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WO2007004049A1 - Oxazolidinones contenant de l'azétidine comme agents antibactériens - Google Patents

Oxazolidinones contenant de l'azétidine comme agents antibactériens Download PDF

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Publication number
WO2007004049A1
WO2007004049A1 PCT/IB2006/001869 IB2006001869W WO2007004049A1 WO 2007004049 A1 WO2007004049 A1 WO 2007004049A1 IB 2006001869 W IB2006001869 W IB 2006001869W WO 2007004049 A1 WO2007004049 A1 WO 2007004049A1
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Prior art keywords
oxo
oxazolidin
difluoro
mmol
phenyl
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PCT/IB2006/001869
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English (en)
Inventor
Vara Prasad Venkata Nagendra Josyula
Adam Robert Renslo
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Pharmacia & Upjohn Company Llc
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Publication of WO2007004049A1 publication Critical patent/WO2007004049A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to novel oxazolidinones derivatives bearing azetidine rings, pharmaceutical compositions thereof, methods for their use, and methods for preparing these compounds. These compounds have potent activities against gram-positive and/or gram-negative bacteria.
  • Antibacterial resistance is a global clinical and public health problem that has emerged with alarming rapidity in recent years and undoubtedly will increase in the near future. Resistance is a problem in the community as well as in health care settings, where transmission of bacteria is greatly amplified. Because multiple drug resistance is a growing problem, physicians are now confronted with infections for which there is no effective therapy. As result, structurally novel antibacterials with a new mode of action have become increasingly important in the treatment of bacterial infections. Among newer antibacterial agents, oxazolidinone compounds are the most recent synthetic class of antimicrobials. This invention provides azetidine derivatives of oxazolidinones as inhibitors of bacterial protein synthesis for the treatment of serious infections caused by a number of human and veterinary pathogens, including multiple resistant strains of bacteria. INFORMATION DISCLOSURE
  • the present invention provides a compound of formula I
  • the present invention also provides: a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I, a method for treating gram-positive microbial infections in a mammal by administering to the subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating gram-positive or gram-negative microbial infections.
  • the invention may also provide novel intermediates and novel processes that are useful for preparing compounds of formula I.
  • alkyl, or alkenyl, etc. refer to both straight and branched groups, but reference to an individual radical such as “propyl” embraces only the straight chain radical, a branched chain isomer such as “isopropyl” being specifically referred to.
  • Cs-gcycloalkyl or "C 3 . 6 cycloalkyl” refers to a cyclic saturated monovalent hydrocarbon group of three to seven carbon atoms, e.g., cyclopropyl, cyclohexyl, and the like.
  • halo refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • a pharmaceutically acceptable salt of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • pharmaceutically acceptable carrier means a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use.
  • a pharmaceutically acceptable carrier as used in the specification and claims includes both one and more than one such carrier.
  • mammal refers to human or warm-blooded animals including livestock and companion animals.
  • livestock and companion animals refers to human or warm-blooded animals including livestock and companion animals.
  • optional or “optionally” means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • treating includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • therapeutically effective amount means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • leaving group has the meaning conventionally associated with it in synthetic organic chemistry i.e., an atom or group capable of being displaced by a nucleophile and includes halogen, alkylsulfonyloxy, ester, or amino such as chloro, bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy, N,O-dimethylhydroxyl-amino, and the like.
  • the compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. "Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h” for an hour or hours and “rt” for room temperature).
  • alkyl is methyl or ethyl.
  • Scheme I illustrates construction of the oxazolidinone ring when acetylaminomethyl substitution is desired at C-5 of the oxazolidinone.
  • the aniline intermediate 1 is first converted to an aryl carbamate using (wherein R may be -CH 2 phenyl) standard procedures that are well known to those skilled in the art, for example using benzyl chloroformate and pyridine in dichloromethane.
  • Step 2 involves formation of the oxazolidinone ring. This can be accomplished using a multi-step procedure as described in Angewandte Cheniie 2003, 42, 2010 (and references therein). Alternatively this conversion can be accomplished in one step using (S)- acetic acid 2-acetylamino-l-chloromethyl-ethyl ester. This reagent is prepared from (S)- epichlorohydrin in three steps (epoxide ring opening with benzaldehyde imine, imine hydrolysis, and peracylation with acetic anhydride) according to the procedure described in US Patent No. 6,833,453.
  • the reaction is performed in the presence of an organic base such as lithium tert-butoxide, in a polar organic solvent such as dimethylformamide or acetonitrile, at temperatures of about 0 0 C to 25 0 C.
  • organic base such as lithium tert-butoxide
  • a polar organic solvent such as dimethylformamide or acetonitrile
  • the product of this reaction is intermediate 2 bearing a tert-butyl carbamate (B oc protected amine) at the C-5 position.
  • step 2 the amine is deprotected by treatment with acids such as hydrochloric acid or trifluoric acid. If less harsh conditions are required, treatment with trimethylsilyltrifluoromethane sulfonate and 2,6-lutidine (as described by Ohfune, Y. and Sakaitani, M. /. Org. Chem. 1990, 55, 870-876) is also effective.
  • the amine can be converted to various amides using well-known coupling reactions (for example by treatment with acid chlorides) or to ureas and carbamates by reaction with isocyanates or alkyl chloroformates, respectively.
  • the products may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.
  • the 3- hydroxyazetidine 1 is prepared by hydrogenolysis (for example with Pd/C in methanol) of 1- benzyl-3-trimethylsilyloxyazetidine (prepared as described by Higgins, R. H. J. Heterocyclic Chem. 1987, 24, 1489). .
  • the product may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.
  • Step 2 of Scheme 4 represents one or more steps required for the protection, oxidation, or otherwise conversion of the hydroxyazetidine ring to a more highly functionalized state.
  • a person of ordinary skill in organic chemistry will be well acquainted with the various reactions that will be required for this functionalization.
  • This may involve, for example, protection as a silyl ether, fluorination, oxidation to the azetidinone, olefination of the azetidione thus obtained, reaction of the azetidinone thus obtained with nucleophiles, or activation of the hydroxy group and substitution with nucleophiles.
  • the products may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like.
  • step 3 involves reduction of the nitro group to provide the aniline intermediate 5.
  • This reduction is generally accomplished by reacting the nitro intermediate 4 with iron metal.
  • the reaction is carried out at temperatures between 6O 0 C and 90 0 C in mixtures of water and alcohol (methanol, ethanol, etc.) as solvent, and in the presence of ammonium chloride to buffer the reaction mixture.
  • reductions of this type are conducted by reaction with other metals such as tin or zinc or by hydrogenation under palladium or platinum catalysis (see Rylander Hydrogenation Methods; Academic Press: New York, 1985, pp. 104-116). .
