Drug and Analog Synthesis PDF

Drug and Analog Synthesis Synthesis in Medicinal Chemistry Discovery synthesis (hit to lead, lead optimization) – – – – Simplification of hit Identification of the pharmacophore Optimization of lead for PD and/or PK Need to synthesis lots of analogs as efficiently as possible! Development synthesis...

Drug and Analog Synthesis Synthesis in Medicinal Chemistry Discovery synthesis (hit to lead, lead optimization) – – – – Simplification of hit Identification of the pharmacophore Optimization of lead for PD and/or PK Need to synthesis lots of analogs as efficiently as possible! Development synthesis (process chemistry) – Synthesis of a clinical candidate – Need to synthesize one compound as efficiently and safely as possible! (and to purity and impurity specifications) Synthetic Route Considerations Starting materials High yielding reactions Easily isolated and purified products Stereospecific reactions Reactions adaptable to scale up Approaches to Designing a Synthetic Route 1. Modification of natural products which share common structural motif – synthesis of synthetic steroids from plant sterol – Example on next slide 2. Identification of compounds with similar structures – Modify synthetic route to apply to target compounds 3. Retrosynthetic analysis – Disconnection approach Partial/Semi-synthesis: Derivitization of a Lead Rifampicin Design of Synthetic Route Linear Synthesis – Overall yield =10.7% assuming an 80% yield per reaction Convergent Synthesis – Overall yield = 26.2% from L assuming an 80% yield per reaction – Overall yield from R = 32.8% Synthesis of Analogs Full synthesis of new analogs Linear Divergent Example of a Retrosynthetic Analysis Example of Designing a Synthetic Route for New Analogs Common reactions used in medicinal chemistry J. Med. Chem. 2016, 59, 4443−4458 MK2 Example (Rheumatoid Arthritis) MK-2/CDK-2 Selectivity Model MK-2 and CDK-2 Differ Here Blue: MK-2 Red CDK-2 Exploratory Synthesis of 2-Phenyl Pyridines O O HN HNO3 Cl POCl3 HN H2SO4 NO2 1. NCCH2CO2Et Ph KOH, DMF N CN 2. 3N HCl NH2 1. NaNO2 H2SO4, AcOH 2. CuBr, 48% HBr Ph N Suzuki Reaction Step 3 of 10 PhB(OH)2 N DDQ DMF NO2 1. NaNO2 H2SO4, AcOH Ph N Pd(PPh3)4 Na2CO3, DME NO2 Ph N CN 2. CuBr, 48% HBr Ph HSCH2CO2Me NH22 N NaOMe, MeOH O S Br Br O S O 1. amine, Pd(OAc)2 BINAP, Cs2CO3, tol 2. 4N HCl/MeOH 3. 0.5 M NaOMe/MeOH Ph N O R HN NH S O R = H PF-3332952-01 R = CH2OH, PF-3332954-51 10 steps Solved chiral amine problem and answered the question about incorporation of the Ph group Not analog friendly Development of an Analog-Friendly Route N mCPBA CN O (86%) N CN O N CN Br O tBuONO S NH2 PhB(OH)2, Pd(PPh3)4 2M Na2CO3, DME 80 C, 2 h (quant.) Suzuki Step 13 of 15 2. 2,2-dimethoxypropane cat. TsOH, DMF, 50 C (94%) HCl Ph N HN S BocN O CO2Me HO HN N S N HN S BocN O CO2Me Ph 1. 4 N HCl/diox, MeOH 2. 0.5 M NaOMe/MeOH NH2 N O NaOMe, MeOH (82%) (87%) f irst chromatography 1. Boc2O, Et3N, DMF OH CO2Me BINAP, Cs2CO3, tol O HSCH2CO2Me O amine, Pd(OAc)2 O S HN Br Br N CuBr2, CH3CN (68%) N 1. POCl3 (89%) 2. NaOMe (67%) Br HO O N BocN S conc HCl O MeOH, reflux (82%) CO2Me TfO Tf 2O N Et3N CH2Cl2 OH HN NH O HN S (89%) second chromatography S O BocN O CO2Me Improved Route for Preparation of Analogs N 5 steps CN HN N NH S Br O N BocN NBoc S O (COCl)2 DMF 50% O Cl N Boc2O DMAP, TEA 63% N NBoc S HCl BocN NBoc S BocN mCPBA 99% O Cl 91% N HN NH S O O Suzuki Step 12 of 12 PMC Suzuki Rxns Amine displacements * 11 steps to chloropyridine advanced intermediate * Scaleable synthesis with little/no chromatography * Analoging step is final step Achievement of CDK-2 Selectivity and Superior Cellular Potency Selectivity Element N N HN NH S N NH S O PF-3514411 MK-2 IC50: 1.5 nM CDK-2 IC50: 0.8 nM (1,000x) U937 IC50: 0.17 M PF-3644022 gives good selectivity against CDK-2 Sub-micromolar potency in cell assay (in mechanism)