Source: http://www.freepatentsonline.com/9328087.html
Timestamp: 2019-03-20 07:28:44
Document Index: 223662233

Matched Legal Cases: ['Application No. 200980140144', 'application No. 09749235', 'application No. 14159112', 'art 2', 'Application No. 200980140144', 'Application No. 2011115109', 'Application No. 2009303301', 'Application No. 200980140144', 'Application No. 2737890', 'Application No. 2011115109', 'Application No. 61']

Methods for preparing oxazolidinones and compositions containing them - Merck Sharp & Dohme Corp.
United States Patent 9328087
Costello, Carrie A. (Troy, NY, US)
Ware, Jacqueline A. (Troy, NY, US)
Duguid, Robert J. (Glenmont, NY, US)
14/089050
C07D401/04; C07D403/10; C07F5/02; C07F9/6558
Download PDF 9328087 PDF help
8604209 Methods for preparing oxazolidinones and compositions containing them 2013-12-10 Ware et al.
8580767 Oxazolidinone containing dimer compounds, compositions and methods to make and use 2013-11-12 Hester, II et al.
8426389 Crystalline form of R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate 2013-04-23 Reichenbächer et al.
8420676 Oxazolidinone derivatives 2013-04-16 Rhee et al.
7816379 Oxazolidinone derivatives 2010-10-19 Rhee et al.
7498350 Oxazolidinones as antibacterial agents 2009-03-03 Gravestock et al.
20090018123 Oxazolidinones Bearing Antimicrobial Activity Composition and Methods of Preparation 2009-01-15 Sindkhedkar et al.
7473699 3-cyclyl-5-(nitrogen-containing 5-membered ring)methyl-oxazolidinone derivatives and their use as antibacterial agents 2009-01-06 Gravestock et al.
7462633 Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof 2008-12-09 Fukuda
7396847 Oxazolidinone and/or isoxazoline as antibacterial agents 2008-07-08 Gravestock et al.
20080064689 3-[4-(6-Pyridin-3-Yl)-3-Phenyl] -5-(1H-1,2,3-Triazol-1-Ylmethyl)-1,3-Oxazolidin-2-Ones as Antibacterial Agents 2008-03-13 Carcanague et al.
20080021071 3-{4-(Pyridin-3-Yl) Phenyl}-5-(1H-1,2,3-Triazol-1-Ylmethyl)-1,3-Oxazolidin-2-Ones as Antibacterial Agents 2008-01-24 Gravestock et al.
20080021012 3-[4-{6-Substituted Alkanoyl Pyridin-3-Yl}-3-Phenyl]-5-(1H-1,2,3-Triazol-1-Ylmethyl)-1,3-Oxazolidin-2-Ones As Antibacterial Agents 2008-01-24 Gravestock et al.
20070208062 3-(4-(2-DIHYDROISOXAZOL-3-YLPYRIDIN-5-YL)PHENYL)-5-TRIAZOL-1-YLMETHYLOXAZOLIDIN-2-ONE DERIVATIVES AS MAO INHIBITORS FOR THE TREATMENT OF BACTERIAL INFECTIONS 2007-09-06 Carcanague et al.
20070203187 Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof 2007-08-30 Fukuda
20070191336 Anti-inflammatory medicaments 2007-08-16 Flynn et al.
20070185132 Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereo 2007-08-09 Fukuda
7202257 Anti-inflammatory medicaments 2007-04-10 Flynn et al.
7144911 Anti-inflammatory medicaments 2006-12-05 Flynn et al.
20060270637 Hydroxymethyl substituted dihydroisoxazole derivatives useful as antibiotic agents 2006-11-30 Gravestock et al.
