An expeditious construction of 3-aryl-5-(substituted methyl)-2- oxazolidinones: a short and efficient synthesis of Linezolid

A short, concise and efficient synthesis of Linezolid was accomplished through a convergent scheme utilizing either ( S )-1-azido-3-chloropropan-2-yl chloroformate or ( S )-1- phthalimido-3-chloropropan-2-yl chloroformate as a key starting material. The synthesis demonstrates utility of ( S )-1-azido-3-chloropropan-2-yl chloroformate and/or ( S )-1-phthalimido-3-chloropropan-2-yl chloroformate to facilitate the expeditious construction of 3-aryl-5-(substituted methyl)-2- oxazolidinones and offers the possibility of accessing related 2-oxazolidinone members easily as well as making additional analogues of Linezolid


Introduction
Oxazolidinones represent a milestone in antibacterial research as they represent the first new class of antibiotics to enter clinical usage within the past 30 years.As of 2011, Linezolid (Zyvox®, Pfizer, Figure 1) represents the first antibacterial with a new mechanism of action approved by the U.S. Food and Drug Administration (FDA). 1 Linezolid has excellent in vitro activity against all of the major Gram-positive bacteria that are pathogenic to humans. 2,35][6] Others of this class have entered development, such as Rivaroxaban (Bay-59-7939), 7 Ranbezolid (RBx 7644), 8 Posizolid (AZD 2563), 9 Torezolid (TR-701), 10 and Radezolid (RX-1741). 11In this context, the reported syntheses of Linezolid [3-aryl-5-(substituted methyl)-2-oxazolidinone] require mention.For instance, the classical method involves conversion of 3-fluoro-4morpholinobenzenamine (ArNH2) to corresponding carbamate which is deprotonated with n-BuLi or lithiumdiisopropyl amide (LDA) in THF followed by reaction with 2-substituted oxirane at −78 °C, or in another method, the aryl carbamate was reacted with 1-substituted 3chloropropan-2-ol (halohydrin) using lithium t-butoxide (LiOtBu) or n-BuLi to generate (R)-3aryl-5-(hydroxymethyl)-2-oxazolidinones.These 3-aryl-5-(hydroxymethyl)-2-oxazolidinone intermediates are elaborated to final products. 12,13However, in these methods for the synthetic key step to 2-oxazolidinone ring, severe conditions with low temperature (−78 °C) and an airsensitive base (n-BuLi) are required, which limit the large-scale production in the industry.Other described synthetic methods involving aryl isocyanate instead of aryl carbamate are effective, but not general.The preparation of aryl isocyanates is cumbersome from multi-substituted aryl amines.Moreover, while preparing aryl isocyanates a major concern is the formation of the corresponding urea as a significant impurity. 14n the other hand, oxirane ring opening of 2-substituted oxirane using 3-fluoro-4morpholinobenzenamine and carbonylation followed by further functional group transformations gave the Linezolid. 15One more method involves the conversion of (R)-1-azido-3-chloropropan-2-ol (halohydrin) to corresponding carbonate derivative followed by reaction with ArNH2 giving required 2-oxazolidinone. 16In addition, there are some other articles describing the construction of 5-(substituted methyl)-2-oxazolidinone followed by coupling with aryl halide using various reaction conditions and further transformations leading to Linezolid formation. 17,18he latest analogs have common functionalities on the C-5 aminomethyl group, such as acetamides, carbamates, ureas, thioamides, thiocarbamates, and thioureas (Figure 1). 19During the conversion of amines to acetamides, carbamates, ureas, thioamides, thiocarbamates, and thioureas, there is a higher chance of obtaining the corresponding symmetrical derivatives.

