- Practical Considerations and Examples in Adapting Amidations to Continuous Flow Processing in Early Development
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Amidation is among the most frequently executed reactions in pharmaceutical research and development. We have explored the feasibility of adapting amidations to plug flow reactor (PFR) process conditions for the preparation of early development compounds. Among coupling reagents possessing good thermal stability, carbodiimides and T3P have been selected, as they are readily soluble, require no preactivation, offer excellent reaction kinetics, and enable convenient product isolation. A carbodiimide/2-hydroxylpyridine oxide (HOPO) protocol was demonstrated in four case studies with homogeneous feed and reaction streams that were readily adaptable to a PFR design. In a head-to-head comparison, T3P was also found to be readily adaptable to a PFR flow process and gave comparable yields. The EDC/HOPO method works well for amidations that do not involve substrates that are highly sensitive to racemization; its water compatibility makes it the reagent of choice when the amine reactant is in a salt form, since water can be added as a cosolvent to aid solubility. For substrates that are extremely sensitive to racemization, we have shown one successful example of peptide coupling using TBTU or COMU under PFR continuous flow conditions.
- Li, Bryan,McWilliams, J. Christopher,Weisenburger, Gerald A.
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- CDK INHIBITORS
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Provided is a compound represented by structural formula (I), or a pharmaceutically acceptable salt, or a stereoisomer thereof useful for treating cancer.
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Page/Page column 87-88
(2020/11/23)
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- Gedatolisib intermediates for preparation of (by machine translation)
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The invention belongs to the organic synthesis and bulk drug intermediate preparation field, in particular to a method for preparing Gedatolisib, key intermediate and a key intermediate in the preparation method. The nitrobenzene nitrile and dicyanodiamine polyisobutylene triazine cyclization, morpholine link guan huan, hydrogenation of nitro reduction to obtain 4 - (4, 6 - II morpholino - 1, 3, 5 - triazine - 2 - yl) aniline; 4 - oxo-piperidine - 1 - carboxylic acid tert-butyl and dimethylamine salt by addition, de-Boc protecting group, amide, hydrogenation of nitro reduction to get new compounds (4 - aminophenyl) (4 - (dimethyl amino) piperidine - 1 - yl) methyl ketone; adopts the one-pot synthesis, (4, 6 - II morpholino - 1, 3, 5 - triazine - 2 - yl) aniline and chloromethane acid ester after the reaction, then adding (4 - aminophenyl) (4 - (dimethyl amino) piperidine - 1 - yl) methanone, to finally obtain the Gedatolisib. This preparation method has the advantages of easy availability of raw materials, process is simple, easy to operate, high yield and low cost and the like. (by machine translation)
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Paragraph 0020; 0109-0111; 0113-0115
(2018/09/14)
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- MECHANISTIC TARGET OF RAPAMYCIN SIGNALING PATHWAY INHIBITORS AND THERAPEUTIC APPLICATIONS THEREOF
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Selective mTOR inhibitors of formulas (I)-(III), processes for their preparation, pharmaceutical compositions containing them, and their use in the treatment of diseases and disorders, arising from abnormal cell growth, functions, or behaviors mediated by an mTOR kinase and/or one or more PI3K enzyme, are provided. Such diseases and disorder include cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.
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Paragraph 00136; 00137
(2018/04/11)
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- 5, 6, 7, 8-TETRAHYDROPYRIDO[4,3-D]PYRIMIDINE COMPOUNDS, THEIR USE AS MTOR, PI3, AND HSMG-1 KINASE INHIBITORS, AND THEIR SYNTHESES
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A compound of the Formula I: or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein, compositions comprising the compounds, and methods for making and using the compounds.
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Page/Page column 45
(2010/11/04)
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- 5,6,7,8-TETRAHYDROPYRIDO[3,4-D]PYRIMIDINE COMPOUNDS, THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES
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A compound of the Formula I: or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein, compositions comprising the compounds, and methods for making and using the compounds.
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Page/Page column 52
(2010/11/04)
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