EP2007740A1 - Process for preparing linezolid - Google Patents

Process for preparing linezolid

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Publication number
EP2007740A1
EP2007740A1 EP07734203A EP07734203A EP2007740A1 EP 2007740 A1 EP2007740 A1 EP 2007740A1 EP 07734203 A EP07734203 A EP 07734203A EP 07734203 A EP07734203 A EP 07734203A EP 2007740 A1 EP2007740 A1 EP 2007740A1
Authority
EP
European Patent Office
Prior art keywords
compound
chloro
benzylidene
amino
temperature
Prior art date
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Application number
EP07734203A
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German (de)
French (fr)
Inventor
Rick Joseph Imbordino
William Roland Perrault
Michael Robert Reeder
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Pfizer Products Inc
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Pfizer Products Inc
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Publication of EP2007740A1 publication Critical patent/EP2007740A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/04—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/06—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
    • C07C251/08—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton being acyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/08—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • the present invention relates to a novel process to prepare an oxazolidinone antibacterial agent. Particularly, the present invention relates to a novel process to prepare linezolid.
  • 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 a result, structurally novel antibacterial agents with a new mode of action have become increasingly important in the treatment of bacterial infections.
  • Linezolid is a recent synthetic class of antimicrobials active against a number of pathogenic microorganisms.
  • Linezolid [(S)-N-[[3- [3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide] is disclosed in U.S. Patent No. 5,688,792. It is marketed in the United States by Pfizer, Inc. as an injection, tablets, and oral suspensions under the name ZYVOX®, Processes for preparation of linezolid are described in U.S. Patent No. 5,688,792, U.S. Patent No. 5,837, 870, PCT publication WO 99/24393, PCT publication WO 2006/004922, J. Med. Chem. 39(3), 673- 679, 1996 and Tetrahedron Lett., 40(26), 4855, 1999.
  • PCT applications PCT/US95/12751 and PCT/US95/ 10992 disclose the reaction of a carbamate with «-butyllithium, lithium diisopropylamide or lithium hexamethyldisilazide.
  • US Patent 4,476,136 discloses a method of transforming 5-hydroxymethyl substituted oxazolidinones to the corresponding 5(S)-aminomethyl substituted oxazolidinones.
  • US patent 5,332,754 discloses racemic oxazolidinone-CE ⁇ -NH-Ac can be synthesized in one step by condensation of a carbamate with racemic glycidyl acetamide.
  • US patent 3,654,298 discloses the synthesis of 5-alkoxymethyl-3-aryl-substituted oxazolidinones by sodium ethoxide induced cyclization of chlorocarbamates.
  • Linezolid which comprises: a) reacting a compound of structure (1)
  • the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Q. j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • C ⁇ .g alkyl refers to alkyl of one to eight carbon atoms, inclusive.
  • alkyl refers 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. Specifically, alkyl is C ⁇ alkyl. More specifically, alkyl is tert ⁇ bxxty ⁇ .
  • ambient temperature refers to a temperature in a range from about 20 0 C to 30 0 C.
  • the synthesis begins with coupling the substituted imine moiety (1) (preferably 1 to 3 eq, most preferably 1.5 to 2 eq) with a carbamate (2) to provide the corresponding (S)-oxazolidinone imine (3).
  • the reaction is carried out preferably at a temperature in a range from ambient temperature to about 65 0 C in the presence of a base with pKa greater than 12, preferably a tertiary alkoxide base, most preferably lithium t-butoxide and an aprotic non-nucleophiiic solvent (preferably DMF, DMAc, THF, Acetonitrile, Ci -6 linear, branched and cyclic ethers and/ or chlorinated solvents and/ or mixtures of these solvents, most preferably MTBE or methylene chloride), Most preferably, the temperature is from about 30-60 0 C and the reaction time is 2 to 24 hours.
  • a base with pKa greater than 12 preferably a tertiary alkoxide base, most preferably lithium t-butoxide and an aprotic non-nucleophiiic solvent (preferably DMF, DMAc, THF, Acetonitrile, Ci -6 linear, branched and cyclic ether
  • the (S)-oxazolidinone imine (2) after an aqueous extractive workup, is crystallized and isolated by filtration from a weakly polar organic solvent, such as an alcohol (including Ci ⁇ branched and linear alcohols and polyols) or ether (including MTBE, THF, and other C ⁇ linear, branched and cyclic ethers); most preferably isopropanol.
  • a weakly polar organic solvent such as an alcohol (including Ci ⁇ branched and linear alcohols and polyols) or ether (including MTBE, THF, and other C ⁇ linear, branched and cyclic ethers); most preferably isopropanol.
  • Hydrolysis of compound (3) with an aqueous acidic solution and subsequent acylation provides crude linezolid.
  • Compound (3) is best hydrolyzed with a mixture of water and a strong acid such as hydrochloric acid and the substituted benzaldehyde byproduct removed by extraction with a water immiscible organic solvent (preferably toluene, MTBE, methylene chloride and ethyl acetate), most preferably ethyl acetate.
  • a water immiscible organic solvent preferably toluene, MTBE, methylene chloride and ethyl acetate
  • the resulting aqueous solution of Amine hydrochloride (4) is preferably acylated with acetic anhydride, preferably in the presence of water and a water immiscible organic solvent (most preferably methylene chloride),
  • the conversion of Amine hydrochloride (4) to linezolid is well known in the literature (Brickner, SI.; et. al. J. Med. Chem. 199639 (3) 673-679, US Patent 5,837,870
  • the key strating material (1) can be prepared by reacting (S)-epichlorohydrin with a mixture of the appropriately substituted benzaldehyde derivative (preferably 0.5 to 2 eq, most preferably 1 eq) and aqueous ammonia (preferably 0.5 to 3 eq, most preferably 1.5 eq).
  • the reaction is best performed in both protic and aprotic non-nucleophilic and non-electrophilic solvents such as alcohols (including C 1 ⁇ branched and linear alcohols and polyols), ethers (including MTBE, THF, and other Q- ⁇ linear, branched and cyclic ethers) as well as chlorinated solvents such as methylene chloride.
  • MTBE is a preferred solvent.
  • Temperatures can be in a range from about 15 to about 60 0 C are preferred, preferably between 30 to 50 0 C most preferred.
  • aprotic hydrocarbon solvents such as, but not limited to, alkanes, mixtures of alkanes (hexane, heptane, octane, isooctane and commercially available alkane mixtures), optionally in the presence of aprotic polar solvents, preferably ethereal solvents such as MTBE or aromatic solvents such as toluene or chlorinated solvents such as methylene chloride or mixtures thereof.
  • aprotic polar solvents preferably ethereal solvents such as MTBE or aromatic solvents such as toluene or chlorinated solvents such as methylene chloride or mixtures thereof.
  • Preferred solvents are a mixture of MTBE and heptane or a mixture of toluene and heptane.
  • the crystallization process can be conducted in a temperature in a range from ambient temperature (about 18-25 0 C) to about 55 0 C, preferably in a range of 30 to 50 0 C, more preferably in a range of 38 to 45 0 C.
  • This crystallization provides surprisingly high yield and with significantly improved enantiomeric purity after isolation by filtration.