  • the product may be used as collected or may first be purifed using conventional techniques such as preparative TLC or HPLC, chromatography, precipitation, crystallization and the like. Medical and Veterinary Uses
  • the compounds of the present invention may be used for the treatment of infectious,
  • Gram-positive bacterial infections caused by a variety of bacterial organisms, including those that require long-term therapy (>28 days).
  • bacterial organisms examples include gram-positive bacteria such as multiple resistant staphylococci, for example S. aureus and S. epiderrnidis; multiple resistant streptococci, for example S. pneumoniae and S. pyogenes; and multiple resistant Enterococci, for example E. faecalis; gram negative aerobic bacteria such as Haemophilus, for example H. influenzae and Moraxella, for example M. catarrhalis; as well as anaerobic organisms such as bacteroides and Clostridia species, and acid-fast organisms such as Mycobacteria, for example M. tuberculosis; and/or Mycobacterium avium.
  • Other examples include Escherichia, for example E. coli. intercellular microbes, for example Chlamydia and Rickettsiae.
  • infections examples include central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients.
  • infectious diseases that may be treated with the compounds of the present invention are gram-positive infections such as osteomyelitis, endocarditis and diabetic foot. Antibacterial Activities
  • the in vitro antibacterial activity of the compounds of the present invention may be assessed by following procedures recommended in (1) National Committee for Clinical Laboratory Standards (Jan. 2003), Methods for dilution antimicrobial tests for bacteria that grow aerobically, Approved Standard (6 th ed), M7-A6, NCCLS, Wayne, PA; (2) National Committee for Clinical Laboratory Standards (Mar.
  • the compound of formula I may be used in its native form or as a salt. In cases where forming a stable nontoxic acid or base salt is desired, administration of the compound as a pharmaceutically acceptable salt may be appropriate.
  • pharmaceutically acceptable salts of the present invention include inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate, bicarbonate, carbonate salts, and organic salts such as tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, etoglutarate, and glycerophosphate.
  • salts may be obtained using standard procedures well known in the art, for example, reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • an oxazolidinone prodrug of the present invention or its pharmaceutical compositions can be administered orally, parenterally, topically, rectally, transmucosally, or intestinally.
  • Parenteral administrations include indirect injections to generate a systemic effect or direct injections to the afflicted area. Examples of parenteral administrations are subcutaneous, intravenous, intramuscular, intradermal, intrathecal, intraocular, intranasal, intravetricular injections or infusions techniques.
  • Topical administrations include the treatment of infectious areas or organs readily accessibly by local application, such as, for example, eyes, ears including external and middle ear infections, vaginal, open wound, skins including the surface skin and the underneath dermal structures, or other lower intestinal tract. It also includes transdermal delivery to generate a systemic effect.
  • the rectal administration includes the form of suppositories.
  • the transmucosal administration includes nasal aerosol or inhalation applications.
  • the preferred routes of administration are oral and parenteral.
  • compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulation, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying.
  • compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, solutions, emulsions, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient.
  • a carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent.
  • Such carriers or excipients include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, sucrose, pectin, dextrin, mannitol, sorbitol, starches, gelatin, cellulosic materials, low melting wax, cocoa butter or powder, polymers such as polyethylene glycols and other pharmaceutical acceptable materials.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, liquid polyethylene glycols, cremophor, capmul, medium or long chain mono-, di- or triglycerides.
  • Stabilizers may be added in these formulations, also.
  • Liquid form compositions include solutions, suspensions and emulsions.
  • solutions of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents.
  • the compounds may also be formulated for parenteral administration, e.g., by injections, bolus injection or continuous infusion.
  • Formulations for parenteral administration may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating materials such as suspending, stabilizing and/or dispersing agents.
  • the compounds of the invention may be formulated in aqueous solution, preferably in physiologically compatible buffers or physiological saline buffer.
  • suitable buffering agents include trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine.
  • Parenteral administrations also include aqueous solutions of a water soluble form, such as, without limitation, a salt, of the active compound.
  • suspensions of the active compounds may be prepared in a lipophilic vehicle.
  • Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers and/or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water
  • the compounds may also be formulated by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and other glycerides.
  • compounds of the present invention can be conveniently delivered through an aerosol spray in the form of solution, dry powder, or suspensions.
  • the aerosol may use a pressurized pack or a nebulizer and a suitable propellant.
  • the dosage unit may be controlled by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin for use in an inhaler may be formulated containing a power base such as lactose or starch.
  • the pharmaceutical composition may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion such as suspensions, emulsion, or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, ceteary alcohol, 2- octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as a benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • the compounds may also be formulated as depot preparations. Such long acting formulations may be in the form of implants.
  • a compound of this invention may be formulated for this route of administration with suitable polymers, hydrophobic materials, or as a sparing soluble derivative such as, without limitation, a sparingly soluble salt.
  • the compounds may be delivered using a sustained-release system.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for 24 hours or for up to several days. Dosage
  • compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount sufficient to achieve the intended purpose, Le., the treatment or prevent of infectious diseases. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • the quantity of active component that is the compound of this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the manner of administration, the potency of the particular compound and the desired concentration. Determination of a therapeutically effective amount is well within the capability of those skilled in the art. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
  • a therapeutically effective amount of dosage of active component will be in the range of about 0.1 to about 400 mg/kg of body weight/day, more preferably about 1.0 to about 50 mg/kg of body weight/day. It is to be understood that the dosages may vary depending upon the requirements of each subject and the severity of the bacterial infection being treated. In average, the effective amount of active component is about 200 mg to 800 mg and preferable 600 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired plasma concentration.
  • the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation.
  • the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day.
  • HATU N-[(dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin
  • TBS tributylsilyl
  • Boc terf-butoxycarbonyl
  • Lithium butoxide solution (1.7 mL of a 1.0 M THF solution, 1.7 mmol) is added to a cooled (0 0 C) solution of benzyl 3,5-difluoro-4-(3-methoxyazetidin-l-yl)phenylcarbamate (0.20 g, 0.57 mmol) in DMF (0.5 mL) and MeOH (0.047 mL, 1.15 mmol).
  • Solid (S)-acetic acid 2-acetylamino-l-chloromethyl-ethyl ester (0.22 g, 1.15 mmol) is then added and the solution allowed to warm to room temperature and stirred for 20 h.
  • the crude azetidin-3-ol (24.3 mmol) is dissolved in DMF (40 mL) and DIEA (5.7 mL, 33 mmol) and treated with 3,4,5-trifluoronitrobenzene (3.9 g, 22.0 mmol).
  • the resulting solution is warmed to 55 °C for 5 hours and cooled to room temperature.