7141583 Oxazolidinone derivatives with antibiotic activity 2006-11-28 Gravestock et al.
7129259 Halogenated biaryl heterocyclic compounds and methods of making and using the same 2006-10-31 Chen et al.
20060116400 Oxazolidinone and/or isoxazoline derivatives as antibacterial agents 2006-06-01 Carcanague et al.
20060116386 Oxazolidinones as antibacterial agents 2006-06-01 Gravestock
20050288286 Anti-inflammatory medicaments 2005-12-29 Flynn et al.
20050107435 Oxazolidinone and/or isoxazoline as antibacterial agents 2005-05-19 Gravestock et al.
20050038092 Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof 2005-02-17 Fukuda
20040180906 Anti-inflammatory medicaments 2004-09-16 Flynn et al.
6689779 Oxazolidinone derivatives and a process for the preparation thereof 2004-02-10 Lee et al.
6627646 Norastemizole polymorphs 2003-09-30 Bakale et al.
20030166620 Novel oxazolidinone derivatives and a process for the preparation thereof 2003-09-04 Lee et al.
20020115669 Oxazolidinone chemotherapeutic agents 2002-08-22 Wiedeman et al.
6365751 Antibiotic oxazolidinone derivatives 2002-04-02 Gravestock
5688792 Substituted oxazine and thiazine oxazolidinone antimicrobials 1997-11-18 Barbachyn et al.
5652238 Esters of substituted-hydroxyacetyl piperazine phenyl oxazolidinones 1997-07-29 Brickner et al.
5565571 Substituted aryl- and heteroaryl-phenyloxazolidinones 1996-10-15 Barbachyn
5523403 Tropone-substituted phenyloxazolidinone antibacterial agents 1996-06-04 Barbachyn
4948801 Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents 1990-08-14 Carlson et al.
4476136 Aminomethyl-5 oxazolidinic derivatives and therapeutic use thereof 1984-10-09 Dostert et al.
4461773 P-Oxooxazolidinylbenzene compounds as antibacterial agents 1984-07-24 Gregory
4340606 3-(p-Alkylsulfonylphenyl)oxazolidinone derivatives as antibacterial agents 1982-07-20 Fugitt et al.
4250318 Novel 5-hydroxymethyl oxazolidinones, the method of preparing them and their application in therapeutics 1981-02-10 Dostert et al.
4128654 5-Halomethyl-3-phenyl-2-oxazolidinones 1978-12-05 Fugitt et al.
EP0312000 1989-04-19 Aminomethyl oxooxazolidinyl aroylbenzene derivatives useful as antibacterial agents
EP0352781 1990-01-31 AMINOMETHYLOXOOXAZOLIDINYL ARYLBENZENE DERIVATIVES USEFUL AS ANTIBACTERIAL AGENTS
JP5799576 June, 1982 パワーステアリング装置
JP02124877 May, 1990
KR10-2011-0071107 June, 2011
RU2278117C2 2006-06-20 ANTIBACTERIAL HETEROBICYCLIC SUBSTITUTED PHENYLOXAZOLIDINONES
WO1993023384A1 1993-11-25 OXAZOLIDINONES CONTAINING A SUBSTITUTED DIAZINE MOIETY AND THEIR USE AS ANTIMICROBIALS
WO1995007271A1 1995-03-16 SUBSTITUTED OXAZINE AND THIAZINE OXAZOLIDINONE ANTIMICROBIALS
WO1995014684A1 1995-06-01 ESTERS OF SUBSTITUTED-HYDROXYACETYL PIPERAZINE PHENYL OXAZOLIDINONES
WO2001042242A1 2001-06-14 ANTIBACTERIAL HETEROBICYCLIC SUBSTITUTED PHENYL OXAZOLIDINONES
WO2001094342A1 2001-12-13 NOVEL OXAZOLIDINONE DERIVATIVES AND A PROCESS FOR THE PREPARATION THEREOF
