CN107778313A - A kind of process for purification of the acetic acid of Minodronate intermediate imidazo [1,2 a] pyridine 3 - Google Patents
A kind of process for purification of the acetic acid of Minodronate intermediate imidazo [1,2 a] pyridine 3 Download PDFInfo
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- CN107778313A CN107778313A CN201610752739.7A CN201610752739A CN107778313A CN 107778313 A CN107778313 A CN 107778313A CN 201610752739 A CN201610752739 A CN 201610752739A CN 107778313 A CN107778313 A CN 107778313A
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- acetic acid
- pyridine
- imidazo
- acid
- purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The present invention relates to medicinal chemistry art, more particularly to a kind of process for purification of the acetic acid of Minodronate intermediate imidazo [1,2 a] pyridine 3.Only make solvent with pure water adds alkali soluble solution to the present invention, after decolouring, adjusts pH value with acid, obtains high-purity intermediate.The present invention is compared with prior art, it is not necessary to using organic solvent, has been inherently eliminated the problems such as traditional handicraft post processing is troublesome, three-waste pollution is serious, with safety simple to operate, high income, production cost is low, has larger implementary value and economic results in society.
Description
Technical field：
The present invention relates to medicinal chemistry art, more particularly to a kind of Minodronate intermediate imidazo [1,2-a] pyridine -3-
The process for purification of acetic acid.
Background technology：
Minodronic acid, entitled 1- hydroxyls -2- [imidazo (1, the 2-a) pyridin-3-yl] ethylidene of chemistry) two banks one are hydrated
Thing, be a kind of bisphosphonate class of drugs, external and animal experiment show can strong inhibition osteoclast and osteoclast absorption function,
Reduce the conversion of osteocyte.It is granted for treating osteoporosis in Japan in 2009.
The key intermediate of synthesis minodronic acid is imidazo [1,2-a] pyridine-3-acetic acid, CAS:17745-04-9, it is existing
Having has the preparation technology of several imidazos [1,2-a] pyridine-3-acetic acid in technology, such as CN101531681A (publication date：2009-
09-16), CN102153585A (publication date：2011-08-17), CN102250090A (publication date：2011-11-23), but synthesize
Imidazo [1, the 2-a] pyridine-3-acetic acid gone out is khaki solid, reacts if direct plungeed into, on the one hand may in next step
Some side reactions occur, waste raw material, produce more new impurity；On the other hand a large amount of impurity can be brought directly to final products,
Refined to finished product brings difficulty so that the relevant material of finished product is difficult control below formulation requirements scope.
Imidazo [1,2-a] pyridine-3-acetic acid
So in the synthesis of minot phosphoric acid, its key intermediate imidazo [1,2-a] pyridine-3-acetic acid is done further
It is refined, it appears it is particularly important.In the prior art to the process for purification of imidazo [1,2-a] pyridine-3-acetic acid generally using having
Solvent is recrystallized, and the ethanol of the organic solvent used such as 95%, methanol etc., refers to CN101531681A (publication date：
2009-09-16), CN102153585A (publication date：2011-08-17), CN102093352A (publication date：2011-06-15).
But the major defect of above-mentioned process for purification is to need to consume substantial amounts of organic solvent, produces waste liquid, causes environmental pollution, reacts
Post processing trouble, industrial production cost are high.
The content of the invention：
It is an object of the invention to provide a kind of new imidazo [1,2-a] pyridine-3-acetic acid process for purification, this method yield
Height, pollution is few, and postprocessing working procedures are simple, reduce production cost, are suitable for large-scale production.
The technical scheme is that be achieved by the steps of：
By imidazo [1,2-a] pyridine-3-acetic acid crude product and pure water, it is added in reactor and stirs, be slowly added to alkali, controls
Warm t1 is 10-50 DEG C of reaction, is stirred to solid all dissolving, adds activated carbon decolorizing, filtering, and filtrate adjusts PH to 5-7 with acid,
Temperature control t2 is 0-50 DEG C, crystallization, is filtered, after pure water filter cake, 50 DEG C of -80 DEG C of vacuum drying.Obtain purity and be more than 98.0%
Imidazo [1,2-a] pyridine-3-acetic acid.
