CN101973993A - Method for preparing 2-[imidazo[1,2-a]pyridine-3-yl]acetic acid - Google Patents
Method for preparing 2-[imidazo[1,2-a]pyridine-3-yl]acetic acid Download PDFInfo
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- CN101973993A CN101973993A CN 201010533260 CN201010533260A CN101973993A CN 101973993 A CN101973993 A CN 101973993A CN 201010533260 CN201010533260 CN 201010533260 CN 201010533260 A CN201010533260 A CN 201010533260A CN 101973993 A CN101973993 A CN 101973993A
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- 0 *OC(CC(CCl)=O)=O Chemical compound *OC(CC(CCl)=O)=O 0.000 description 4
- RYQVTSDSBBNYKM-UHFFFAOYSA-N CC1=CC=C=C2N1C=CC=C2 Chemical compound CC1=CC=C=C2N1C=CC=C2 RYQVTSDSBBNYKM-UHFFFAOYSA-N 0.000 description 1
- ICSNLGPSRYBMBD-UHFFFAOYSA-N Nc1ccccn1 Chemical compound Nc1ccccn1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 1
- ZVBVKRNOISRONE-UHFFFAOYSA-N OC(Cc1cnc2[n]1cccc2)=O Chemical compound OC(Cc1cnc2[n]1cccc2)=O ZVBVKRNOISRONE-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a method for preparing 2-[imidazo[1,2-a]pyridine-3-yl]acetic acid, which comprises the following steps of: reacting 4-chloro-acetoacetic acid ester and 2-aminopyridine in an organic solvent in the presence of an acid binding agent to obtain 2-[imidazo[1,2-a]pyridine-3-yl]acetic acid ester; and hydrolyzing the 2-[imidazo[1,2-a]pyridine-3-yl]acetic acid under the acid or alkaline condition to obtain the 2-[imidazo[1,2-a]pyridine-3-yl]acetic acid. In the method, raw materials have high stability and low price and are readily available; deadly toxic cyanides or high corrosion and unstable bromides are not used; the reaction step is short; the operation is simple; the method is safe and environment-friendly; special equipment is not needed; and the method is suitable for industrial production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, in particular to a kind of preparation osteosporosis resistant medicament minodronic acid (Minodronate) intermediate 2-[imidazo (1,2-a) pyridin-3-yl] method of acetate.
Background technology
Minodronic acid (Minodronate) is by the new type heterocycle bis-phosphonic acids compounds of Japanese Yamanouchi company exploitation, is used for the treatment of the hypercalcemia that is caused by osteoporosis and malignant tumour.Get permission listing on January 21st, 2009 first in Japan, trade(brand)name is respectively Recalbon
(little wild medicine) and Bonoteo
(Astellas pharmacy).The 2-[imidazo (1,2-a) pyridin-3-yl] acetate is the important intermediate of synthetic minodronic acid.
The synthetic method of minodronic acid is existing report in European patent EP 0354806, but this patent not about the 2-[imidazo (1,2-a) pyridin-3-yl] report of the synthetic method of acetate.At non-patent literature: Chinese Journal of Pharmaceuticals, 35 (4), 2004, P193～194 and J Med.Chem. have reported with imidazo (1 in 1969,12 (1) P122～126,2-a) pyridine is a raw material, through 5 step prepared in reaction target product 2-[imidazos (1,2-a) pyridin-3-yl] method of acetate, concrete chemical reaction is as follows, this method not only reactions steps is long, complex operation, but also used hypertoxic sodium cyanide and monobromethane, environment and operator are caused great harm.
In Chinese patent CN101531681A, adopting the single-ethyl succinate acyl chlorides is raw material, through 4 step prepared in reaction target product 2-[imidazos (1,2-a) pyridin-3-yl] acetate, highly corrosive, strong and stimulating and volatile bromine and trimethylchlorosilane have wherein been used, concrete chemical reaction is as follows, and this method can cause bigger harm to environment, operator and equipment equally, is unfavorable for suitability for industrialized production.
Summary of the invention
The present invention is directed to above-mentioned synthetic target product 2-[imidazo (1,2-a) pyridin-3-yl] problem that exists in the method for acetate, a kind of raw material good stability is provided, cheap and easy to get, do not re-use hypertoxic prussiate or highly corrosive and unsettled bromide, reactions steps is short, simple to operate, safety and environmental protection need not specific installation, the finished product purity height that makes is more suitable for the preparation method of suitability for industrialized production.
