CN102443002A - Method for preparing 2-( imidazo[1,2-alpha] pyridine-3-yl) acetic acid - Google Patents
Method for preparing 2-( imidazo[1,2-alpha] pyridine-3-yl) acetic acid Download PDFInfo
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- CN102443002A CN102443002A CN2010105038717A CN201010503871A CN102443002A CN 102443002 A CN102443002 A CN 102443002A CN 2010105038717 A CN2010105038717 A CN 2010105038717A CN 201010503871 A CN201010503871 A CN 201010503871A CN 102443002 A CN102443002 A CN 102443002A
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Abstract
The invention discloses a method for preparing 2-( imidazo[1,2-alpha] pyridine-3-yl) acetic acid, which is characterized in that: 2-aminopyridine is used as starting material, reacted with trans-4-oxygroup-2-butenolide and a catalyst in an organic solvent to obtain 2-( imidazo[1,2-alpha] pyridine-3-yl) acetate compound; an intermediate does not need to be purified, is directly hydrolyzed in an alkaline solution and acidized, thus obtaining a target product. Particularly, a water separating device is used in the reaction to separate moisture generated in the reaction out of a reaction system, thus carrying out the reaction continuously, in this way, yields are all greater than 80%, and reaction yield is greatly increased.
Description
Technical field
the present invention relates to the pharmaceutical chemistry synthesis technical field, the 2-that says so more specifically (imidazo [1,2-α] pyridin-3-yl) acetate chemistry synthetic preparation method.
Background technology
2-(imidazo [1,2-α] pyridin-3-yl) acetate (formula I) is the key intermediate of preparation minodronic acid, and the compound method of this compound has following pertinent literature report:
In Chinese Journal of Pharmaceuticals 2004., 35 (4) 193-194, its synthetic route is seen following reaction equation:
are starting raw material with imidazo [1,2-α] pyridine (formula A), obtain 3-[(N with paraformaldehyde and dimethylamine hydrochloride reaction; N-(dimethylin) methyl] imidazo [1; 2-α] pyridine (formula B), form quaternary ammonium salt (formula C) with the haloalkane reaction, obtain 2-(imidazo [1 through the cyanic acid replacement; 2-α] pyridin-3-yl) acetonitrile (formula D), hydrolysis obtains target compound under alkaline condition.
employed starting raw material of this route is imidazo [1, a 2-α] pyridine, is difficult for buying; Used the highly toxic product sodium cyanide in the route, be unfavorable for environmental protection and amplify production.
J.Med.Chem.2004,47, its synthetic route of 3934-3937 is seen following reaction equation:
are starting raw material with the 2-EL-970, with trans-4-oxygen base-2-butylene acetoacetic ester reacting by heating 6 hours in acetonitrile, obtain 2-(imidazo [1,2-α] pyridin-3-yl) ETHYLE ACETATE through column chromatography, and yield is 50%; Adopted the column chromatography operation in the route, be unfavorable for amplifying and produce.
Summary of the invention
the invention provides the preparation method of 2-(imidazo [1,2-α] pyridin-3-yl) acetate to the defective of prior art.Selected starting raw material cheap and easy to get, synthetic route is short, and gentleness easy and simple to handle has been avoided the silica gel column chromatography operation steps, is suitable for amplifying producing, and yield improves a lot than document.
For realizing technical scheme of the present invention; The preparation method of 2-(imidazo [1,2-α] pyridin-3-yl) acetate (formula I) may further comprise the steps: with the 2-EL-970 is starting raw material, reacts in organic solvent with trans-4-oxygen base-2-butylene acid esters and catalyzer to obtain 2-(imidazo [1; 2-α] pyridin-3-yl) acetate compounds; This midbody need not purifying, and directly hydrolysis under basic soln, acidifying can obtain title product 2-(imidazo [1,2-α] pyridin-3-yl) acetate:
wherein, R represent methylidene, ethyl; Said catalyzer is a tosic acid; Said organic solvent is selected from benzene, toluene, hexanaphthene or benzene/cyclohexane mixed solvent, toluene/hexanaphthene mixed solvent; Said basic soln is the aqueous solution of sodium hydroxide or Pottasium Hydroxide or the mixing solutions of water and alcohol.
Division box has wherein been used in
in the reaction of preparation formula II, go out reaction system through the moisture that will produce in constantly will reacting, and reaction is constantly carried out, thereby has improved the yield of reaction greatly.We repeat document, use acetonitrile to make solvent, do not take the reflux water-dividing device, and actual recovery is 40% (experimental example 1), and after using division box instead and being with water solvent, yield is all greater than 80% (embodiment 1-4).Yield obviously improves.
Embodiment
below in conjunction with embodiment, describe in further detail the present invention, but should not be construed as the restriction to contriver's right.