Wherein, the mass volume ratio (kg of imidazo [1,2-a] pyridine-3-acetic acid crude product and pure water：L it is) 1：2-10, it is excellent
It is 1 to select ratio：4-7.
Imidazo [1,2-a] pyridine-3-acetic acid crude product is 1 by the amount ratio of material with alkali:0.5-5, it is preferably in a proportion of 1：1-
2。
The mass ratio of imidazo [1,2-a] pyridine-3-acetic acid crude product and activated carbon is 0.02-0.50, is preferably in a proportion of
0.05-0.20。
Imidazo [1,2-a] pyridine-3-acetic acid crude product is 1 by the amount ratio of material with acid:0.5-5, it is preferably in a proportion of 1：1-
2, acid therein is converted into monoacid and calculated.
Described acid is selected from least one of following material：Formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, it is preferably following
At least one of material：Acetic acid, hydrochloric acid.
Described t1 is 10 DEG C -50 DEG C, and preferable temperature is 20 DEG C -30 DEG C.
Described t2 is 0 DEG C -50 DEG C, and preferable temperature is 10 DEG C -20 DEG C.
The crystallization time is too short, and crystallization is insufficient, easily causes yield reduction, and the crystallization time is oversize, and crystal easily adsorbs miscellaneous
Matter, purity is caused to decline.So crystallization time control, in 0.5-3 hours, the preferably time is 1-2 hours.
Described alkali is at least one of following alkaline matter：Ammoniacal liquor, sodium carbonate, potassium carbonate, sodium hydroxide, hydroxide
Potassium.It is preferred that at least one of following alkaline matter：Sodium hydroxide, potassium hydroxide.
Compared with prior art, its advantage is embodied in the present invention：
1) refine and make solvent with pure water, environment is not polluted；
2) it has been inherently eliminated the problems such as traditional handicraft post-reaction treatment is troublesome, quantity of three wastes is big, seriously polluted.
Therefore, the present invention has safety simple to operate, and reaction yield is high, and production cost is low, and quantity of three wastes is few, has larger
Implementary value and economic results in society.
Embodiment：
Herein below is to combine specific preferred embodiment further description made for the present invention, it is impossible to is assert
The specific implementation of the present invention is confined to these explanations.For general technical staff of the technical field of the invention,
On the premise of not departing from present inventive concept, some simple deduction or replace can also be made, should all be considered as belonging to the present invention's
Protection domain.
Embodiment 1
By 1kg imidazos [1,2-a] pyridine-3-acetic acid crude product and 2L pure water, it is added in reactor and stirs, slowly adds
Enter 0.19kg 25% ammoniacal liquor, 10 DEG C of reactions of temperature control, stir to solid all dissolving, add 0.02kg activated carbon decolorizings, mistake
Filter, filtrate is adjusted PH to 5.0,0 DEG C, crystallization 0.5h of temperature control, filtered with 0.05L acetic acid, after pure water filter cake, 50 DEG C of vacuum
Dry.Obtain imidazo [1,2-a] pyridine-3-acetic acid of purity 98.0%, yield 86.0%.
Embodiment 2
By 1kg imidazos [1,2-a] pyridine-3-acetic acid crude product and 4L pure water, it is added in reactor and stirs, slowly adds
0.23kg enters sodium hydroxide, 20 DEG C of reactions of temperature control, stirs to solid all dissolving, adds 0.05kg activated carbon decolorizings, filter,
Filtrate is adjusted PH to 5.0,10 DEG C, crystallization 1h of temperature control, filtered with 0.07L hydrochloric acid, after pure water filter cake, 50 DEG C of vacuum drying.
Obtain imidazo [1,2-a] pyridine-3-acetic acid of purity 98.5%, yield 92.0%.
