Europaisches Patentamt (19) European Patent Office Office europeenpeen des brevets EP 0 674 618 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) intci.6: C07C 317/32, C07C 233/22, of the grant of the patent: C07C 315/04, C07D 301/19, 09.09.1998 Bulletin 1998/37 C07D 263/14, A61K31/16 (21) Application number: 94903599.2 (86) International application number: PCT/US93/12071 (22) Date of filing: 15.12.1993 (87) International publication number: WO 94/14764 (07.07.1994 Gazette 1994/15) (54) ASYMMETRIC PROCESS FOR PREPARING FLORFENICOL, THIAMPHENICOL, CHLORAMPHENICOL AND OXAZOLINE INTERMEDIATES ASYMMETRISCHES HERSTELLUNGSVERFAHREN FUR FLORFENICOL, THIAMPHENICOL, CHLORAMPHENICOL UND OXAZOLIN-ZWISCHENPRODUKTE PROCEDE ASYMETRIQUE DE PREPARATION DE FLORFENICOL, THIAMPHENICOL, CHLORAMPHENICOL ET D'INTERMEDI AIRES OXAZOLINE (84) Designated Contracting States: (74) Representative: AT BE CH DE DK ES FR GB GR IE IT LI LU NL PT von Kreisler, Alek, Dipl.-Chem. et al SE Patentanwalte, von Kreisler-Selting-Werner, (30) Priority: 18.12.1992 US 993932 Bahnhofsvorplatz 1 (Deichmannhaus) 50667 Koln (DE) (43) Date of publication of application: 04.10.1995 Bulletin 1995/40 (56) References cited: EP-A- 0 423 705 EP-A- 0 472 790 (73) Proprietor: SCHERING CORPORATION WO-A-92/07824 US-A- 4 235 892 Kenilworth New Jersey 07033 (US) US-A- 4 876 352 US-A- 4 900 847 (72) Inventors: • CHEMICAL ABSTRACTS, vol. 107, no. 1, 06 July • WU, Guang-Zhong 1987, Columbus, Ohio, US; abstract no. 6859M, Somerville, NJ 08876 (US) JOMMI, GIANCARLO ET AL '2-Oxazolidinones • TORMOS, Wanda, I. as regioselective protection of beta-amino Elizabeth, NJ 07202 (US) alcohols in the synthesis of 2-amino-1-aryl-3-fluoro-1-propanols' page 632; column 1; & GAZZ. CHIM. ITAL. vol. 116, no. 9, 1986,, pages 485 - 489 DO 00 CO ^> Is- CD Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice the Patent Office of the Notice of shall be filed in o to European opposition to European patent granted. opposition a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. a. 99(1) European Patent Convention). LU Printed by Jouve, 75001 PARIS (FR) EP0 674 618 B1 Description The present invention relates to a stereospecific process for preparing florfenicol, thiamphenicol and chloramphen- icol having the correct relative and absolute stereochemistry from achiral starting materials. The present invention also 5 relates to a process for isomerizing the S,S-enantiomer of florfenicol to florfenicol having the proper R,S stereochem- istry. In addition, the present invention relates to a stereospecific process for preparing oxazoline intermediates useful in the synthesis of florfenicol, thiamphenicol, chloramphenicol, and related antibiotics. BACKGROUND OF THE INVENTION 10 Florfenicol (I) is a broad spectrum antibiotic having activity against Gram positive, Gram negative and thiamphen- icol-resistant bacteria, as disclosed in U.S. Patent No. 4,235,892. OH 40 I ^ o2n- ny o Several approaches to the synthesis of florfenicol have been reported, e.g. Tyson, Chem Ind., (1 988) pp. 1 1 8-1 22; so and U.S. 4,743,700. However, these processes typically suffer from low overall yields and require either a resolution step or expensive chiral starting materials. Schumacher et al., J. Org. Chem., 55, 18 (1990) pp. 5291-5294, describes a synthesis of florfenicol starting from a commercially available chiral starting material, e.g. compound (1). Compound (1) is converted to the oxazoline (2), to protect the secondary hydroxyl group, and (2) is converted to the fluoride (3). The oxazoline protecting group is 55 removed by treatment with acid and the resulting amino-alcohol (4) converted to florfenicol I. However, the Schumacher et al. process again requires the use of expensive chiral starting materials. 2 EP0 674 618 B1 I Clark et al., in Synthesis, (1991) pp. 891-894, disclose a process for the synthesis of florfenicol via the stereose- lective hydrolysis of ethyl D,L-f/ireo-3-(4-methylthiophenyl)-serinate hydrochloride (5) using enzymes to give (2S,3R)- 3-(4-methyl-thiophenyl)serine (7) and the unreacted ester ethyl (2R,3S)-3-(4-methyl-thiophenyl)serinate hydrochloride (6). The acid (7), and the ester (6), are then converted via alternative multi-step sequences to the R,R-oxazoline (2). Compound (2) is then converted to florfenicol by the process of Schumacher et al., described above. EP0 674 618 B1 CH3 ^"y^l NH-fHCl (5) COzCjJ-ls OH 10 15 CH3 NH2«Ha COzCzHs CO2H 20 OH (7) 25 30 \ (2) " OH V ' 35 CH3-SO2 The Clark et al. process, while avoiding the use of expensive chiral starting materials, is chemically inefficient, 40 producing a mixture of chiral ester (6) and acid (7) which must be separately converted to (2). Thus, the prior art does not teach a chemically efficient stereoselective process for the synthesis of florfenicol that avoids the use