Development of a Practical Synthesis of the 8-FDC Fragment of OPC-167832

A concise and practical synthesis has been developed to provide the 8-fluoro-5-hydroxy-3,4-diydrocarbostyril (8-FDC) fragment of OPC-167832 in 41% yield and in >99% purity over four steps from 3-amino-4-fluorophenol. The key feature of this process is the development of a telescoped one-pot synthesis of the quinolone via a chemoselective amidation/acid-induced cyclization that allows for simple product isolation without the need for column chromatography.

Due to the biological significance of 1, efficient synthetic access to this compound is important to enable supply. The current reported synthesis of 1 3b,c utilizes a final coupling of two fragments (2 and 8-FDC, Figure 1). In collaboration with Otsuka Pharmaceuticals Co., Ltd., our group became interested in investigating improved synthetic routes to one of the key coupling fragments, 8-FDC. Access to 8-FDC suffers from a long synthetic sequence (9 chemical steps, 8 "reaction pots") starting from fluorinated nitrobenzene 3 (Scheme 1). 3b This approach mainly suffers from multiple functional group interconversion steps, including replacement of the 5-fluoro group of 3 with the requisite OH-group of 8-FDC. This F to O swap leads to the incorporation of several additional steps in the synthetic route. As a result, we decided to investigate an alternative synthetic design from aniline 4 with the requisite 5-OH group already present in reaction with methyl 3,3-dimethoxypropionate (5) to access the desired pyridone scaffold of 8-FDC. Importantly, both 4 and 5 are commercially available, and synthetic procedures to access 4 on up to 5 kg scale have been reported. 5 Herein, we describe the successful synthesis of 8-FDC utilizing this approach.

Scheme 2. Planned Forward Synthesis of 8-FDC.
To realize our proposed synthesis plan in Scheme 1, the envisioned forward synthesis is given in Scheme 2. Chemoselective amide formation between 4 and 5 was envisioned to provide 6 that may be converted to quinolone 7 by a Friedel-Crafts type process. Recently, this approach for the synthesis of quinolones was reported. 6 However, we were unsuccessful in identifying chemoselective conditions for formation of amide 6 over the ester formed from reaction of 5 with the phenol-group of 4. As a result, we next investigated the synthesis of amide 6 from the coupling of acid 8 prepared from the hydrolysis of 5 with aqueous NaOH (Table 1). Of the various carboxylic acid activating agents studied, MsCl and PivCl appeared to be the most promising for formation of the product 6 (entries 1 -4). A subsequent survey of bases and solvents utilizing PivCl as the activating agent was then carried out (entries 4 -15). Amongst the bases analyzed, DBU and Hunig's base afforded the highest amounts of the desired amide 6 (entries 8 and 9), but the latter was preferred for its lower cost. In regards to reaction solvent, toluene provided the maximum conversion to 6 and also accounted for the highest yield (entry 13). With the intent to telescope the overall synthesis, a solvent study for the cyclization of amide 6 to the quinolone 7 was next performed. A comparative analysis of the efficiency of the reaction in various solvents was made on the basis of the amount of the product isolated post precipitation from the reaction mixture by pouring into ice cold water, and the results are as captured in Figure 2. Although CPME and Toluene gave excellent mass recovery, toluene was preferred for telescoping the reaction due to its better performance than CPME in the amidation step. In toluene, 67 % assay yield of the quinolone was obtained in 75 wt% purity by quantitative 1 HNMR analysis after direct precipitation from the reaction mixture using water (normal quench). Telescoping the process into a one-pot synthesis of quinolone 7 was found to be successful (Scheme 3), and the quinolone was isolated in 65 wt% purity (quantitative 1 HNMR analysis) after precipitation. Due to the significant exotherm observed during the normal quenching procedure, a reverse-quench by transferring the reaction mixture to ice cold water was next tested in an effort to increase the reaction yield. Gratifyingly, this led to an improved yield of 75% on a 10 g scale. The stages of this one-pot sequence are shown in Figure 3. The initial reaction solution of acid 8 in toluene was homogeneous, however, upon addition of the pivaloyl chloride, the reaction becomes biphasic. After addition of DIPEA, the reaction remained biphasic and resulted in the formation of precipitated DIPEAꞏHCL and amide 6 (solubility of 6 in toluene is ~0.3 mg/mL) after overnight agitation. H2SO4 was then slowly added by addition funnel at 0 o C to control the exotherm leading to the formation of a triphasic reaction mixture. Final reverse-quenching into water induces the precipitation of the quinolone 7 that was isolated by filtration. Losses of 7 to the filtrate were determined to be 348 mg in 390 mL (~3 %) when using a normal quench mode and 656 mg in 448 mL (~6 %) when a reverse quench was employed as determined by quantitative reverse phase HPLC analysis.