  • CDI 1 10-carbodiimidazole d doublet dd doublet of doublets dq doublet of quartets dt doublet of triplets
  • Boc rerf-butoxycarbonyl
  • the reaction is stirred at 4O 0 C for 18 hours at which time 8.4% area of epichorohydrin remained by GC.
  • the reaction mixture is transferred to a separatory funnel and the layers are separated. The lower aqueous layer is discarded.
  • the organic layer is transferred to a 3L round bottom flask, concentrated in vacuo to about half the volume (800- 900 mL) at which time iso-octanes is slowly added from a feed tube (-750 mL) until cloudiness is observed.
  • the biphasic mixture is seeded with ⁇ 4 mgs of the title compound.
  • the reaction is cooled with an ice bath for 45 minutes while stirring.
  • a 5L three neck round bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser and heating mantel is charged with 4-chlorobenzaldehyde (375 g, 2.67 mol, 1.0 eq.). Methanol or THF is added and mixture warmed from 10 to 23 0 C. Aqueous ammonia (28.4 wt%, 264 mL, 3.95 mol, 1.5 eq.) is added in a single portion resulting in a biphasal solution forming after stirring for 15 minutes at 23 to 26 °C. (SM+)- epichlorohydrin ( 99.3 % ee, 207 mL, 2.64 mol, 1.0 eq.) is then added in one portion.
  • 4-chlorobenzaldehyde 375 g, 2.67 mol, 1.0 eq.
  • Methanol or THF is added and mixture warmed from 10 to 23 0 C.
  • Aqueous ammonia 28.4 wt
  • reaction mixture is stirred at 23-24 0 C for 18 h, then warmed to 40 to 45 0 C and stirred for 2.5 h at which time 0.26% area of S-epichorohydrin remains by GC (GC conditions, 0.050 ml reaction mixture in 1 ml acetonitrile, inject 1 microliter; 15 M DB-I column, 0.25mm ID and 0.25 micron film and 15 psi head pressure, 1.O ⁇ l injection size; Tj n , ⁇ 38°C, ramp of 10
  • the mixture is concentrated in vacuo to a total volume of 1250 ml.
  • Toluene (250 ml) is added and the mixture concentrated in vacuo to a total volume of 1250 ml.
  • Toluene (250 ml) is added and the mixture concentrated in vacuo to a total volume of 1145 ml.
  • Toluene (355 ml) is added and the mixture concentrated in vacuo to a total volume of 900 ml.
  • Toluene (600 ml) is added and the mixture concentrated in vacuo to a total volume of 1120 ml. While maintaining 45 to 50 0 C, heptane (1500 ml) is added. The resulting biphasal solution is cooled to 45 0 C and seeded. The mixture is then further cooled to 38 0 C over 1/2 h while seeding after every 1 degree of cooling. The mixture is then further allowed to slowly cool to 23 0 C over 16 h. The white crystals are then collected by vacuum filtration and washed with room temperature heptane (180 ml). The product is dried in a nitrogen stream to give the title compound.
  • a 5L three neck round bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser and heating mantel is charged with 4-chlorobenzaldehyde (375 g, 2.67 mol, 1.0 eq.).
  • MTBE (1.50 L) is then added to give a homogeneous solution after warming from 9 to 24 0 C.
  • Aqueous ammonia (28.4 wt%, 265 mL, 3.97 mol, 1.5 eq.) is added in a single portion resulting in a biphasal solution forming after stirring for 15 minutes at 23 to 26 0 C.
  • the resulting thin suspension is heated to reflux (41 0 C) for 5h. After cooling to room temperature, the organic layer is washed with water (1 x 100 mL, I x 50 mL), these aqueous washes are then discarded. The organic phase is concentrated in vacuo to about Vz volume, at which time isopropyl alcohol (200 mL) is added and the concentration continued to a volume of less than 200 mL. The resultant suspension is cooled to -10 0 C to -20 0 C and the solids isolated by filtration and washed with cold isopropyl alcohol (less than 100 mL) then dried at 55°C under vacuum to afford the title compound as a crystalline in solid.
  • SFC achiral assay indicates a purity of 99.4 area% and SFC chiral assay identified 0.11% of the (R) enantiomer.
  • HPLC conditions YMC 5 ⁇ ODS-AM 150 nm X 4.6 nm column, eluting with CH 3 CN /water + 0.1% TFA from 20% CH 3 CN to 80% CH 3 CN in 8 min at 0.5 mL/min, detecting at 254nm.
  • the resultant slurry is added to a solution of acetic acid (85.2 g, 1.42 mol, 1.26 eq) in methanol (800 ml) while maintaining reflux and rinsed in with methanol (40 ml).
  • the resultant slurry is concentrated via atmospheric distillation to a total volume of 3200 ml.
  • Methanol (2500 ml) is added while concentrating via atmospheric distillation to maintain a total volume of 3200- 3800 ml.
  • the resultant slurry is cooled to 3 0 C and the precipitate collected by vacuum filtration, washed with methanol and dried in a nitrogen stream to give the title compound as crystalline in solid.
  • HPLC assay After stirring the emulsion at ambient temperature for 2 hours, HPLC assay showed the hydrolysis reaction to be complete (HPLC conditions: YMC 5 ⁇ ODS-AM 150 nm X 4.6 nm column, eluting with CH 3 CN /water + 0.1% TFA from 20% CH 3 CN to 80% CH 3 CN in 8 min at 0.5 mL/min, detecting at 254nm, Retention time of (S)-N-[3-(3-fluoro-4-morpholin-4-yl- phenyl)-2-oxo-oxazolidin-5-ylmethyl]-amine is 3.2 min).
  • the phases are separated, the organic layer is discarded, and the aqueous layer is washed with ethyl acetate (500 mL).
  • CH 2 Cl 2 (900 mL) is added and the pH is adjusted to 6.7 with ⁇ 25 mL aq. 50% aq. NaOH.
  • Ac 2 O (58.49 mL, 620 mmol, 2.0 eq.) is added in one portion and the pH dropped to 2.
  • the pH is then readjusted to 6 using 50% aq. NaOH.
  • the pH is adjusted to ca. 7.1 with 50% aq. NaOH and the phases separated.
  • the aqueous phase is extracted with CHiCl 2 (800 mL) and the organics are combined and concentrated to ⁇ 1L in volume.
  • Ethyl acetate is added and the volume is reduced to 1.5 L under vacuum. Another IL of ethyl acetate is added and volume is reduced again to IL under vacuum. The resultant slurry is cooled to 0 0 C and the precipitate collected by vacuum filtration. The resulting solid is washed with ethyl acetate (250 mL). The crude product is dried under vacuum at 50 0 C for 2 hours to give the title compound as Hnezolid crystalline Form I.
  • Example 4 Trituration (convert linezolid crystalline Form I to linezolid crystalline Form E)
  • the product from Example (89.18 g) is transferred to a 3L round bottom flask equipped with a mechanical stirrer, thermocouple and heating mantel.
  • Ethyl acetate (2.23 L, 15 mL/g) is added and seeded with Linezolid form II crystals and the slurry is heated to ca. 50 0 C. A slight exotherm of 3 0 C is observed. After 30 minutes of heating the form change is observable as the solid is changing to long needles. Stirring is continued for 2 hours at 50 0 C, at which time the contents are cooled to ambient temperature and stirred for an additional 30 minutes.