Results and Discussion
In view of these limitations for accessing related 2-oxazolidinone members easily as well as making additional analogues of Linezolid and our interest in developing the small chiral building blocks, 17 herein we wish to report the synthesis of novel chiral synthons, (S)-1-azido-3chloropropan-2-yl chloroformate 3a or (S)-phthalimido-3-chloropropan-2-yl chloroformate 3b by phosgenation of corresponding chlorohydrin with triphosgene (Scheme 1) and demonstrated their application in the synthesis of Linezolid (Figure 2).One of the early methods in the synthesis of 2-oxazolidinones involves the reaction of phosgene and aniline with β-chloroethanol to produce β-chloroethyl-N-phenyl carbamate which is cyclized by boiling in potassium hydroxide solution. 20However, this methodology is not well utilized in synthetic organic chemistry and drug discovery probably due to the fear of limited (low) stability of 1-chloroalkan-2-yl chloroformates.Providentially, compounds 3a and 3b are quite stable for several days in the reaction condition and even after isolation.Accordingly, (S)-epichlorohydrin was stereoselectively ring-opened with either NaN3 or phthalimide to give corresponding chlorohydrin 2. The chlorohydrin 2 on treatment with triphosgene using triethylamine as a base in tetrahydrofuran gave corresponding chloroformate 3. It is worthwhile to mention that under these conditions (S)-1-azido-3-chloropropan-2-yl chloroformate 3a and (S)-1-phthalimido-3-chloropropan-2-yl chloroformate 3b are quite stable and isolated readily without a trace of the corresponding chloride or symmetrical carbonate.
During initial reactions while preparing (S)-1-azido-3-chloropropan-2-yl chloroformate 3a (by using molar excess triethylamine), formation of a major impurity was observed (>25% by TLC), isolated (by column chromatography) and identified as ((S)-1-azido-3-chloropropan-2yloxycarbonyl)triethylammonium chloride 4 (Figure 3).The formation of impurity 4 could be explained by either of the following two reasons: (i) side reaction of 3a with Et3N, or (ii) reaction of excess phosgene with Et3N resulting in formation of corresponding unstable complex 4a (Figure 3) which on further reaction with 2a gave impurity 4. The formation of ((S)-1-azido-3chloropropan-2-yloxycarbonyl)triethylammonium chloride 4 was confirmed by its preparation starting from 3a on reaction with triethylamine in tetrahydrofuran.However, the side formation of 4 was restricted in the preparation of 3a by controlled addition of Et3N and also by reducing the molar quantity.The impurity 4 formed is unstable and collapses, with elimination of ethyl chloride, to give a stable carbamoyl chloride derivative 4b.The chiral synthon 3a can be derivatized on both ends to develop new oxazolidinone antibacterial analogs as well as monoamine oxidase-B (MAO-B) inhibitors used in the treatment of Parkinson's disease. 21The chlorocarbonyl functionality in 3a and 3b can be converted to either carbamate or 2-oxazolidinone by reaction with amines. 20The azide functionality in 3a provides the required site for preparing different analogues of the oxazolidinone.The azide functionality can also be converted to carbamates, ureas, thiocarbamates and thioureas via iminophosphorane 22 and isocyanate or thiocyanate 23 intermediates, respectively.Many established procedures are available for reductive conversion of azides to acetamides 24 and carbamates. 25he utility of chiral synthons 3a and 3b has been exemplified by synthesizing Linezolid as shown in Scheme 2. The 2-oxazolidinone ring was constructed expeditiously by using chlorocarbonyl group in chloroformate 3 in a one-pot two step sequence.Accordingly, either 3a or 3b was treated with 3-fluoro-4-morpholinobenzenamine using molar excess K2CO3 in acetone resulting in corresponding 2-oxazolidinone 6.This reaction proceeded via the carbamate 5 and the reaction mixture was maintained under reaction conditions until the completion of 3 as well as 5. Initially, the carbamate 5a was isolated exclusively using triethylamine or molar equivalent K2CO3 in dichloromethane.In these conditions no formation of 6a was observed.As a summary, we developed a facile condition for the one-pot construction of 2-oxazolidinone ring (via carbamate) by the reaction of 3 with K 2 CO 3 in acetone.Finally, the compound 6 was converted to Linezolid by reported conditions.12,15 The enantiomeric purity of Linezolid was readily assessed by chiral HPLC (Chiralpak ASH) and was found to be 99.9%.This was confirmed by comparing the chromatogram of the Linezolid to that of racemic Linezolid synthesized starting from racemic epichlorohydrin.Scheme 2. Synthesis of Linezolid starting from either (S)-1-azido-3-chloropropan-2-yl chloroformate 3a or (S)-1-phthalimido-3-chloropropan-2-yl chloroformate 3b.
Moreover, impurity 4 was not traceable in the initial reaction of 3a (contains ~25% of 4) with 3-fluoro-4-morpholinobenzenamine while synthesizing (R)-6a.In order to understand the further conversion of 4, a reaction was performed on chemically pure 4 with K2CO3 in acetone at room temperature which also resulted in the formation of (R)-6a.However, the reactivity of 4 with ArNH2 is quite low when compared to (S)-1-azido-3-chloropropan-2-yl chloroformate 3a and 3b.