of expensive chiral precursors. SUMMARY OF THE INVENTION 45 The present invention comprises a process for the asymmetric synthesis of florfenicol, thiamphenicol or chloram- phenicol comprising the steps: (c) regioselectively opening a chiral epoxide of the formula 50 55 4 EP0 674 618 B1 wherein R is nitro or methanesulfonyl, by sequentially treating with a strong base, a Lewis acid and dichloroace- tonitrile to form an oxazoline of the formula OH 10 is wherein R is as defined above; (d) stereoselective inversion/isomerization of the oxazoline of step (c) by sequentially treating with: (i) a lower alkylsulfonyl chloride and a tertiary amine base; (ii) aqueous acid; and (iii) an alkali metal hydroxide; to form an oxazoline of the formula 20 25 30 wherein R is as defined above; and (e) either: 35 (i) wherein R is methanesulfonyl, treating the oxazoline of step (d) with a fluorinating agent, then hydrolyzing the oxazoline with acid to obtain florfenicol; or (ii) hydrolyzing the oxazoline of step (d) with acid to obtain: 40 (a) wherein R is methanesulfonyl, thiamphenicol; or (b) wherein R is nitro, chloramphenicol. Preferably the chiral epoxide of step (c) is prepared from a trans cinnamic acid derivative of the formula H O 50 55 wherein R is nitro or methanesulfonyl, by: (a) converting the acid to an acid chloride using a chlorinating agent, and reducing the acid chloride to a trans allylic alcohol with a reducing agent; 5 EP0 674 618 B1 (b) asymmetrically epoxidizing the allylic alcohol of step (a), by reacting with t-butylhydroperoxide in the presence of a chiral epoxidation catalyst prepared from titanium (IV) isopropoxide and L-diisopropyltartaric acid, to form the chiral epoxide of the formula 5 10 wherein R is as defined above. is Preferred is a process as described above wherein the chlorinating agent of step (a) isthionyl chloride, the reducing agent of step (a) is NaBH4, the lower alkylsulfonyl chloride of step (d) is MsCI, the tertiary amine base of step (d) is triethylamine, the aqueous acid of step (d) is sulfuric acid, the alkali metal hydroxide of step (d) is NaOH, the fluorinating agent of step (e) is CF3CH(F) 20 CF2N(C2H5)2, and the acid of step (e) is AcOH. More preferred is a process as described above wherein the strong base of step (c) is an alkali metal hydride, preferably sodium hydride, and the Lewis acid of step (c) is zinc chloride. In an alternative embodiment, the process of the instant invention comprises the isomerization of the S,S-isomer 25 of florfenicol to the R,S-isomer (I) by sequentially treating with: (i) a lower alkylsulfonyl chloride and a tertiary amine base; (ii) an alkali metal hydroxide; (iii) aqueous acid. In a third embodiment the process of present invention comprises a process for regioselectively opening an epoxide of the formula 30 35 wherein R1 is methanesulfonyl, nitro or hydrogen by sequentially treating with a strong base, a Lewis acid and dichlo- roacetonitrile to form a f/ireo-oxazoline of the formula 40 OH OH 45 50 respectively, wherein R1 is as defined above. The epoxide opening process can be carried out on chiral (as shown) or racemic starting materials. Where chiral starting materials are used the reaction is both regio- and stereo-selective, producing chiral oxazolines. Preferred is a process for preparing an oxazoline as described above wherein the strong base is an alkali metal 55 hydride, preferably sodium hydride, and the Lewis acid is zinc chloride. The process of the present invention does not suffer the shortcomings of the prior art processes. It is chemically efficient, proceeds in high yield, and avoids the problems of expensive chiral starting materials by utilizing a reusable chiral auxiliary to introduce optical activity. 6 EP0 674 618 B1 DETAILED DESCRIPTION As used herein: 5 "fluorinating agent" is a reagent or combination of reagents capable of converting a primary alcohol to the analogous fluoride. Preferred fluorinating agents include: a,a-difluoroalkylamine fluorinating agents disclosed in U.S. Patent No. 4,876,352, such as N-(1 ,1 ,2,3,3, 3-hexafluoropropyl)diethylamine; HF; phosphorous fluorides; 2-chloro- 1 ,1 ,2-trifluorotriethylamine; and inorganic fluoride, such as LiF, in a polyol solvent. Most preferred is N- (1 ,1 ,2,3,3,3-hexafluoropropyl)-diethylamine. 10 "lower alkyl" means a saturated hydrocarbon chain having from 1-6 carbon atoms, the chain being straight or branched; "alkali metal hydroxide" means sodium, lithium or potassium hydroxide, preferably NaOH; "strong base" means a strong nonaqueous base selected from the group consisting of alkali metal hydride, alkali metal alkoxide and lower alkyllithium; is "alkali metal hydride" means sodium, lithium or potassium hydride, preferably sodium hydride; "alkali metal alkoxide" means an alkali metal salt of a lower alkyl alcohol.