TEDIZOLID torezolid

TEDIZOLID PHOSPHATE

[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxo-5-oxazolidinyl]methyl]phosphate,

DA 7157

THERAPEUTIC CLAIM Treatment of complicated skin and skin structure infections
CHEMICAL NAMES
1. 2-Oxazolidinone, 3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5- [(phosphonooxy)methyl]-, (5R)-
2. [(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxooxazolidin-5- yl]methyl hydrogen phosphate

http://www.ama-assn.org/resources/doc/usan/tedizolid-phosphate.pdf

MOLECULAR FORMULA C17H16FN6O6P

MOLECULAR WEIGHT 450.3
TRADEMARK None as yet
SPONSOR Trius Therapeutics
CODE DESIGNATION TR-701 FA
CAS REGISTRY NUMBER 856867-55-5
Note: This adoption statement supersedes the USAN torezolid phosphate (N09/81), which is hereby rescinded and replaced by the USAN tedizolid phosphate (N10/118).\

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ChemSpider 2D Image | Torezolid | C17H15FN6O3

Tedizolid, 856866-72-3

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one

(5R)-3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5-(hydroxymethyl)-2-oxazolidinone,

TR 700

  • Molecular Formula: C17H15FN6O3
  • Average mass: 370.337799

 

Torezolid (also known as TR-701 and now tedizolid[1]) is an oxazolidinone drug being developed by Trius Therapeutics (originator Dong-A Pharmaceuticals) for complicated skin and skin-structure infections (cSSSI), including those caused by Methicillin-resistantStaphylococcus aureus (MRSA).[2]

As of July 2012, tedizolid had completed one phase III trial, with another one under way. [3]Both trials compare a six-day regimen of tedizolid 200mg once-daily against a ten-day regimen of Zyvox (linezolid) 600mg twice-daily.

The prodrug of tedizolid is called “TR-701″, while the active ingredient is called “TR-700″.[4][5]

Trius Therapeutics will soon be reporting data from its second phase III trial (ESTABLILSH-2) and the recently announced publication of the data from its first phase III trial (ESTABLISH-1) in the Journal of the American Medical Association (JAMA)

  1. “Trius grows as lead antibiotic moves forward”. 31 Oct 2011.
  2. “Trius Completes Enrollment In Phase 2 Clinical Trial Evaluating Torezolid (TR-701) In Patients With Complicated Skin And Skin Structure Infections”. Jan 2009.
  3. http://clinicaltrials.gov/ct2/results?flds=Xf&flds=a&flds=b&term=tedizolid&phase=2&fund=2&show_flds=Y
  4. PMID 19528279 In vitro activity of TR-700, the active ingredient of the antibacterial prodrug TR-701, a novel oxazolidinone antibacterial agent.
  5. PMID 19218276 TR-700 in vitro activity against and resistance mutation frequencies among Gram-positive pathogens.

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Emergence of bacterial resistance to known antibacterial agents is becoming a major challenge in treating bacterial infections. One way forward to treat bacterial infections, and especially those caused by resistant bacteria, is to develop newer antibacterial agents that can overcome the bacterial resistance. Coates et al. (Br. J. Pharmacol. 2007; 152(8), 1147-1154.) have reviewed novel approaches to developing new antibiotics. However, the development of new antibacterial agents is a challenging task. For example, Gwynn et al. (Annals of the New York Academy of Sciences, 2010, 1213: 5-19) have reviewed the challenges in the discovery of antibacterial agents.

Several antibacterial agents have been described in the prior art (for example, see PCT International Application Nos. PCT/US2010/060923, PCT/EP2010/067647, PCT/US2010/052109, PCT/US2010/048109, PCT/GB2009/050609, PCT/EP2009/056178 and PCT/US2009/041200). However, there remains a need for potent antibacterial agents for preventing and/or treating bacterial infections, including those caused by bacteria that are resistant to known antibacterial agents.