Embodiment 3
By 1kg imidazos [1,2-a] pyridine-3-acetic acid crude product and 5L pure water, it is added in reactor and stirs, slowly adds
Enter 0.34kg sodium hydroxide, 25 DEG C of reactions of temperature control, stir to solid all dissolving, add 0.1kg activated carbon decolorizings, mistake
Filter, filtrate are adjusted PH to 5.0,15 DEG C, crystallization 1.5h of temperature control, filtered, after pure water filter cake, 50 DEG C true with 0.10L hydrochloric acid
Sky is dried.Obtain imidazo [1,2-a] pyridine-3-acetic acid of purity 99.2%, yield 95%.
Embodiment 4
By 1kg imidazos [1,2-a] pyridine-3-acetic acid crude product and 6L pure water, it is added in reactor and stirs, slowly adds
Enter 0.64kg potassium hydroxide, 30 DEG C of reactions of temperature control, stir to solid all dissolving, add 0.2kg activated carbon decolorizings, mistake
Filter, filtrate is adjusted PH to 5.0,20 DEG C, crystallization 2h of temperature control, filtered with 0.19L acetic acid, after pure water filter cake, 50 DEG C of vacuum
Dry.Obtain imidazo [1,2-a] pyridine-3-acetic acid of purity 98.7%, yield 93%.
Embodiment 5
By 1kg imidazos [1,2-a] pyridine-3-acetic acid crude product and 7L pure water, it is added in reactor and stirs, slowly adds
Enter 0.68kg sodium hydroxide, 35 DEG C of reactions of temperature control, stir to solid all dissolving, add 0.3kg activated carbon decolorizings, mistake
Filter, filtrate is adjusted PH to 5.0,30 DEG C, crystallization 2.5h of temperature control, filtered with 0.29L acetic acid, after pure water filter cake, 50 DEG C
Vacuum drying.Obtain imidazo [1,2-a] pyridine-3-acetic acid of purity 98.1%, yield 90%.
Embodiment 6
By 1kg imidazos [1,2-a] pyridine-3-acetic acid crude product and 10L pure water, it is added in reactor and stirs, slowly
1.59kg potassium hydroxide is added, 50 DEG C of reactions of temperature control, stirs to solid all dissolving, adds 0.5kg activated carbon decolorizings, mistake
Filter, filtrate is adjusted PH to 5.0,50 DEG C, crystallization 3h of temperature control, filtered with 0.34L hydrochloric acid, after pure water filter cake, 50 DEG C of vacuum
Dry.Obtain imidazo [1,2-a] pyridine-3-acetic acid of purity 97.5%, yield 87%.
Claims (10)
- A kind of 1. process for purification of Minodronate intermediate imidazo [1,2-a] pyridine-3-acetic acid, it is characterised in that this method Comprise the following steps：By imidazo [1,2-a] pyridine-3-acetic acid crude product and pure water, it is added in reactor and stirs, temperature control t1For 20-50 DEG C, alkali is slowly added to, is stirred to solid all dissolving, adds activated carbon decolorizing, filtering, filtrate adjusts PH to 5- with acid 7, temperature control t2For 0-50 DEG C, crystallization, filter, after pure water filter cake, 50 DEG C of -80 DEG C of vacuum drying, obtain purity and be more than 98.0% imidazo [1,2-a] pyridine-3-acetic acid.
- 2. a kind of process for purification of Minodronate intermediate imidazo [1,2-a] pyridine-3-acetic acid as claimed in claim 1, Characterized in that, the mass volume ratio of imidazo [1,2-a] pyridine-3-acetic acid crude product and pure water is 1：2-10；Imidazo [1,2- A] pyridine-3-acetic acid crude product and alkali by the amount ratio of material is 1:0.5-5；Imidazo [1,2-a] pyridine-3-acetic acid crude product and activity The mass ratio of charcoal is 0.02-0.20；Imidazo [1,2-a] pyridine-3-acetic acid crude product is with acid by the amount of material than 1:0.5-5.
