KR20080104178A - Process for preparing linezolid - Google Patents

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. ® KIPO & WIPO 2009

Description

Production method of linezolid {PROCESS FOR PREPARING LINEZOLID}

The present invention relates to a novel method for preparing an oxazolidinone antimicrobial agent. In particular, the present invention relates to a novel method of making linezolid.

Antimicrobial resistance has emerged surprisingly rapidly in recent years and is arguably a global clinical public health problem that will increase in the near future. Resistance is a problem not only in health care settings but also in the community, where bacterial transmission is greatly increased. Since combined drug resistance is an emerging problem, doctors now face infection problems that do not have effective treatment. As a result, structurally novel antimicrobials with new modes of action are becoming increasingly important in the treatment of bacterial infections.

Among the newer antibacterial agents, linezolid is a recent synthetic class with antimicrobial activity against many pathogenic microorganisms. Linezolide [(S) -N-[[3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide] is a US patent 5,688,792. This is a tablet and oral suspension, as an infusion, named ZYVOX®, marketed in the United States by Pfizer, Inc. Methods of making linezolid are described in US Pat. Nos. 5,688,792 and 5,837,870, PCT International Application Publication Nos. WO 99/24393 and WO 2006/004922, J. Pat. Med. Chem. 39 (3), 673-679, 1996 and Tetrahedron Lett., 40 (26), 4855, 1999.

The present invention finds and develops a novel method of making linezolid. This method has the potential to significantly lower the commercial production cost of linezolid. This is a highly convergent three step method with very short cycle times. This is environmentally friendly since the amount of large amounts of solvents used in currently known methods is reduced. In addition, the present invention has found important intermediates that crystallize rapidly for the method of the present invention.

Information disclosure

US Pat. Nos. 4,150,029, 4,250,318, 4,476,136, 4,340,606 and 4,461,773 disclose the synthesis of 5-hydroxymethyloxazolidinone from amines.

J. Med. Chem. , 32, 1673 (1989); Tetrahedron 45, 1323 (1989) and US Pat. No. 4,948,801 disclose a process for the preparation of oxazolidinones.

PCT International Application Publications WO 93/09103, WO 93/09103, WO 95/07271 and WO 93/23384 and PCT International Applications PCT / US95 / 12751 and PCT / US95 / 10992 Discloses the reaction of carbamate with n-butyllithium, lithium diisopropylamide or lithium hexamethyldisilazide.

WO 95/07271 discloses amonolisis of 5R-methylsulfonyloxymethyl substituted oxazolidinones.

US Pat. No. 4,476,136 discloses a process for converting 5-hydroxymethyl substituted oxazolidinone to the corresponding 5 (S) -aminomethyl substituted oxazolidinone.

US Pat. No. 5,332,754 discloses that racemic oxazolidinone-CH ₂ -NH-Ac can be synthesized in one step by condensation of carbamate and racemic glycidyl acetamide.

U. S. Patent No. 3,654, 298 discloses the synthesis of 5-alkoxymethyl-3-aryl-substituted oxazolidinones by cyclization of sodium ethoxide derived chlorocarbamate.

Summary of the Invention

The present invention comprises the steps of: a) reacting a compound having the structure of formula 1 at a temperature in the range of from about 65 ° C to a compound having the structure of formula 2 to obtain a compound having the structure of formula 3; And b) hydrolyzing and then acylating the compound having the structure of Formula 3 to obtain linezolide:

Where

X is chlorophenyl, bromophenyl or 2,4-dichlorophenyl,

R is benzyl or C _1-8 alkyl.

Another aspect of the present invention is a compound having the structures of the formulas (1) and (3) shown above, their crystal structures and their crystallization methods.

Unless stated otherwise, the terms used in the present specification and claims have the following meanings.

The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix indicating the minimum and maximum number of carbon atoms in the moiety, ie the prefix C _ij represents a carbon atom of integer "i" to integer "j" (inclusive). It refers to the residue having. Thus, for example, C _1-8 alkyl refers to alkyl having from 1 to 8 carbon atoms inclusive.

The term "alkyl" refers to straight and branched chain groups, but references to individual radicals such as "propyl" include only straight chain radicals, and branched chain isomers such as "isopropyl" are specifically referred to. Specifically, alkyl is C _1-4 alkyl. More specifically, alkyl is tert-butyl.

The term "ambient temperature" refers to a temperature in the range of about 20 to 30 ° C.

