Improved synthesis of DQ-113, a new quinolone antibacterial agent, utilizing the Reformatsky reaction

A new improved synthetic route for the C-7 substituent in DQ-113, a new quinolone antibacterial agent for infections caused by Gram-positive pathogens, has been developed which does not use low temperatures and avoids the use of expensive fluorinating agents. The key step is a Reformatsky reaction between ethyl bromofluoroacetate and ethyl 1-acetyl-cyclopropanecarboxylate.


Results and Discussion
The new synthetic route for 6 is shown in Scheme 2. The Reformatsky reaction of 1acetylcyclopropanecarboxylate 3 1 with bromofluoroacetate proceeded under standard conditions to give the fluoro-diester 8.The crude 8 was then treated with thionyl chloride/pyridine to give a chlorinated product.Treatment of the crude chlorinated product with 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) gave the α-fluoro-α,β-unsaturated ester 9 as a 1:1 mixture of (E)-and (Z)-isomers in 79% yield from 1. Bromination of the allylic position of the E/Z mixture 9 with N-bromosuccinimide (NBS) catalyzed by 2,2'-azo-bis-isobutyronitrile (AIBN) gave a 1.35:1 mixture of the (E)-bromo-diester (E)-10 and (Z)-bromo-diester (Z)-10 in 87% yield, which was separated to give the two isomers (silica gel column chromatography).The (Z)isomer (Z)-10, which could not be converted into the unsaturated lactam 11, could be converted into the mixture of (E)-10 and (Z)-10 by heating with 0.1 eq. of NBS and 0.1 eq. of AIBN in benzene.After the isomerization process was repeated three times, the collected (E)-isomer (E)-10 (83% from 9) was treated with (S)-1-phenylethylamine and sodium hydrogencarbonate in ethanol to give the lactam 11 in 81% yield.Finally, hydrogenation of 11 catalyzed by Raney Nickel gave a 3:1 mixture of the (3S,4S)-lactam 5 reported before, 1 and the unwanted (3R,4R)lactam 12, in 86% yield, although other conditions using other catalysts lost face-selectivity and/or gave more des-fluorine products.The mixture of 5 and 12 could be separated easily into the two isomers by silica gel column chromatography.The (3S,4S)-lactam 5 obtained by this route could be transformed into 6 in about the same yield as reported before.In order to avoid the chromatographic separation of (Z)-10 and (E)-10, and to obtain 11 more efficiently with shorter routes, we tried to develop two new synthetic routes for 11, shown in Scheme 3. The key step of one route (1→13→14→15→16→11) is a Reformatsky reaction between the amino-ketone 14 and bromofluoroacetate, and of the other (1→13→17→16→11) is the intramolecular Reformatsky reaction of 17.However, under standard conditions, both of the Reformatsky reactions gave complex mixtures and did not afford the key intermediates 15 or 16.Using other reaction conditions, it is possible that these new processes might be achieved in future.

Conclusions
Thus, we have developed a new synthetic route for 6 utilizing the Reformatsky reaction between the 1-acetylcyclopropanecarboxylate 1 and ethyl bromofluoroacetate.In this route, expensive fluorinating agents or operations at very low temperature were not needed.The total yield from 1 to 5 (6 steps, and 3 times isomerization process) was improved to 41%, from the earlier quoted value of 10% (8 steps).

Experimental Section
General Procedures.Unless otherwise stated, materials were from commercial suppliers were used without further purification.Optical rotations were measured in a 0.5-dm cell at 25°C at 589 nm with a HORIBA SEPA-300 polarimeter. 1 H NMR spectra were determined on a JEOL JNM-EX400 spectrometer.Chemical shifts are reported in ppm relative to tetramethylsilane as internal standard.Significant 1 H NMR data are tabulated in the order: number of protons, multiplicity (s, singlet; d, doublet; t, triplet; q; quartet; m, multiplet), coupling constant(s) in Hz.
High-resolution mass spectra were obtained on a JEOL JMS-700 mass spectrometer under electron impact ionization (EI), electron spray ionization (ESI), or fast-atom bombardment conditions (FAB).Column chromatography refers to flash column chromatography using on Merck silica gel 60, 230-400 mesh ASTM.Thin-layer chromatography (TLC) was performed with Merck silica gel 60 F 254 TLC plates, and compound visualization was effected with a 5% solution of molybdophosphoric acid in ethanol, UV-lamp, iodine, or Wako Ninhydrin Spray.