  • T R (Linezolid) 4.4 min; HPLC conditions: Chiralcel OJ-H 250 nm X 4.6 nm column, eluting with 90% CO 2 / 10%MeOH at 3.0 mL/min, detecting at 255 nm.
  • Example 5 Preparation of (S)-I -chloro-3-[(4-bromo-benzylidene)-amino3 ⁇ propan-2-ol
  • the organics layer is dried on MgSO 4 (2 g) clarified with an MTBE rinse (10 ml) and isopar C (100 ml) is added to the filtrate.
  • the solution is concentrated in vacuo to 75 ml total volume.
  • the resultant biphasal mixture is allowed to stand at room temperature for 24 hours.
  • the resultant waxy solid is collected by vacuum filtration at room temperature and washed with isooctanes.
  • the resultant slurry is added to a solution of acetic acid (1.76 g, 29.3 mmol, 1.29 eq) in methanol (46 g) and rinsed in with methanol (24 g).
  • the resultant slurry is concentrated via atmospheric distillation to a total volume of 100 ml.
  • the resultant slurry is cooled to 3 0 C and the precipitate collected by vacuum filtration, washed with methanol and dried in a nitrogen stream to give the title compound as crystalline in solid.
  • the resultant slurry is added to a solution of acetic acid ( 1.76 g, 29.3 mmol, 1.27 eq) in methanol (46 g) and rinsed in with methanol (24 g).
  • the resultant mixture is concentrated via atmospheric distillation to 51 g net weight.
  • the resultant slurry is cooled to 0 0 C and the precipitate collected by vacuum filtration, washed with methanol and dried in a nitrogen stream to give the title compound as crystalline in solid.

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Abstract

The present invention relates to a new process for preparing the oxazolidinone antibacterial agent linezolid which comprises the reaction of an (S)-I -chloro-3- (benzyIidenylamino)-propan-2-ol with a morpholinyl fluorophenyl carbamate to afford a protected imine intermediate which, upon hydrolysis and acylation, yields linezolid in high yield.

Description

PROCESS FOR PREPARING LINEZOLID
FIELD OF INVENTION The present invention relates to a novel process to prepare an oxazolidinone antibacterial agent. Particularly, the present invention relates to a novel process to prepare linezolid.
BACKGROUND OF THE INVENTION
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 a result, structurally novel antibacterial agents with a new mode of action have become increasingly important in the treatment of bacterial infections.
Among newer antibacterial agents, linezolid is a recent synthetic class of antimicrobials active against a number of pathogenic microorganisms. Linezolid [(S)-N-[[3- [3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide] is disclosed in U.S. Patent No. 5,688,792. It is marketed in the United States by Pfizer, Inc. as an injection, tablets, and oral suspensions under the name ZYVOX®, Processes for preparation of linezolid are described in U.S. Patent No. 5,688,792, U.S. Patent No. 5,837, 870, PCT publication WO 99/24393, PCT publication WO 2006/004922, J. Med. Chem. 39(3), 673- 679, 1996 and Tetrahedron Lett., 40(26), 4855, 1999.
We have discovered and developed a novel process to prepare linezolid. The process has the potential to significantly lower the cost of commercial production of linezolid. It is a highly convergent three-step process with a much shorter cycle time. It is environmentally friendly because it reduces the large solvent volumes used in the currently known processes. We also discovered rapidly crystallized key intermediates for the process of the present invention. INFORMATION DISCLOSURE
US 4,150,029, 4,250,318, 4,476,136, 4,340,606 and 4,461 ,773 disclose the synthesis of 5-hydroxymethyloxazolidinones from amines.
/. Med. Chem., 32, 1673 (1989), Tetrahedron 45, 1323 (1989) and US Patent 4,948,801 disclose a method of producing oxazolidinones. PCT Publications WO93/09103, WO93/09103, WO95/07271 and WO93/23384;
PCT applications PCT/US95/12751 and PCT/US95/ 10992 disclose the reaction of a carbamate with «-butyllithium, lithium diisopropylamide or lithium hexamethyldisilazide.
International Publication WO95/07271 discloses the ammonolysis of 5R- methylsulfonyloxyraethyl substituted oxazolidinones.
US Patent 4,476,136 discloses a method of transforming 5-hydroxymethyl substituted oxazolidinones to the corresponding 5(S)-aminomethyl substituted oxazolidinones.
US patent 5,332,754 discloses racemic oxazolidinone-CE^-NH-Ac can be synthesized in one step by condensation of a carbamate with racemic glycidyl acetamide. US patent 3,654,298 discloses the synthesis of 5-alkoxymethyl-3-aryl-substituted oxazolidinones by sodium ethoxide induced cyclization of chlorocarbamates.
SUMMARY OF THE INVENTION The present invention provide a process to prepare linezolid
Linezolid which comprises: a) reacting a compound of structure (1)
(i) wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl; with a compound of structure (2)
(2) at a temperature in a range from ambient temperature to about 650C, wherein R is benzyl or Ci.salkyl to provide a compound of structure (3);
(3) where X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl; b) hydrolyzing the compound of structure (3) and subsequent acylation to provide linezolid.
Other aspects of the present invention are the compounds of structures (1) and (3) as shown above, their crystal structures, and their methods of crystallizations.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Q.j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example, Cι.g alkyl refers to alkyl of one to eight carbon atoms, inclusive.
The term alkyl refers 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. Specifically, alkyl is C^alkyl. More specifically, alkyl is tert~bxxty\.
The term "ambient temperature" refers to a temperature in a range from about 20 0C to 300C.
SCHEME I
As shown in Scheme I (wherein X and R are defined above), the synthesis begins with coupling the substituted imine moiety (1) (preferably 1 to 3 eq, most preferably 1.5 to 2 eq) with a carbamate (2) to provide the corresponding (S)-oxazolidinone imine (3). The reaction is carried out preferably at a temperature in a range from ambient temperature to about 650C in the presence of a base with pKa greater than 12, preferably a tertiary alkoxide base, most preferably lithium t-butoxide and an aprotic non-nucleophiiic solvent (preferably DMF, DMAc, THF, Acetonitrile, Ci-6 linear, branched and cyclic ethers and/ or chlorinated solvents and/ or mixtures of these solvents, most preferably MTBE or methylene chloride), Most preferably, the temperature is from about 30-600C and the reaction time is 2 to 24 hours. Preferably, the (S)-oxazolidinone imine (2), after an aqueous extractive workup, is crystallized and isolated by filtration from a weakly polar organic solvent, such as an alcohol (including Ci^ branched and linear alcohols and polyols) or ether (including MTBE, THF, and other C^ linear, branched and cyclic ethers); most preferably isopropanol. Hydrolysis of compound (3) with an aqueous acidic solution and subsequent acylation provides crude linezolid. Compound (3) is best hydrolyzed with a mixture of water and a strong acid such as hydrochloric acid and the substituted benzaldehyde byproduct removed by extraction with a water immiscible organic solvent (preferably toluene, MTBE, methylene chloride and ethyl acetate), most preferably ethyl acetate. The resulting aqueous solution of Amine hydrochloride (4) is preferably acylated with acetic anhydride, preferably in the presence of water and a water immiscible organic solvent (most preferably methylene chloride), The conversion of Amine hydrochloride (4) to linezolid is well known in the literature (Brickner, SI.; et. al. J. Med. Chem. 199639 (3) 673-679, US Patent 5,837,870, US 5,688,792).
