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Relevant academic research and scientific papers

Stereocontrolled Synthesis of Delgocitinib, a JAK Inhibitor for the Treatment of Atopic Dermatitis

Herein is reported the nine-step commercial synthesis of delgocitinib, a Janus kinase inhibitor approved for the treatment of atopic dermatitis in 2020. Its chiral spirodiamine core was selectively constructed by an intramolecular SN2 reaction of the suitably designed γ-lactone substrate and a few subsequent steps including a selective γ-lactone ring-opening reaction with potassium phthalimide, hydrazine-free mild dephthaloylation, and one-pot reduction of β- and γ-lactams. The route affords chemically and stereochemically pure delgocitinib in 39% yield.

Delgocitinib intermediate and preparation method thereof

The invention discloses a delgocitinib intermediate (3S, 4R)-3-methyl-beta-oxo-1,6-diazaspiro [3, 4] octane-1-propionitrile and a preparation method thereof. Common compounds are usually used as starting materials and successively subjected to reactions such as bromination, acylation, cyclization, substitution, reduction condensation and the like, so that the raw materials in the preparation process are easily available, and the preparation method is economical and environmentally friendly. Delgocitinib can be prepared through one-step condensation between the intermediate and 4-chloro-7H-pyrrole [2, 3-d] pyrimidine, so that a new way is provided for the preparation of the raw material medicine.

Discovery of a Janus Kinase Inhibitor Bearing a Highly Three-Dimensional Spiro Scaffold: JTE-052 (Delgocitinib) as a New Dermatological Agent to Treat Inflammatory Skin Disorders

Dermatologic disorders such as atopic dermatitis arise from genetic and environmental causes and are complex and multifactorial in nature. Among possible risk factors, aberrant immunological reactions are one of the leading etiologies. Immunosuppressive agents including topical steroids are common treatments for these disorders. Despite their reliability in clinical settings, topical steroids display side effects, typified by skin thinning. Accordingly, there is a need for alternate effective and well-tolerated therapies. As part of our efforts to investigate new immunomodulators, we have developed a series of JAK inhibitors, which incorporate novel three-dimensional spiro motifs and unexpectedly possess both excellent physicochemical properties and antidermatitis efficacy in the animal models. One of these compounds, JTE-052 (ent-60), also known as delgocitinib, has been shown to be effective and well-tolerated in human clinical trials and has recently been approved in Japan for the treatment of atopic dermatitis as the first drug among Janus kinase inhibitors.

PROCESS FOR PREPARING 7H-PYRROLO[2,3-d]PYRIMIDINE DERIVATIVES AND SYNTHETIC INTERMEDIATES THEREOF

The present invention provides processes for preparing 7H-pyrrolo[2,3-d]pyrimidine derivatives, which are useful as a Janus kinase (JAK) inhibitor, intermediates thereof, and processes for preparing the intermediates. The present invention provides processes for preparing 3-[(3S, 4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile using salts of (3S,4R)-1-benzyl-3-methyl-1,6-diazaspiro[3.4]octane with organic acids.

Delgocitinib intermediate and preparation method thereof

The invention discloses a delgocitinib intermediate, namely (3S,4R)-3-methyl-beta-oxo-1,6-diazaspiro[3,4]octane-1-propionitrile, and a preparation method thereof. According to the preparation method,common compounds are used as starting materials and are subjected to bromination, acylation, cyclization, substitution, condensation reduction and other reactions sequentially so as to prepare the delgocitinib intermediate; and raw materials used in the preparation process are easy to obtain, and the preparation method is economical and environmentally friendly. Delgocitinib can be prepared through one-step condensation between the intermediate and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, so a novel way is provided for the preparation of the bulk drug delgocitinib.

Preparation method of delgocitinib

The invention discloses a preparation method of delgocitinib. According to the preparation method, common compounds are used as initial raw materials, and bromination, acylation, cyclization, substitution, reduction condensation and other reactions are sequentially carried out, so that the raw materials in the preparation process are easy to obtain, economical and environment-friendly, a new preparation way is provided for the raw material medicine, and the method is suitable for large-scale industrial production.

Preparation method of delgocitinib

The invention discloses a preparation method of a delgocitinib intermediate. Common compounds are used as starting materials, and bromination, acylation, cyclization, substitution, condensation reduction and other reactions are sequentially carried out. The raw materials in the preparation process are easy to obtain, economical and environmentally friendly, a new preparation way is provided for the raw material medicine, and the preparation method is suitable for large-scale industrial production.

Method for Producing 7h-pyrrolo[2, 3-d]pyrimidine Derivative and Intermediate Thereof

The present invention provides a method for producing a 7H-pyrrolo[2,3-d]pyrimidine derivative that is useful as a janus kinase (JAK) inhibitor; an intermediate of the 7H-pyrrolo[2,3-d]pyrimidine derivative; and a method for producing the intermediate. The present invention provides a method for producing 3-[(3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile, which uses a salt of an organic acid and (3S,4R)-3-methyl-1,6-diazaspiro[3.4]octane-1-carboxylic acid benzyl.

CRYSTALLINE FORMS OF A JANUS KINASE INHIBITOR

The present invention relates to crystalline forms of the Janus kinase (JAK) inhibitor 3-((3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl)-3-oxopropanenitrile (Compound A), as well as, compositions thereof, methods of their preparation, methods of use thereof, and methods of quantitation.

NITROGEN-CONTAINING SPIROCYCLIC COMPOUNDS AND PHARMACEUTICAL USES THEREOF

A compound of the following general formula [I]: wherein each symbol has the same meaning as defined herein, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutical use of the same in treating organ transplant rejection, graft versus host reaction after transplantation, autoimmune disease, allergic disease and chronic myeloproliferative disease.