The preparation method of embodiment 1 2-(imidazo [1,2-α] pyridin-3-yl) acetate
add 184g 2-EL-970,5g tosic acid in the 5L reaction flask, add 2.5L hexanaphthene and 1L toluene again, install division box additional; Reflux water-dividing is after half a hour, with 99g trans-the 100mL toluene solution of 4-oxygen base-2-butylene acetoacetic ester slowly was added dropwise in the reaction flask in 2 hours, dropwised the continued reflux water-dividing 7 hours; Concentration of reaction solution after reaction finishes adds 500mL ethanol, 500mL water and 34.3g sodium hydroxide, refluxing and stirring 9 hours in resistates; Reaction finishes the back steaming except that ethanol, and water layer is regulated pH to 6 with 6M hydrochloric acid after washing with chloroform; Separate out a large amount of faint yellow solids, filter washing with acetone; Get 2-(imidazo [1,2-α] pyridin-3-yl) acetate 116g, yield 85.3% after the oven dry.
1
HNMR?(400MHz,DMSO)：δ?4.037(s,?2H)，6.911-6.944(q,?1H)，7.220-7.260(q,?1H)，7.474(s,?1H)，7.550-7.572(d,1H)，8.295-8.312(d,1H)?ppm。
The preparation method of embodiment 2 2-(imidazo [1,2-α] pyridin-3-yl) acetate
add 184g 2-EL-970,5g tosic acid in the 5L reaction flask, add 3.5L toluene again, install division box additional; Reflux water-dividing is after half a hour, with 99g trans-the 100mL toluene solution of 4-oxygen base-2-butylene acetoacetic ester slowly was added dropwise in the reaction flask in 2 hours, dropwised the continued reflux water-dividing 8 hours; Concentration of reaction solution after reaction finishes adds 500mL ethanol, 500mL water and 34.3g sodium hydroxide, refluxing and stirring 9 hours in resistates; Reaction finishes the back steaming except that ethanol, and water layer is regulated pH to 6 with 6M hydrochloric acid after washing with chloroform; Separate out a large amount of faint yellow solids, filter washing with acetone; Get 2-(imidazo [1,2-α] pyridin-3-yl) acetate 112g, yield 82.2% after the oven dry.
The preparation method of embodiment 3 2-(imidazo [1,2-α] pyridin-3-yl) acetate
add 184g 2-EL-970,5g tosic acid in the 5L reaction flask, add 3.5L benzene again, install division box additional; Reflux water-dividing is after half a hour, with 99g trans-the 100mL benzole soln of 4-oxygen base-2-butylene acetoacetic ester slowly was added dropwise in the reaction flask in 2 hours, dropwised the continued reflux water-dividing 8 hours; Concentration of reaction solution after reaction finishes adds 500mL ethanol, 500mL water and 34.3g sodium hydroxide, refluxing and stirring 9 hours in resistates; Reaction finishes the back steaming except that ethanol, and water layer is regulated pH to 6 with 6M hydrochloric acid after washing with chloroform; Separate out a large amount of faint yellow solids, filter washing with acetone; Get 2-(imidazo [1,2-α] pyridin-3-yl) acetate 120g, yield 88.1% after the oven dry.
The preparation method of embodiment 4 2-(imidazo [1,2-α] pyridin-3-yl) acetate
add 365g 2-EL-970,5g tosic acid in the 5L reaction flask, add 3.5L benzene again, install division box additional; Reflux water-dividing is after half a hour, with 99g trans-the 100mL benzole soln of 4-oxygen base-2-butylene acetoacetic ester slowly was added dropwise in the reaction flask in 2 hours, dropwised the continued reflux water-dividing 8 hours; Concentration of reaction solution after reaction finishes adds 500mL ethanol, 500mL water and 34.3g sodium hydroxide, refluxing and stirring 9 hours in resistates; Reaction finishes the back steaming except that ethanol, and water layer is regulated pH to 6 with 6M hydrochloric acid after washing with chloroform; Separate out a large amount of faint yellow solids, filter washing with acetone; Get 2-(imidazo [1,2-α] pyridin-3-yl) acetate 113.3g, yield 83.2% after the oven dry.
The preparation method of embodiment 5 2-(imidazo [1,2-α] pyridin-3-yl) acetate
add 73g2-EL-970,5g tosic acid in the 5L reaction flask, add 3.5L benzene again, install division box additional; Reflux water-dividing is after half a hour, with 99g trans-the 100mL benzole soln of 4-oxygen base-2-butylene acetoacetic ester slowly was added dropwise in the reaction flask in 2 hours, dropwised the continued reflux water-dividing 8 hours; Concentration of reaction solution after reaction finishes adds 500mL ethanol, 500mL water and 34.3g sodium hydroxide, refluxing and stirring 9 hours in resistates; Reaction finishes the back steaming except that ethanol, and water layer is regulated pH to 6 with 6M hydrochloric acid after washing with chloroform; Separate out a large amount of faint yellow solids, filter washing with acetone; Get 2-(imidazo [1,2-α] pyridin-3-yl) acetate 88.8g, yield 65.2% after the oven dry.