WO2002081470A1 2002-10-17 OXAZOLIDINONES CONTAINING A SULFONIMID GROUP AS ANTIBIOTICS
WO2003022824A1 2003-03-20 OXAZOLIDINONE AND/OR ISOXAZOLINE AS ANTIBACTERIAL AGENTS
WO2003035648A1 2003-05-01 ARYL SUBSTITUTED OXAZOLIDINONES WITH ANTIBACTERIAL ACTIVITY
WO2003047358A1 2003-06-12 CHEESE FLAVOUR INGREDIENT AND METHOD OF ITS PRODUCTION
WO2003072575A1 2003-09-04 3-CYCLYL-5-(NITROGEN-CONTAINING 5-MEMBERED RING) METHYL-OXAZOLIDINONE DERIVATIVES AND THEIR USE AS ANTIBACTERIAL AGENTS
WO2003072576A2 2003-09-04 OXAZOLIDINONE DERIVATIVES, PROCESSES FOR THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
WO2004048350A2 2004-06-10 OXAZOLIDINONES AS ANTIBACTERIAL AGENTS
WO2004056818A1 2004-07-08 OXAZOLIDINONE DERIVATIVES AS ANTIBACTERIAL
WO2004083205A1 2004-09-30 ANTIBACTERIAL 1, 3- OXAZOLIDIN -2- ONE DERIVATIVES
WO2005005398A2 2005-01-20 CYCLOPROPYL GROUP SUBSTITUTED OXAZOLIDINONE ANTIBIOTICS AND DERIVATIVES THEREOF
WO2005051933A1 2005-06-09 AN IMPROVED PROCESS FOR THE SYNTHESIS OF 4-(4-BENZYLOXY-CARBONYLAMINO-2-FLUOROPHENYL)-PIPERAZINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER, A KEY INTERMEDIATE FOR OXAZOLIDINONE ANTIMICROBIALS AND COMPOUNDS PREPARED THEREBY
WO2005058886A1 2005-06-30 NOVEL OXAZOLIDINONE DERIVATIVES
WO2005116017A1 2005-12-08 PROCESS FOR THE PREPARATION OF ARYL SUBSTITUTED OXAZOLIDINONES AS INTERMEDIATES FOR ANTIBACTERIAL AGENTS
WO2006038100A1 2006-04-13 OXAZOLIDINONE DERIVATIVES AS ANTIMICROBIALS
WO2007023507A2 2007-03-01 OXAZOLIDINONES BEARING ANTIMICROBIAL ACTIVITY COMPOSITION AND METHODS OF PREPARATION
WO2007138381A2 2007-12-06 PHOSPHONATED OXAZOLIDINONES AND USES THEREOF FOR THE PREVENTION AND TREATMENT OF BONE AND JOINT INFECTIONS
WO2009020616A1 2009-02-12 ANTIMICROBIAL ORTHO-FLUOROPHENYL OXAZOLIDINONES FOR TREATMENT OF BACTERIAL INFECTIONS
WO2010091131A1 2010-08-12 CRYSTALLINE FORM OF R)-3-(4-(2-(2-METHYLTETRAZOL-5-YL)PYRIDIN-5-YL)-3-FLUOROPHENYL)-5-HYDROXYMETHYL OXAZOLIDIN-2-ONE DIHYDROGEN PHOSPHATE
WO2010138649A1 2010-12-02 OXAZOLIDINONE CONTAINING DIMER COMPOUNDS, COMPOSITIONS AND METHODS TO MAKE AND USE
JPH02124877A 1990-05-14
KR20110071107A 2011-06-28
JPS5799576A 1982-06-21
Third Office Action in Chinese Application No. 200980140144.4 dated May 23, 2014.
Office Action in Mexico Application No. MX/a/2011/003820 dated Jun. 4, 2013.
Examination Report dated Jun. 6, 2014 in European patent application No. 09749235.9.
Extended European Search Report dated Jun. 24, 2014 in patent application No. 14159112.3.
Bae et al., “High-Performance liquid chromatographic analysis of DA-7867, a new oxazolidinone, in human plasma and urine and in rat tissue homogenates”, In Journal of Chromatography B, Sep. 5, 2003, 794:397-403.
Bae, Soo K., et al., “Pharmacokinetics of DA-7218, a New Oxazolidinone, and Its Active Metabolite, DA-7157, After Intravenous and Oral Administration of DA-7218 and DA-7157 to Rats”, Journal of Pharmacy and Pharmacology, 2007, 59:955-963.