Figure 3. Reaction progress at different stages utilizing reverse-quenching
Purification of the resultant quinolone obtained from direct precipitation with water can be achieved using either recrystallization from 80:20 MeOH:H2O or by treatment with 10 V aqueous sodium bicarbonate solution. Using these procedures, 7 could be obtained in 100 wt% purity with 78% recovery after recrystallization with MeOH/H2O or in 93 wt% purity in 88% recovery if treated with aqueous NaHCO3. As a result, the overall yield of 7 from acid 8 was 59% when recrystallization was employed or 62% when utilizing a NaHCO3 reslurry.
Since an increased overall yield of 7 was obtained when purifying the material from aqueous NaHCO3, this quality material was attempted to be converted to 8-FDC by the established literature procedure 3b,c to ascertain if 93 wt% material was acceptable (Scheme 4). Gratifyingly, 7 was smoothly converted to 8-FDC in comparable yields without issue.

Scheme 4. Conversion of quinolone 7 to 8-FDC
In conclusion, we have developed a concise process using cheap reagents and starting materials accessible on a bulk scale for the preparation of the key dihydroquinolone (8-FDC) fragment of OPC-167832. The novel process described herein features a telescoped one-pot operation for the preparation of quinolone 7 from 3-amino-4-fluorophenol and 3,3-dimethoxy propionic acid without the need for isolation of any of the intermediates. The method described herein should in principle be broadly applicable for selective acylation of a wide variety of aminophenols, and would therefore be significant for efficient synthesis of various biologically active molecules.

EXPERIMENTAL SECTION
General. All reactions were carried out under nitrogen atmosphere unless otherwise indicated.
Glassware was pre-dried in an oven prior to use. 3-Amino-4-fluorophenol was purchased from Oakwood, Methyl 3,3-dimethoxy propionate was purchased from TCI chemicals, acetic anhydride from Chem Impex, trimethylacetyl chloride, 10 % Pd/C and N,N-Diisopropylethylamine from Sigma Aldrich. Toluene and Methanol reagent grade were purchased from J T Baker whereas MTBE, NaOH (pellets), dimethyl fumarate, mesitylene, Hydrochloric acid, sulfuric acid, Acetic acid were purchased from Sigma Aldrich.

3,3-dimethoxpropanoic acid (8).
To a 100 mL round bottom flask with stir bar is charged 20 mL of water followed by 8.1 mL of 10 M NaOH (30%). The ester 5 (10 g) was charged and stirred at 55 o C for 2 h. TLC (30% EtOAc/hex) and NMR of a worked-up aliquot (obtained by quenching 20 µl of solution with a few drops of concentrated HCl until pH was acidic, extraction with MTBE (2 ml) and concentration) showedconsumption of the starting ester. The reaction mixture was then cooled to rt and washed with MTBE (1x30 mL). To the aqueous layer was then added 6.7 mL of conc. HCl over ~10min keeping the internal temperature below 18 o C using an ice bath. The batch was warmed up to room temperature and 4.5 g of sodium chloride was added.
The reaction mixture was stirred for about 10 min to dissolve the salt, and the organic layer was extracted with MTBE (3x50mL). The organics were further dried with Na2SO4, filtered and concentrated in vacuo to provide 9.72 g (99%) of 8 as a near colorless oil in 91.7 wt % purity as determined by quantitative 1 HNMR spectroscopic analysis using dimethyl fumarate as the analytical standard. Spectral data was identical to the literature.

Supporting Information
The Supporting Information is available free of charge on the ACS Publication website at DOI: Copies of 1 H and 13 C NMR spectra of all new compounds (below).