Various oxazolidinone-containing compounds have been disclosed for use asantibiotics. For example, oxazolidinone-containing compounds have been described in U.S. patent application Ser. No. 10/596,412 (filed Dec. 17, 2004), and WO 04/048350, WO 03/022824 and WO 01/94342, which are incorporated herein by reference.

U.S. patent application Ser. No. 12/577,089 (filed Oct. 9, 2009) and U.S. patent application Ser. No. 12/699,864 (filed Feb. 3, 2010), which are assigned to the same assignee as in the present application, disclose phosphate dimer impurities made during the process of making of the compounds disclosed therein. Surprisingly, it has been found that compounds containing at least two phosphates binding two oxazolidinone-containing moieties, such as dimers of oxazolidinone-containing compounds have antibacterial activity similar to their dihydrogen monophosphate analog

active drug of Formula I is (5R)-3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5-(hydroxymethyl)-2-oxazolidinone, i.e.,

Figure US20100305069A1-20101202-C00012

These active compounds have been disclosed in WO 05/058886 and US Patent Publication No. 20070155798, while processes for making these and related compounds have been disclosed in U.S. patent application Ser. No. 12/577,089 (filed Oct. 9, 2009), and a crystalline form of the phosphate ester and related salts of the above compound has been disclosed in U.S. patent application Ser. No. 12/699,864 (filed Feb. 3, 2010).

US Patent Publication No. 20070155798,  recently disclosed a series of potently anti-bacterial oxazolidinones including

Figure US08426389-20130423-C00001

wherein R═H, PO(OH)2, and PO(ONa)2.

Cubist Announces Submission of New Drug Application for Investigational Antibiotic Tedizolid for Treatment of Serious Skin Infections

LEXINGTON, Mass.–(BUSINESS WIRE)– Cubist Pharmaceuticals, Inc. today announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of its investigational antibiotic tedizolid phosphate (TR-701). Cubist is seeking approval of tedizolid phosphate for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Tedizolid phosphate is a once daily oxazolidinone being developed for both intravenous (I.V.) and oral administration for the treatment of serious Gram-positive infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA).

http://www.drugs.com/nda/tedizolid_131023.html

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Efficacy of DA-7218, a new oxazolidinone prodrug, in the treatment of experimental actinomycetoma produced by Nocardia brasiliensis.

Espinoza-González NA, Welsh O, de Torres NW, Cavazos-Rocha N, Ocampo-Candiani J, Said-Fernandez S, Lozano-Garza G, Choi SH, Vera-Cabrera L.

Molecules. 2008 Jan 11;13(1):31-40.

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imp patents

US2010305069 12-3-2010 OXAZOLIDINONE CONTAINING DIMER COMPOUNDS, COMPOSITIONS AND METHODS TO MAKE AND USE
US7816379 10-20-2010 Oxazolidinone derivatives
US2009192197 7-31-2009 NOVEL OXAZOLIDINONE DERIVATIVES

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TEDIZOLID disodium salt

59 nos in

http://www.google.com/patents/US20130102523

Figure US20130102523A1-20130425-C00064

Figure US20130102523A1-20130425-C0004338 nos

Tedizolid (formerly known as torezolid or TR-700) is the active hydroxymethyl oxazolidinone having the following formula:

Figure US20130102523A1-20130425-C00083

Pharmaceutical prodrugs such as tedizolid phosphate (also referred to as TR-701, torezolid phosphate, and TR-701 “free acid” or FA) have the following formula:

Figure US20130102523A1-20130425-C00084

The disodium salt of tedizolid phosphate, has the following structure:

