Synthesis of ABT

Most recently, the Abbott group disclosed a series of benzofurans with potent affinity for the human and rat receptors. ABT-239 (29) is one of the more extensively profiled members of this series. (29) has a K of 0.45 nM at the human receptor [95], good rat pharmacokinetics and demonstrated efficacy in models of cognition [96]. Recently, a scaleable synthesis of ABT-239 has been reported [97] and the researchers have published detailed accounts on the pre-clinical pharmacokinetics and efficacy of this compound [98, 99], indicating continued interest in this series of H3 antagonists. 

Researchers at Abbott have been investigating the use of pyrrolidinylisoxazolesas nicotinic cholinergic channel activators (138). Until recently, ABT-418 (97) was undergoing clinical trials as a potential treatment for cognitive impairment and decline and for Alzheimer s disease. A short synthesis of ABT-418 was devised starting from commercially avail-... 

One of the most impressive synthetic achievements with the P-based mediators is the deoxygenation of an erythromycin B derivative towards the industrial synthesis of ABT-229, a potent motilin receptor agonist. Clean... 

Acetoxy-3-Nitrophenylmethyl)-1 -H-Imidazole-1 -Sulfonamide, a Key Intermediate in the Synthesis of ABT-866... 

The large scale cGMP synthesis of ABT-866 required reduction of the nitro group and hydrogenolysis of the acetate moiety of intermediate I. The palladium catalyzed hydrogenation of compound I was carefully studied in a systematic fashion for the effect of solvent, catalyst, pH, teirqierature, and concentration. Key to the success of our approach was the combination of rapid screening techniques and HPLC analysis. 

The synthesis of ABT-866 requires the nitro group reduction and benzylic deoxygenation of intermediate I. The goal was to define conditions for dependable catalytic reduction of I for use in a cGMP delivery of ABT-866. 

Substituted derivatives thus prepared did not overcome CAM (16a) in activity in vitro except for the aromatic amine derivatives A-181785 (50a) and A-181978 (50b) (Fig. 8). Although none of them are effective against macrolide-resistant pathogens, this work was later extended to the synthesis of ABT-773 (95) (described in Section II.D), a ketolide. 6-Deoxy-EMs A (51a), B (51b), C (51c), and D (51d) (Fig. 8) were reported to show acid stability and reduced in vitro activity [64, 65]. 

The original synthesis of ABT-839 (2) efficiently provided material for early studies and provided the flexibility to vary the sidechains in order to study SAR. However, e route required at least three chronmtographic separations, which prohibited synthesis of kilogram quantities of material. The penultimate intermediate was purified by column chromatography prior to the final ester hydrolysis and the final product was isolated as an amorphous foam. We were seeking an efficient process that addressed the concerns of purification of intermediates, allowed for isolation of a crystalline final product and could be used to synthesize kilogram quantities of material. 

The original synthesis of ABT-839 utilized a selective hydrolysis of the less-hindered ester followed by borane reduction of the resulting acid. An alternative approach would be to exploit the different steric environments of the... 

The synthesis of ABT-839 H2S04 was completed in eight chemical operations (10 steps total) in an overall yield of 43%. This synthesis was used to produce 4 kg of ABT-839 free amine and 2 kg of ABT-839 H2S04. The general approach was to utilize disconnections similar to those used in the original synthesis with an emphasis on streamlined work-up procedures and a single purification prior to final isolation. The steps for appending the two sidechains to... 

A number of routes can be envisioned for the preparation of polysubstituted pyrrolidines, and the intramolecular addition of a silyl ketene acetal to an oxime ether has been employed in the synthesis of ABT-627 (4). However, the reductive cyclization of a nitroketone, which could be obtained via the conjugate addition of a ketoester to a nitrostyrene, was viewed as being the most direct, convergent approach to ABT-546. In this approach, the nitro functionality is reduced to generate the cyclic imine, which is then further reduced to the trisubstituted pyrrolidine (Figure 2). As the trans-trans isomer is thermodynamically favored, both it and the cis-cis isomer are usable intermediates. 

In fact, as shown in Figure 3, this approach has been employed in the synthesis of ABT-627. The coupling of ketoester 1 with nitrostyrene 2 was accomplished with a catalytic quantity of KOtAm. Product nitroketone 3 was reduced over Raney nickel to prepare cyclic imine 4, which was further reduced on addition of TFA to produce Ae cis-cis pyrrolidine 5 with good selectivity. Following epimerization with DBU, trans-trans pyrrolidine 6 was resolved with good efficiency as the mandelate salt. 

With this encouraging precedent, a similar approach was investigated in the Hrst-generation synthesis of ABT-546 (Figure 4). The Michael addition was again carried out in the presence of catalytic base. The reductive cyclization of nitroketone 9 was carried out employing modified conditions to yield directly the trans-trans pyrrolidine, 10. However, despite significant effort, only tartaric acid was found to resolve this pyrrolidine, and then the optically enriched product was obtained with low recovery. 

With a reliable Michael addition in hand, we initiated the large-scale synthesis of ABT-546. 

Whereas the nitroketone intermediate in the synthesis of ABT-627 was reduced to the pyrrolidine by treatment first with Raney nickel, then by the addition of TEA to provide the cis-cis substituted pyrrolidine selectively, nitroketone 9 gave a mixture of products under those conditions. Modified conditions were identified under which the nitroketone was reduced to the cyclic imine over Raney nickel (Eigure 7). Eurther reduction was carried out with NaHB(OAc)3 to provide the trans-trans substituted pyrrolidine directly in 91% yield over two steps, with less than 2% of diastereomeric products. 

Thus, the synthesis of ABT-546 was accomplished in 11 linear steps from ethyl dimethylacrylate, in 39% overall yield. This represented an 8-fold yield increase from the first generation synthesis. 

In summary, a catalytic asynometric Michael addition of 1,3-dicarbonyl compounds to nitroalkenes was developed. This reaction was employed in the synthesis of ABT-546 in order to prepare multi-kilogram lots for toxicology and clinical studies. The reaction scope has been found to include a variety of ketoesters, as well as malonates and nitroalkenes. 

Scheme 42.23 One-pot synthesis of ABT-341 in an uninterrupted sequence of reactions. Protocol point the strategy requires careful choice of low-boiling reagents and solvents, to avoid possible detrimental interactions...

As detailed in Scheme 42.23, the one-pot synthesis of ABT-341, potentially useful in the therapy for type 2 diabetes, was designed around the highly stereoselective Michael addition of acetaldehyde 90 to nitroalkene 91 catalyzed by the Jorgensen-Hayashi catalyst (R)-27. Then, exploiting the reactivity of the resulting nucleophilic intermediate 92, a domino transformation was carried out the... 

SCHEME 21.31. Michael/HWE/retro-aldol/intramolecular HWE cascade for the synthesis of ABT-341. 

Scheme 12 Large-Scale Synthesis of ABT-74 via Pd-Catalyzed N-Arylation...

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