Brittain ed., Polymorphism in Pharmaceutical Science, NY: Marcel Dekker, Inc. 1999, 1-2, 183-226; 235-238.
Espinoza-Gonzalez, et al.: “Efficacy of DA-7218, a new oxazolidinone prodrug, in the treatment of experimental actinomycetoma produced by Nocardia brasiliensis”, Molecules (Basel, Switzerland) 2008 LNKD-PUBMED: 18259127, vol. 13, No. 1, 2008, pp. 31-40.
Ettmayer, et al.: “Lessons Learned from Marketing and Investigational Prodrugs”, J. Med. Chem., 2004, 47(10): 2393-2404.
Gregory et al., “Antibacterials. Synthesis and structure-activity studies of 3-aryl-2-oxooxazolidines. 1. The “B” group.” J. Med. Chem., vol. 32, pp. 1673-1681 (1989).
Gregory et al., “Antibacterials. Synthesis and structure-activity studies of 3-aryl-2-oxooxazolidines. 2. The “A” group.” J. Med. Chem., vol. 33, pp. 2569 (1990).
Hiroshi, Nagase ed. Medicinal Chemistry, Technomics, Sep. 25, 1999, The Second vol., pp. 368-382.
Miyaura, et al.: “Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds”, Chemical Reviews, ACS, Washington, DC, US, vol. 95, No. 7, Jan. 1, 1995, pp. 2457-2483.
Muzaffar et al., Polymorphism and Drug Availability, etc., J. of Pharm (Lahore), 1979, 1(1), 59-66.
Otsuka et al., Effect of Polymorphic forms of bulk powders on pharmaceutical properties of carbamazepine granules, Chem. Pharm. Bull., 47(6) 852-856 (1999).
Prado-Prado, Francisco, J., et al. 2007 “Unified QSAR Approach to Antimicrobials. Part 2: Predicting Activity Against More Than 90 Different Species in Order to Halt Antibacterial Resistance”, Bioorganic & Medicinal Chemistry, 15:897-902.
Rondestvedt et al. 1955. “Unsaturated sulfonic acids. V”, Journal of the American Chemical Society, 77:6532-6540.
Rouhi, “The Right Stuff, From research and development to the clinic, getting drug crystals right is full of pitfalls” Chemical & Engineering News, Feb. 2003, 32-35.
Rowland et al., Clinical Pharmacokinetics, etc., p. 123 (1995).
Stella, “Prodrugs as therapeutics”, Expert Opin. Ther. Patents, 14(3): 277-280 (2004).
Testa, “Prodrug research: futile or fertile?”, Biochemical Pharmacology, 68 (2004): 2393-2404.
Vera-Cabrera, Lucio, et al. 2006 “In Vitro Activities of DA-7157 and DA-7218 Against Mycobacterium Tuberculosis and Nocardia Brasiliensis”, Antimicrobial Agents and Chemotherapy 50:3170-3172.
Vera-Cabrera, Lucio, et al. 2006 “In Vitro Activities of the Novel Oxazolidinones DA-7867 and DA-7157 Against Rapidly and Slowly Growing Mycobacteria”, Antimicrobial Agents and Chemotherapy 50:4027-4029.
Wang et al., Chiral Synthesis of DUP 721, A New Antibacterial Agent, Tetrahedron, 45(5):1323-1326 (1989).
Wolff, et al.: “Metabolic Considerations in Prodrug Design”, Burger's Medicinal Chemistry and Drug Discovery, 5th ed. vol. 1: Principles and Practice, 1997, pp. 949-982.
First Office Action in Chinese Application No. 200980140144.4 dated Feb. 1, 2013.
Office Action dated Jul. 15, 2013 in Russian Application No. 2011115109, filed Oct. 9, 2009.
EPO Communication re Correction of deficiencies noted in the written opinion and amended. Re EPO App. No. 09749235.9, dated Jun. 24, 2011.
Examination Report in Australia Application No. 2009303301 dated Nov. 20, 2013.
Second Office Action in Chinese Application No. 200980140144.4 dated Oct. 17, 2013.