As shown in Scheme I above, where X and R are as defined above, the synthesis comprises a substituted imine residue (1) (preferably 1 to 3 equivalents, most preferably 1.5 to 2 equivalents) Started by coupling of the mate (2) to give the corresponding (S) -oxazolidinone imine (3). Preferably, bases having a pKa greater than 12 at temperatures ranging from ambient temperature to about 65 ° C. (preferably tertiary alkoxide bases, most preferably lithium tert-butoxide) and aprotic non-nucleophilic solvents (preferably Preferably in the presence of DMF, DMAc, THF, acetonitrile, C _1-6 linear, branched and cyclic ethers and / or chlorinated solvents and / or mixtures of these solvents, most preferably MTBE or methylene chloride) The reaction is carried out. Most preferably, the temperature is about 30 to 60 ° C. and the reaction time is 2 to 24 hours. Preferably, (S) -oxazolidinone imine (2) is crystallized after aqueous extraction workup and a weakly polar organic solvent such as alcohols (including C _1-6 branched and linear alcohols and polyols) or ethers (MTBE, THF and other C _1-6 linear, branched and cyclic ethers), most preferably isopropanol. Crude lineride is provided by hydrolysis and subsequent acylation of compound (3) with an acidic aqueous solution. Compound (3) is best hydrolyzed by a mixture of water and strong acid (e.g. hydrochloric acid), and the substituted benzaldehyde by-products are incompatible organic solvents (preferably toluene, MTBE, methylene chloride and ethyl) Acetate, most preferably ethyl acetate). The resulting aqueous solution of amine hydrochloride (4) is preferably acylated by acetic anhydride, preferably in the presence of water and an organic solvent (most preferably methylene chloride) which cannot be mixed with water. The conversion of amine hydrochloride (4) to linezolid is described by Brickner, SJ, et al. J. Med. Chem. 1996 39 (3) 673-679 and US Pat. Nos. 5,837,870 and 5,688,792.

As shown in Scheme II, wherein X is as defined above, the important starting material (1) is a benzaldehyde derivative (preferably between 0.5 and 2) (S) -epichlorohydrin. It can be prepared by reacting with a mixture of equivalents, most preferably one equivalent, and aqueous ammonia (preferably between 0.5 and 3 equivalents, most preferably 1.5 equivalents). Reactions include proton and aprotic nonnucleophilic and nonelectrophilic solvents such as alcohols (including C _1-6 branched and linear alcohols and polyols), ethers (MTBE, THF and other C _1-6 linear, branched and cyclic ethers). And chlorinated solvents such as methylene chloride. MTBE is the preferred solvent. Preferably, the temperature may be in the range of about 15 to about 60 ° C, most preferably 30 to 50 ° C. After extraction isolation and concentration, the imine residue (1) is obtained. Thereafter, in the presence of a nonpolar aprotic hydrocarbon solvent, such as, but not limited to, alkanes, alkanes mixtures (hexane, heptane, octane, isooctane and commercial alkanes mixtures), optionally aprotic polar Crystallized from the second liquid phase in the presence of a solvent, preferably an ethereal solvent such as MTBE or an aromatic solvent such as toluene or a chlorinated solvent such as methylene chloride or mixtures thereof. Preferred solvents are mixtures of MTBE and heptane or mixtures of toluene and heptane. The crystallization process may be carried out at a temperature in the range of ambient temperature (about 18-25 ° C.) to about 55 ° C., preferably 30 to 50 ° C., more preferably 38 to 45 ° C. This crystallization surprisingly gives a high yield and has enantiomeric purity significantly improved after isolation by filtration.

In the above description and the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has the generally accepted meaning:

bm = wide polyline

BOC = tert-butoxycarbonyl

bd = wide doublet

bs = wide single line

CDI = 1,1 O -carbodiimidazole

d = doublet

dd = doublet of doublets

dq = doublet of quadruple

dt = triplet of triplets

DMF = dimethylformamide

DMAP = dimethylaminopyridine

DMSO = dimethyl sulfoxide

eq. = Equivalent

g = grams

h = hours

HPLC = high pressure liquid chromatography

HATU = N-[(dimethylamino) -1H-1,2,3-triazolo- [4,5-b] pyridin-1-yl-methylene] -N-methylmethaneammonium hexafluorophosphate N- Oxide

LG = leaving machine

m = polyline

M = molarity

M% = mole percent

max = maximum

meq = milliequivalents

mg = milligrams

mL = milliliters

mm = millimeters

mmol = millimoles

MTBE = methyl tert-butyl ether

q = quadruple

s = single line

t or tr = triplet

TBS = tributylsilyl

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TLC = thin layer chromatography

p-TLC = preparative thin layer chromatography

μL = microliters

N = normal concentration

MeOH = Methanol

DCM = dichloromethane

HCl = hydrochloric acid

ACN = acetonitrile

MS = mass spectrometry

rt = room temperature

EtOAc = ethyl acetate

EtO = ethoxy

Ac = acetate

NMP = 1-methyl-2-pyrrolidinone

μL = microliters

J = coupling constant

NMR = nuclear magnetic resonance

MHz = Megahertz

Hz = hertz

m / z = mass-to-charge ratio

min = minutes

Boc = tert-butoxycarbonyl

CBZ = benzyloxycarbonyl

DCC = 1,3-dicyclohexylcarbodiimide

PyBop = Benzotriazol-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate

Example 1 Preparation of (S) -1-Chloro-3-[(4-chloro-E-benzylidene) -amino] -propan-2-ol