  • the reaction mixture is diluted with 200 mL of ethyl acetate and washed with 130 mL of 0.25 M HCl, saturated NaHCO 3 , brine, and dried (MgSO 4 ), filtered, and concentrated.
  • the crude residue is triturated thrice with hexane to provide the title compound as a yellow solid.
  • Sodium hydride (0.11 g of a 60% dispersion in mineral oil, 2.7 mmol) is added to an oven-dried flask and washed with three portions of dry hexane. The resulting solid is suspended in DMF (5 mL) and cooled to 0 0 C. To this suspension is added l-(2,6-difluoro-4- nitrophenyl)azetidin-3-ol (0.51 g, 2.22 mmol) and the reaction mixture became a think brown suspension. After stirring for 10 minutes at 0 0 C, methyl iodide (0.35 mL, 5.6 mmol) is added to produce an orange solution.
  • reaction mixture is poured into saturated NH4C1 solution and extracted twice with dichloromethane.
  • dichloromethane phases are washed with water, brine, and dried (MgSO 4 ), filtered, and concentrated to provide the title compound as an oil that required no additional purification.
  • Iron metal (0.35 g, 6.3 mmol) is added in five portions over 1 h to a refluxing solution of l-(2,6-difluoro-4-nitrophenyl)-3-methoxyazetidine (0.51 g, 2.1 mmol) and ammonium chloride (1.12 g, 21 mmol) in 15 mL of 2:1 ethanol-H 2 O.
  • the rust colored mixture is refluxed for another 30 min and then cooled, diluted with dichloromethane and filtered to remove iron oxide.
  • the organic layer in the filtrate is separated and the aqueous phase extracted with more dichloromethane.
  • the combined dichloromethane phases are washed with water, brine, and dried (MgSO 4 ), filtered, and concentrated to provide crude 1- (4-amino-2,6-difluorophenyl)-3-methoxyazetidine.
  • the crude amine is dissolved in 16 mL of dichloromethane and cooled to 0 0 C. Pyridine (0.34 mL, 4.2 mmol) and then benzyl chloroformate (0.34 mL, 2.4 mmol) are then added to the amine solution. The mixture is stirred for 1 h at 0 °C and for 90 min at room temperature.
  • Trimethylsilyltrifluoromethanesulfonate (0.12 mL, 0.63 mmol) is added in two portions to a solution of f ⁇ ??-butyl ⁇ (5S)-3-[3,5-difluoro-4-(3-methoxyazetidin-l-yl)phenyl]- 2-oxo-l,3-oxazolidin-5-yl ⁇ methylcarbamate (0.102 g, 0.25 mmol) in dichloromethane (1.5 mL) and 2,6-lutidine (0.10 mL, 0.86 mmol). After stirring one hour, 2 mL of methanol is added and the reaction mixture stirred for another hour and concentrated to provide the crude amine.
  • Propionic anhydride (0.042 mL, 0.33 mmol) is added to a cooled (0 0 C) solution of the crude amine (0.25 mmol) dissolved in dichloromethane and DIEA (0.22 mL, 1.25 mmol). After warming to room temperature and stirring for 30 minutes, the reaction mixture is diluted with dichloromethane and washed with dilute NaHCO 3 , 10 mL of a 0.2 N HCl solution, satd NaHCO 3 , brine, and dried (MgSO 4 ), filtered and concentrated. The crude residue is purified by preparative TLC (5% MeOH-dichloromethane) to afford the title compound.
  • Trimethylsilyltrifluoromethanesulfonate (0.11 mL, 0.60 mmol) is added in three portions over a period of one hour to a solution of tert-butyl ⁇ (5S)-3-[3,5-difluoro-4-(3- methoxyazetidin-l-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl ⁇ methylcarbamate (0.10 g, 0.24 mmol) in dichloromethane (1.5 mL) and 2,6-lutidine (0.097 mL, 0.84 mmol).
  • Lithium butoxide solution (3.1 mL of a 1.0 M THF solution, 3.1 mmol) is added to a cooled (0 0 C) solution benzyl 3,5-difluoro-4-(3-fluoroazetidin-l-yl)phenylcarbamate (0.42 g, 1.25 mmol) in DMF (1.2 mL) and MeOH (0.10 mL, 2.5 mmol).
  • Solid (£)-acetic acid 2- acetylamino-1-chloromethyl-ethyl ester (0.48 g, 2.5 mmol) is then added and the solution allowed to warm to room temperature and stirred for 20 h.
  • the DAST reagent (0.87 mL, 6.6 mmol) is added in three portions over Ih to a cooled solution of l-(2,6-difluoro-4-nitrophenyl)azetidin-3-ol (0.5 g, 2.2 mmol) in 20 mL of dichloromethane at - 78 0 C. After stirring at - 78°C for another 2 hours, the reaction mixture is allowed to warm to room temperature and stirred for 18 hours. The reaction solution is diluted with dichloromethane and washed with sat. NaHCO 3 , brine, and dried (MgSO 4 ), filtered, and concentrated. The residue is subjected to column chromatography on silica gel (elution with 0-20% ethyl acetate-hexane) to provide the title compound.
  • reaction mixture is then diluted with dichloromethane and washed with H 2 O, brine and then dried (MgSO 4 ), filtered and concentrated.
  • the residue is subjected to column chromatography on silica gel (elution with 0-20% ethyl acetate-hexane) to provide the title compound.
  • Trimethylsilyltrifluoromethanesulfonate (0.24 mL, 1.26 mmol) is added in two portions to a solution of tert-butyl ⁇ (5S)-3-[3,5-difluoro-4-(3-fluoroazetidin-l-yl)phenyl]-2- oxo-l,3-oxazolidin-5-yl ⁇ methylcarbamate (0.200 g, 0.50 mmol) in dichloromethane (3.0 mL) and 2,6-lutidine (0.20 mL, 1.72 mmol). After stirring one hour, 2 mL of methanol is added and the reaction mixture stirred for another hour and concentrated to provide the crude amine.
  • Propionic anhydride (0.084 mL, 0.66 mmol) is added to a cooled (0 0 C) solution of the crude amine (0.50 mmol) dissolved in dichloromethane and DIEA (0.44 mL, 2.5 mmol). After warming to room temperature and stirring for 30 minutes, the reaction mixture is diluted with dichloromethane and washed with dilute NaHCO 3 , 20 mL of a 0.2 N HCl solution, satd NaHCO 3 , brine, and dried (MgSO 4 ), filtered and concentrated. The crude residue is purified by preparative TLC (3% MeOH-dichloromethane) to afford the title compound.
  • Trimethylsilyltrifluoromethanesulfonate (0.24 mL, 1.26 mmol) is added in three portions over a period of one hour to a solution of fe ⁇ t-butyl ⁇ (5S)-3-[3,5-difluoro-4-(3- fluoroazetidin-l-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl ⁇ methylcarbamate (0.20 g, 0.5 mmol) in dichloromethane (3.0 mL) and 2,6-lutidine (0.20 mL, 1.72 mmol).