SCHEME D
As shown in Scheme II (wherein X is defined above), the key strating material (1) can be prepared by reacting (S)-epichlorohydrin with a mixture of the appropriately substituted benzaldehyde derivative (preferably 0.5 to 2 eq, most preferably 1 eq) and aqueous ammonia (preferably 0.5 to 3 eq, most preferably 1.5 eq). The reaction is best performed in both protic and aprotic non-nucleophilic and non-electrophilic solvents such as alcohols (including C1^ branched and linear alcohols and polyols), ethers (including MTBE, THF, and other Q-β linear, branched and cyclic ethers) as well as chlorinated solvents such as methylene chloride. MTBE is a preferred solvent. Temperatures can be in a range from about 15 to about 60 0C are preferred, preferably between 30 to 50 0C most preferred. After extractive isolation and concentration, the imine moiety (1) is obtained. It is then crystallized from a second liquid phase, in the presence of non-polar aprotic hydrocarbon solvents such as, but not limited to, alkanes, mixtures of alkanes (hexane, heptane, octane, isooctane and commercially available alkane mixtures), optionally in the presence of aprotic polar solvents, preferably ethereal solvents such as MTBE or aromatic solvents such as toluene or chlorinated solvents such as methylene chloride or mixtures thereof. Preferred solvents are a mixture of MTBE and heptane or a mixture of toluene and heptane. The crystallization process can be conducted in a temperature in a range from ambient temperature (about 18-25 0C) to about 55 0C, preferably in a range of 30 to 50 0C, more preferably in a range of 38 to 45 0C. This crystallization provides surprisingly high yield and with significantly improved enantiomeric purity after isolation by filtration.
EXAMPLES
In the discussion above and in the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. bm broad multiplet
BOC fejt-butoxycarbonyl bd broad doublet bs broad singlet
CDI 1 , 10-carbodiimidazole d doublet dd doublet of doublets dq doublet of quartets dt doublet of triplets
DMF dimethylformamide
DMAP dimethylaminopyridine
DMSO dimethyl sulfoxide eq. equivalents g grams h hours HPLC high pressure liquid chromatography
HATU N-[(dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin- l-yl-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide
LG leaving group m multiplet
M molar
M% mole percent max maximum meq milliequivalent mg milligram mL milliliter mm millimeter mmol millimol
MTBE methyl t-butyl ether q quartet s singlet t or tr triplet
TBS tributylsilyl
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography p-TLC preparative thin layer chromatography μL microliter N = normality
MeOH = methanol
DCM = dichloromethane
HCl = hydrochloric acid
ACN = acetonitrile
MS = mass spectrometry
It = room temperature
EtOAc = ethyl acetate
EtO = ethoxy
Ac = acetate
NMP = 1 -methyl-2-pyrrol idinone μL = microliter
J = coupling constant
NMR = Nuclear magnetic resonance
MHz = megahertz
Hz = hertz m/z = mass to charge ratio min = minutes
Boc = rerf-butoxycarbonyl
CBZ = benzyloxycarbonyl
DCC = l^-dicyclohexylcarbodiimide
PyBop = benzotriazole- 1 -yl-oxy-trispyrrolidinophosphonium hexafluorophosphate
Example 1 Preparation of (S)-l-chloro-3-[(4-chloro-E-benzylidene)-amino]-propan-2-ol
Method A
A 5L three neck round bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser and heating mantel is charged with 4-chlorobenzaldehyde (351. g, 2.5 mol, 1.0 eq.). MTBE (1.5 L) is then charged into the round bottom to give a homogeneous solution. Aqueous ammonia (28 wt%, 252.98 mL, 3.75 mol, 1.5 eq.) is added in a single portion resulting in a white precipitate that turned into a thin slurry within 15 minutes of stirring. (S)-(+)-epichlorohydrin (> 99 % ee, 196.0 mL, 2.5 mol, 1.0 eq.) is then slowly charged into the vessel. After 40 minutes, the contents are then slowly heated to
43°C. The reaction is stirred at 4O0C for 18 hours at which time 8.4% area of epichorohydrin remained by GC. Upon cooling to rt, the reaction mixture is transferred to a separatory funnel and the layers are separated. The lower aqueous layer is discarded. The organic layer is transferred to a 3L round bottom flask, concentrated in vacuo to about half the volume (800- 900 mL) at which time iso-octanes is slowly added from a feed tube (-750 mL) until cloudiness is observed. The biphasic mixture is seeded with ~ 4 mgs of the title compound. The reaction is cooled with an ice bath for 45 minutes while stirring. The precipitate is collected and rinsed with cold iso-octane (500 mL). The solid is dried for 18 hours at 5O0C under vacuum to give the title compound as a white crystalline in solid. GC assay: 100%, 99,7% ee by Chiral SFC). GC (conditions: column - 30 meter HP-I, 0.25mm E) and 0.25 micron film and 15 psi head pressure, 1.Oμl injection size; T1n, = 70 0C, ramp of 20 °C/min) TR (epichlorohydrin) = 2.4 min, TR (4-chlorobenzaldehyde) = 4.8 min and TR (title compound) = 9.7min; HPLC conditions: Chiralpak AD-H 250 nm X 4.6 nm column, eluting with 70% CO2/ 30%MeOH at 3.0 mL/min, detecting at 255 nm. TR [title compound] = 3.9 min; TR (enantiomer of title compound) = 2.8 min; 1H NMR (400 MHz, CDCl3) δ 3.69 (bs, 2 H), 3.80 (m, 2 H), 4.15 (s, 1 H), 7.41 (d, J= 8 Hz, 2 H), 7.69 (d, J - 8 Hz, 2 H), 8.33 (s, 1 H); 13C NMR (CDCl3) 547.05, 63.09, 70.82, 128.93, 129.39, 134.08, 137.07, 162.30; IR (KBr Pellet) 1630 cm"1;
X-ray crystal structure: crystal system = monoclinic, space group = P2(l), unit cell dimensions a = 8.791(2) A, b = 4.6556(11) A, c = 14.372(3) A, α= 90°, β= 106.819(4)°, γ = 90°, Volume = 563.0(2) A3; Z =2; F(OOO) = 240; Ortep Drawing:
Method B
A 5L three neck round bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser and heating mantel is charged with 4-chlorobenzaldehyde (375 g, 2.67 mol, 1.0 eq.). Methanol or THF is added and mixture warmed from 10 to 23 0C. Aqueous ammonia (28.4 wt%, 264 mL, 3.95 mol, 1.5 eq.) is added in a single portion resulting in a biphasal solution forming after stirring for 15 minutes at 23 to 26 °C. (SM+)- epichlorohydrin ( 99.3 % ee, 207 mL, 2.64 mol, 1.0 eq.) is then added in one portion. The reaction mixture is stirred at 23-24 0C for 18 h, then warmed to 40 to 45 0C and stirred for 2.5 h at which time 0.26% area of S-epichorohydrin remains by GC (GC conditions, 0.050 ml reaction mixture in 1 ml acetonitrile, inject 1 microliter; 15 M DB-I column, 0.25mm ID and 0.25 micron film and 15 psi head pressure, 1.Oμl injection size; Tjn, ~ 38°C, ramp of 10