Office Action in Japanese Application No. 2737890 dated Feb. 25, 2014.
Office Action in Russian Application No. 2011115109 dated Jul. 15, 2013.
Office Action in Mexico Application No. MX/a/2011/003820 dated Oct. 11, 2013.
Robbins, Jennifer L.
This application is a divisional of U.S. application Ser. No. 12/577,089, filed Oct. 9, 2009, now issued as U.S. Pat. No. 8,604,209, which claims priority to U.S. Provisional Application No. 61/104,469, filed Oct. 10, 2008.
1. A compound of the formula: wherein: R1a and R1b are independently selected from H and F, provided that at least one of R1a and R1b is F, R2 is selected from the group consisting of optionally substituted benzyl and optionally substituted C1-C6 alkyl, and Het is tetrazolyl optionally substituted with methyl.
2. The compound of claim 1 wherein R1a is F and R1b is H.
3. The compound of claim 1 wherein Het is substituted with methyl.
4. The compound of claim 3 wherein Het is 2-methyl-tetrazol-5-yl.
5. The compound of claim 1 wherein R2 is benzyl.
6. The compound of claim 1 wherein R1a is F, R1b is H, R2 is benzyl, and Het is 2-methyl-tetrazol-5-yl.
7. The compound of claim 1 wherein the optionally substituted benzyl and the optionally substituted C1-C6 alkyl are independently unsubstituted or substituted with halogen or C1-C4 alkyloxy.
In some embodiments, methods include synthesizing substituted N-(pyridinyl)aryloxazolidinones by the following route.
Also in Scheme 1, R2 is optionally substituted benzyl or optionally substituted C1-C6 alkyl. In some embodiments, benzyl and C1-C6 alkyl are unsubstituted or independently optionally substituted with halogen or alkoxy such as C1-C4 alkyloxy. In some embodiments, R2 is benzyl and R is H.
The resulting dihydrogen phosphate compound 1 (R═PO(OH)2) can further be converted to a pharmaceutically acceptable salt such as the disodium salt of compound 1 (R═PO(O)2 2Na) by reaction with NaOMe or other suitable sodium-containing base.
(min) (mL/min) % A %B
To a 22-L, four-neck, round-bottom flask equipped with an overhead stirrer, nitrogen inlet/outlet, and thermocouple placed in an ice/brine bath was charged the tetrazole ammonium salt (835.0 g, 3.44 mol, 1 weight), tetrahydrofuran (7.5 L, 9 volumes), N,N-dimethylformamide (2.5 L, 3 volumes) and sodium hydroxide powder (343.5 g, 8.59 mol, 2.5 equivalents) while stirring. The internal reactor temperature was allowed to reach 12° C., whereupon iodomethane (1.22 kg, 8.59 mol, 2.5 equivalents) was added dropwise over 50 minutes, maintaining the reaction temperature below 20° C. After 20 minutes addition time, due to a rapid increase in temperature, the addition was paused and the reaction continued to self-heat from 15-20° C. over ten minutes. The remainder of the addition was completed at constant temperature (18° C.). Upon completion of the addition, the ice/brine bath was removed and the reactor was equipped with a water condenser and a heating mantle. The internal reactor temperature was adjusted to 40° C., however the reaction continued to self-heat to 48° C. The reaction was judged to be complete after 6 hours by HPLC analysis by complete consumption of the starting material. The reaction mixture was cooled to room temperature overnight for convenience. The THF was removed by distillation, and water (8.35 L, 10 volumes) was charged to the reactor. The slurry was stirred for 30 minutes and filtered by vacuum filtration and the reactor and filter cake were washed with water (4.2 L, 5 volumes) to afford crude 4/N1 isomer mixture as a peach colored solid (500.7 g, 61% yield, 3.85:1 4:N1).
