Functional group filters

There are, in addition to these simple functional group filters, a number of property-based filters that may be applied. These fdters take the form of calculated metrics, such as the Lipinski Rule of Five (LRoF Hydrogen-bond donors. Hydrogen-bond acceptors, Lipophilicity, Molecular weight). Solubility, total Polar Surface Area (tPS A), Blood-brain-barrier (BBB) Permeability, calculated metabolic filters (cADMET Absorption-Distribution-Metabolism-Excretion-Toxicity) and Bioavailability. 

Functional group filters are mainly utilized to remove unstable, reactive, toxic, or otherwise unsuitable compounds from compound libraries. The rapid elimination of swill (REOS) method introduced by Vertex was the first realization of this concept. REOS effectively combines physicochemical filters with a set of functional group filters. Databases are first subjected to property filtering similar to ROF that is followed by checking a set of rules based on the presence of functional groups expected to be problematic. Some examples of these rule-based functional group filters are illustrated in Fig. 2. It is important to note that REOS allows the user to customize each functional group filter as well as the set of rules applied. 

The property filter of Walters et al. is implemented in the program REOS where a set of more than 200 functional group filters is also available to enable one to remove compounds with toxic, reactive, and otherwise undesirable moieties. 

Functional group filters are applied to exclude from a chemical database those structures that possess undesired functionalities. These can be structures having more than one aldehyde group, structures containing metals, reactive alkyl halides, peroxides, carbazides. 

Table PIO List of REOS functional group filters from [Walters and Murcko, 2002].

To remove potentially toxic compounds, functional group filters primarily draw from mutagenicity, carcinogenicity, and acute toxicity database [Muegge, 2003]. 

Three-Dimensional Vector of Atomic Interaction Field descriptors = 3D-VAIF descriptors > Threshold Toxicological Concern —> property filters (0 functional group filters)... 

AH corrosion inhibitors in use as of this writing are oil-soluble surfactants (qv) which consist of a hydrophobic hydrocarbon backbone and a hydrophilic functional group. Oil-soluble surfactant-type additives were first used in 1946 by the Sinclair Oil Co. (38). Most corrosion inhibitors are carboxyhc acids (qv), amines, or amine salts (39), depending on the types of water bottoms encountered in the whole distribution system. The wrong choice of inhibitors can lead to unwanted reactions. Eor instance, use of an acidic corrosion inhibitor when the water bottoms are caustic can result in the formation of insoluble salts that can plug filters in the distribution system or in customers vehicles. Because these additives form a strongly adsorbed impervious film at the metal Hquid interface, low Hquid concentrations are usually adequate. Concentrations typically range up to 5 ppm. In many situations, pipeline companies add their own corrosion inhibitors on top of that added by refiners. 

Filter/dry OH-functionality of polyol depends on structure of R Difficult to "cap all 2° OH groups with EO Side reactions (esp. proton abstraction) limit functionality of Urethane-grade polyol product and create unwanted functional groups... 

These unwanted functional groups can be easily encoded as SMARTS [37] to be used as structural alerts for HTS compound prioritization or compound acquisition. OpenEye s Filter [38] is an excellent example of such a filtering tool. 

Compound Quality Filters Aka Functional Groups to Avoid... 

In order to overcome these two issues, we reversed the order of the reaction sequence, as summarized in Scheme 1.20. We took advantage of the alcohol functional group in 50. Oxidation ofpMB of 50 with DDQ proceeded smoothly to form cyclic aminal 52 (as a mixture of a and P = 11.5 1) in toluene at 0-10 °C. The resulting DDQH, which is insoluble in toluene, was filtered off, and isolated DDQH could be recycled as we demonstrated in the Proscar process (see p. 92) [32]. Thus, this process minimizes the impact to the environment from an oxidizing reagent. Cyclic aminal 52 was solvolyzed with NaOH in MeOH at 40 °C. The resulted anisaldehyde was reduced in situ to pMBOH 43 by addition of NaBH4 and the desired amino alcohol 53 was isolated by direct crystallization from the reaction mixture, upon neutralization with acetic acid, in 94% yield and >99.9% ee after crystallization from toluene-heptane. 

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