CN105801574A - Preparation method of 1H-pyrazolo[3,4-b]pyridine compound - Google Patents
Preparation method of 1H-pyrazolo[3,4-b]pyridine compound Download PDFInfo
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- CN105801574A CN105801574A CN201410845687.9A CN201410845687A CN105801574A CN 105801574 A CN105801574 A CN 105801574A CN 201410845687 A CN201410845687 A CN 201410845687A CN 105801574 A CN105801574 A CN 105801574A
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- Prior art keywords
- pyrazolo
- preparation
- chloro
- pyridine compound
- reaction
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- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- -1 1H-pyrazolo[3,4-b]pyridine compound Chemical class 0.000 title abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 9
- KHPAGGHFIDLUMB-UHFFFAOYSA-N 2-chloropyridine-3-carbaldehyde Chemical compound ClC1=NC=CC=C1C=O KHPAGGHFIDLUMB-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 6
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 239000003054 catalyst Substances 0.000 claims abstract 3
- GVLRTOYGRNLSDW-UHFFFAOYSA-N 1h-pyrazolo[3,4-b]pyridine Chemical class C1=CC=C2C=NNC2=N1 GVLRTOYGRNLSDW-UHFFFAOYSA-N 0.000 claims description 5
- 150000003222 pyridines Chemical class 0.000 claims description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000012805 post-processing Methods 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000003217 pyrazoles Chemical class 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108010001789 Calcitonin Receptors Proteins 0.000 description 1
- 102100038520 Calcitonin receptor Human genes 0.000 description 1
- 102000005483 Cell Cycle Proteins Human genes 0.000 description 1
- 108010031896 Cell Cycle Proteins Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 description 1
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 230000003023 adrenocorticotropic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a preparation method of a 1H-pyrazolo[3,4-b]pyridine compound. The 1H-pyrazolo[3,4-b]pyridine compound is generated through a ring closing reaction of a raw material 2-chloro-3-pyridinecarboxaldehyde in a solvent dimethyl formamide (DMF) under the action of a catalyst hydroxylamine hydrochloride, and the total yield of the reaction can reach 85%. The method has the advantages of cheap and easily available raw materials, mild reaction conditions, simple post-treatment process, simple operation, high chemical yield, good application prospect, environmental protection, and suitableness for industrial production.
Description
Technical field
The preparation method that the present invention relates to a kind of medicine intermediate, the specifically preparation method of 1H-pyrazolo [3,4-b] pyridine compounds.
Background technology
1H-pyrazolo [3,4-b] pyridine is important chemical intermediate.Due to its specific physiologically active and and indoles structure on similarity, cause people's interest widely.Pharmaceutical research shows: many pyrazoles and pyridine compounds and their are that glycogen closes kinases-3(GSK-3), the inhibitor of cell cycle protein dependent kinase (CDKS), simultaneously can also as the local stimulant of calcitonin receptor and platelet activating factor, adrenotrophic hormone and short kidney business's glandular hormone releasing factor etc. with regard to antagonist.This compounds has good curative effect in preventing kirschner feminine gender and positive bacteria, tumor and cancer, asthma, nervous system disease, skeleton bulking disease and senile dementia.Therefore people are to the research of this compounds more and more deeply with extensive, synthesized thousands of kinds of pyrazoles and pyridine derivatives at present.
null" the Synthesisandbiologicalevaluationofimidazo [4 published for 2012,5-b] pyridineand4-heteroaryl-pyrimidinederivativesasanti-canc eragents " document is mentioned，Initiation material as CDKS synthesis，Synthetic route about this compound is: by 2-chloro-3-pyridyl formaldehyde，3 dehydrated alcohol，85% hydrazine hydrate，React，Obtain target product，Yield is 43%，This process route is relatively simple，But in practical operation，Find that the shortcoming using the existence of this technique is: if expecting highly purified product，Column chromatography must be carried out and be easily separated purification，According to this technique，When amplifying, cost is too big，It is unfavorable for industrialized synthesis.
Summary of the invention
Disclosure one 1H-pyrazolo [3,4-b] preparation method of pyridine compounds, using dimethylformamide (DMF) as solvent, raw material 2-chloro-3-pyridyl formaldehyde is under the effect of hydrochloric azanol, there is ring-closure reaction, generating 1H-pyrazolo [3,4-b] pyridine compounds, overall yield of reaction can reach 85%.
The present invention has cheaper starting materials and is easy to get, and reaction condition is gentle, and last handling process is simple, easy and simple to handle；Chemical yield is advantages of higher relatively, has a good application prospect, and these process conditions are gentle, easy and simple to handle, yield high-environmental, is suitable for the advantages such as industrialized production.