Technical scheme of the present invention is as follows:
2-[imidazo shown in a kind of preparation formula (I) (1,2-a) pyridin-3-yl] method of acetate, this method comprises the steps:
(1) make 4-chloro acetylacetic ester shown in the formula (III) and 2-aminopyridine in the presence of acid binding agent, in organic solvent, react, obtain the 2-[imidazo shown in the formula (II) (1,2-a) pyridin-3-yl] acetic ester; And
(2) the 2-[imidazo that step (1) is made (1,2-a) pyridin-3-yl] acetic ester is hydrolyzed under acidity or alkaline condition, obtain described 2-[imidazo (1,2-a) pyridin-3-yl] acetate
Wherein, R is an alkane, is preferably methyl, ethyl, propyl group, sec.-propyl, butyl or isobutyl-.
Preferably, described acid binding agent is selected from one or more in triethylamine, sodium bicarbonate and the yellow soda ash.
Preferably, described organic solvent is selected from one or more in fatty alcohol, dioxane, methylene dichloride, chloroform, benzene and the toluene.
Preferably, described fatty alcohol is selected from one or more in ethanol, methyl alcohol, propyl alcohol, Virahol, butanols and the isopropylcarbinol.
Preferably, in step (1), the mol ratio of described 4-chloro acetylacetic ester and described 2-aminopyridine is 0.5: 1～2: 1, is preferably 0.8: 1～1.2: 1.
Preferably, in step (1), the mol ratio of described acid binding agent and described 4-chloro acetylacetic ester is 1: 1～10: 1, is preferably 1.1: 1～3: 1.
Preferably, in step (1), temperature of reaction is 0 ℃～150 ℃, is preferably 0 ℃～100 ℃.
Preferably, in step (1), the reaction times is 3～30 hours, is preferably 10～24 hours.
Compared with prior art, the present invention has following beneficial effect at least:
Preparation method's raw material good stability of the present invention, cheap and easy to get, do not contain the severe toxicity prussiate or highly corrosive and unsettled bromide, safety and environmental protection need not specific installation; Preparation method of the present invention had only for two steps, and reactions steps is short, and is simple to operate; Prepared according to the methods of the invention 2-[imidazo (1,2-a) pyridin-3-yl] acetate purity height.
Embodiment
Describe the present invention in detail below by embodiment, should be appreciated that following embodiment only is used to illustrate the present invention, and the scope that does not limit the present invention in any way.
Embodiment 1
(1) the 2-[imidazo (1,2-a) pyridin-3-yl] preparation of methyl acetate
The 2-aminopyridine of 56.5g (0.60mol) is dissolved in 550ml ethanol, is cooled to about 0～5 ℃, add 78ml triethylamine (0.55mol), then, slowly drip 4-chloro methyl acetoacetate 75.3g (0.50mol), drip off in the 1.5h.Be warming up to backflow, behind the reaction 20h, with the reaction solution evaporated under reduced pressure, residue adds chloroform 500ml dissolving, separates with silica gel chromatographic column, after concentrating crystallization, the crude product re-crystallizing in ethyl acetate obtains white solid 50.4g, is 2-[imidazo (1,2-a) pyridin-3-yl] methyl acetate, yield 53% (with respect to 4-chloro methyl acetoacetate);
(2) the 2-[imidazo (1,2-a) pyridin-3-yl] preparation of acetate
With 2-[imidazo (1,2-a) pyridin-3-yl] methyl acetate 19g (0.10mol), be dissolved in 500ml methyl alcohol, add potassium hydroxide 20g, be warming up to backflow, after HPLC (high performance liquid chromatography) monitoring reaction was finished, concentrating under reduced pressure was used the 200ml water dissolution, acetate adjust pH to 6, separate out white solid 11g, be the 2-[imidazo (1,2-a) pyridin-3-yl] acetate.Yield 62.2%.258～259 ℃ of fusing points (MP) (258～259 ℃ of document MP).