  • Lithium butoxide solution (2.0 mL of a 1.0 M THF solution, 2.0 mmol) is added to a cooled (0 0 C) solution of benzyl 3,5-difluoro-4-(3,3-difluoroazetidin-l-yl)phenylcarbamate (0.24 g, 0.67 mmol) in DMF (0.7 mL) and MeOH (0.055 mL, 1.34mmol).
  • Solid (S)-acetic acid 2-acetylamino-l-chloromethyl-ethyl ester (0.26 g, 1.36 mmol) is then added and the solution allowed to warm to room temperature and stirred for 20 h.
  • the reaction mixture is diluted with 50 mL of ethyl acetate and washed with 30 mL of 0.25 M HCl, saturated NaHCO 3 , brine, and dried (MgSO 4 ), filtered, and concentrated.
  • the crude residue is triturated thrice with hexane to provide the title compound as a yellow solid.
  • Hydrogen fluoride triethylamine complex (0.18 mL, 1.09 mmol) is added to a THF (3.6 mL) solution of ⁇ -( ⁇ (5S)-2-oxo-3-[3,5-difluoro-4-(3- ⁇ fc?rt- butyldimethylsilyloxy ⁇ azetidin- 1 -yl)phenyl] - 1 ,3-oxazolidin-5-yl ⁇ methyl)propionamide (0.17 g, 0.36 mmol) at room temperature. After 4 hours, the solution is treated with dilute NaHCO 3 dropwise and extracted with dichloromethane.
  • Iron metal (0.53 g, 9.4 mmol) is added in five portions over 1 h to a refluxing solution of l-(2,6-difluoro-4-nitrophenyl)-3-(fer ⁇ -butyldimethylsilyloxy)azetidine (1.08 g, 3.14 mmol) and ammonium chloride (1.7 g, 31.4 mmol) in 30 mL of 2:1 ethanol-H 2 O.
  • the rust colored mixture is refluxed for another 30 min and then cooled, diluted with dichloromethane and filtered to remove iron oxide.
  • the organic layer in the filtrate is separated and the aqueous phase extracted with more dichloromethane.
  • the combined dichloromethane phases are washed with water, brine, and dried (MgSO 4 ), filtered, and concentrated to provide the crude aniline intermediate.
  • This material is dissolved in 4 mL of dichloromethane and cooled to 0 0 C. Pyridine (0.51 mL, 6.28 mmol) and then benzyl chloroformate (0.5 mL, 3.45 mmol) are then added to the amine solution. The mixture is warmed to room temperature and stirred for 4 hours at room temperature. The reaction mixture is then diluted with dichloromethane and washed with H 2 O, brine and dried (MgSO 4 ), filtered, and concentrated.
  • the mixture is treated with LiOtBu solution (1.0 M in THF, 4.3 mL, 4.3 mmol) dropwise.
  • the reaction mixture is slowly warmed to room temperature and stirred for 18 h.
  • the solution is then is quenched with saturated NH 4 Cl, followed by addition of water and brine.
  • the mixture is extracted with dicholromethane and the combined organic phases washed with water, brine, and dried (MgSO 4 ), filtered and concentrated.
  • the residue is subjected to column chromatography on silica gel (elution with 0-30% ethyl acetate-hexane) to provide the title compound.
  • Trimethylsilyltrifluoromethanesulfonate (0.48 mL, 2.68 mmol) is added to a solution of tert-butyl ⁇ (5S)-3-[3,5-difluoro-4-(3- ⁇ erf-butyldimethylsilyloxy ⁇ azetidin-l-yl)phenyl]-2- oxo-l,3-oxazolidin-5-yl ⁇ methylcarbamate (0.55 g, 1.07 mmol) in dichloromethane (4.3 mL) and 2,6-lutidine (0.44 mL, 3.75 mmol).
  • Hydrogen fluoride triethylamine complex (0.19 mL, 1.2 mmol) is added to a THF (4 mL) solution of methyl ⁇ (5S)-3-[3,5-difluoro-4-(3- ⁇ tert-butyldimethylsilyloxy ⁇ azetidin-1- yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl ⁇ methylcarbamate (0.19 g, 0.4 mmol) at room temperature. After 3 hours, the solution is treated with dilute NaHCO 3 dropwise and extracted with dichloromethane. The combined organic extracts are washed with brine, dried (MgSO 4 ), filtered, and concentrated. Purification by pTLC (5% MeOH-dichloromethane) afforded the title compound.
  • Trimethylsilyltrifluoromethanesulfonate (0.26 mL, 1.46 mmol) is added to a solution of tert-butyl ⁇ (5S)-3 -[3 ,5-difluoro-4-(3- ⁇ t ⁇ ?t-butyldimethylsilyloxy ⁇ azetidin- 1 -y l)pheny 1] -2- oxo-l,3-oxazolidin-5-yl ⁇ methylcarbamate (0.3 g, 0.58 mmol) in dichloromethane (2.5 mL) and 2,6-lutidine (0.23 mL, 2.03 mmol).
  • Hydrogen fluoride triethylamine complex (0.50 mL, 3.2 mmol) is added to a THF (5 mL) solution of ⁇ -( ⁇ (5S)-3-[3,5-difluoro-4-(3- ⁇ t ⁇ rrtutyldimethylsilyloxy ⁇ hydroxyazetidin- l-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl ⁇ methyl)acetamide (0.49 g, 1.07 mmol) at room temperature. After 4 hours, the solution is treated with dilute NaHCO 3 dropwise and extracted with dichloromethane.
  • Example 10 Intermediates for the synthesis of Example 10 are prepared as follows.
  • Lithium butoxide solution (4.8 mL of a 1.0 M THF solution, 4.8 mmol) is added to a cooled (0 0 C) solution of benzyl 3,5-difluoro-4-(3- ⁇ ?err-butyldimethylsilyloxy ⁇ -azetidin-l- yl)phenylcarbamate (0.72 g, 1.61 mmol) in DMF (1.1 mL) and MeOH (0.13 mL, 3.21 mmol).
  • Solid (S)-acetic acid 2-acetylamino-l-chloromethyl-ethyl ester (0.62 g, 3.21 mmol) is then added and the solution allowed to warm to room temperature and stirred for 20 h.
  • Saturated aqueous ammonium chloride (4 mL) is added, along with 20 mL of H 2 O and 20 mL of brine.
  • reaction mixture is stirred for 15 minutes at -50 0 C and then treated with triethylamine (0.15 mL, 1.1 mmol) and allowed to warm to room temperature. After stirring for 1.5 hours, additional triethylamine (0.25 mL) is added and the reaction mixture stirred for another 1.5 hours.