°C/min) TR (epichlorohydrin) = 1.1 min, TR (4-chlorobenzaldehyde) = 6.9 min and TR (title compound) = 16.0 min). The mixture is concentrated in vacuo to a total volume of 1250 ml. Toluene (250 ml) is added and the mixture concentrated in vacuo to a total volume of 1250 ml. Toluene (250 ml) is added and the mixture concentrated in vacuo to a total volume of 1145 ml. Toluene (355 ml) is added and the mixture concentrated in vacuo to a total volume of 900 ml. Toluene (600 ml) is added and the mixture concentrated in vacuo to a total volume of 1120 ml. While maintaining 45 to 50 0C, heptane (1500 ml) is added. The resulting biphasal solution is cooled to 45 0C and seeded. The mixture is then further cooled to 38 0C over 1/2 h while seeding after every 1 degree of cooling. The mixture is then further allowed to slowly cool to 23 0C over 16 h. The white crystals are then collected by vacuum filtration and washed with room temperature heptane (180 ml). The product is dried in a nitrogen stream to give the title compound. HPLC 95 area% [Kromasil 150 mm X 4.6 mm column, 254 nm, flow rate 1.5 ml/ min; A = 1000 ml water + 0.52 ml trifluoroacetic acid + 1.20 ml triethylamine; B = acetonitrile; Isocratic 47: 53 A: B for 5 min then gradient to 100% B over 5 min TR [title compound] = 2.1 min,; TR (4-chlorobenzaldehyde) = 2.3 min]; 99.72% ee by Chiral SFC. Chiral HPLC conditions: Chiralpak AD-H 250 nm X 4.6 nm column, eluting with 70% CO2/ 30%MeOH at 3.0 mL/min, detecting at 255 nm. TR [title compound] - 3.9 min; TR (enantiomer of title compound) = 2.8 min; 1H NMR (400 MHz, CDCl3) δ 3.69 (bs, 2 H), 3.80 (m, 2 H), 4.15 (s, 1 H), 7.41 (d, J = 8 Hz, 2 H), 7.69 (d, J = 8 Hz, 2 H), 8.33 (s, 1 H); 13C NMR (CDCl3) 647.05, 63.09, 70.82, 128.93, 129.39, 134.08, 137.07, 162.30. Method C
A 5L three neck round bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser and heating mantel is charged with 4-chlorobenzaldehyde (375 g, 2.67 mol, 1.0 eq.). MTBE (1.50 L) is then added to give a homogeneous solution after warming from 9 to 24 0C. Aqueous ammonia (28.4 wt%, 265 mL, 3.97 mol, 1.5 eq.) is added in a single portion resulting in a biphasal solution forming after stirring for 15 minutes at 23 to 26 0C. (S)-(+)-epichlorohydrin ( 99,3 % ee, 209 mL, 2.67 mol, 1.0 eq.) is then added in one portion. The reaction mixture is stirred at 23-24 0C for 3 days. The phases are separated and the upper phase concentrated under atmospheric pressure from 2000 to 1000 ml total volume (boiling point 58 to 67 0C). While maintaining 45 to 50 0C, heptane (1700 ml) is added. The resulting biphasal solution is cooled to 45 0C and seeded. The mixture is then further cooled to 38 0C over 1/2 h while seeding after every 1 degree of cooling. The mixture is then further allowed to slowly cool to 23 0C over 1 h. The white crystals are then collected by vacuum filtration and washed with room temperature heptane (180 ml). The product is dried in a nitrogen stream to give the title compound. HPLC 94 area% [Kromasil 150 nm X 4.6 nm column, 254 nm, flow rate 1.5 ml/ min; A = 1000 ml water + 0.52 ml trfluoroacetic acid + 1.20 ml triethylamine; B = acetonitrile Isocratic 47: 53 A: B for 5 min then gradient to 100% B over 5 min TR [title compound] = 2.1 min,; TR (4- chlorobenzaldehyde) = 2.3 min]; 99.92% ee by Chiral SFC. Chiral HPLC conditions: Chiralpak AD-H 250 nm X 4.6 nm column, eluting with 70% CO2/ 30%MeOH at 3.0 mL/min, detecting at 255 nm. TR [title compound] = 3.9 min; TR (enantiomer of title compound) = 2.8 min; !H NMR (400 MHz, CDCl3) δ 3.69 (bs, 2 H), 3.80 (m, 2 H), 4.15 (s, 1 H), 7.41 (d, / = 8 Hz, 2 H), 7.69 (d, J = 8 Hz, 2 H), 8.33 (s, 1 H); 13C NMR (CDCl3) δ 47.05, 63.09, 70.82, 128.93, 129.39, 134.08, 137.07, 162.30.
Example 2 Preparation of (S)-5-{[(4-chloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4- morpholin-4-yl-phenyI)-oxazolidin-2-one
Method A To (3-fluoro-4-moφholin-4-yl-phenyl)-carbamic acid benzyl ester (20 g, 60.05 mmoles, 1 eq) is added lithium t-butoxide (12.1 1 g, 151.4 mmoles, 2.5 eq), followed by methylene chloride (80 mL) and the mixture stirred at room temperature. To the resultant suspension is added (S)-l-chIoro-3-[(4-chloro-benzylidene)-amino]-propan-2-ol (21.07 g, 90.81 mmoles, 1.5 eq) in methylene chloride (40 mL) in one portion. The resulting thin suspension is heated to reflux (410C) for 5h. After cooling to room temperature, the organic layer is washed with water (1 x 100 mL, I x 50 mL), these aqueous washes are then discarded. The organic phase is concentrated in vacuo to about Vz volume, at which time isopropyl alcohol (200 mL) is added and the concentration continued to a volume of less than 200 mL. The resultant suspension is cooled to -100C to -200C and the solids isolated by filtration and washed with cold isopropyl alcohol (less than 100 mL) then dried at 55°C under vacuum to afford the title compound as a crystalline in solid. SFC achiral assay indicates a purity of 99.4 area% and SFC chiral assay identified 0.11% of the (R) enantiomer. HPLC conditions; YMC 5μ ODS-AM 150 nm X 4.6 nm column, eluting with CH3CN /water + 0.1% TFA from 20% CH3CN to 80% CH3CN in 8 min at 0.5 mL/min, detecting at 254nm. TR [(3- fluoro-4-morpholin-4-yl-phenyl)-carbamic acid benzyl ester] = 8.5 min; TR (title compound) = 7.9 min; HPLC conditions: Chiralcel OJ-H 250 nm X 4.6 nm column, eluting with 75% CO2/ 25%MeOH at 3.0 mL/min, detecting at 255 nm. TR [title compound] = 3.8 min; TR (enantiomer of title compound) = 4.4 min; 1H NMR (400 MHz, CDCl3) δ 3.05 (d, / = 4 Hz, 4 H), 3.87 (d, J = 4 Hz, 4 H), 3.90 (m, 2 H), 4.12 (m, 2 H), 4.95 (m, 1 H), 6.92 (t, / = 8 Hz, 1 H), 7.12 (d, J = 2 Hz, 1 H), 7.36 (d, J = 8 Hz, 2 H), 7.44 (dd, / = 16, 4 Hz, 1 H); 7.63 (d, J = 8 Hz, 2 H), 8.34 (s, 1 H); 13C NMR (CDCl3) δ 48.23, 51.00, 63.19, 66.94, 71.69, 107.42 (d, / = 27 Hz), 113.88, 118.74, 128.93, 129.50, 133.36 (d, J - 1 1 Hz), 133.94, 136.30,137.22, 154.46, 155.48 (d, 7 = 244 Hz), 163.46. Method B
To (3-fluoro-4-morpholin-4-yl-phenyl)-carbamic acid benzyl ester (372 g, 1.13 mol, 1 eq) is added lithium t-butoxide (225 g, 2.81 mol, 2.5 eq), followed by methylene chloride (2.2 L) and the mixture stirred at room temperature. To the resultant suspension is added (S)-I- chloro-3-[(4-chloro-benzylidene)-amino]-propan-2-ol (400 g, 1.72 mol, 1.5 eq) in one portion. The resulting thin suspension is heated to reflux (410C) for 10 h. The resultant slurry is added to a solution of acetic acid (85.2 g, 1.42 mol, 1.26 eq) in methanol (800 ml) while maintaining reflux and rinsed in with methanol (40 ml). The resultant slurry is concentrated via atmospheric distillation to a total volume of 3200 ml. Methanol (2500 ml) is added while concentrating via atmospheric distillation to maintain a total volume of 3200- 3800 ml. The resultant slurry is cooled to 3 0C and the precipitate collected by vacuum filtration, washed with methanol and dried in a nitrogen stream to give the title compound as crystalline in solid. (HPLC conditions: Kromasil C 18 3.5 micron 250 mm X 4.6 mm column, mobile phase A = 0.52 ml TFA, 1.20 ml triethylamine, 1000 ml water; mobile phase B = acetonitrile, isocratic 53: 47 A:B for 5 min then gradient to 100% B over 5 min at 1.5 rnL/min, detecting at 254 nm; TR [title compound] = 6.66 min.