Embodiment 2
(1) the 2-[imidazo (1,2-a) pyridin-3-yl] preparation of methyl acetate
The 2-aminopyridine of 56.5g (0.60mol) is dissolved in 550ml ethanol, is cooled to about 0～5 ℃, add 78ml triethylamine (0.55mol), slowly drip 4-chloro methyl acetoacetate 75.3g (0.50mol), drip off in the 1.5h.Be warming up to backflow, behind the reaction 6h, with the reaction solution evaporated under reduced pressure, residue adds chloroform 500ml dissolving, separates with silica gel chromatographic column, after concentrating crystallization, the crude product re-crystallizing in ethyl acetate obtains white solid 33.3g, is 2-[imidazo (1,2-a) pyridin-3-yl] methyl acetate, yield 35% (with respect to 4-chloro methyl acetoacetate);
(2) the 2-[imidazo (1,2-a) pyridin-3-yl] preparation of acetate
With 2-[imidazo (1,2-a) pyridin-3-yl] methyl acetate 19g (0.10mol) is dissolved in 500ml ethanol, add potassium hydroxide 20g, be warming up to backflow, after the HPLC monitoring reaction is finished, concentrating under reduced pressure, use the 200ml water dissolution, acetate adjust pH to 6 is separated out white solid 10g, be the 2-[imidazo (1,2-a) pyridin-3-yl] acetate.Yield 56.5%.258～259 ℃ of MP (258～259 ℃ of document MP).
Embodiment 3
(1) the 2-[imidazo (1,2-a) pyridin-3-yl] preparation of ethyl acetate
The 2-aminopyridine of 56.5g (0.60mol) is dissolved in the 550ml dioxane, is cooled to about 0～5 ℃, add 78ml triethylamine (0.55mol), slowly drip 4-chloro ethyl acetoacetate 82.3g (0.50mol), drip off in the 1.5h.Be warming up to 80 ℃, behind the reaction 20h, with the reaction solution evaporated under reduced pressure, residue adds chloroform 500ml dissolving, separates with silica gel chromatographic column, after concentrating crystallization, the crude product ethyl alcohol recrystallization obtains white solid 52.0g, is 2-[imidazo (1,2-a) pyridin-3-yl] ethyl acetate, yield 51% (with respect to the 4-chloro ethyl acetoacetate);
(2) the 2-[imidazo (1,2-a) pyridin-3-yl] preparation of acetate
With 2-[imidazo (1,2-a) pyridin-3-yl] methyl acetate 19g (0.10mol) is dissolved in 500ml methyl alcohol, add sodium hydroxide 22g, be warming up to backflow, after the HPLC monitoring reaction is finished, concentrating under reduced pressure, use the 200ml water dissolution, acetate adjust pH to 6 is separated out white solid 9.8g, be the 2-[imidazo (1,2-a) pyridin-3-yl] acetate.Yield 55.4%.258～259 ℃ of MP (258～259 ℃ of document MP).
Embodiment 4
(1) the 2-[imidazo (1,2-a) pyridin-3-yl] preparation of ethyl acetate
The 2-aminopyridine of 56.5g (0.60mol) is dissolved in the 550ml dioxane, is cooled to about 0～5 ℃, add 78ml triethylamine (0.55mol), slowly drip 4-chloro ethyl acetoacetate 82.3g (0.50mol), drip off in the 1.5h.Be warming up to 80 ℃, behind the reaction 6h, with the reaction solution evaporated under reduced pressure, residue adds chloroform 500ml dissolving, separates with silica gel chromatographic column, after concentrating crystallization, the crude product ethyl alcohol recrystallization obtains white solid 30.6g, is 2-[imidazo (1,2-a) pyridin-3-yl] ethyl acetate, yield 30% (with respect to the 4-chloro ethyl acetoacetate);
(2) the 2-[imidazo (1,2-a) pyridin-3-yl] preparation of acetate
With the 2-[imidazo (1,2-a) pyridin-3-yl] methyl acetate 19g (0.10mol), be dissolved in 500ml water, add sodium hydroxide 22g, be warming up to backflow, after the HPLC monitoring reaction is finished, concentrating under reduced pressure, use the 200ml water dissolution, acetate adjust pH to 6 is separated out white solid 6.7g.Yield 38%.258～259 ℃ of MP (258～259 ℃ of document MP).
