86825-70-9

Upstream product

• 1088-00-2 9-phenyl-9-phosphafluorene 
• 2446-83-5 di-isopropyl azodicarboxylate 
• 603-35-0 triphenylphosphine 
• 2446-83-5 diisopropyl (E)-azodicarboxylate 

Downstream Products

• 791-28-6 Triphenylphosphine oxide 

Relevant academic research and scientific papers

Phosphitylation via the Mitsunobu reaction

Treatment of a dialkyl phosphite with triphenylphosphine and diisopropyl azodicarboxylate in toluene, followed by addition of an alcohol, results in the formation of the corresponding trialkyl phosphite. Similarly, dialkyl phosphonites can be synthesised from monoalkyl phosphites (alkyl phosphinates).

Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase í (PI3Kí) Inhibitor for the Treatment of Immunological Disorders

PI3Kí plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kí inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4′-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.

Intermediates for macrocyclic compounds

The present invention is directed to novel macrocyclic compounds of formula (I) and their pharmaceutically acceptable salts, hydrates or solvates: wherein R1, R2, R3, R4, R5, R6, n1, m, p Z1, Z2, and Z3 are as describe in the specification. The invention also relates to compounds of formula (I) which are antagonists of the motilin receptor and are useful in the treatment of disorders associated with this receptor and with or with motility dysfunction.

The mechanism of the first step of the Mitsunobu reaction

Previous DFT calculations employing phosphine (PH3) and dimethyl azodicarboxylate showed that a cyclic O,N-phosphorane was energetically favored relative to betaine formation. In this study strong experimental support for the formation of the phosphorane is described. The question of whether betaine formation occurs via nucleophilic attack of the phosphine on the azodicarboxylate as has been previously assumed, or via a [4+2] cycloaddition (cheletropic) reaction to give the O,N-phosphorane, followed by ring-opening to give the betaine has not been resolved. An answer to this intriguing question is provided.

MACROCYCLIC ANTAGONISTS OF THE MOTILIN RECEPTOR FOR TREATMENT OF GASTROINTESTINAL DYSMOTILITY DISORDERS

The present invention provides conformationally-defined macrocyclic compounds that bind to and/or are functional modulators of the motilin receptor including subtypes, isoforms and/or variants thereof. These macrocyclic compounds, at a minimum, possess adequate pharmacological properties to be useful as therapeutics for a range of disease indications. In particular, these compounds are useful for treatment and prevention of disorders characterized by hypermotilinemia and/or gastrointestinal hypermotility, including, but not limited to, diarrhea, cancer treatment-related diarrhea, cancer-induced diarrhea, chemotherapy-induced diarrhea, radiation enteritis, radiation-induced diarrhea, stress-induced diarrhea, chronic diarrhea, AIDS-related diarrhea, C. difficile associated diarrhea, traveller's diarrhea, diarrhea induced by graph versus host disease, other types of diarrhea, dyspepsia, irritable bowel syndrome, chemotherapy-induced nausea and vomiting (emesis) and post-operative nausea and vomiting and functional gastrointestinal disorders. In addition, the compounds possess utility for the treatment of diseases and disorders characterized by poor stomach or intestinal absorption, such as short bowel syndrome, celiac disease and cachexia. The compounds also have use for the treatment of inflammatory diseases and disorders of the gastrointestinal tract, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease and pancreatitis. Accordingly, methods of treating such disorders and pharmaceutical compositions including compounds of the present invention are also provided.

Preparation of isocyanates from primary amines and carbon dioxide using Mitsunobu chemistry

Primary alkylamines 1 and hindered arylamines 1 give high yields of isocyanates 5 when reacted with carbon dioxide and the Mitsunobu zwitterions 4 generated from dialkyl azodicarboxylates and Bu3P in dichloromethane at - 78°C. Use of Ph3P still gave high yields of isocyanates from reactions of primary alkylamines, but only low yields were obtained from reactions of aromatic amines. Reactions which failed to give high yields of isocyanates gave either carbamoylhydrazines 6 and/or dicarbamoylhydrazines 10 and/or triazolinones 7. The triazolinones were shown to arise from reactions of reactive aryl isocyanates with the Mitsunobu zwitterion. The carbamoylhydrazines were shown not to arise from reaction of isocyanate with reduced dialkyl azodicarboxylates, and a mechanism for their formation is proposed. Single-crystal X-ray analyses confirmed the structures of 6, 7, and 10.