Example 3 Preparation of (S)~N-[3-(3-fiuoro~4~morpholin-4-yI-ρhenyI)~2-oxo- oxazolidin-5~ylmethyl]-acetarnide (Linezo!id)
Method A
To (S)-5-{[(4-chloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl- phenyl)-oxazolidin-2-one (129.5g, 31 mmol, 1.0 eq.) is added ethyl acetate (935 mL) and water (935 mL). To the heterogeneous mixture is added 12M aq. HCl (51.58 mL, 620 mmol, 2.0 eq.). Within minutes, the solid went into solution and the reaction mixture is biphasic. After stirring the emulsion at ambient temperature for 2 hours, HPLC assay showed the hydrolysis reaction to be complete (HPLC conditions: YMC 5μ ODS-AM 150 nm X 4.6 nm column, eluting with CH3CN /water + 0.1% TFA from 20% CH3CN to 80% CH3CN in 8 min at 0.5 mL/min, detecting at 254nm, Retention time of (S)-N-[3-(3-fluoro-4-morpholin-4-yl- phenyl)-2-oxo-oxazolidin-5-ylmethyl]-amine is 3.2 min). The phases are separated, the organic layer is discarded, and the aqueous layer is washed with ethyl acetate (500 mL). CH2Cl2 (900 mL) is added and the pH is adjusted to 6.7 with ~ 25 mL aq. 50% aq. NaOH. With constant stirring, Ac2O (58.49 mL, 620 mmol, 2.0 eq.) is added in one portion and the pH dropped to 2. The pH is then readjusted to 6 using 50% aq. NaOH. The pH is adjusted to ca. 7.1 with 50% aq. NaOH and the phases separated. The aqueous phase is extracted with CHiCl2 (800 mL) and the organics are combined and concentrated to ~1L in volume. Ethyl acetate (IL) is added and the volume is reduced to 1.5 L under vacuum. Another IL of ethyl acetate is added and volume is reduced again to IL under vacuum. The resultant slurry is cooled to 00C and the precipitate collected by vacuum filtration. The resulting solid is washed with ethyl acetate (250 mL). The crude product is dried under vacuum at 500C for 2 hours to give the title compound as Hnezolid crystalline Form I.
Following the general procedure of method A and making non-critical variations, but substituting (S)-5- { [2,4-dichloro-benzylidene)-amino]-methyl } -3-(3-fluoro-4-morphoIin-4-yl- phenyl)-oxazolidin-2-one (example 11) for (S)-5-{[(4-chloro-benzylidene)-amino]- methyl}-3-(3-fluoro-4-morρholin-4-yl-phenyl)-oxazolidin-2-one, the title compound is obtained.
Following the general procedure of method B and making non-critical variations, but substituting (S)-5-{ [4-bromo-benzylidene)-amino] -methyl }-3-(3-fluoro-4-morpholin-4-yl~ phenyl)-oxazolidin-2-one (example 9) for (S)-5-{[(4-chloro-benzylidene)-amino]- methyl}-3-(3-fluoro-4-morph.olin-4-yl-phenyl)-oxazoIidin-2-one, the title compound is obtained.
Example 4 Trituration (convert linezolid crystalline Form I to linezolid crystalline Form E) The product from Example (89.18 g) is transferred to a 3L round bottom flask equipped with a mechanical stirrer, thermocouple and heating mantel. Ethyl acetate (2.23 L, 15 mL/g) is added and seeded with Linezolid form II crystals and the slurry is heated to ca. 500C. A slight exotherm of 30C is observed. After 30 minutes of heating the form change is observable as the solid is changing to long needles. Stirring is continued for 2 hours at 500C, at which time the contents are cooled to ambient temperature and stirred for an additional 30 minutes. The contents are then cooled to 30C for 1.5 hours, filtered and washed with cold ethyl acetate (300 mL total). The resultant solids are dried under vacuum at 50°C for 18 hours to give Linezolid (78.12 g) Form II by XRD, 99.8 wt%, 99.9% ee. HPLC conditions: YMC 5μ ODS-AM 150 nm X 4.6 nm column, etuting with CH3CN /water + 0.1% TFA from 20% CH3CN to 80% CH3CN in 8 min at 0.5 mL/min, detecting at 254nm. TR (Linezolid) = 4.4 min; HPLC conditions: Chiralcel OJ-H 250 nm X 4.6 nm column, eluting with 90% CO2/ 10%MeOH at 3.0 mL/min, detecting at 255 nm. TR [title compound] = 3.6 min; TR (enantiomer of title compound) = 4.1 rain. Example 5 Preparation of (S)-I -chloro-3-[(4-bromo-benzylidene)-amino3~propan-2-ol
To a solution of 4-bromobenzaldehyde (20.8 g, 112 mmol) in MTBE (48 g) is added ammonia (28 wt%, 10.9 ml, 167 mmol, 1.54 eq) at room temperature. The biphasal mixture is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 8.5 mL, 108 mmol, 1.0 eq.) is added. The mixture is stirred for 3 days at room temperature and the phases separated. The organics layer is dried on MgSO4 (2 g) clarified with an MTBE rinse (10 ml) and isopar C ( 100 ml) is added to the filtrate. The solution is concentrated in vacuo to 75 ml total volume and the resultant precipitate collected by vacuum filtration at room temperature and washed with isooctanes. Drying in a nitrogen stream afforded the title compound as crystalline in solid. 1H NMR (400 MHz, CDCl3) δ 3.69 (m, 2 H), 3.77 (dd, / = 6, 13 Hz, 1 H), 3.84 (dd, / = 13, 5 Hz, 1 H), 4.15 (m, 1 H), 7.57 (d, J = 8 Hz, 2 H), 7.62 (d, J = 8 Hz, 2 H), 8.31 (s, 1 H); 13C NMR (CDCl3) δ 47.05, 63.1 1 , 70.80, 129.60, 131.89, 134.49, 137.36, 162.41.