Method A

The 4-chlorobenzaldehyde (351.g, 2.5 mol, 1.0eq.) Was charged to a 5L three neck round bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser and heating mantle. MTBE (1.5 L) was then charged to the round bottom flask to obtain a homogeneous solution. Aqueous ammonia (28 wt.%, 252.98 mL, 3.75 mol, 1.5 eq.) Was added in one portion to produce a white precipitate that turned into a thin slurry within 15 minutes of stirring. Then (S)-(+)-epichlorohydrin (> 99% ee, 196.0 mL, 2.5 mol, 1.0 eq.) Was slowly charged into the vessel. After 40 minutes, the contents were slowly heated to 43 ° C. The reaction was stirred at 40 ° C. for 18 h, at which time 8.4% of epichlorohydrin was left by GC. Upon cooling to room temperature, the reaction mixture was transferred to a separatory funnel and the layers separated. The low aqueous layer was discarded. The organic layer was transferred to a 3L round bottom flask and concentrated in vacuo to about half of the volume (800-900 mL), at which point isooctane was slowly added from the feed tube (about 750 mL) until cloudy was observed. About 4 mg of the title compound was seeded in the biphasic mixture. The reaction was cooled by an ice bath for 45 minutes with stirring. The precipitate was collected and rinsed with cold isooctane (500 mL). The solid was dried under vacuum at 50 ° C. for 18 h to afford the title compound as white crystalline in solid state. GC analysis: 100%, 99.7% by chiral SFC ee. GC (Conditions: column-30 meter HP-1, 0.25 mm ID and 0.25 micron film and 15 psi head pressure, 1.0 μL injection size; T _inj = 70 ° C., 20 ° C./min slope). T _R (epichlorohydrin) = 2.4 min, T _R (4-chlorobenzaldehyde) = 4.8 min and T _R (title compound) = 9.7 min; HPLC conditions: Chiralpak AD-H 250 nm × 4.6 nm column, eluting with 70% CO ₂ /30% MeOH at 3.0 mL / min, detection at 255 nm. T _R [title compound] = 3.9 min; T _R (enantiomer of the title compound) = 2.8 min; ¹ H NMR (400 MHz, CDCl ₃ ) 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, 2H), 8.33 (s, 1H); ¹³ C NMR (CDCl ₃ ) δ 47.05, 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 system, space group = P2 (1), unit cell dimension a = 8.791 (2) Å, b = 4.6556 (11) Å, c = 14.372 (3) Å, α = 90 ° , β = 106.819 (4) °, γ = 90 °, volume = 563.0 (2) Å ³ ; Z = 2; F (000) = 240; Orepp Picture:

Method B

The 4-chlorobenzaldehyde (375 g, 2.67 mol, 1.0 eq.) Was charged to a 5 L three neck round bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser and heating mantle. Methanol or THF was added and the mixture was warmed from 10 ° C to 23 ° C. Aqueous ammonia (28.4 wt.%, 264 mL, 3.95 mol, 1.5 eq.) Was added in one portion to produce a biphasic solution formed after stirring at 23-26 ° C. for 15 minutes. Then (S)-(+)-epichlorohydrin (99.3% ee, 207 mL, 2.64 mol, 1.0 eq.) Was added in one portion. The reaction mixture was stirred at 23-24 ° C. for 18 hours, then warmed to 40-45 ° C. and stirred for 2.5 hours, at which time GC (GC conditions, 0.050 mL reaction mixture in 1 mL acetonitrile, 1 μL injection; 15 M DB- 1 column, 0.25 mm ID and 0.25 micron film and 15 psi head pressure, 1.0 μL injection size; T _inj = 38 ° C., gradient of 10 ° C./min). T _R (epichlorohydrin) = 1.1 min, T _R (4-chlorobenzaldehyde) = 6.9 min and T _R (title compound) = 16.0 min) left 0.26% area of S-epichlorohydrin. The mixture was concentrated in vacuo to 1250 mL total wealth. Toluene (250 mL) was added and the mixture concentrated in vacuo to a total volume of 1250 mL. Toluene (250 mL) was added and the mixture concentrated in vacuo to a total volume of 1145 mL. Toluene (355 mL) was added and the mixture concentrated in vacuo to a total volume of 900 mL. Toluene (600 mL) was added and the mixture concentrated in vacuo to a total volume of 1120 mL. Heptane (1500 mL) was added while maintaining 45-50 ° C. The resulting biphasic solution was cooled to 45 ° C. and seeded. The mixture was then seeded after every 1 degree of cooling with further cooling to 38 ° C. over 1/2 hour. The mixture was then slowly cooled further to 23 ° C. over 16 hours. Thereafter, white crystals were collected by vacuum filtration and washed with room temperature heptane (180 mL). The product was dried in a nitrogen stream to afford the title compound. HPLC 95 area% [Kromasil 150 mm × 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 Gradient to 100% B over 5 min T _R [title compound] = 2.1 min; T _R (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% CO ₂ /30% MeOH at 3.0 mL / min, detection at 255 nm. T _R [title compound] = 3.9 min; T _R (enantiomer of the title compound) = 2.8 min; ¹ H NMR (400 MHz, CDCl ₃ ) 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, 2H), 8.33 (s, 1H); ¹³ C NMR (CDCl ₃ ) δ 47.05, 63.09, 70.82, 128.93, 129.39, 134.08, 137.07, 162.30.