  • Dichloromethane and water are then added, the layers separated and the aqueous phase extracted with more dichloromethane.
  • the combined organic phases washed with dilute ⁇ aHC ⁇ 3 , brine, and dried (MgSO 4 ), filtered and concentrated. The residue is subjected to preparative TLC (6% MeOH- dichloromethane) to provide the title compound.
  • Lithium butoxide solution (0.84 mL of a 1.0 M THF solution, 0.84 mmol) is added to a cooled (0 0 C) solution benzyl 3,5-difluoro-4-[3-(methoxyimino)azetidin-l- yl]phenylcarbamate (0.10 g, 0.28 mmol) in DMF (0.3 mL) and MeOH (0.025 mL, 0.56 mmol).
  • Solid (S)-acetic acid 2-acetylamino-l-chloromethyl-ethyl ester (0.11 g, 0.56 mmol) is then added and the solution allowed to warm to room temperature and stirred for 20 h.
  • Palladium catalyst (10% Pd/C, 0.24 g) is added to a solution of l-(2,6-Difluoro-4- nitrophenyl)azetidin-3-one (1.2 g, 5.3 mmol) in ethyl acetate (30 mL) in a Parr shaker flask.
  • the solution is agitated under a hydrogen atmosphere at 50 psi for 16 hours and then filtered through a pad of celite.
  • the filtrate is cooled (0 0 C) and treated directly (without concentration) with pyridine (0.82 mL, 10.3 mmol) and benzyl chloroformate (0.93 mL, 6.4 mmol). The mixture is warmed to room temperature and stirred for two hours.
  • Methoxylamine hydrochloride (0.15 g, 1.8 mmol) is added to benzyl 3,5-difluoro-4-
  • Trimethylsilyltrifluoromethanesulfonate (0.12 mL, 0.63 mmol) is added in two portions to a solution of tert-butyl ((5S)-3- ⁇ 3,5-difluoro-4-[3-(methoxyimino)azetidin-l- yl]phenyl ⁇ -2-oxo-l,3-oxazolidin-5-yl)methylcarbamate (0.105 g, 0.25 mmol) in dichloromethane (1.5 mL) and 2,6-lutidine (0.10 mL, 0.86 mmol). After stirring one hour, 2 mL of methanol is added and the reaction mixture stirred for another hour and concentrated to provide the crude amine.
  • Propionic anhydride (0.042 mL, 0.33 mmol) is added to a cooled (0 0 C) solution of the crude amine (0.25 mmol) dissolved in dichloromethane and DIEA (0.22 mL, 1.25 mmol). After warming to room temperature and stirring for 30 minutes, the reaction mixture is diluted with dichloromethane and washed with dilute NaHCO 3 , 10 mL of a 0.2 N HCl solution, satd NaHCO 3 , brine, and dried (MgSO 4 ), filtered and concentrated. The crude residue is purified by preparative TLC (3% MeOH-dichloromethane) to afford the title compound.
  • Trimethylsilyltrifluoromethanesulfonate (0.12 mL, 0.63 mmol) is added in three portions over a period of one hour to a solution of tert-butyl ((5S)-3- ⁇ 3,5-difluoro-4-[3- (methoxyimino)azetidin- 1 -yl]phenyl ⁇ -2-oxo- 1 ,3 -oxazolidin-5-yl)methylcarbamate (0.105 g, 0.25 mmol) in dichloromethane (1.5 mL) and 2,6-lutidine (0.10 mL, 0.86 mmol).
  • Hydrogen fluoride triethylamine complex (0.11 mL, 0.64 mmol) is added in two portions to a THF (2 mL) solution of ⁇ -[((5S)-3- ⁇ 3,5-difluoro-4-[3-(teft- butyldimethylsilyloxy imino)azetidin- 1 -yl]phenyl ⁇ -2-oxo- 1 ,3 -oxazolidin-5- yl)methyl]acetamide (0.15 g, 0.32 mmol) at room temperature. After 3 hours, the solution is treated with dilute NaHCO ⁇ dropwise and extracted with twice with chloroform. The combined chloroform extracts are washed with brine, dried (MgSO 4 ), filtered, and concentrated. Purification by column chromatography (0-4% MeOH-dichloromethane) afforded the title compound.
  • Lithium butoxide solution (2.4 mL of a 1.0 M THF solution, 2.4 mmol) is added to a cooled (0 0 C) solution of benzyl 3,5-difluoro-4-[3-( ⁇ rf-butyldimethylsilyloxyimino)- azetidin-l-yl]phenylcarbamate (0.37 g, 0.79 mmol) in DMF (0.8 mL) and MeOH (0.063 mL, 1.6 mmol).
  • Hydrogen fluoride triethylamine complex (0.14 mL, 0.84 mmol) is added in two portions to a THF (2 mL) solution of N-[((5S)-3- ⁇ 3,5-difluoro-4-[3-(terf- butyldimethy lsilyloxy imino)azetidin- 1 -yl]phenyl ⁇ -2-oxo- 1 ,3 -oxazolidin-5- yl)methyl]propanamide (0.20 g, 0.42 mmol) at room temperature. After 3 hours, the solution is treated with dilute NaHCO 3 dropwise and extracted with twice with chloroform.
  • Trimethylsilyltrifluoromethanesulfonate (0.23 mL, 1.19 mmol) is added in two portions to a solution of tert-butyl ((5S)-3- ⁇ 3,5-difluoro-4-[3-(te7t- butyldimethylsilyloxyimino)azetidin- 1 -yl]phenyl ⁇ -2-oxo- 1 ,3-oxazolidin-5- yl)methylcarbamate (0.25 g, 0.48 mmol) in dichloromethane (3 mL) and 2,6-lutidine (0.12 mL, 0.96 mmol).
  • Lithium butoxide solution (1.7 mL of a 1.0 M THF solution, 1.7 mmol) is added to a cooled (0 0 C) solution of benzyl 3,5-difluoro-4-(3-hydroxy-3-methylazetidin-l- yl)phenylcarbamate (0.20 g, 0.57 mmol) in DMF (0.5 mL) and MeOH (0.047 mL, 1.15 mmol).
  • Solid (S)-acetic acid 2-acetylamino-l-chloromethyl-ethyl ester (0.22 g, 1.15 mmol) is then added and the solution allowed to warm to room temperature and stirred for 20 h.
  • Methylmagnesium bromide (5.5 ml of 1.4 M THF solution, 7.7 mmol) is added to a cooled (0 0 C) solution of benzyl 3,5-difluoro-4-(3-oxoazetidin-l-yl)phenylcarbamate (1.27 g, 3.8 mmol) in THF (70 mL). The reaction solution stirred at 0 0 C for 3 hours and warmed to room temperature. Saturated aqueous ammonium chloride (50 mL) is added, along with 50 mL of H 2 O and 50 mL of brine.