Example 6 Preparation of (S)-I -chloro-3-[(4-nitro-benzylidene)-amino]-propan-2-ol
To a mixture of 4-nitrobenzaldehyde (2.69 g, 17.8 mmol), THF (10 ml), and aqueous ammonia (28%, 1.80 ml, 26.7 mmol, 1.5 eq) at 18 0C is added (S)-(+)-epichlorohydrin (> 99 % ee, 1.39 mL, 17.8 mmol, 1.0 eq.). The mixture is stirred at 40 0C for 18 h then concentrated to in vacuo to provide the title compound as oil. GC (column - 30 meter HP-I, 0.25mm ID and 0.25 micron film and 15 psi head pressure, 1.Oμl injection size; Tini = 70 0C, ramp of 20 °C/min) TR (title compound) = 11.16 min, 64 area%.
Example 7 Preparation of (S)-l-chloro-3-t(2>4-dimethoxy-benzylidene)-amino]-propan-2-ol
To a solution of 2,4-dimethoxybenzaldehyde (18.0 g, 112 mmol) in MTBE (48 g) is added ammonia (28 wt%, 10.9 ml, 167 mmol, 1.54 eq) at room temperature. The biphasal mixture is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 8.5 mL, 108 mmol, 1.0 eq.) is added. The mixture is stirred for 3 days at room temperature and the phases separated. The organics layer is dried on MgSO4 (2 g) clarified with an MTBE rinse (10 ml) and isopar C (100 ml) is added to the filtrate. The solution is concentrated in vacuo to 75 ml total volume. The resultant biphasal mixture is allowed to stand at room temperature for 24 hours. The resultant waxy solid is collected by vacuum filtration at room temperature and washed with isooctanes. Drying in a nitrogen stream to provide the title compound 1HNMR (400 MHz, CDCl3) δ 3.74 (m, 4 H), 3.85 (s, 6 H), 4.11 (m, 1 H), 6.44 (s, 1 H), 6.53 (q, J = 12 Hz, 1 H), 7.89 (d, J = 8 Hz, 1 H), 8.68 (s, 1 H); 13C NMR (CDCl3) δ 47.11, 55.44, 55.46, 63.39; 13C NMR (CDCl3) δ 71.07, 97.94, 105.32, 117.40, 128.45, 159.13, 160.20, 163.35.
Example 8 Preparation of (S)- 1 -chloro-3-[(2,6-dichloro-benzylidene)-amino3-propan-2-ol
To a solution of 2,6-dichlorobenzaldehyde ( 18.9 g, 112 mmol) in MTBE (48 g) is added ammonia (28 wt%, 10.9 ml, 167 mmol, 1.54 eq) at room temperature. The biphasal mixture is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 8.5 mL, 108 mmol, 1.0 eq.) is added. The mixture is stirred for 3 days at room temperature and the phases separated. The organics layer is dried on MgSθ4 (2 g) clarified with an MTBE rinse (10 ml) and isopar C (100 ml) is added to the filtrate. The solution is concentrated in vacuo to give the title compound as oil. 1H NMR (400 MHz, CDCl3) δ 3.74 (m, 4 H), 3.85 (s, 6 H), 4.11 (in, 1 H), 6.44 (s, 1 H), 6.53 (q, 7 = 12 Hz, 1 H), 7.89 (d, J = 8 Hz, 1 H), 8.68 (s, 1 H); 13C NMR (CDCl3) δ 47.11, 55.44, 55.46, 63.39; 13C NMR (CDCl3) δ 71.07, 97.94, 105.32, 1 17.40, 128.45, 159.13, 160.20, 163.35.
Example 9 Preparation of (S)~5-{[4-bromo-benzylidene)~amino]-methyl}~3-(3-fluoro-4- morρholin-4-yl-phenyl)-oxazolidin-2-one
To (3-fluoro-4-morpholin-4-yl-phenyl)-carbamic acid benzyl ester (7.51 g, 22.7 mmol, 1 eq) is added lithium t-butoxide (4.64 g, 57.9 mmol, 2.55 eq), followed by methylene chloride (45 ml) and the mixture stirred at room temperature. To the resultant suspension is added (S)-l-chloro-3-[(4-bromo-benzylidene)-amino]-proρan-2-ol (8.55 g, 30.9 mmol, 1.36 eq) in one portion. The resulting thin suspension is heated to reflux (41°C) for 21 h. The resultant slurry is added to a solution of acetic acid (1.76 g, 29.3 mmol, 1.29 eq) in methanol (46 g) and rinsed in with methanol (24 g). The resultant slurry is concentrated via atmospheric distillation to a total volume of 100 ml. The resultant slurry is cooled to 3 0C and the precipitate collected by vacuum filtration, washed with methanol and dried in a nitrogen stream to give the title compound as crystalline in solid. IH NMR (CDCI3) δ 3.05 (t, J = 5 Hz, 4 H), 3.87 (t, J = 5 Hz, 4 H), 3.90 (dd, J = 5, 14 Hz, 1 H), 3.96 (dd, / « 5, 13 Hz, 1 H), 4.04 (dd, / = 6, 9 Hz, 1 H), 4.12 (t, / » 9 Hz, 1 H), 4.95 (p, / = 5 Hz, 1 H), 6.92 (t, / = 9 Hz, 1 H), 7.13 (dd, J = 10, 2 Hz, H), 7.43 (dd, / = 14, 3 Hz, 1 H), 7.52 (d, / = 9 Hz, 2 H), 7.56 (d, J = 9 Hz, 2 H), 8.33 (s, 1 H); 13C NMR (CDCl3) δ 48.05, 50.84 (JC.F = 4 Hz), 63.03, 66.77, 71.49, 107.25 (J0-F = 26 Hz), 113.70 (JtF = 4 Hz), 118.60, 125.56, 129.54, 131.72, 133.18 (Jc-F = 10 Hz), 134.20, 136.09 (JC.F = 6 Hz), 154.30, 155.32 (JC-F = 245 Hz), 163.41.