- A kind of 3. refined side of Minodronate intermediate imidazo [1,2-a] pyridine-3-acetic acid as claimed in claim 1 or 2 Method, it is characterised in that the mass volume ratio (kg of imidazo [1,2-a] pyridine-3-acetic acid crude product and pure water：L it is) 1：4-7；Miaow The azoles amount ratio that simultaneously [1,2-a] pyridine-3-acetic acid crude product presses material with alkali is 1：1-2；Imidazo [1,2-a] pyridine-3-acetic acid is thick The mass ratio of product and activated carbon is 0.05-0.10；Imidazo [1,2-a] pyridine-3-acetic acid crude product is with acid by the amount of material than 1： 1-2。
- A kind of 4. refined side of Minodronate intermediate imidazo [1,2-a] pyridine-3-acetic acid as claimed in claim 1 or 2 Method, it is characterised in that described acid is selected from least one of following material：Formic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid.
- A kind of 5. refined side of Minodronate intermediate imidazo [1,2-a] pyridine-3-acetic acid as claimed in claim 1 or 2 Method, it is characterised in that described acid is selected from least one of following material：Acetic acid, hydrochloric acid.
- 6. a kind of process for purification of Minodronate intermediate imidazo [1,2-a] pyridine-3-acetic acid as claimed in claim 1, Characterized in that, described t1For 20 DEG C -30 DEG C.
- 7. a kind of process for purification of Minodronate intermediate imidazo [1,2-a] pyridine-3-acetic acid as claimed in claim 1, Characterized in that, described t2For 10 DEG C -20 DEG C.
- 8. a kind of process for purification of Minodronate intermediate imidazo [1,2-a] pyridine-3-acetic acid as claimed in claim 1, Characterized in that, the described crystallization time is 0.5-3 hours.
- 9. a kind of process for purification of Minodronate intermediate imidazo [1,2-a] pyridine-3-acetic acid as claimed in claim 1, Characterized in that, described alkali is at least one of following alkaline matter：Ammoniacal liquor, sodium carbonate, potassium carbonate, sodium hydroxide, hydrogen Potassium oxide.
- 10. a kind of process for purification of Minodronate intermediate imidazo [1,2-a] pyridine-3-acetic acid as claimed in claim 1, Characterized in that, described alkali is at least one of following alkaline matter：Sodium hydroxide, potassium hydroxide.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610752739.7A CN107778313A (en) | 2016-08-29 | 2016-08-29 | A kind of process for purification of the acetic acid of Minodronate intermediate imidazo [1,2 a] pyridine 3 |
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| CN201610752739.7A CN107778313A (en) | 2016-08-29 | 2016-08-29 | A kind of process for purification of the acetic acid of Minodronate intermediate imidazo [1,2 a] pyridine 3 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108276405A (en) * | 2018-03-12 | 2018-07-13 | 南安市创培电子科技有限公司 | A kind of synthesis technology of medicine intermediate imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104693241A (en) * | 2015-03-02 | 2015-06-10 | 北京万全德众医药生物技术有限公司 | Method for synthetizing minodronic acid intermediate and preparing minodronic acid by virtue of one-pot process |
| CN105111238A (en) * | 2015-07-01 | 2015-12-02 | 中山海泓药业有限公司 | Method for producing minodronic acid monohydrate by using water as solvent |
| 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 |
-
2016
- 2016-08-29 CN CN201610752739.7A patent/CN107778313A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104693241A (en) * | 2015-03-02 | 2015-06-10 | 北京万全德众医药生物技术有限公司 | Method for synthetizing minodronic acid intermediate and preparing minodronic acid by virtue of one-pot process |
| CN105111238A (en) * | 2015-07-01 | 2015-12-02 | 中山海泓药业有限公司 | Method for producing minodronic acid monohydrate by using water as solvent |
| 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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108276405A (en) * | 2018-03-12 | 2018-07-13 | 南安市创培电子科技有限公司 | A kind of synthesis technology of medicine intermediate imidazo [1,2-A] pyridine-2-carboxylic acids ethyl ester |
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