  • Lithium butoxide solution (0.78 mL of a 1.0 M THF solution, 0.78 mmol) is added to a cooled (0 0 C) solution benzyl 3,5 ⁇ difluoro-4-(3-fluoro-3-methylazetidin-l- yl)phenylcarbamate (0.11 g, 0.31 mmol) in DMF (0.3 mL) and MeOH (0.025 mL, 0.62 mmol).
  • Solid (S)-acetic acid 2-acetylamino-l-chloromethyl-ethyl ester (0.12 g, 0.62 mmol) is then added and the solution allowed to warm to room temperature and stirred for 20 h.
  • the DAST reagent (0.44 mL, 3.3 mmol) is added in three portions over Ih to a cooled solution of benzyl S ⁇ -difluoro ⁇ - ⁇ -hydroxy-S-methylazetidin ⁇ -yOphenylcarbamate (0.40 g, 1.1 mmol) in 20 mL of dichloromethane at - 78 0 C. After stirring at - 78°C for another 2 hours, the reaction mixture is allowed to warm to room temperature and stirred for
  • reaction solution is diluted with dichloromethane and washed with sat.
  • Lithium tert-butoxide solution (2.1 mL of a 1.0 M THF solution, 2.1 mmol) is added to a cooled (0 0 C) solution of benzyl 4-[3-(cyanomethylene)azetidin-l-yl]-3,5- difluorophenylcarbamate (0.30 g, 0.85 mmol) in DMF (0.8 mL) and MeOH (0.08 mL, 1.7 mmol).
  • Solid (S)-acetic acid 2-acetylamino-l-chloromethyl-ethyl ester (0.36 g, 1.7 mmol) is then added and the solution allowed to warm to room temperature and stirred for 20 h.
  • Lithium butoxide solution (1.6 mL of a 1.0 M THF solution, 1.6 mmol) is added to a cooled (0 °C) solution of benzyl 4-[3-(cyanomethyl)azetidin-l-yl]-3,5- difluorophenylcarbamate (0.20 g, 0.56 mmol) in DMF (0.6 mL) and MeOH (0.05 mL, 1.1 mmol).
  • Solid (5)-acetic acid 2-acetylamino-l-chloromethyl-ethyl ester (0.23 g, 1.1 mmol) is then added and the solution allowed to warm to room temperature and stirred for 20 h.
  • Hydrogen fluoride triethylamine complex (0.13 mL, 0.77 mmol) is added in two portions to a THF (2 mL) solution of ⁇ -( ⁇ (5S)-2-oxo-3-[2,3,5-trifluoro-4-(3- ⁇ terf- butyldimethylsilyloxy ⁇ azetidin- 1 -yl)phenyl] - 1 ,3-oxazolidin-5-yl ⁇ methyl)acetamide (0.18 g, 0.39 mmol) at room temperature. After 3 hours, the solution is treated with dilute NaHCO 3 dropwise and extracted with twice with chloroform.
  • a solution of l-benzyl-3-trimethylsilyloxyazetidine (2.5 g, 10.6 mmol) in 35 mL of methanol is treated with 10% Pd(OH) 2 /C (1.25 g) and the mixture stirred under a hydrogen balloon for 7 hours.
  • the mixture is then filtered through a pad of celite with the aid of methanol and the filtrate concentrated to provide azetidin-3-ol as a glassy solid that is used directly in the next step.
  • the crude azetidin-3-ol (10.6 mmol) is dissolved in DMF (20 mL) and DIEA (2.7 mL, 15.9 mmol) and treated with 2,3,4,5-tetrafluoronitrobenzene (1.87 g, 9.6 mmol).
  • the resulting solution is warmed to 40 0 C for 18 hours and cooled to room temperature.
  • the reaction mixture is diluted with 100 mL of ethyl acetate and washed with 65 mL of 0.25 M HCl, saturated NaHCO 3 , brine, and dried (MgSO 4 ), filtered, and concentrated.
  • Iron metal (0.41 g, 7.4 mmol) is added in five portions over 1 h to a refluxing solution of l-(2,3,6-trifluoro-4-nitrophenyl)-3-(ferf-butyldimethylsilyloxy)azetidine (0.89 g, 2.5 mmol) and ammonium chloride (1.32 g, 24.6 mmol) in 18 mL of 2:1 ethanol-H 2 O.
  • the rust colored mixture is refluxed for another 30 min and then cooled, diluted with dichloromethane and filtered to remove iron oxide.
  • the organic layer in the filtrate is separated and the aqueous phase extracted with more dichloromethane.
  • Lithium butoxide solution (1.95 mL of a 1.0 M THF solution, 1.95 mmol) is added to a cooled (0 0 C) solution of benzyl 2,3,5-trifluoro-4-(3- ⁇ f ⁇ rt-butyldimethylsilyloxy ⁇ azetidin-l- yOphenylcarbamate (0.31 g, 0.65 mmol) in DMF (0.5 mL) and MeOH (0.052 mL, 1.3 mmol).
  • Trifluoroacetic acid (6mL) is added to a cooled (O 0 C) stirred solution of tert- butyl ⁇ (5S)-3-[3,5-difluoro-4-(3-hydroxy-3-methylazetidin-l-yl)phenyl]-2-oxo-l,3-oxazolidin- 5-yl ⁇ methylcarbamate (0.62 g, 1.5 mmol) in 1,2-dichloroethane (3OmL). The resulting mixture is stirred at (O 0 C) for 10 minutes, then allowed to warm to room temperature for 25 mins and concentrated to dryness to provide the crude amine as a trifluoroacetate salt which is used without further purification.
  • the reaction mixture is then quenched with saturated NH 4 Cl solution (3OmL), followed by the addition of water (6OmL) and brine (6OmL).
  • the solution is then extracted twice with ethyl acetate and the combined organics phases washed with brine, dried (MgSO 4 ), filtered and concentrated.
  • the crude product is purified by silica gel chromatography (elution with 33-50% ethyl acetate-hexane) to provide the title compound.
  • Trimethylsilyltrifluoromethanesulfonate (0.75 mL, 3.88 mmol) is added to a solution of tert-butyl methyl ⁇ (5S)-3-[4-(3-ethoxyazetidin-l-yl)-3,5-difluorophenyl]-2-oxo-l,3- oxazolidin-5-yl ⁇ methylcarbamate (0.59 g, 1.38 mmol) in dichloromethane (10 mL) and 2,6- lutidine (0.65 mL, 5.58 mmol) at O 0 C.