Embodiment 5
(1) the 2-[imidazo (1,2-a) pyridin-3-yl] preparation of ethyl acetate
The 2-aminopyridine of 56.5g (0.60mol) is dissolved in the 550ml dioxane, is cooled to about 0～5 ℃, add 98ml triethylamine (0.70mol), slowly drip 4-chloro ethyl acetoacetate 98.8g (0.60mol), drip off in the 1.5h.Be warming up to 80 ℃, behind the reaction 24h, with the reaction solution evaporated under reduced pressure, residue adds chloroform 500ml dissolving, separates with silica gel chromatographic column, after concentrating crystallization, the crude product ethyl alcohol recrystallization obtains white solid 53.0g, is 2-[imidazo (1,2-a) pyridin-3-yl] ethyl acetate, yield 43.3% (with respect to the 4-chloro ethyl acetoacetate).
(2) the 2-[imidazo (1,2-a) pyridin-3-yl] preparation of acetate
With 2-[imidazo (1,2-a) pyridin-3-yl] methyl acetate 19g (0.10mol) is dissolved in 500ml methyl alcohol, add potassium hydroxide 20g, be warming up to backflow, after the HPLC monitoring reaction is finished, concentrating under reduced pressure, use the 200ml water dissolution, acetate adjust pH to 6 is separated out white solid 10.5g, be the 2-[imidazo (1,2-a) pyridin-3-yl] acetate.Yield 59.3%.258～259 ℃ of MP (258～259 ℃ of document MP).
Embodiment 6
(1) the 2-[imidazo (1,2-a) pyridin-3-yl] preparation of methyl acetate
The 2-aminopyridine of 56.5g (0.60mol) is dissolved in 550ml ethanol, adds sodium bicarbonate 46.2g (0.55mol), slowly drip 4-chloro methyl acetoacetate 75.3g (0.50mol), drip off in the 1.5h.Be warming up to backflow, behind the reaction 24h, filter the filtrate decompression evaporate to dryness, residue adds chloroform 500ml dissolving, separate with silica gel chromatographic column, behind the concentrated crystallization, the crude product re-crystallizing in ethyl acetate, obtain white solid 47.5g, be the 2-[imidazo (1,2-a) pyridin-3-yl] methyl acetate, yield 49.9% (with respect to 4-chloro methyl acetoacetate);
(2) the 2-[imidazo (1,2-a) pyridin-3-yl] preparation of acetate
With 2-[imidazo (1,2-a) pyridin-3-yl] methyl acetate 19g (0.10mol) is dissolved in 500ml ethanol, add potassium hydroxide 20g, be warming up to backflow, after the HPLC monitoring reaction is finished, concentrating under reduced pressure, use the 200ml water dissolution, acetate adjust pH to 6 is separated out white solid 10g, be the 2-[imidazo (1,2-a) pyridin-3-yl] acetate.Yield 56.5%.258～259 ℃ of MP (258～259 ℃ of document MP).
Embodiment 7
(1) the 2-[imidazo (1,2-a) pyridin-3-yl] preparation of methyl acetate
The 2-aminopyridine of 56.5g (0.60mol) is dissolved in 550ml ethanol, adds yellow soda ash 58.3g (0.55mol), slowly drip 4-chloro methyl acetoacetate 75.3g (0.50mol), drip off in the 1.5h.Be warming up to backflow, behind the reaction 24h, filter the filtrate decompression evaporate to dryness, residue adds chloroform 500ml dissolving, separate with silica gel chromatographic column, behind the concentrated crystallization, the crude product re-crystallizing in ethyl acetate, obtain white solid 46.0g, be the 2-[imidazo (1,2-a) pyridin-3-yl] methyl acetate, yield 48.3% (with respect to 4-chloro methyl acetoacetate);
(2) the 2-[imidazo (1,2-a) pyridin-3-yl] preparation of acetate
With 2-[imidazo (1,2-a) pyridin-3-yl] methyl acetate 19g (0.10mol) is dissolved in 500ml ethanol, add potassium hydroxide 20g, be warming up to backflow, after the HPLC monitoring reaction is finished, concentrating under reduced pressure, use the 200ml water dissolution, acetate adjust pH to 6 is separated out white solid 10g, be the 2-[imidazo (1,2-a) pyridin-3-yl] acetate.Yield 56.5%.258～259 ℃ of MP (258～259 ℃ of document MP).