Be will assist in by following embodiment and understand the present invention, but be not restricted to present disclosure.
The synthesis of embodiment 11H-pyrazolo [3,4-b] pyridine compounds.
1L there-necked flask adds 20g(141.3mmol) 2-chloro-3-pyridyl formaldehyde, 200ml dimethylformamide, 10g oxammonium hydrochloride. (namely be 1:1 with the mol ratio of raw material), triethylamine 100ml, 60 DEG C are reacted 6 hours, and TLC follows the tracks of.React complete, carry out post processing, obtain product about 7.3 grams.Yield is 43%.
The synthesis of embodiment 21H-pyrazolo [3,4-b] pyridine compounds.
1L there-necked flask adds 20g(141.3mmol) 2-chloro-3-pyridyl formaldehyde, 200ml dimethylformamide, 50g oxammonium hydrochloride. (namely be 5:1 with the mol ratio of raw material), triethylamine 100ml, 60 DEG C are reacted 8 hours, and TLC follows the tracks of.React complete, carry out post processing, obtain product about 12 grams.Yield is 71%.
The synthesis of embodiment 31H-pyrazolo [3,4-b] pyridine compounds.
1L there-necked flask adds 20g(141.3mmol) 2-chloro-3-pyridyl formaldehyde, 200ml dimethylformamide, 25g oxammonium hydrochloride. (namely be 2.5:1 with the mol ratio of raw material), triethylamine 100ml, 60 DEG C are reacted 8 hours, and TLC follows the tracks of.React complete, carry out post processing, obtain product about 15.2 grams.Yield is 85%.
Its physicochemical data is: [m+H]=120；HNMR(CDCl3): 7.2 (1H), 8.15 (2H), 8.66 (1H), 12.49 (1H).
Claims (3)
1. a 1H-pyrazolo [3,4-b] preparation method of pyridine compounds, it includes using dimethylformamide (DMF) as solvent, 2-chloro-3-pyridyl formaldehyde is under the effect of catalyst, there is ring-closure reaction, generate 1H-pyrazolo [3,4-b] pyridine compounds, it is characterised in that catalyst adopts oxammonium hydrochloride..
2. the method for claim 1, it is characterised in that the mol ratio of the 2-chloro-3-pyridyl formaldehyde reaction of described hydrochloric azanol and raw material is 5-1:1.
3. the method for claim 1, it is characterised in that the mol ratio of the 2-chloro-3-pyridyl formaldehyde reaction of described hydrochloric azanol and raw material is 2.5:1.
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| CN105801574A true CN105801574A (en) | 2016-07-27 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113354638A (en) * | 2021-07-12 | 2021-09-07 | 天津敬康生物科技有限公司 | Preparation method of 5-fluoro-3-iodo-1H-pyrazolo [3,4-b ] pyridine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008039359A2 (en) * | 2006-09-25 | 2008-04-03 | Janssen Pharmaceutica N.V. | Bicyclic pyrimidine kinase inhibitors |
| CN101242839A (en) * | 2005-06-22 | 2008-08-13 | 凯莫森特里克斯股份有限公司 | Azaindazole compounds and methods of use |
-
2014
- 2014-12-31 CN CN201410845687.9A patent/CN105801574A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101242839A (en) * | 2005-06-22 | 2008-08-13 | 凯莫森特里克斯股份有限公司 | Azaindazole compounds and methods of use |
| WO2008039359A2 (en) * | 2006-09-25 | 2008-04-03 | Janssen Pharmaceutica N.V. | Bicyclic pyrimidine kinase inhibitors |
Non-Patent Citations (3)
| Title |
|---|
| KAMAL M. EL-GAMAL等: "Synthesis, characterization and antimicrobial evaluation of some novel quinoline derivatives bearing different heterocyclic moieties", 《BULLETIN OF FACULTY OF PHARMACY, CAIRO UNIVERSITY》 * |
| KIRTI S. NIRALWAD等: "SYNTHESIS OF BIOLOGICALLY ACTIVE ISOXAZOLO [5, 4-B] QUINOLINES AT ROOM TEMPERATURE", 《INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACEUTICAL AND NANO SCIENCES》 * |
| V. NADARAJ等: "Synthesis and Characterization of some Quinoline bearing Isoxazoles nucleus", 《JOURNAL OF CHEMICAL AND PHARMACEUTICAL RESEARCH》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113354638A (en) * | 2021-07-12 | 2021-09-07 | 天津敬康生物科技有限公司 | Preparation method of 5-fluoro-3-iodo-1H-pyrazolo [3,4-b ] pyridine |
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