Method C

The 4-chlorobenzaldehyde (375 g, 2.67 mol, 1.0 eq.) Was charged to a 5 L three neck round bottom flask equipped with a mechanical stirrer, thermocouple, reflux condenser and heating mantle. After warming from 9 ° C. to 24 ° C., MTBE (1.50 L) was added to obtain a homogeneous solution. Aqueous ammonia (28.4 wt%, 265 mL, 3.97 mol, 1.5 eq.) Was added in one portion to produce a biphasic solution that formed after stirring at 23-26 ° C. for 15 minutes. Then (S)-(+)-epichlorohydrin (99.3% ee, 209 mL, 2.67 mol, 1.0 eq.) Was added in one portion. The reaction mixture was stirred at 23-24 ° C. for 3 days. The phases were separated and the stomach phase concentrated under atmospheric pressure to a total volume of 2000 mL to 1000 mL (boiling point 58-67 ° C.). Heptane (1700 mL) was added while maintaining 45-50 ° C. The resulting biphasic solution was cooled to 45 ° C. and seeded. The mixture was then seeded after every 1 degree of cooling with further cooling to 38 ° C. over 1/2 hour. The mixture was then slowly cooled further to 23 ° C. over 1 hour. Thereafter, white crystals were collected by vacuum filtration and washed with room temperature heptane (180 mL). The product was dried in a nitrogen stream to afford the title compound. HPLC 94 area% [Clomasil 150 nm × 4.6 nm column, 254 nm, flow rate 1.5 mL / min; A = 1000 mL water + 0.52 mL trifluoroacetic acid + 1.20 mL triethylamine; B = isocratic 47:53 A: B for 5 minutes of acetonitrile then gradient to 100% B over 5 minutes T _R [title compound] = 2.1 minutes; T _R (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% CO ₂ /30% MeOH at 3.0 mL / min, detection at 255 nm. T _R [title compound] = 3.9 min; T _R (enantiomer of the title compound) = 2.8 min; ¹ H NMR (400 MHz, CDCl ₃ ) 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, 2H), 8.33 (s, 1H); ¹³ C NMR (CDCl ₃ ) δ 47.05, 63.09, 70.82, 128.93, 129.39, 134.08, 137.07, 162.30.

Example 2 (S) -5-{[(4-Chloro-benzylidene) -amino] -methyl} -3- (3-fluoro-4-morpholin-4-yl-phenyl) -oxazolidine Preparation of 2-one

Method A

(3-fluoro-4-morpholin-4-yl-phenyl) -carbasam benzyl ester (20 g, 60.05 mmol, 1 eq.) Was charged with lithium tert-butoxide (12.11 g, 151.4 mmol, 2.5 eq.). After addition methylene chloride (80 mL) was added and the mixture was stirred at room temperature. To the resulting suspension was added (S) -1-chloro-3-[(4-chloro-benzylidene) -amino] -propan-2-ol (21.07 g, 90.81 mmol, 1.5 eq.) In methylene chloride (40 mL). Add at once. The resulting thin suspension was heated to reflux (41 ° C.) for 5 hours. After cooling to room temperature, the organic layer was washed with water (1 × 100 mL, 1 × 50 mL) and then this aqueous wash was discarded. The organic layer was concentrated in vacuo to about 1/2 volume, at which time isopropyl alcohol (200 mL) was added and continued to volume below 200 mL. The resulting suspension is cooled to −10 ° C. to −20 ° C., the solid is isolated by filtration, washed with cold isopropyl alcohol (<100 mL) and dried in vacuo at 55 ° C. to afford the title compound as a crystalline solid. It was. Purity of 99.4 area% was shown by SFC achiral analysis, and 0.11% of (R) enantiomer was confirmed by SFC chiral analysis. HPLC conditions: YMC 5μ ODS-AM 150 nm × 4.6 nm column, eluting from 20% CH ₃ CN to 80% CH ₃ CN using CH ₃ CN / water + 0.1% TFA in 8 min at 0.5 mL / min, at 254 nm detection. T _R [(3-Fluoro-4-morpholin-4-yl-phenyl) -carbamic acid benzyl ester] = 8.5 min; T _R (title compound) = 7.9 min; HPLC conditions: Chiralcel OJ-H 250 nm × 4.6 nm column, eluting with 75% CO ₂ /25% MeOH at 3.0 mL / min, detection at 255 nm. T _R [title compound] = 3.8 min; T _R (enantiomer of the title compound) = 4.4 min; ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.05 (d, J = 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, 1H), 6.92 (t, J = 8 Hz, 1H), 7.12 (d, J = 2 Hz, 1H), 7.36 (d, J = 8 Hz, 2H), 7.44 (dd, J = 16, 4 Hz, 1 H); 7.63 (d, J = 8 Hz, 2H), 8.34 (s, 1H); ¹³ C NMR (CDCl ₃ ) δ 48.23, 51.00, 63.19, 66.94, 71.69, 107.42 (d, J = 27 Hz), 113.88, 118.74, 128.93, 129.50, 133.36 (d, J = 11 Hz), 133.94, 136.30, 137.22, 154.46, 155.48 (d, J = 244 Hz), 163.46.