  • reaction mixture After stirring at room temperature for oune hour, the reaction mixture is treated with 1OmL of methanol and stirred for an additional hour and concentrated. The residue is dissolved in dichloromethane (25 mL) and pyridine (1 mL, 12.4 mmol), cooled in an ice bath and treated with propionic anhydride (0.8 mL, 6.22 mmol).
  • Sodium hydride (270 mg of a 60% dispersion in mineral oil, 6.25 mmol) is pre- washed with three portions of hexane and suspended in anhydrous DMF (2OmL). The suspension is cooled (O 0 C) and treated with l-(2,6-difluoro-4-nitrophenyl)azetidin-3-ol (1.2g , 5.21 mmol). The resulting thick reddish slurry is stirred at O 0 C for 15 minutes and then ethyl iodide (1. ImL, 13.75 mmol) is added to produce a wine red solution.
  • the filtrate is washed with water, brine, dried (Na 2 SO 4 ), filtered and concentrated to provide the crude l-(4-amino- 2,6-difluorophenyl)-3-ethoxyazetidine,
  • the crude amine is dissolved in 25 mL of dichloromethane and cooled (O 0 C). Pyridine (0.6 mL, 7.43 mmol) and then benzylchloroformate (0.6 mL, 3.65 mmol) are added to the amine solution. The mixture is stirred for Ih at O 0 C and for 90 mins at room temperature.
  • reaction mixture is diluted with dichloromethane, washed sequentially with 10% aqueous citric acid, saturated aqueous NaHCO 3 , brine, dried (Na 2 SO 4 ). Concentration and co-evaporation with benzene provided the titled compound as an off- white solid.
  • Trimethylsilyltrifluoromethanesulfonate (0.75 mL, 3.88mmol) is added to a solution of tert-butyl ⁇ (5S)-3-[3,5-difluoro-4-(3-ethoxyazetidin-l-yl)phenyl]-2-oxo-l,3-oxazolidin-5- yl ⁇ methylcarbamate (0.59 g, 1.38 mmol) in dichloromethane (2OmL) and 2,6-lutidine (0.65 mL, 5.58 mmol) at O 0 C. After stirring at room temperature for Ih, 1OmL of methanol is added and after an additional Ih the mixture is concentrated to provide the crude amine.
  • Acetic anhydride (0.8 mL, 8.46 mmol) is added to a cooled (O 0 C) solution of the crude amine dissolved in dichloromethane (2OmL) and pyridine (1 mL, 12.4 mmol). After warming to room temperature and stirring for Ih, the reaction mixture is diluted with dichloromethane and washed sequentially with 10% aqueous citric acid, saturated aqueous NaHCO 3 , brine, and dried (Na 2 SO 4 ), filtered and concentrated. The crude residue is purified by silica gel chromatography (elution with 2.5-3% methanol-dichloromethane) to provide the title compound.
  • Lithium butoxide solution (6.1 mL of a 1.0M THF solution, 6.1 mmol)was added to a cooled (O 0 C) solution of benzyl 3,5-difluoro-4-(3-methoxy-3-methylazetidin-l- yl)phenylcarbamate (0.74 g, 2.03 mmol) in DMF (1.3mL) and MeOH (0.2 mL,4.94mmol).
  • Solid (S)-acetic acid 2-acetylamino-l-chloromethyl-ethyl ester (0.77 g, 4.06 mmol) is then added and the solution is allowed to warm to room temperature and stirred for 20 h.
  • the crude 3-methylazetidin-3-ol (2.42 g, 27.8 mmol) is dissolved in DMF (25 mL) and triethylamine (12 mL, 86.6 mmol) and treated with 3,4,5-trifluoronitrobenzene (4.92 g, 27.8 mmol).
  • the resulting solution is stirred and heated at 6O 0 C for 18 hrs and then cooled to room temperature.
  • the reaction mixture is diluted with 700 mL of ethyl acetate and washed sequentially with 20OmL of 10% aqueous citric acid, 200 mL of saturated NaHCOs, 200 mL of brine, dried (Na 2 SO 4 ), filtered and concentrated.
  • Trifluoroacetic acid (1.0 mL) is added to a cooled (0 0 C) solution of tert-butyl ((5S)- 3- ⁇ 3,5-difluoro-4-[3-hydroxy-3-(trifluoromethyl)azetidin-l-yl]phenyl ⁇ -2-oxo-l,3-oxazolidin- 5-yl)methylcarbamate (0.15 g, 0.32 mmol) in dichloromethane (3.0 mL) and stirred for 30 minutes. The reaction mixture is concentrated to provide the crude amine.
  • Acetic anhydride (0.060 mL, 0.64 mmol) is added to a cooled (0 0 C) solution of the crude amine (0.32 mmol) dissolved in dichloromethane (6.5 mL) and pyridine (0.13 mL, 1.6 mmol). After warming to room temperature and stirring for 18 hours, the reaction mixture is diluted with dichloromethane and washed with dilute NaHCO 3 , water, brine, and dried (MgSO 4 ), filtered and concentrated. The crude residue is purified by preparative TLC (5% MeOH- dichloromethane) to afford the title compound.
  • Trimethyl(trifluoromethyl)silane (1.06 mL, 6.58 mmol) is added to a cooled (0 0 C) solution of l-(2,6-Difluoro-4-nitrophenyl)azetidin-3-one (0.75 g, 3.29 mmol) in THF (16.0 mL), followed by addition of hydrogen fluoride triethylamine complex (1.1 mL, 6.58 mmol). After 3 hours, the reaction mixture is warmed to room temperature and quenched with saturated aqueous NH 4 Cl.
  • the rust colored mixture is refluxed for another 30 min and then cooled, diluted with dichloromethane and filtered to remove iron oxide.
  • the organic layer in the filtrate is separated and the aqueous phase extracted with more dichloromethane.
  • the combined dichloromethane phases are washed with water, brine, and dried (MgSO 4 ), filtered, and concentrated to provide crude aniline.
  • This material is dissolved in 3.4 mL of dichloromethane and cooled to 0 0 C. Pyridine (0.27 mL, 3.36 mmol) and benzyl chloroformate (0.26 mL, 1.85 mmol) are then added to the aniline solution. The mixture is stirred at room temperature for 16 hours.
  • reaction mixture is then diluted with dichloromethane and washed with H 2 O, brine and then dried (MgSO 4 ), filtered and concentrated.
  • the residue is subjected to column chromatography on silica gel (elution with 0-30% ethyl acetate-hexane) to provide the title compound.
  • Trifluoroacetic acid .75 mL is added to a cool "edr (0 0 C) solution of tert-butyl ((5S)-
  • Lithium butoxide solution (1.6 mL of a 1.0 M THF solution, 1.6 mmol) is added to a cooled (0 0 C) solution of benzyl 4-(3-ethyl-3-hydroxyazetidin-l-yl)-3,5- difluorophenylcarbamate (0.15 g, 0.41 mmol) in DMF (0.27 mL) and MeOH (0.033 mL, 0.82 mmol).
