 ℃ successive reaction 0 ~ 24 hour.
7. the synthetic method of the chloro-8-hydroxyl-imidazo of 6-according to claim 2 (1,2a) pyridine hydrochloride, is characterized in that: described purification step comprises extraction agent extraction, evaporation concentration, recrystallization etc. successively.
8. the synthetic method of the chloro-8-hydroxyl-imidazo of 6-according to claim 7 (1,2a) pyridine hydrochloride, is characterized in that: the solvent of described recrystallization is ethyl acetate, ethanol, methylene dichloride, one or both materials in normal hexane.
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| CN102131806A (en) * | 2008-06-20 | 2011-07-20 | 百时美施贵宝公司 | Triazolopyridine compounds useful as kinase inhibitors |
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