Method B

Lithium tert-butoxide (225 g, 2.81 mmol, 2.5 eq.) Was added to (3-fluoro-4-morpholin-4-yl-phenyl) -carbasam benzyl ester (372 g, 1.13 mmol, 1 eq.) Methylene chloride (2.2 L) was then added and the mixture was stirred at room temperature. To the resulting suspension was added (S) -1-chloro-3-[(4-chloro-benzylidene) -amino] -propan-2-ol (400 g, 1.72 mol, 1.5 eq.) In one portion. The resulting thin suspension was heated to reflux (41 ° C.) for 10 hours. The resulting slurry was added to a solution of acetic acid (85.2 g, 1.42 mol, 1.26 eq.) In methanol (800 mL), maintaining reflux and rinsing therein with methanol (40 mL). The resulting slurry was concentrated by atmospheric distillation to a total volume of 3200 mL. Methanol (2500 mL) was added while concentrated by atmospheric distillation to maintain a total volume of 3200 to 3800 mL. The resulting slurry was cooled to 3 ° C. and the precipitate collected by vacuum filtration, washed with methanol and dried in a stream of nitrogen to afford the title compound as crystalline in solid state. (HPLC conditions: Kromasil C18 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 for 5 minutes A: B then gradient to 100% B over 5 min at 1.5 mL / min, detection at 254 nm; T _R [title compound] = 6.66 min.

Example 3: (S) -N- [3- (3-Fluoro-4-morpholin-4-yl-phenyl) -2-oxo-oxazolidin-5-ylmethyl] -acetamide (linezoli De) manufacture

Method A

(S) -5-{[(4-chloro-benzylidene) -amino] -methyl} -3- (3-fluoro-4-morpholin-4-yl-phenyl) -oxazolidin-2-one To (129.5 g, 31 mmol, 1.0 eq.) Was added ethyl acetate (935 mL) and water (935 mL). To the heterogeneous mixture was added 12M aqueous HCl (51.58 mL, 620 mmol, 2.0 eq.). Soon, the solid became a solution and the reaction mixture was biphasic. After stirring the emulsion for 2 hours at room temperature, it was confirmed by HPLC analysis that the hydrolysis reaction was complete (HPLC condition: YMC 5μ ODS-AM 150nm × 4.6nm column, CH ₃ CN / in 8 minutes at 0.5mL / min. Elution from 20% CH ₃ CN to 80% CH ₃ CN using water + 0.1% TFA, detection at 254 nm. (S) -N- [3- (3-fluoro-4-morpholin-4-yl- Phenyl) -2-oxo-oxazolidin-5-ylmethyl] -amine = 3.2 min). The phases were separated, the organic layer was discarded and the aqueous layer was washed with ethyl acetate (500 mL). CH ₂ Cl ₂ (900 mL) was added and the pH was adjusted to 6.7 with about 25 mL of 50% aqueous NaOH. With constant stirring, Ac ₂ O (58.49 mL, 620 mmol, 2.0 eq.) Was added at once and the pH was dropped to 2. The pH was then adjusted back to 6 with 50% aqueous NaOH. The pH was adjusted to about 7.1 with 50% aqueous NaOH and the phases separated. The aqueous phase was extracted with CH ₂ Cl ₂ (800 mL), the organics combined and concentrated to about 1 L in bulk. Ethyl acetate (1 L) was added and the volume was reduced to 1.5 L under vacuum. Another 1 L of ethyl acetate was added and the volume was reduced back to 1 L under vacuum. The resulting slurry was cooled to 0 ° C. and the precipitate was collected by vacuum filtration. The resulting solid was washed with ethyl acetate (250 mL). The crude product was dried under vacuum at 50 ° C. for 2 hours to afford the title compound as linezolid crystalline Form I.

Method B

The non-significant variant was made according to the general procedure of Method A, but (S) -5-{[(4-chloro-benzylidene) -amino] -methyl} -3- (3-fluoro-4-morpholine- (S) -5-{[2,4-Dichloro-benzylidene) -amino] -methyl} -3- (3-fluoro-4 instead of 4-yl-phenyl) -oxazolidin-2-one -Morpholin-4-yl-phenyl) -oxazolidin-2-one (Example 11) was used to give the title compound.

Method C

The non-significant variant was made following the general procedure of Method B, but (S) -5-{[(4-chloro-benzylidene) -amino] -methyl} -3- (3-fluoro-4-morpholine- (S) -5-{[4-bromo-benzylidene) -amino] -methyl} -3- (3-fluoro-4-morphine instead of 4-yl-phenyl) -oxazolidin-2-one Polin-4-yl-phenyl) -oxazolidin-2-one (Example 9) was used to give the title compound.

Example 4: Grinding (Conversion of Lineezolide Crystalline Form I to Lineazolelide Crystalline Form II)

The product from Example (89.18 g) was transferred to a 3L round bottom flask equipped with a mechanical stirrer, thermocouple and heating mantle. Ethyl acetate (2.23 L, 15 mL / g) was added and seeded with linezolide form II crystals, and the slurry was heated to about 50 ° C. A weak exotherm of 3 ° C. was observed. After 30 minutes of heating, a morphological change was observed in which the solid turned into a long needle. Stirring was continued at 50 ° C. for 2 hours, at which time the contents were cooled to ambient temperature and stirred for an additional 30 minutes. The contents were then cooled to 3 ° C. for 1.5 hours, filtered and washed with cold ethyl acetate (300 mL total). The resulting solid was dried under vacuum at 50 ° C. for 18 hours to give Linezolide (78.12 g) Form II (99.8 wt.%, 99.9% ee) by XRD. HPLC conditions: YMC 5μ ODS-AM 150 nm × 4.6 nm column, eluting from 20% CH ₃ CN to 80% CH ₃ CN using CH ₃ CN / water + 0.1% TFA in 8 min at 0.5 mL / min, at 254 nm detection. T _R (linezolide) = 4.4 min; HPLC conditions: Chiralcel OJ-H 250 nm × 4.6 nm column, eluting with 90% CO ₂ /10% MeOH at 3.0 mL / min, detection at 255 nm. T _R [title compound] = 3.6 min; T _R (enantiomer of the title compound) = 4.1 min.