  • Solid (S)-acetic acid 2-acetylamino-l-chloromethyl-ethyl ester (0.16 g, 0.82 mmol) is then added and the solution allowed to warm to room temperature and stirred for 16 hours.
  • Trimethylsilyltrifluoromethanesulfonate (0.5mL,2.64 mmol) is added to a soution of tert- butyl ⁇ (5S)-3-[3,5-difluoro-4-(3-fluoro-3-methylazetidin-l-yl)phenyl]-2-oxo-l,3-oxazolidin-5- yljmethylcarbamate (0.36g, 0.88 mmol) in dichloromethane (5 mL) and 2,6- lutidine (0.5 mL, 4.40 mmol). After stirring for one hour, 5 mL of methanol is added and the reaction mixture stirred for another hour and concentrated to provide the crude amine.
  • Propionic anhydride (0.4 mL, 3.39 mmol) is added to a cooled (0 0 C) solution of the crude amine (0.88 mmol) in dichloromethane (5 mL) and pyridine (0.5 mL, 6.20 mmol). After warming to r.t. and stirring for 30 min, the reaction mixture is diluted with ethyl acetate (400 mL), washed with 10% citric acid, saturated NaHCO 3 , brine and dried (Na 2 SO 4 ), filtered and concentrated. The crude product is purified by preparative TLC (2% MeOH-dichloromethane) to provide the title compound.
  • Iron metal (0.6g, 10.74 mmol) is added to a stirred mixture of l-(2,6-difluoro-4- nitrophenyl)-3-ethoxymethoxyazetidine (1.03 g, 3.57 mmol ) and ammonium chloride in 6OmL of 2:1 ethanol - H 2 O.
  • the rust-colored mixture is refluxed for 1 h, cooled, diluted with dichloromethane (400 mL) and filtered. The filtrate is washed with water, brine, and dried (Na 2 SO 4 ), filtered and concentrated to provide crude l-(4-amino-2,6-difluorophenyl)-3- ethoxymethoxyazetidine.
  • the crude amine is dissolved in 30 mL of dichloromethane and cooled to 0 0 C. Pyridine (0.7 mL, 8.67 mmol ) and then benzyl chloroformate (O.,7mL,4.O8 mmol ) are added to the amine solution with stirring. The mixture is stirred for 1 h at 0 0 C and for 90 min at r.t. The reaction mixture is then diluted with dichloromethane (400 mL) and washed with 10% citric acid, saturated NaHCO 3 , brine, dried (Na 2 SO 4 ), and filtered.
  • Hydrogen fluoride triethylamine complex (0.22 mL, 1.38 mmol) is added to a THF (5 mL) solution of the intermediate HI (0.23 g, 0.46 mmol) at room temperature. After 16 hours, the solution is treated with dilute NaHCO 3 dropwise and extracted with dichloromethane. The combined organic extracts are washed with brine, dried (MgSO 4 ), filtered, and concentrated. Purification by prep. TLC (5% MeOH-dichloromethane) afforded the title compound.
  • Iron metal (0.11 g, 2.0 mmol) is added in portions over 1 h to a refluxing solution of the intermediate I (0.26 g, 0.67 mmol) and ammonium chloride (0.36 g, 6.7 mmol) in 6 mL of 2:1 ethanol-H 2 O.
  • the rust colored mixture is refluxed for another 30 min and then cooled, diluted with dichloromethane.
  • the organic layer is separated and the aqueous phase extracted with more dichloromethane.
  • the combined dichloromethane phases are washed with water, brine, and dried (MgSO 4 ), filtered, and concentrated to provide the crude aniline intermediate. This material is dissolved in 2 mL of dichloromethane and cooled to 0 0 C.

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne un composé de la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, où R1 et R2 sont indépendamment H, F, OH, C1-2alkyle, CF3, OC1-2alkyle, éventuellement substitué par OCH3 ou OH, ou R1 et R2 pris ensemble forment =O, =N-OH, =N-OC1-2alkyle, =CH-CN ; R3 est C1-2alkyle, ou OC1-2alkyle ; et X est H ou F.
PCT/IB2006/001869 2005-07-06 2006-06-26 Oxazolidinones contenant de l'azétidine comme agents antibactériens WO2007004049A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009020616A1 (fr) * 2007-08-06 2009-02-12 Micurx Pharmaceuticals, Inc. Orthofluorophényle oxazolidinones antimicrobiennes pour le traitement d'infections bactériennes
CN101798302B (zh) * 2009-02-06 2014-11-05 上海盟科药业有限公司 抗生素类药物1-(邻-氟苯基)二氢吡啶酮的合成及生产的方法和工艺
US9382276B2 (en) 2014-02-21 2016-07-05 Micurx Pharmaceuticals, Inc. Water-soluble O-carbonyl phosphoramidate prodrugs for therapeutic administration

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996013502A1 (fr) * 1994-10-26 1996-05-09 Pharmacia & Upjohn Company Composes antimicrobiens de phenyloxazolidinone
US6277985B1 (en) * 1995-09-15 2001-08-21 Pharmacia & Upjohn Company Aminoaryl oxazolidinone N-oxides
WO2005054234A2 (fr) * 2003-09-08 2005-06-16 Wockhardt Limited Piperidino phenyloxazolidinones substituees dont l'activite antimicrobienne a un meilleur rendement in vivo

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996013502A1 (fr) * 1994-10-26 1996-05-09 Pharmacia & Upjohn Company Composes antimicrobiens de phenyloxazolidinone
US6277985B1 (en) * 1995-09-15 2001-08-21 Pharmacia & Upjohn Company Aminoaryl oxazolidinone N-oxides
WO2005054234A2 (fr) * 2003-09-08 2005-06-16 Wockhardt Limited Piperidino phenyloxazolidinones substituees dont l'activite antimicrobienne a un meilleur rendement in vivo

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009020616A1 (fr) * 2007-08-06 2009-02-12 Micurx Pharmaceuticals, Inc. Orthofluorophényle oxazolidinones antimicrobiennes pour le traitement d'infections bactériennes
US8178683B2 (en) 2007-08-06 2012-05-15 Micurx Pharmaceuticals, Inc. Antimicrobial ortho-fluorophenyl oxazolidinones for treatment of bacterial infections
CN101798302B (zh) * 2009-02-06 2014-11-05 上海盟科药业有限公司 抗生素类药物1-(邻-氟苯基)二氢吡啶酮的合成及生产的方法和工艺
US9382276B2 (en) 2014-02-21 2016-07-05 Micurx Pharmaceuticals, Inc. Water-soluble O-carbonyl phosphoramidate prodrugs for therapeutic administration

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