Ethyl (E/Z)-3-(1-ethoxycarbonylcycloprop-1-yl)-2-fluoro-2-butenoate (9).
To a solution of ethyl 1-acetylcyclopropanecarboxylate (1) (124.5 g, 0.797 mol) in 1.5 L of PhH was added Zn powder (156.4 g, 2.393 mol) and a catalytic amount of I 2 .To the mixture, heated under reflux, a solution of ethyl bromofluoroacetate (94.2 ml, 0.797 mol) in 200 mL of PhH was added dropwise over 1 h, and the mixture was heated under reflux for another 1 h.The mixture was cooled on an ice bath, and 1 L of aqueous 1 M HCl solution was added.After stirring for 1 h, the organic layer was separated.The organic solution was washed with aqueous 1 M HCl solution, water, brine, dried over Na 2 SO 4 , and concentrated in vacuo to give crude 8. To the crude 8 in pyridine (387 mL, 4.78 mol) was added thionyl chloride (69.8 mL, 0.957 mol) at -10 °C, and the mixture was stirred for 3 h at the same temperature.The resultant mixture was poured into 2 L of ice cold aqueous 1 M HCl solution, and was extracted with 1.5 L of AcOEt.The organic layer was washed with aqueous 1 M HCl solution, water, brine, dried over Na 2 SO 4 , and concentrated in vacuo to give the crude chlorinated product.To this, in 0.5 L of CH 2 Cl 2 , was added DBU (131 mL, 0.877 mol) at 0°C, and the mixture was stirred for 17 h at ambient temperature.The reaction mixture was partitioned between 1 L of CHCl 3 and 2 L of aqueous 1 M HCl solution, and the organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo to give crude 9.This was purified by silica gel chromatography, eluting with AcOEt:hexane = 1:4 to yield 9 as an E/Z mixture (152.8 g, 79%, E/Z = 1/1, by 1 H NMR) as a colorless oil.This E/Z mixture was used for the next reaction without separation of isomers.625 mol) and a catalytic amount of AIBN, and the mixture was heated under reflux for 16 h.After cooling to ambient temperature, the mixture was concentrated in vacuo.0.3 L of benzene was added to the residue, and the resultant suspension was filtered.The filtrate was concentrated in vacuo, and the resultant crude product was separated into two isomers by silica gel chromatography.(E)-10 (100.5 g, 50%) was obtained as a pale yellow oil, eluting with AcOEt:hexane = 1:4.Isomerization of (Z)-10 to a mixture of (Z)-10 and (E)-10.A mixture of ethyl (Z)-4-bromo-3-(1-ethoxycarbonylcycloprop-1-yl)-2-fluoro-2-butenoate (Z)-10, 0.1 eq. of NBS, and 0.1 eq. of AIBN was dissolved in benzene, and heated under reflux under nitrogen for 12-16 h.After the solvent was evaporated, the remaining residue was purified and separated by silica gel chromatography, eluting with AcOEt:hexane = 1:20 → 1:10 → 1:4 → 1:2 to give (E)-10 and a mixture of (E)-10 and (Z)-10.Using the mixture of (E)-10 and (Z)-10, the same isomerization procedure was repeated three times to give total 89% of (E)-10 from (Z)-10.

a
Scheme 1. a The reported synthetic route for DQ-113 1 .

a
Scheme 2. aThe new improved synthetic route for DQ-113 utilizing the Reformatsky reaction with bromofluoroacetate.

a
Scheme 3. a Two possible (unachieved) synthetic routes for 11.