Figure US20130102523A1-20130425-C00085
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Example 1 Preparation of the Phosphate Monohydrogen Diester, Formula III
In this and the following Examples, “Formula III” refers to a compound wherein Z is
Figure US20100305069A1-20101202-C00024
and M=OH.
A 1-L, three-neck round-bottom flask equipped with a magnetic stirrer, nitrogen inlet/outlet and thermocouple was charged with the compound of Formula Ia below (16.0 g, 0.0499 mol], THF (320 mL, 20 vol) and Et3N (21.9 g, 0.216 mol, 5.0 equiv.).
Figure US20100305069A1-20101202-C00025
POCl3 (3.31 g, 0.0216 mol, 0.5 equiv.) was added dropwise via syringe over 5 minutes. The reaction temperature was maintained below 25° C. The batch was aged for 16 hours at room temperature at which point HPLC analysis (XBridge, C18) indicated that the reaction was complete. The reaction vessel was then immersed in an ice-water bath and a 500-mL addition funnel charged with 320 mL of H2O was attached to the reaction vessel. When the temperature of the reaction reached 2.7° C., H2O was added drop wise over 30 minutes. The temperature of the reaction was maintained below 10° C. Upon completion of the H2O addition, the ice-water bath was removed and the batch was aged for 3 hours. The solution was transferred to a 2-L round-bottom flask and concentrated under reduced pressure on a rotary evaporator. After removal of most of the THF from the solution, the aqueous mixture was extracted with 5 1-L portions of CH2Cl2:MeOH (9:1). The CH2Cl2 layers were combined and concentrated to a dark oil. This crude material was purified on 200 g of silica gel, eluting with 10% MeOH/CH2Cl2 to 20% 2 N NH3 in MeOH/CH2Cl2. Fractions containing mostly the bis-ester (as judged by TLC Rf=0.3 eluting with 20% 2 N NH3 in MeOH/CH2Cl2) were combined and concentrated under reduced pressure on a rotary evaporator, during which time a white precipitate was observed. The flask containing the slurry was removed from the rotary evaporator and equipped with a magnetic stir bar and allowed to stir while cooling to room temperature over 3 hours, during which time the slurry thickened. The solid was filtered and dried in a vacuum oven at 45° C. for 16 hours to give 3.55 g of bis-ester as an off-white solid (20% yield). HPLC analysis (Method A): 99.0% (AUC), tR=16.3 min. This reaction was repeated and the combined lots of the compound of Formula III (6.7 g) were slurried in 100 mL of MeOH (15 vol). The slurry was heated to 40° C. for 30 minutes and then allowed to cool to room temperature over 1 hour. The off-white solid was filtered and dried in a vacuum oven at 40° C. for 16 hours to give 6.15 g of the compound of Formula III (92% yield). The 1H NMR analysis of the product was consistent with the assigned structure. HPLC analysis (Method A): 99.0% (AUC), tR=16.3 min.

Example 2 Preparation of the Diphosphate Dihydrogen Diester, Formula IV
In Examples 2-5, “Formula IV” refers to a compound wherein Z is
Figure US20100305069A1-20101202-C00026
n=0 and M=O-imidazolium salt.

A 250-mL 3-neck round-bottom flask equipped with a magnetic stirrer, nitrogen inlet/outlet and thermocouple was charged with the compound of Formula IIa below (5.0 g, 11.1 mmol), carbonyldiimidazole (890 mg, 5.55 mmol, 0.5 equiv.) and DMF (100 mL, 20 vol).
Figure US20100305069A1-20101202-C00027
The suspension was heated to 50° C. and held at that temperature for 4 hours at which point HPLC analysis (XBridge, C18) indicated that the reaction was complete. The reaction was filtered at 50° C. and dried in a vacuum oven at 50° C. for 24 hours to give 5.15 g of the imidazolium salt (i.e., the compound of Formula IV) as an off-white solid (98% yield). The 1H NMR analysis of the product was consistent with the assigned structure. HPLC analysis (Method A): 94.5% (AUC), tR=14.6 min.
TABLE 1
Method A (Waters XBridge C18 Column)
Time (min) Flow (mL/min) % A % B
0.0 1.0 98.0 2.0
15.0 1.0 5.0 95.0
25.0 1.0 5.0 95.0
27.0 1.0 98.0 2.0
30.0 1.0 98.0 2.0
A = 87% 25 mM ammonium bicarbonate solution in water/13% Acetonitrile
B = Acetonitrile
Wavelength = 300 nm

Figure US20100305069A1-20101202-C00016disodium salt is TR 701

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US8580767

Various oxazolidinone-containing compounds have been disclosed for use as antibiotics. For example, oxazolidinone-containing compounds have been described in U.S. patent application Ser. No. 10/596,412 (filed Dec. 17, 2004), and WO 04/048350, WO 03/022824 and WO 01/94342, which are incorporated herein by reference.