Claims (8)
- 2-[imidazo shown in the preparation formula (I) (1,2-a) pyridin-3-yl] method of acetate, this method comprises the steps:(1) make 4-chloro acetylacetic ester shown in the formula (III) and 2-aminopyridine in the presence of acid binding agent, in organic solvent, react, obtain the 2-[imidazo shown in the formula (II) (1,2-a) pyridin-3-yl] acetic ester; And(2) the 2-[imidazo that step (1) is made (1,2-a) pyridin-3-yl] acetic ester is hydrolyzed under acidity or alkaline condition, obtain described 2-[imidazo (1,2-a) pyridin-3-yl] acetate
Wherein, R is an alkane, is preferably methyl, ethyl, propyl group, sec.-propyl, butyl or isobutyl-. - 2. method according to claim 1 is characterized in that described acid binding agent is selected from one or more in triethylamine, sodium bicarbonate and the yellow soda ash.
- 3. method according to claim 1 and 2 is characterized in that described organic solvent is selected from one or more in fatty alcohol, dioxane, methylene dichloride, chloroform, benzene and the toluene.
- 4. method according to claim 3 is characterized in that described fatty alcohol is selected from one or more in ethanol, methyl alcohol, propyl alcohol, Virahol, butanols and the isopropylcarbinol.
- 5. according to each described method in the claim 1 to 4, it is characterized in that in step (1), the mol ratio of described 4-chloro acetylacetic ester and described 2-aminopyridine is 0.5: 1～2: 1, is preferably 0.8: 1～1.2: 1.
- 6. according to each described method in the claim 1 to 5, it is characterized in that in step (1), the mol ratio of described acid binding agent and described 4-chloro acetylacetic ester is 1: 1～10: 1, is preferably 1.1: 1～3: 1.
- 7. according to each described method in the claim 1 to 6, it is characterized in that in step (1), temperature of reaction is 0 ℃～150 ℃, be preferably 0 ℃～100 ℃.
- 8. according to each described method in the claim 1 to 7, it is characterized in that in step (1), the reaction times is 3～30 hours, is preferably 10～24 hours.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102311433A (en) * | 2011-08-23 | 2012-01-11 | 南京工业大学 | Method for preparing imidazo [1,2-a ] pyridine-3-acetic acid by one-pot method |
| CN102603739A (en) * | 2012-02-27 | 2012-07-25 | 贵阳昊臻药物开发有限公司 | Method for preparing compound, i.e., 2-(imidazo[1,2-alpha]pyridine-3-radical)acetic acid |
| CN104945436A (en) * | 2015-07-09 | 2015-09-30 | 山东罗欣药业集团股份有限公司 | Minodronic acid preparing method |
| CN105153232A (en) * | 2015-10-17 | 2015-12-16 | 青岛辰达生物科技有限公司 | Preparation method of minodronic acid for treating osteoporosis |
| CN105175446A (en) * | 2015-10-17 | 2015-12-23 | 青岛辰达生物科技有限公司 | Preparation method of minodronic acid for treating osteoporosis |
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| CN101812062A (en) * | 2010-03-31 | 2010-08-25 | 北京京卫信康医药科技发展有限公司 | Novel method for preparing important intermediate of minodronate |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102311433A (en) * | 2011-08-23 | 2012-01-11 | 南京工业大学 | Method for preparing imidazo [1,2-a ] pyridine-3-acetic acid by one-pot method |
| CN102603739A (en) * | 2012-02-27 | 2012-07-25 | 贵阳昊臻药物开发有限公司 | Method for preparing compound, i.e., 2-(imidazo[1,2-alpha]pyridine-3-radical)acetic acid |
| CN102603739B (en) * | 2012-02-27 | 2014-06-04 | 贵阳昊臻药物开发有限公司 | Method for preparing compound, i.e., 2-(imidazo[1,2-alpha]pyridine-3-radical)acetic acid |
| CN104945436A (en) * | 2015-07-09 | 2015-09-30 | 山东罗欣药业集团股份有限公司 | Minodronic acid preparing method |
| CN105153232A (en) * | 2015-10-17 | 2015-12-16 | 青岛辰达生物科技有限公司 | Preparation method of minodronic acid for treating osteoporosis |
| CN105175446A (en) * | 2015-10-17 | 2015-12-23 | 青岛辰达生物科技有限公司 | Preparation method of minodronic acid for treating osteoporosis |
| CN105175446B (en) * | 2015-10-17 | 2017-03-22 | 青岛辰达生物科技有限公司 | Preparation method of minodronic acid for treating osteoporosis |
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Application publication date: 20110216 |