Example 5: Preparation of (S) -1-Chloro-3-[(4-bromo-benzylidene) -amino] -propan-2-ol

To a solution of 4-bromobenzaldehyde (20.8 g, 112 mmol) in MTBE (48 g) was added ammonia (28 weight%, 10.9 mL, 167 mmol), 1.54 eq.) At room temperature. The biphasic mixture was stirred for 15 minutes and (S)-(+)-epichlorohydrin (> 97% ee, 8.5 mL, 108 mmol, 1.0 eq.) Was added. The mixture was stirred at rt for 3 days and the phases separated. The organic layer was dried over MgSO ₄ (2 g), cleared by MTBE rinse (10 mL) and Isopar C (100 mL) was added to the filtrate. The solution was concentrated in vacuo to a total volume of 75 mL and the resulting precipitate was collected at rt by vacuum filtration and washed with isooctane. Drying in a nitrogen stream gave the title compound as crystalline in solid state. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.69 (m, 2 H), 3.77 (dd, J = 6, 13 Hz, 1 H), 3.84 (dd, J = 13, 5 Hz, 1 H), 4.15 (m, 1H), 7.57 (d, J = 8 Hz, 2H), 7.62 (d, J = 8 Hz, 2H), 8.31 (s, 1H); ¹³ C NMR (CDCl ₃ ) δ 47.05, 63.11, 70.80, 129.60, 131.89, 134.49, 137.36, 162.41.

Example 6: Preparation of (S) -1-Chloro-3-[(4-nitro-benzylidene) -amino] -propan-2-ol

(S)-(+)-epi 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 ° C. Chlorohydrin (> 99% ee, 1.39 mL, 17.8 mmol, 1.0 eq.) Was added. The mixture was stirred at 40 ° C. for 18 h and then concentrated in vacuo to afford the title compound as an oil. GC (column-30 meter HP-1, 0.25 mm ID and 0.25 micron film and 15 psi head pressure, 1.0 μL injection size; T _inj = 70 ° C., slope of 20 ° C./min) T _R (title compound) = 11.16 min, 64 area%.

Example 7: Preparation of (S) -1-Chloro-3-[(2,4-dimethoxy-benzylidene) -amino] -propan-2-ol

To a solution of 2,4-dimethoxybenzaldehyde (18.0 g, 112 mmol) in MTBE (48 g) was added ammonia (28 wt%, 10.9 mL, 167 mmol, 1.54 eq.) At room temperature. The biphasic mixture was stirred for 15 minutes and (S)-(+)-epichlorohydrin (> 97% ee, 8.5 mL, 108 mmol, 1.0 eq.) Was added. The mixture was stirred at rt for 3 days and the phases separated. The organic layer was dried over MgSO ₄ (2 g), cleared by MTBE rinse (10 mL) and Isopar C (100 mL) was added to the filtrate. The solution was concentrated in vacuo to 75 mL total volume. The resulting biphasic mixture was left at room temperature for 24 hours. The resulting waxy solid was collected by vacuum filtration at room temperature and washed with isooctane. Drying in nitrogen stream afforded the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) 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, 1H), 7.89 (d, J = 8 Hz, 1H), 8.68 (s, 1H); ¹³ C NMR (CDCl ₃ ) δ 47.11, 55.44, 55.46, 63.39; ¹³ C NMR (CDCl ₃ ) 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) -amino] -propan-2-ol

To a solution of 2,4-dichlorobenzaldehyde (18.9 g, 112 mmol) in MTBE (48 g) was added ammonia (28 wt%, 10.9 mL, 167 mmol, 1.54 eq.) At room temperature. The biphasic mixture was stirred for 15 minutes and (S)-(+)-epichlorohydrin (> 97% ee, 8.5 mL, 108 mmol, 1.0 eq.) Was added. The mixture was stirred at rt for 3 days and the phases separated. The organic layer was dried over MgSO ₄ (2 g), cleared by MTBE rinse (10 mL) and Isopar C (100 mL) was added to the filtrate. The solution was concentrated in vacuo to afford the title compound as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) 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, 1H), 7.89 (d, J = 8 Hz, 1H), 8.68 (s, 1H); ¹³ C NMR (CDCl ₃ ) δ 47.11, 55.44, 55.46, 63.39; ¹³ C NMR (CDCl ₃ ) δ 71.07, 97.94, 105.32, 117.40, 128.45, 159.13, 160.20, 163.35.