U.S. patent application Ser. No. 12/577,089 (filed Oct. 9, 2009) and U.S. patent application Ser. No. 12/699,864 (filed Feb. 3, 2010), which are assigned to the same assignee as in the present application, disclose phosphate dimer impurities made during the process of making of the compounds disclosed therein. Surprisingly, it has been found that compounds containing at least two phosphates binding two oxazolidinone-containing moieties, such as dimers of oxazolidinone-containing compounds have antibacterial activity similar to their dihydrogen monophosphate analog,

These active compounds have been disclosed in WO 05/058886 and US Patent Publication No. 20070155798, while processes for making these and related compounds have been disclosed in U.S. patent application Ser. No. 12/577,089 (filed Oct. 9, 2009), and a crystalline form of the phosphate ester and related salts of the above compound has been disclosed in U.S. patent application Ser. No. 12/699,864 (filed Feb. 3, 2010). The latter two applications are assigned to the same assignee as in the present application

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SYNTHESIS

US20070155798

Figure US20070155798A1-20070705-C00077

DESCRIPTION OF COMPDS

10,

(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-on (compound 10)

Figure US20070155798A1-20070705-C00013

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18

Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-fluoromethyl oxazolidin-2-on (compound 18)

Figure US20070155798A1-20070705-C00013

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33

(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methoxymethyl oxazolidin-2-on (compound 33)

Figure US20070155798A1-20070705-C00013

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59

(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl disodiumphosphate (compound 59)

Figure US20070155798A1-20070705-C00062

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72

mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 72)

Figure US20070155798A1-20070705-C00075

COMPLETE SYNTHESIS

Example 5

Preparation of 2-cyano-5-bromopyridine

In 1 L of dimethylformamide was dissolved 100 g of 2,5-dibromopyridine, 32 g of cupper cyanide and 17.8 g of sodium cyanide were added to the solution at room temperature and the solution was stirred at the temperature of 150° C. for 7 hours for reaction. After being cooled to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated in vacuo. The title compound 54 g was obtained. Yield 70%.

1HNMR(CDCl3) δ 8.76(s,1H), 7.98(dd,1H), 7.58(dd,1H)

Example 6

Preparation of 2-(tetrazol-5-yl)-5-bromopyridine

10 g of 2-cyano-5-bromopyridine prepared in the Preparation example 5 was dissolved in 100 ml of dimethylformamide, 5.33 g of sodiumazide, and 4.4 g of ammonium chloride were added to the solution at room temperature, and the solution was stirred at the temperature of 110° C. for 3 hours for reaction. The reaction mixture was added with water and then was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtrated and concentrated in vacuo thereby to obtain 10.5 g of the title compound. Yield 85%.

Preparation Example 7 Preparation of 2-(1-methyltetrazol-5-yl)-5-bromopyridine and 2-(2-methyltetrazol-5-yl)-5-bromopyridine

10.5 g of 2-(tetrazol-5-yl)-5-bromopyridine prepared in the Preparation example 6 was dissolved in 100 ml of dimethylformamide. And then 6.5 g of sodium hydroxide was added to the solution and 9.3 g of iodomethane was slowly added to the solution at the temperature of 0° C. The solution was stirred for 6 hours at room temperature, added with water, extracted with ethyl acetate. And then the organic layer was washed with brine, dehydrated, filtrated, concentrated in vacuo and purified by column chromatography to obtain 4 g of 2-(1-methyltetrazol-5-yl)-5-bromopyridine and 5 g of 2-(2-methyltetrazol-5-yl)-5-bromopyridine.