Example 10 Preparation of (S)-l-chloro-3-[(2,4-dichloro-benzylidene)-amino]-propan-2-ol
To a solution of 2,4-dichlorobenzaldehyde (112 g, 639 mmol) in MTBE (267 g) is added ammonia (28 wt%, 63.0 ml, 943 mmol, 1.48 eq) at room temperature. The biphasal mixture is stirred for 15 minutes and (S)-(+)-epichlorohydrin (>97 % ee, 50.0 mL, 639 mmol, 1.0 eq.) is added. The mixture is stirred for 3 days at room temperature and the phases separated. The organics layer is dried on MgSO4 (2 g) clarified with an MTBE rinse (50 ml) and the solution concentrated to 200 ml. Heptane (300 ml) is added and the resultant precipitate collected by vacuum filtration, at room temperature and washed with heptane. Drying in a nitrogen stream to provide the title compound as crystalline in solid. 1H NMR (CDCl3) δ 3.66 (dd, / = 6, U Hz, 1 H), 3.70 (dd, 7 = 5, 11 Hz, 1 H), 3.80 (ddd, 7= 1, 6, 13 Hz, 1 H), 3.86 (ddd, / = 2, 5, 13 Hz, 1 H), 4.14 (p, 7 = 6 Hz, 1 H)1 7.28 (dd, 7 = 2, 8 Hz, 1 H), 7.40 (d, 7 = 2 Hz, 1 H), 7.96 (d, 7 = 8 Hz, 1 H), 8.71 (s, 1 H); 13C NMR (CDCl3) δ 46.98, 63.21, 70.66, 127.37, 128.95, 129.49, 131.06, 135.64, 137.22, 159.13.
Example 11 Preparation of (S)-5-{ [2,4-dichloro-benzylidene)-amino]-methyl}-3-(3- fluoro-4-morpholin-4-yl-phenyl)-oxazoIidin-2-one
To (3-fluoro-4~rnorpholin-4-yl-ρhenyl)-carbamic acid benzyl ester (7.59 g, 23.0 mmol, 1 eq) is added lithium t-butoxide (4.69 g, 58.5 mmol, 2.55 eq), followed by methylene chloride (45 ml) and the mixture stirred at room temperature. To the resultant suspension is added (S)-I- chloro-3-[(2,4-dichloro-benzylidene)-amino]-propan-2-ol (8.24 g, 30.9 mmol, 1.35 eq) in one portion. The resulting thin suspension is heated to reflux (410C) for 21 h. The resultant slurry is added to a solution of acetic acid ( 1.76 g, 29.3 mmol, 1.27 eq) in methanol (46 g) and rinsed in with methanol (24 g). The resultant mixture is concentrated via atmospheric distillation to 51 g net weight. The resultant slurry is cooled to 0 0C and the precipitate collected by vacuum filtration, washed with methanol and dried in a nitrogen stream to give the title compound as crystalline in solid. 1H NMR (CDCl3) δ 3.05 (t, 7 = 4 Hz, 4 H), 3.87 (t, 7 = 4 Hz, 4 H), 3.98 (t, 7 = 4 Hz, 1 H), 4.04 (dd, 7 = 6, 9 Hz, 1 H), 4.13 (t, 7 = 9 Hz, 1 H), 4.97 (p, 7 = 5 Hz, 1 H), 6.92 (t, 7 = 9 Hz, 1 H), 7.14 (dd, 7 = 2, 9 Hz1 1 H), 7.22 (dd, 7 = 2, 9 Hz, 1 H), 7.39 (d, 7 = 2 Hz, 1 H), 7.44 (dd, 7 = 3, 14 Hz, 1 H)1 7.87 (d, 7 = 2 Hz1 1 H), 8.75 (s, 1 H); 13C NMR (CDCl3) δ 48.03, 50.83, 63.16, 66.78, 71.44, 107.20 (Jc-F = 26 Hz), 113.62, 118.59, 127.37, 129.05, 129.46, 130.93, 133.16 (JC.F = 11 Hz), 135.71, 136.09 (JC-F = 9 Hz), 137.38, 154.26, 155.32 (JC.F = 245 Hz), 160.24.

Claims

1. A process to prepare linezolid
Linezolid which comprises: a) reacting a compound of structure (1) .
(D wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl; with a compound of structure (2)
(2) at a temperature in a range from ambient temperature to about 650C, wherein R is benzyl or Ci-galkyl to provide a compound of structure (3);
(3) wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl; b) hydrolyzing the compound of structure (3) and subsequently acylation to provide linezolid.
2. A compound of structure (1) in claim 1 which is (S)-l-chloro-3-[(4-chloro-E- benzylidene)-amino]-propan-2-ol.
3. A compound of structure (1) in claim 1 which is (S)-l-chloro-3-[(4~bromo-E- benzylidene)-amino]-propan-2~ol.
4. A compound of structure (1) in claim 1 which is (S)-I -chloro-3-[(2,4-dichloro- benzyIidene)-araino]-propan-2-ol.
5. A compound of structure (3) in claim 1 which is (S)-5-{ [(4-chloro-benzylidene)- amino]-methyl}-3-(3-fluoro-4-moφholin-4-yl-phenyl)-oxazolidin-2-one.
6. A compound of structure (3) (S)-5-{ [4-bromo-benzylidene)-amino]-methyl}-3-(3- fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2~one
7. A compound of structure (3) in claim 1 which is (S)-5-{[2,4-dichloro-benzylidene)- amino]-methyl } -3-(3-fluoro-4-moφholin-4-yl-phenyl)-oxazolidin-2-one.
8. The temperature of claim 1 which is in a range from about 30-65 0C.
9. A compound of structure (2) in claim i where R is benzyl.
10. A compound of structure (2) in claim 1 where R is tert-butyl.
11. A process to prepare a compound of structure (3)
(3) wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl; which comprises a) reacting a compound of structure (1)
(D wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl; with a compound of structure (2)
(2) at a temperature in a range from ambient temperature to about 650C, wherein R is benzyl or Cualkyl.
12. The temperature of claim 8 which is in a range from about 30-65 0C.
13. A compound of structure (1)
(D Wherein X is chlorophenyl, bromophenyl, or 2,4-dichlorophenyl.
14. A compound of claim 12 which is (S)-I -chloro-3-[(4-chloro-E-benzylidene)-amino]- propan-2-ol.
15. A compound of claim 12 which is (S)-l-chloro-3-[(4-bromo-E-benzylidene)-amino]- propan-2-ol.
16 A compound of claim 12 which is (S)-l-chloro-3-[(2,4-dichloro-benzylidene)- amino] -propan-2-ol .
17. (S)-5-{[(4-chloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl- phenyl)-oxazolidin-2-one,
18. A method of crystallization a compound of structure (1)
(1) which comprises a) liquefying a compound of structure (1) in the presence of a non-polar aprotic hydrocarbon solvent at a temperature in a range from ambient temperature to about 55 0C, optionally in the presence of an aprotic polar solvent; and b) Slowly cooling the temperature to ambient temperature or lower.
19. The method of claim 18 wherein the hydrocarbon solvent is an alkane or mixtures of alkanes.
20. The method of claim 18 wherein the hydrocarbon solvent is hexane, heptane, octane, isooctane, or mixtures thereof.
21. The method of claim 18 wherein the aprotic polar solvent is an ethereal solvent, a chlorinated solvent, an aromatic solvent, or mixtures thereof.
22. The method of claim 18 wherein the aprotic plar solvent is MTBE.
23. The method of claim 18 wherein the aprotic plar solvent is toluene.
24. The method of claim 18 wherein the aprotic plar solvent is methylene chloride.
25. The method of claim 18 wherein the temperature is in a range from about 30 to 50 0C.
26. The method of claim i 8 wherein the temperature is in a range from about 38 to 45 0C.
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MX2012012627A (en) 2010-04-30 2013-05-09 Univ Indiana Res & Tech Corp Processes for preparing linezolid.
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WO2013072923A1 (en) 2011-09-19 2013-05-23 Cadila Healthcare Limited Process for the preparation of crystalline linezolid
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