Example 9: (S) -5-{[4-Bromo-benzylidene) -amino] -methyl} -3- (3-fluoro-4-morpholin-4-yl-phenyl) -oxazolidine Preparation of 2-one

Lithium tert-butoxide (4.64g, 57.9mmol, 2.55eq.) In (3-fluoro-4-morpholin-4-yl-phenyl) -carbamic acid benzyl ester (7.51g, 22.7mmol, 1eq.) After addition of methylene chloride (45 mL) was added and the mixture was stirred at room temperature. To the resulting suspension was added (S) -1-chloro-3-[(4-bromo-benzylidene) -amino] -propan-2-ol (8.55 g, 30.9 mmol, 1.36 eq.) In one portion. . The resulting thin suspension was heated to reflux (41 ° C.) for 21 hours. The resulting slurry was added to a solution of atetic acid (1.76 g, 29.3 mmol, 1.29 eq.) In methanol (16 g) and rinsed in with methanol (24 g). The resulting slurry was concentrated by atmospheric distillation to a total volume of 100 mL. The resulting slurry was cooled to 3 ° C. and the precipitate was collected by vacuum filtration, washed with methanol and dried in a stream of nitrogen to afford the title compound as crystalline in solid state. ¹ H NMR (CDCl ₃ ) 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, J = 5, 13 Hz, 1 H), 4.04 (dd, J = 6, 9 Hz, 1 H), 4.12 (t, J = 9 Hz, 1 H), 4.95 (p, J = 5 Hz , 1 H), 6.92 (t, J = 9 Hz, 1 H), 7.13 (dd, J = 10, 2 Hz, H), 7.43 (dd, J = 14, 3 Hz, 1 H), 7.52 (d , J = 9 Hz, 2H), 7.56 (d, J = 9 Hz, 2H), 8.33 (s, 1H); ¹³ C NMR (CDCl ₃ ) δ 48.05, 50.84 (J _CF = 4 Hz), 63.03, 66.77, 71.49, 107.25 (J _CF = 26 Hz), 113.70 (J _CF = 4 Hz), 118.60, 125.56, 129.54, 131.72 , 133.18 (J _CF = 10 Hz), 134.20, 136.09 (J _CF = 6 Hz), 154.30, 155.32 (J _CF = 245 Hz), 163.41.

Example 10 Preparation of (S) -1-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) was added ammonia (28 wt%, 63.0 mL, 943 mmol, 1.48 eq.) At room temperature. The biphasic mixture was stirred for 15 minutes and (S)-(+)-epichlorohydrin (> 97% ee, 50.0 mL, 639 mmol, 1.0 eq.) Was added. The mixture was stirred at rt for 3 days and the phases separated. The organic layer was dried over MgSO ₄ (2 g), cleared by MTBE rinse (50 mL) and the solution was concentrated to 200 mL. Heptane (300 mL) was added and the resulting precipitate was collected at rt by vacuum filtration and washed with heptane. Drying in a nitrogen stream gave the title compound as crystalline in solid state. ¹ H NMR (CDCl ₃ ) δ 3.66 (dd, J = 6, 11 Hz, 1 H), 3.70 (dd, J = 5, 11 Hz, 1 H), 3.80 (ddd, J = 1, 6, 13 Hz , 1 H), 3.86 (ddd, J = 2, 5, 13 Hz, 1 H), 4.14 (p, J = 6 Hz, 1 H), 7.28 (dd, J = 2, 8 Hz, 1 H), 7.40 (d, J = 2 Hz, 1 H), 7.96 (d, J = 8 Hz, 1 H), 8.71 (s, 1 H); ¹³ C NMR (CDCl ₃ ) δ 46.98, 63.21, 70.66, 127.37, 128.95, 129.49, 131.06, 135.64, 137.22, 159.13.

Example 11: (S) -5-{[2,4-Dichloro-benzylidene) -amino] -methyl} -3- (3-fluoro-4-morpholin-4-yl-phenyl) -oxa Preparation of Zolidin-2-one

Lithium tert-butoxide (4.69 g, 58.5 mmol, 2.55 eq.) In (3-fluoro-4-morpholin-4-yl-phenyl) -carbamic acid benzyl ester (7.59 g, 23.0 mmol, 1 eq.) After addition of methylene chloride (45 mL) was added and the mixture was stirred at room temperature. To the resulting suspension was added (S) -1-chloro-3-[(2,4-dichloro-benzylidene) -amino] -propan-2-ol (8.24 g, 30.9 mmol, 1.35 eq.) At a time. Added. The resulting thin suspension was heated to reflux (41 ° C.) for 21 hours. The resulting slurry was added to a solution of atetic acid (1.76 g, 29.3 mmol, 1.27 eq.) In methanol (46 g) and rinsed in with methanol (24 g). The resulting mixture was concentrated to 51 g net weight by atmospheric distillation. The resulting slurry was cooled to 0 ° C. and the precipitate was collected by vacuum filtration, washed with methanol and dried in a stream of nitrogen to afford the title compound as crystalline in solid state. ¹ H NMR (CDCl ₃ ) δ 3.05 (t, J = 4 Hz, 4 H), 3.87 (t, J = 4 Hz, 4 H), 3.98 (t, J = 4 Hz, 1 H), 4.04 (dd , J = 6, 9 Hz, 1 H), 4.13 (t, J = 9 Hz, 1 H), 4.97 (p, J = 5 Hz, 1 H), 6.92 (t, J = 9 Hz, 1 H) , 7.14 (dd, J = 2, 9 Hz, 1 H), 7.22 (dd, J = 2, 9 Hz, 1 H), 7.39 (d, J = 2 Hz, 1 H), 7.44 (dd, J = 3, 14 Hz, 1 H), 7.87 (d, J = 2 Hz, 1 H), 8.75 (s, 1 H); ¹³ C NMR (CDCl ₃ ) δ 48.03, 50.83, 63.16, 66.78, 71.44, 107.20 (J _CF = 26 Hz), 113.62, 118.59, 127.37, 129.05, 129.46, 130.93, 133.16 (J _CF = 11 Hz), 135.71, 136.09 (J _CF = 9 Hz), 137.38, 154.26, 155.32 (J _CF = 245 Hz), 160.24.

