Solution-Phase Parallel Synthesis of Carbamates ... - ACS Publications

Nov 8, 2007 - Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033. ReceiVed June 22, 2007. A novel methodology ...
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J. Comb. Chem. 2008, 10, 56–62

Solution-Phase Parallel Synthesis of Carbamates as γ-Secretase Inhibitors Henry A. Vaccaro,† Zhiqiang Zhao,† John W. Clader,† Lixin Song,‡ Giuseppe Terracina,‡ Lili Zhang,‡ and Dmitri A. Pissarnitski*,† Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 ReceiVed June 22, 2007 A novel methodology for parallel liquid-phase synthesis of carbamates suitable for the preparation of sterically hindered molecules is disclosed. The alcohols are converted to 4-nitrophenylcarbonates, followed by the reaction with amines. Side product 4-nitrophenol and the unreacted excess amines are scavenged by appropriately chosen cleanup resins, selected among Amberlyst A26 (hydroxide form) and macroporous sulfonic acid (MP-TsOH) or polystyrene isocyanate (PS-NCO) and polystyrene benzaldehyde (PS-PhCHO) resins. As a part of a medicinal chemistry program directed toward finding γ-secretase inhibitors as prospective drug candidates for Alzheimer’s disease, a 6 × 24 library of carbamates was prepared. Out of 144 library members, 133 had a purity for the targeted compound of 80% or better. The prepared compounds were assessed in the γ-secretase inhibition assay and demonstrated activity with IC50 values in the range from 1 µM to 5 nM, with the activity of 7 compounds being better than 10 nM. Introduction Molecules containing a carbamate functional group are common in the drug discovery process. Carbamates are often incorporated into biologically active molecules with high oral bioavailability and low clearance, as in the case of the urinary incontinence drug solifenacin (1)1 (Figure 1). Alternatively, attachment of the carbamate side chain to a known biologically active molecule may improve its physicochemical properties, which makes carbamates useful as prodrugs. For instance, a carbamate modification of an antitumor agent camptothecin2 accounts for the improvement of the aqueous solubility of the resulting drug irinotecan (2)3 (Figure 1). Carbamates remain an active field of drug research for diverse medicinal chemistry programs throughout the world, including antitumor,4 anti-infective,5 immunosuppressive,6 and central nervous system7 areas. We became interested in the synthesis of carbamates in the course of a drug discovery program targeted to Alzheimer’s disease (AD). This common degenerative brain disorder accounts for up to 70% of all cases of dementia and is the third most-common cause of death in the United States.8 One of the major pathological hallmarks of AD is abnormal extracellular deposition of β-amyloid peptide (Aβ) in the form of plaques in the brains of AD patients. Although the exact cause of AD is unknown, a large body of evidence suggests9 that overproduction of Aβ is central to its pathogenesis. Aβ is produced by proteolysis of the larger amyloid precursor protein (APP) by sequential action of βand γ-secretases. Because γ-secretase plays a central role * To whom correspondence should be addressed. Phone: (908)451-9169. Fax: (908)740-7152. E-mail: [email protected]. † Department of Chemical Research. ‡ Department of Central Nervous System.

in the generation of Aβ peptide, inhibition of this enzyme was proposed as a target for the treatment of AD.10 Recently, a few cyclic sulfonamides of type 3 (Figure 2), bearing a carbamate side chain, were shown to inhibit γ-secretase in vitro and to reduce amyloid burden in vivo in the animal model of AD.11 To effectively explore structure– activity relationship (SAR) of Ar and NR1R2 groups in 3, an expeditious parallel synthesis of new analogs of 3 was required. Although several methodologies for parallel solid12 and liquid-phase13 synthesis of carbamates have been reported previously, their practicality for the needs of drug discovery has not been demonstrated. Herein, we disclose a new and practical method for the liquid-phase parallel synthesis of sterically hindered carbamates, exemplified by the synthesis of a targeted library of γ-secretase inhibitors 3 in a 6 × 24 format (Figure 2). Results and Discussion Chemistry. Synthesis of the Scaffolds. Synthesis of the chemset 6{1–6} is depicted in Scheme 1. Suzuki coupling of methyl 6-bromopicolinate with 3-fluorophenylboronic acid was conducted using sodium carbonate as the base in a 6:3 mixture of toluene and ethanol as the solvent at 90 °C over a period of 16 h. When subsequent catalytic hydrogenation

Figure 1. Solifenacin (1) and irinotecan (2) as examples of carbamate-based marketed drugs.