The method of experimental example 1 prior art for preparing 2-(imidazo [1,2-α] pyridin-3-yl) acetate
add 184g2-EL-970,5g tosic acid in the 5L reaction flask, add the 3.5L acetonitrile again, after the half a hour of refluxing; With 99g trans-the 100mL acetonitrile solution of 4-oxygen base-2-butylene acetoacetic ester slowly was added dropwise in the reaction flask in 2 hours, dropwise continued and refluxed 6 hours, the reaction back concentration of reaction solution that finishes; In resistates, add 500mL ethanol, 500mL water and 34.3g sodium hydroxide, refluxing and stirring 9 hours, reaction finishes the back steaming except that ethanol; Water layer is regulated pH to 6 with 6M hydrochloric acid after washing with chloroform, separates out a large amount of faint yellow solids; Filter, washing with acetone gets 2-(imidazo [1 after the oven dry; 2-α] pyridin-3-yl) acetate 54.5g, yield 40.0%.
Claims (6)
1.
A kind of suc as formula the (imidazo [1 of the 2-shown in the I; 2-α] pyridin-3-yl) preparation method of acetate, may further comprise the steps: with the 2-EL-970 is starting raw material, reacts in organic solvent with trans-4-oxygen base-2-butylene acid esters and catalyzer to obtain 2-(imidazo [1; 2-α] pyridin-3-yl) acetate compounds (formula II); This midbody need not purifying, directly can obtain title product 2-(imidazo [1,2-α] pyridin-3-yl) acetate (formula I) after hydrolysis under basic soln, the acidifying:
In
formula, R represent methylidene, ethyl.
2.
method according to claim 1 is characterized in that in reaction, having used division box.
3.
method according to claim 1 is characterized in that the mol ratio of 2-EL-970 and trans-4-oxygen base-2-butylene acid esters is 1:1-5:1.
4.
method according to claim 1 is characterized in that wherein said organic solvent is benzene, toluene, hexanaphthene or benzene/cyclohexane mixed solvent, toluene/hexanaphthene mixed solvent.
5.
method according to claim 1 is characterized in that wherein said catalyzer is a tosic acid.
6.
method according to claim 1 is characterized in that wherein said alkali selects from sodium hydroxide or Pottasium Hydroxide, and reaction soln is selected from the aqueous solution or water/methanol mixed solution, water/alcohol mixed solution.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1639152A (en) * | 2002-03-08 | 2005-07-13 | 伊莱利利公司 | Pyrrole-2,5-dione derivatives and their use as GSK-3 inhibitors |
| 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 |
-
2010
- 2010-10-12 CN CN2010105038717A patent/CN102443002A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1639152A (en) * | 2002-03-08 | 2005-07-13 | 伊莱利利公司 | Pyrrole-2,5-dione derivatives and their use as GSK-3 inhibitors |
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| THOMAS A. ENGLER，等: "Substituted 3-Imidazo[1,2-a]pyridin-3-yl-4-(1,2,3,4-tetrahydro-[1,4]diazepino-[6,7,1-hi]indol-7-yl)pyrrole-2,5-diones as Highly Selective and Potent Inhibitors of Glycogen Synthase Kinase-3", 《J. MED. CHEM.》 * |
| 郑巍，等: "GSK3 抑制剂的合成", 《复旦学报(自然科学版)》 * |
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Address after: 611731, No. 1, South Road, hi tech West, Sichuan, Chengdu Applicant after: Sichuan Dihon Medical Development Co., Ltd. Co-applicant after: Dihon Pharmaceutical Group Co., Ltd. Co-applicant after: Yunnan Dihon Pharmaceutical Co., Ltd. Address before: 611731, No. 1, South Road, hi tech West, Sichuan, Chengdu Applicant before: Sichuan Dihon Medical Development Co., Ltd. Co-applicant before: Kuning Dianhong Pharmaceutical Co., Ltd. Co-applicant before: Yunnan Dihon Pharmaceutical Group Co., Ltd. |
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Effective date of registration: 20130220 Address after: 611731, No. 1, South Road, hi tech West, Sichuan, Chengdu Applicant after: Sichuan Dihon Medical Development Co., Ltd. Applicant after: Dihon Pharmaceutical Group Co., Ltd. Address before: 611731, No. 1, South Road, hi tech West, Sichuan, Chengdu Applicant before: Sichuan Dihon Medical Development Co., Ltd. Applicant before: Dihon Pharmaceutical Group Co., Ltd. Applicant before: Yunnan Dihon Pharmaceutical Co., Ltd. |
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