Claims (26)

a) reacting a compound having a structure of Formula 1 at a temperature ranging from ambient temperature to about 65 ° C. with a compound having the structure of Formula 2 to obtain a compound having the structure of Formula 3; And b) hydrolyzing and then acylating the compound having the structure of formula 3 to obtain linezolid Including, the production method of linezolide:

Formula 1

Formula 2

Formula 3

Where X is chlorophenyl, bromophenyl or 2,4-dichlorophenyl, R is benzyl or C _1-8 alkyl. A compound having the structure of formula 1 as defined in claim 1 which is (S) -1-chloro-3-[(4-chloro-E-benzylidene) -amino] -propan-2-ol. A compound having the structure of formula 1 as defined in claim 1 which is (S) -1-chloro-3-[(4-bromo-E-benzylidene) -amino] -propan-2-ol. A compound having the structure of formula 1 as defined in claim 1 which is (S) -1-chloro-3-[(2,4-dichloro-benzylidene) -amino] -propan-2-ol. (S) -5-{[(4-Chloro-benzylidene) -amino] -methyl} -3- (3-fluoro-4-morpholin-4-yl-phenyl) -oxazolidin-2-one A compound having the structure of formula (3) as defined in claim 1. (S) -5-{[(4-Bromo-benzylidene) -amino] -methyl} -3- (3-fluoro-4-morpholin-4-yl-phenyl) -oxazolidine-2- A compound having the structure of formula 3 as defined in claim 1 which is on. (S) -5-{[2,4-Dichloro-benzylidene) -amino] -methyl} -3- (3-fluoro-4-morpholin-4-yl-phenyl) -oxazolidine-2 A compound having the structure of formula (3) as defined in claim 1 which is -ON. The method of claim 1, The temperature is in the range of about 30 to 65 ° C. A compound having the structure of formula 2 wherein R is benzyl in a compound having the structure of formula 2 as defined in claim 1. In the compound having the structure of formula (2) as defined in claim 1, the compound having the structure of formula (2) wherein R is tert-butyl. a) reacting a compound having the structure of Formula 1 with a compound having the structure of Formula 2 at a temperature ranging from ambient temperature to about 65 ° C: Method for producing a compound having a structure of Formula 3, comprising: Formula 1

Formula 2

Formula 3

Where X is chlorophenyl, bromophenyl or 2,4-dichlorophenyl, R is benzyl or C _1-8 alkyl. The method of claim 8, The temperature is in the range of about 30 to 65 ° C. A compound having the structure of Formula 1 Formula 1

Where X is chlorophenyl, bromophenyl or 2,4-dichlorophenyl. The method of claim 12, (S) -1-Chloro-3-[(4-chloro-E-benzylidene) -amino] -propan-2-ol. The method of claim 12, (S) -1-Chloro-3-[(4-bromo-E-benzylidene) -amino] -propan-2-ol. The method of claim 12, (S) -1-Chloro-3-[(2,4-dichloro-benzylidene) -amino] -propan-2-ol. (S) -5-{[(4-chloro-benzylidene) -amino] -methyl} -3- (3-fluoro-4-morpholin-4-yl-phenyl) -oxazolidin-2-one . a) liquefying a compound having the structure of Formula 1 at temperatures ranging from ambient to about 55 ° C., in the presence of a non-polar aprotic hydrocarbon solvent, optionally in the presence of an aprotic polar solvent; And b) slowly cooling the temperature below ambient temperature Crystallization method of a compound having a structure of Formula 1, comprising: Formula 1

The method of claim 18, Crystallization process wherein the hydrocarbon solvent is an alkane or a mixture of alkanes. The method of claim 18, Wherein the hydrocarbon solvent is hexane, heptane, octane, isooctane or mixtures thereof. The method of claim 18, And wherein the aprotic polar solvent is an ether solvent, a chlorinated solvent, an aromatic solvent or a mixture thereof. The method of claim 18, And wherein the aprotic polar solvent is MTBE. The method of claim 18, And wherein the aprotic polar solvent is toluene. The method of claim 18, The crystallization method wherein the aprotic polar solvent is methylene chloride. The method of claim 18, Wherein the temperature is in the range of about 30 to 50 ° C. The method of claim 18, Wherein the temperature is in the range of about 38-45 ° C.