10.1021/cc700100r CCC: $40.75  2008 American Chemical Society Published on Web 11/08/2007

Synthesis of Carbamates as γ-Secretase Inhibitors

Journal of Combinatorial Chemistry, 2008 Vol. 10, No. 1 57

Figure 2. Library format for the synthesis of γ-secretase inhibitors.

Scheme 1. Synthesis of tertiary alcohols 6{1–6}a

a For the definition of the Ar groups, see Figure 2. Reaction conditions: (i) 3-fluorophenylboronic acid, cat Pd(PPh3)4, Na2CO3, toluene/EtOH ) 2:1, 90 °C, 10 h; (ii) H2 (1 atm), cat PtO2, MeOH/AcOH ) 4:1; (iii) ArSO2Cl, Pyr, 70 °C, overnight; (iv) EtMgBr (3 equiv), Ti(OPr-i)4 (0.3 equiv), THF, 0 °C.

of the product was conducted at atmospheric pressure (rubber balloon), reduction of the pyridine ring took precedence over hydrogenation of the 3-fluorophenyl ring, selectively providing piperidine 4. Sulfonylation of relatively hindered 4 with an array of six phenyl-substituted sulfonyl chlorides was achieved at elevated temperatures in pyridine as solvent. After acidic workup, compounds 5{1–6} were purified using prepacked silica gel SPE cartridges. In the next step, tertiary alcohols 6{1–6} were obtained by Kulinkovich cyclopropanation.14 Slow addition of methylmagnesium bromide to a chilled mixture of the esters 5{1–6} and titanium tetraisopropoxide in THF was essential to ensure good yields (70–80%) in this transformation. Once again, silica gel SPE cartridges were used to purify the products 6 from the highly polar baseline material. Synthesis of the Carbamate Library 3. In general, carbamates 3 can be accessed by the union of alcohols 6 and amines via a carbonyl linker derived from a synthetic equivalent of phosgene (Figure 3). Initially, we considered the pros and cons of several literature procedures described for the parallel synthesis of carbamates. While N,N-disuc-

cinimidyl carbonate (DSC)-mediated synthesis was shown to be compatible with automated synthetic stations, the final compounds had to be purified by normal or reverse-phase chromatography to remove the side product N-hydroxysuccinimide.13a Experiments with polymer-supported chloroformate resin13b failed in our hands to generate synthetically useful yields of 3 for the test reactions, probably because the intrinsic steric hindrance of tertiary alcohols 6 was exacerbated by the polymer support. Although phosgene represents a case of an unencumbered molecule which could overcome steric hindrance in 6, we were concerned with the high toxicity of this chemical, which could render preparation of a large library unsafe.15 Here, we describe the application of 4-nitrophenylchlorocarbonate as a convenient phosgene equivalent suitable for the synthesis of sterically hindered carbamate libraries, as exemplified by the preparation of 3, with the byproducts of the reaction, including 4-nitrophenol, scavenged by the appropriately chosen commercial resins. In the first stage of the library synthesis, alcohols 6{1–6} were converted into corresponding 4-nitrophenylcarbonates 7{1–6} by reaction with 4-nitrophenylchlorocarbonate. Although an excess of the reagent was needed for full consumption of the starting material, the virtue of derivatives

Figure 3. Methods for the formation of a carbamate linker.

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Vaccaro et al.

Scheme 2. Conversion of tertiary alcohols 6{1–6} into the final targets 3a

identified, using this model system, as having the best performance in the removal of 4-nitrophenol (Table 1).

a For the definition of HNR1R2, see Figure 2. Reaction conditions: (i) 4-nitrophenylchlorocarbonate (2 equiv), pyridine (3 equiv), CH3CN/THF)1: 3, 1–3 days; (ii) HNR1R2, DCE, 60 °C, 2.5 days; (iii) Amberlyst A26 basic resin, MP–TsOH or PS–isocyanate and PS–benzaldehyde resins.

Table 1. Scavenging of 4-Nitrophenol with Resins resin PS–DIEA TBD–Me PS–trisamine Amberlyst A26

manufacturer Argonaut/Biotage Argonaut/Biotage Argonaut/Biotage Alfa Aesar

remaining 4-nitrophenol (%) 18.3 2.6 4.2