68968-12-7

Upstream product

• 1878-65-5 3-chlorophenylacetic acid 
• 108-90-7 chlorobenzene 
• 108-37-2 1-bromo-3-chlorobenzene 
• 99-91-2 para-chloroacetophenone 
• 1126-46-1 Methyl 4-chlorobenzoate 
• 122-01-0 4-chloro-benzoyl chloride 
• 620-20-2 1-Chloro-3-chloromethyl-benzene 
• 41904-39-6 3-chloro-benzeneacetyl chloride 

Downstream Products

• 1352074-13-5 (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one 
• 1352072-73-1 (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one 
• 1388625-18-0 (S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-((S)-1-hydroxybutan-2-yl)-2-methylpent-4-enamide 
• 1352073-44-9 (3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium trifluoromethanesulfonate 
• 1352072-34-4 (S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-((2S,3S)-2-hydroxypentan-3-yl)-2-methylpent-4-enamide 
• 1388625-21-5 (2R,3R,5S)-5-allyl-3-(3-chlorophenyl)-2-(4-chlorophenyl)-2-hydroxy-5-methylcyclopentanone 
• 1388625-26-0 C₂₁H₂₂Cl₂O₃ 
• 1352072-35-5 (1R,2R,4S)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-4-((4S,5S)-4-ethyl-5-methyl-4,5-dihydrooxazol-2-yl)-4-methylhept-6-en-1-ol 
• 1352072-36-6 (2S,3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,8-dimethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium trifluromethanesulfonate 
• 1388625-22-6 C₂₁H₂₀Cl₂O⁽¹⁸⁾O 
• 1388625-23-7 C₂₆H₃₃Cl₂NO₂⁽¹⁸⁾O 
• 1388625-11-3 (4R,5R)-methyl 4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxypentanoate 
• 1388625-10-2 (4R,5R)-isopropyl 4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxypentanoate 
• 1352076-45-9 (3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one 

Relevant academic research and scientific papers

Development of a Robust and Highly Selective Ru(II)-Catalyzed Dynamic Kinetic Resolution Used to Manufacture AMG 232

We describe herein the development of a scalable Noyori reductive dynamic kinetic resolution to manufacture DLAC, a ? -lactone precursor to the active pharmaceutical ingredient AMG 232. Central to this work was the identification of the ruthenabicyclic complex RuCl[(S)-daipena][(S)-xylBINAP] ((S)-RUCY-xylBINAP), which afforded the product with >98:2 enantiomeric ratio at a substrate to catalyst loading (S/C) of 2000:1. By transesterification to a more sterically hindered isopropyl ester prior to the hydrogenation, we were able to curb unexpected ester reduction. Optimization of base equivalents in the final alkylation step to form DLAC prevented product degradation. The optimized process was scaled to >200 kg, providing 147 kg of DLAC in 56percent overall yield with 99.9percent optical purity.

PROCESSES FOR PREPARING A MDM2 INHIBITOR

The present invention provides commercial processes for preparing 2- ((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-l-((S)-l-(isopropylsulfonyl)-3-methylbutan-2-yl)-3 -m ethyl-2-oxopiperi din-3 -yl)acetic acid as well as intermediates thereof.

COMBINATION THERAPY INCLUDING AN MDM2 INHIBITOR AND ONE OR MORE ADDITIONAL PHARMACEUTICALLY ACTIVE AGENTS FOR THE TREATMENT OF CANCERS

The present invention provides combination therapy that includes an MDM2 inhibitor and one or more additional pharmaceutically active agents, particularly for the treatment of cancers. The invention also relates to pharmaceutical compositions that contain

Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer

We recently reported the discovery of AMG 232 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 protein-protein interaction. Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer. This article provides an overview of its discovery from the de novo design of the piperidinone series to the structure-activity studies leading to the identification of 1. In addition, this article also describes the preclinical pharmacology and pharmacokinetics of 1, along with its drug metabolism and safety assessment.

PROCESSES OF MAKING AND CRYSTALLINE FORMS OF A MDM2 INHIBITOR

The present invention provides processes for making 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid as well as intermediates and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates.

BENZOIC ACID DERIVATIVE MDM2 INHIBITOR FOR THE TREATMENT OF CANCER

The present invention provides a MDM2 inhibitor compound, or a pharmaceutically acceptable salt thereof, which compound is useful as a therapeutic agent, particularly for the treatment of cancers. The present invention also relates to pharmaceutical compositions that contains the MDM2 inhibitor.

An expeditious synthesis of the MDM2-p53 inhibitor AM-8553

The development of the structurally complex MDM2/p53 inhibitor AM-8553 was impeded by the low yield of the initial synthesis. A second generation synthesis is described that features a Noyori dynamic kinetic resolution, a highly diastereoselective allylation, and a novel oxazoline-assisted piperidinone forming reaction to provide AM-8553 in 35.6% yield and 11 steps.

Structure-based design of novel inhibitors of the MDM2-p53 interaction

Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.

Preparation of functionalized organomanganese(II) reagents by direct insertion of manganese to aromatic and benzylic halides

Functionalized arylmanganese compounds were prepared using commercial manganese powder in the presence of LiCl and catalytic amounts of both 2.5% InCl3 and 2.5% PbCl2 (THF, 0-50 °C). In addition, benzylic manganese reagents are obtained at 25 °C in ca. 70-80% yield (in the absence of LiCl) using commercial manganese powder and catalytic amounts of 2.5% InCl3 and 2.5% PbCl2. The resulting organomanganese reagents undergo smooth 1,2-addition, acylation, allylic substitution, Pd-catalyzed cross-coupling, and copper-catalyzed conjugate addition, affording the desired products in good yields.