1) 2-(1-methyltetrazol-5-yl)-5-bromopyridine

1HNMR(CDCl3) δ 8.77(t,1H), 8.23(dd,1H), 8.04(dd,1H), 4.46(s,3H)

2) 2-(2-methyltetrazol-5-yl)-5-bromopyridine

1HNMR(CDCl3) δ 8.80(t,1H), 8.13(dd,1H), 7.98(dd,1H), 4.42(s,3H)

Example 1

Preparation of N-Carbobenzyloxy-3-fluoroaniline

3-fluoroaniline 100 g was dissolved in 1 L of tetrahydrofuran (THF) and the solution was added with 150 g (1.8 mol) of sodium bicarbonate (NaHCO3). After being cooled to 0° C., the solution was slowly added with 154 ml of N-carbobenzyloxy chloride (CbzCl) for reaction. While the temperature was maintained at 0° C., the reaction mixture was let to react for 2 hours with stirring. Afterwards, the reaction was extracted with 0.5 L of ethyl acetate. The organic layer, after being separated, was washed with brine, dried over anhydrous magnesium sulfate (MgSO4) and concentrated in vacuo. The residue was washed twice with n-hexane to afford the title compound as white crystal. 132 g. Yield 85%.

Example 2

Preparation of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol

132 g of N-carbobenzyloxy-3-fluoroaniline 132 g prepared in the Preparation example 1 was dissolved in 1.3 L of tetrahydrofuran and the solution was cooled to −78° C. 370 ml of n-buthyllitium (n-BuLi, 1.6M/n-hexane) was slowly added to the solution in a nitrogen atmosphere, followed by stirring for 10 min. And 84 ml of (R)-(−)-glycidylbuthylate was slowly added to the reaction mixture, stirred at the same temperature for 2 hours and allowed to react for 24 hours at room temperature. After completion of the reaction, the solution was added with ammonium chloride (HH4Cl) solution and extracted with 0.5 L of ethyl acetate at room temperature. The organic layer, thus separated, was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate and washed with n-hexane to give white crystals, which were purified to the title compound. 80 g. Yield 70%.

1H NMR (DMSO-d6) δ 7.85(t,1H), 7.58(dd,1H), 7.23(dd,1H), 4.69(m,1H), 4.02 (t,1H), 3.80(dd,1H), 3.60(br dd,2H).

Example 3

Preparation of (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol

In 300 ml of acetonitryl was dissolved 30 g of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in the Preparation example 2, and 46 g of trifluoroacetic acid silver salt (CF3COOAg) and 43 g of iodide were added to the solution. After being stirred for one day at room temperature, the solution was added with water and was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine and dehydrated. And then the residue was filtered, concentrated in vacuo and dried thereby to form the title compound 44 g. Yield 94%.

1H NMR (DMSO-d6) δ 7.77(t,1H), 7.56(dd,1H), 7.20(dd,1H), 5.20(m,1H), 4.70 (m,1H), 4.07(t,1H), 3.80(m,1H), 3.67(m,2H), 3.56(m,3H)

Example 4

Preparation of (R)-3-(4-tributhylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol

In 660 ml of 1,4-dioxan was dissolved 50 g of (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in the Preparation example 3, 52 g of hexabutylditin ((Bu3Sn)2) and 9.3 g of dichlorobistriphenylphosphinpalladium were added into the solution, and stirred for 2 hours. The solution was filtered using celite and concentrated in vacuo. The residue was purified by column chromatography and 45 g of the title compound was formed.

1H NMR (DMSO-d6) δ 7.74(m,3H), 5.20(t,1H), 4.71(m,1H), 4.08(t,1H), 3.82(dd,1H), 3.68(m,1H), 3.52(m,1H), 1.48(m, 6H), 1.24(m, 6H), 1.06(m,6H), 0.83(t,9H)

COMPD 10

Example 1 Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-on (compound 10)

In 150 ml of 1-methyl-2-pyrrolidone was dissolved 37 g of (R)-3-(4-tributhylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol. The solution was added with 19.7 g of 2-(2-methyltetrazol-5-yl)-5-bromopyridine, 10.44 g of lithium chloride and 2.9 g of dichlorobistriphenylphospine palladium(II) at room temperature and then stirred at the temperature of 120° C. for 4 hours. The reaction mixture was added with water and then extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtrated, concentrated in vacuo and purified by column chromatography to provide 8 g of the title compound. Yield 26%.

