What is 2-(4-Methoxy-benzyl)-2H-pyrazol-3-ylamine?

2-(4-Methoxy-benzyl)-2H-pyrazol-3-ylamine is always used as synthesis intermediate for compounds which is used as medicament.

Uwe Grether and his coworkers synthesized the organic compounds, which is useful for therapy and/or prophylaxis in a mammal, and in particular to compounds that are preferential agonists of the Cannabinoid Receptor 2 [1]. The CB1 receptor is mainly expressed in the central nervous system and to a lesser amount in the periphery. CB2, which is encoded by the CNR2 gene, is mostly expressed peripherally, on cells of the immune system, such as macrophages and T-cells, and in the gastrointestinal system. The CB2 receptor is also widely distributed in the brain where it is found primarily on microglia and not neurons. Uwe used 4 steps reaction to synthesis the functional compound as the CB2 agonists. The first step is the preparation of 1-[(4-Methoxyphenyl) methyl]-1H-pyrazolo[3,4-b] pyridine-4,6-diol. 1-[(4-Methoxyphenyl) methyl]-1H-pyrazol-5-amine and diethyl malonate were stirred for 15 minutes at room temperature and subsequently warmed in a microwave oven for 3 hours to 130° C. After cooling the solid product was filtered off and dried to yield the title compound as a light yellow solid. Step 2 is the preparation of 4,6-Dichloro-1-[(4-methoxyphenyl) methyl]-1H-pyrazolo[3,4-b] pyridine. A mixture of 1-[(4-methoxyphenyl) methyl]-1H-pyrazolo[3,4-b] pyridine-4,6-diol and phenylphosphonic dichloride was stirred at 170° C. for 20 hours. After cooling, the mixture was diluted with Dichloromethane (DCM), basicified with 25% sodium hydroxide in ice water and partitioned into DCM (3×100 mL); the organic phase was separated, dried with MgSO4, filtered and concentrated in vacuo.

The crude material was purified by flash chromatography (silica, ethyl acetate/DCM gradient) to afford the desired product as light-yellow solid. After the preparation of 6-Chloro-4-(3,3-difluoro-pyrrolidin-1-yl)-1-[(4-methoxyphenyl) phenyl]-1H-pyrazolo[3,4-b] pyridine in the third step and obtained 6-Cyclopropyl-4-(3,3-difluoro-pyrrolidin-1-yl)-1-[(4-methoxyphenyl) methyl]-1H-pyrazolo[3,4-b] pyridine in the fourth step. The end compound is in particular useful in the treatment or prophylaxis of diabetic retinopathy, retinal vein occlusion or uveitis.


Scheme 1 Synthesis of kinase inhibitors with 2-(4-Methoxy-benzyl)-2H-pyrazol-3-ylamine

Raj and his team synthesized series special compounds, which have pharmacological properties, in particular, the compounds are inhibitors of protein kinases such as the cyclin dependent kinases (cdks). The novel compounds are expected to be useful in the therapy of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative disorders and cardiovascular disease. There are 8 steps to get the compounds from 2-(4-Methoxy-benzyl)-2H-pyrazol-3-ylamine as shown in scheme 1.

Reference

[1] Uwe Grether et. al., Pyrazole compounds as CB2 agonists, US9512132B2.
[2] By Misra, Raj N. et. al., Preparation of benzoylpyrazolo[3,4-b] pyridines and analogs as cyclin dependent kinase inhibitors, PCT Int. Appl., 9930710, 24 Jun 1999
3] https://pubchem.ncbi.nlm.nih.gov/compound/3161262

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