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Usage

Uses

Used in Pharmaceutical Synthesis:
1H-Pyrazole-5-carbonitrile, 1-methyl-3-[(methylamino)methyl]is utilized as an intermediate in the synthesis of pharmaceuticals. Its unique structure allows it to be a key component in the development of new drugs, contributing to the advancement of medicinal chemistry.
Used in Agrochemical Production:
1H-Pyrazole-5-carbonitrile, 1-methyl-3-[(methylamino)methyl]also serves as an intermediate in the synthesis of agrochemicals, playing a crucial role in the development of crop protection products. Its application in this industry helps to enhance agricultural productivity and protect crops from pests and diseases.
Used as a Reagent in Organic Synthesis:
1H-Pyrazole-5-carbonitrile, 1-methyl-3-[(methylamino)methyl]can be employed as a reagent in organic synthesis, facilitating various chemical reactions and the creation of new organic compounds for research and development purposes.
Used in Chemical Research:
Due to its structure and properties, Methyl 1H-pyrazole-5-carbonitrile is considered valuable in chemical research. It can be used to study the properties of 1H-pyrazole derivatives and their potential applications in different fields, further expanding the understanding of organic chemistry.

Upstream product

• 136678-93-8 1,3-dimethyl-1H-pyrazole-5-carboxamide 
• 4027-57-0 ethyl 5-methyl-2H-pyrazole-3-carboxylate 
• 74-89-5 methylamine 
• 1454848-70-4 tert-butyl[(5-cyano-1-methyl-1Hpyrazol-3-yl)methyl]methylcarbamate 
• 5744-40-1 ethyl 1,3-dimethylpyrazole-5-carboxylate 
• 1454848-24-8 ((4-bromo-5-cyano-1-methyl-1H-pyrazol-3-yl)methyl)(methyl)carbamic acid tert-butyl ester 

Downstream Products

• 1612891-02-7 2-{(1R)-1-[(2-aminopyridin-3-yl)oxy]ethyl}-N-[(5-cyano-1-methyl-1H-pyrazol-3-yl)methyl]-4-fluoro-N-methylbenzamide 
• 1454846-35-5 (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile 
• 1612891-03-8 2-{(1R)-1-[(2-amino-5-bromopyridin-3-yl)oxy]ethyl}-N-[(5-cyano-1-methyl-1H-pyrazol-3-yl)methyl]-4-fluoro-N-methylbenzamide 
• 1612891-04-9 2-[(1R)-1-{[5-bromo-2-(diacetylamino)pyridin-3-yl]oxy}-ethyl]-N-[(5-cyano-1-methyl-1H-pyrazol-3-yl)methyl]-4-fluoro-N-methylbenzamide 

Relevant academic research and scientific papers

1-methyl-3-((methylamino)methyl)-1H-pyrazole-5-nitrile synthesis method

The invention belongs to the technical field of medicine and relates to a 1-methyl-3-((methylamino)methyl)-1H-pyrazole-5-nitrile synthesis method. Diethyl oxalate and acetone are easily acquirable andused as starting materials to obtain 1-methyl-3-((methylamino)methyl)-1H-pyrazole-5-nitrile through 7-step reaction including condensation, cyclization, methylation, amidation, oxidation, brominationand amination. By adoption of the method, preparation of 1-methyl-3-((methylamino)methyl)-1H-pyrazole-5-nitrile which is a key intermediate of antitumor drug lorlatinib (PF-06463922) is realized, thetotal yield reaches 5.7% or above, and simplicity in operation, convenience in aftertreatment, short time consumption and low cost are realized while industrialization can be realized beneficially. The intermediate and 5-fluoro-3-methyl isobenzofuran-1(3H)-ketone are subjected to reaction steps including ammonolysis, substitution, coupling, chiral resolution and the like to finally synthesize lorlatinib, and a novel method is provided for synthesis of the antitumor drug lorlatinib.

Discovery of (10 R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17- tetrahydro- 2H -8,4-(metheno)pyrazolo[4,3- h ][2,5,11]- benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.