Conclusions
In summary, we describe herein the synthesis of novel chiral synthons, (S)-1-azido-3chloropropan-2-yl chloroformate 3a and (S)-phthalimido-3-chloropropan-2-yl chloroformate 3b which are precursors for further transformations into potential 2-oxazolidinone antibacterial agents.By using these chiral synthons, an efficient method has been demonstrated for 2oxazolidinone ring construction in a one-pot two step sequence via the corresponding carbamate.The applicability of this approach was shown by the synthesis of Linezolid.The application of this strategy to develop a series of 2-oxazolidinone analogues where the morpholine moiety of Linezolid could be replaced with new heterobicyclic systems 17b is currently underway in our laboratory.

Experimental Section
General.All reagents and solvents employed were of commercial grade and were used as such, unless otherwise specified.Reaction flasks were oven-dried at 200°C, flame-dried and flushed with dry nitrogen prior to use.All moisture and air-sensitive reactions were carried out under an atmosphere of dry nitrogen.TLC was performed on Kieselgel 60 F254 silica-coated aluminium plates (Merck) and visualized by using either UV light (λ = 254 nm) or by spraying with a solution of ninhydrin or KMnO4.Organic extracts were dried over anhydrous Na2SO4.Flash column chromatography was performed using Kieselgel 60 brand silica gel (230-400 mesh).The melting points were determined in an open capillary tube using a Büchi B-540 melting point instrument and were uncorrected.Optical rotations were measured on an Autopol V, serial number 80455 (manufactured by Rudolph Research Analytical, Hackettstown, NJ, USA) at the sodium D line (589 nm) and are reported as follows: [α] t°C D (concentration in g/100 mL, solvent).The IR spectra were obtained on a Nicolet 380 FT-IR instrument (neat for liquids and as KBr pellets for solids).NMR spectra were recorded with a Varian 300 MHz Mercury Plus Spectrometer at 300 MHz ( 1 H) and at 75 MHz ( 13 C).Chemical shifts were given in ppm relative to trimethylsilane (TMS).Data are reported as follows: s, singlet; d, doublet; t, triplet; q, quartet; qn, quintuplet; m, multiplet; and br, broad.Mass spectra were recorded on Waters Quattro Premier XE triple quadrupole spectrometer using either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI) technique.The chromatographic system used for the chiral HPLC studies consisted of a Shimadzu LC-10AT HPLC system equipped with a Shimadzu SPD-10A UV absorbance detector, with the wavelength set to 240 nm.Injections were made using an auto sampler Model Shimadzu SIL-20AC.Separation of the enantiomers of Linezolid were performed using a Chiralpak ASH column of dimensions 250 × 4.6 × 5.0 mm.The column was fitted in a column oven Model Shimadzu CTO-10AS.UV absorbance (λ = 240 nm) chromatograms were recorded using an Advanced Computer Interface equipped with Chromatography Automation software Shimadzu CLASS-VP version 6.14 SP1.The isocratic mobile phase was a 60:40:0.1 (v/v) mixture of n-hexane : ethanol : diethylamine.The flow rate was 1.0 mL min −1 (Run time -20 min).