1H NMR (DMSO-d6) δ 8.90(s,1H), 8.18(m,2H), 7.70(m,2H), 7.49(dd,1H), 5.25(t,1H), 4.74(m,1H), 4.46(s,3H), 4.14(t,1H), 3.88(dd,1H), 3.68(m,1H), 3.58 (m,1H)

COMPD 18

Figure US20070155798A1-20070705-C00013

Example 28 Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-fluoromethyl oxazolidin-2-on (compound 18)

In 5 ml of methylenchloride was dissolved 100 mg of the compound 10. The solution was added with 43 mg of diethylaminosulfurtrifloride (DAST) and 0.078 ml of triethylamine and then stirred for 24 hours. After being concentrating, the reaction mixture was purified by column chromatography to obtain the title compound 75 mg. Yield 75%.

1H NMR (DMSO-d6) δ 8.91(s,1H), 8.19(m,2H), 7.74(t,1H), 7.66(dd,1H) 7.49 (dd,1H), 5.06(m,1H), 4.89(m,2H), 4.46(s,3H), 4.23(t,1H), 3.95(dd,1H)

COMPD 33

Figure US20070155798A1-20070705-C00013

Example 37 Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methoxymethyl oxazolidin-2-on (compound 33)

In 10 ml of methanol was dissolved 400 mg of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyl oxazolidin-2-on prepared in the secondary step of the Example 24. The solution was added with 90 mg of sodium methoxide at room temperature and then stirred for one day at room temperature. The solution was extracted with ethyl acetate and the organic layer, thus separated, was washed with water and brine. The organic layer was dehydrated, filtered, concentrated in vacuo and purified by column chromatography to provide the title compound 200 mg. Yield 58%.

1H NMR(CDCl3) δ 8.90(s,1H), 8.29(d,1H), 8.04(d,1H), 7.61(dd,1H), 7.58 (t,1H), 7.38(dd,1H), 4.80(m,1H), 4.45(s,3H), 4.08(t,1H), 3.96(dd,1H), 3.67 (m,2H), 3.43(s,3H)

COMPD 59

Figure US20070155798A1-20070705-C00062

Example 58 Preparation of mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 72) and (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl disodiumphosphate (compound 59)

1. The Primary Step

In 10 ml of mixture solvent (tetrahydrofuran:methylenchloride=1:1) was dissolved 1 g of compound 10. The solution was added with 0.6 g of tetrazole and 2.3 g of di-tetrabutyl diisoprophylphosphoamidite and stirred for 15 hours at room temperature. The reaction mixture was refrigerated to −78° C., added with 0.7 g of metachloroperbenzoic acid and stirred for 2 hours. After being cooling to −78° C., the reaction mixture was added with metachloroperbenzoic acid (0.7 g). When the reaction mixture was stirred for 2 hours, the temperature of the reaction mixture was raised to room temperature. The reaction mixture was then added with ethyl acetate. The organic layer, thus separated, was washed with sodium bisulfate, sodium bicarbonate and brine, dehydrated, filtered and concentrated in vacuo, followed by purification with column chromatography thereby to provide (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl phosphoric acid ditetrabuthylester (0.71 g, 71%).

1H NMR (DMSO-d6) δ 8.90(s,1H), 8.18(m,2H), 7.74(t,1H), 7.68 (dd,1H), 7.49(dd,1H), 4.98(m,1H), 4.46(s,3H), 4.23(t,1H), 4.18(m,1H), 4.09(m,1H), 3.89 (dd,1H), 1.39(s,9H), 1.38(s,9H)

The crystal prepared the above method was dissolved in a mixture of methanol and chloroform. And then the solution added with 3.4 ml of sodium methoxide (0.3M methanol solution) at the room temperature and stirred for 10 hours. The reaction mixture was concentrated to prepare the residue. The residue was crystallized and filtered thereby to obtain the title compound (compound 59) 300 mg.

1H NMR (D2O) δ 8.27(s,1H), 7.56(dd,2H), 7.06(m,2H), 6.90(m,1H), 4.79 (m,1H), 4.63(s,3H), 3.90(m,4H)

COMPD 72

Figure US20070155798A1-20070705-C00075

The Secondary Step

In 30 ml of methylenchloride was dissolved the compound (0.7 g) in the Primary Step. The solution was added with 15 ml of trifluoroacetic acid and then stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo to prepare the residue. The residue was crystallized with ethanol and ethyl ether to obtain mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 72) 400 mg.

1H NMR (DMSO-d6) δ 8.92(s,1H), 8.20(m,2H), 7.74(t,1H), 7.66(dd,1H), 7.500(dd,1H), 4.95 (m,1H), 4.46(s,3H), 4.21(t,1H), 4.05(m,2H), 3.91(dd,1H)

US20070155798

………………………………………………………

IMPURITIES

US8426389

Organic Impurities in TR-701 FA Drug Substance
Impurity
‘Name’ Structure and Chemical Name
Rx600013 ‘Des-methyl TR- 701’ Figure US08426389-20130423-C00010
dihydrogen ((5R)-3-{3-fluoro-4-[6-(2H-1,2,3,4-tetrazol-5-
yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-yl)methyl
phosphate
Rx600024 ‘Pyrophosphate’ Figure US08426389-20130423-C00011
trihydrogen ((5R)-3-{3-fluoro-4-[6-(1-methyl-1H-1,2,3,4-
tetraazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-
yl)methyl pyrophosphate
Rx600014 ‘Ring opened’ Figure US08426389-20130423-C00012
dihydrogen 3-{3-fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetraazol-5-
yl)-3-pyridinyl]aniline}-2-hydroxypropyl phosphate
Rx600023 ‘Me-isomer’ Figure US08426389-20130423-C00013
dihydrogen ((5R)-3-{3-fluoro-4-[6-(1-methyl-1H-1,2,3,4-
tetraazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-
yl)methyl phosphate
Rx600025 ‘Overalkylated- phosphorylated impurity’
Figure US08426389-20130423-C00014
Figure US08426389-20130423-C00015
(R)-1-((3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-
yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methoxy)-3-
hydroxypropan-2-yl dihydrogen phosphate;
(R)-3-((3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-
yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methoxy)-2-
hydroxypropyl dihydrogen phosphate
Rx600020 ‘Dimer impurity’ Figure US08426389-20130423-C00016
dihydrogen bis-O-O′-[(5R)-3-{3-fluoro-4-[6-(2-methyl-
2H-1,2,3,4-tetrazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-
oxazolidin-5-yl]methyl pyrophosphate
Rx600026 “Chloro” Figure US08426389-20130423-C00017
(R)-5-(chloromethyl)-3-(3-fluoro-4-(6-(2-methyl-2H-
tetrazol-5-yl)pyridin-3-yl)phenyl)oxazolidin-2-one
Rx600001 TR-700 Figure US08426389-20130423-C00018
5R)-3-{3-Fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)-
pyridin-3-yl]-phenyl}-5-hydroxymethyl-1,3-oxazolidin-2-one
Rx600022 ‘Bis phosphate’ Figure US08426389-20130423-C00019
hydrogen bis-O-O′-[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-1,2,3,4-
tetrazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl
phosphate
Rx600042 Figure US08426389-20130423-C00020
3-{[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methoxy}-2-hydroxypropyl
[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl hydrogen phosphate
Rx600043 Figure US08426389-20130423-C00021
2-{[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methoxy}-1-hydroxyethyl
[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl hydrogen phosphate

……………………………………………..

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………………………………………………………………………………………. art    animation

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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