The solids (500.7 g) were dissolved in CH2Cl2 (2.5 L, 5 volumes) to which 6 N aqueous HCl (7.5 L, 15 volumes) was added. The biphasic mixture was stirred and the layers were separated. At this point, the desired product is in the aqueous HCl layer. The CH2Cl2 layer was washed with 6 N aqueous HCl (4.5 L, 3×3 volumes) until <5% AUC 4 was present by HPLC analysis. The combined 6 N HCl extracts were transferred to a reactor and the pH was adjusted to 10.6 with 50% aqueous NaOH (˜3.2 L) while maintaining the internal temperature below 40° C. The solids were isolated by vacuum filtration and the reactor and filter cake were rinsed with water (1 L, 2 volumes) to afford crude 4 as a yellow/orange solid (322.4 g, 64% recovery, 39% yield, 93.5% AUC 4, 4.1% AUC N-1 isomer) as confirmed by HPLC and 1H NMR analyses.
The intermediate 7 was recrystallized from ethyl acetate to further reduce the level of palladium. Intermediate 7 (130 g) and ethyl acetate (3.9 L, 30 volumes) were charged to a 5-L, three-neck, round-bottom flask. The slurry was warmed to 75° C. at which point the solids dissolved. The hot solution was filtered to remove any palladium black (0.2- to 0.45-μ filters the best) and returned to a clean 5-L flask. The ethyl acetate solution was distilled at atmospheric pressure to remove 2.2 L of the ethyl acetate (b.p. 77-78° C.). The solution was cooled to 22° C. and the resulting slurry was filtered. The flask and filter cake were washed with ethyl acetate (3×130 mL) of ethyl acetate. The purifed intermediate 7 was dried in a vacuum oven at 50° C. to give 110.5 g of intermediate 7 (85% recovery). The HPLC assay of the purified intermediate 7 was 98.5% (AUC). The palladium level in the purified product was 6 ppm. The mother liquor was evaporated to recover 18 g of crude product (14% recovery, 2254 ppm Pd).
Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one, 1 (R═H), also referred to as “TR-700”
Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate 1 (R═PO(OH)2) also referred to as “TR-701FA”
Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one phosphate, disodium salt 1 (R═PO3 2Na) also referred to as “TR-701”
Crude 1 (R═PO(OH)2) (60.0 g, 0.133 mol) was charged to a 2-L reactor. Methanol (720 mL, 12 vol) was added and the slurry was stirred at room temperature. The 25% sodium methoxide in methanol (86.1 g, 0.398 mol, 3 eq) was added dropwise over 13 minutes. The reaction temperature increased from 20.4° C. to 26.8° C. during the addition of sodium methoxide. The slurry was stirred one hour at room temperature and then was filtered. The reactor and filter cake were rinsed with methanol (300 mL, 5 vol) and acetone (300 mL, 5 vol). The product was dried in a vacuum oven at 50-60° C. to give 65.3 g of crude TR-701 (99% yield). The crude product was dissolved in water (653 mL, 10 vol) to give a straw colored solution. The solution was stirred with Darco G-60 carbon (3.3 g, 0.05 wt) at room temperature for 30 minutes. The pH of the slurry was 7.2, so 5-10 mL of 2 N NaOH was added to the solution to raise the pH to 11. The slurry was filtered through Celite 545 (65 g, wetted with water). Some black color passed through. The filtrate was refiltered through a 0.45-μ filter, but some carbon passed through again. The filtrate was added dropwise to acetone (2.6 L, 40 vol), and the resulting slurry was stirred overnight for convenience. The slurry was then filtered, rinsed with acetone (650 mL), and dried in a vacuum oven at 50° C. to give 46.9 g of 1 (R═PO3Na2) (71% yield) that was gray in color. The HPLC purity of this material was 99.0% (AUC), but since it was gray, it was re-dissolved in water (470 mL). The aqueous solution was pH 9.6, so sodium hydroxide solution was added to raise the pH to 10. The solution was then filtered through a 0.45-μ filter to remove color. The filtrate was added dropwise to acetone (1.88 L). The white slurry was filtered and was washed with acetone (470 mL). After drying the product, the TR-701 weighed 43.2 g (66% overall yield). The HPLC purity (Method B) was 99.6% (AUC). The other analyses conducted on this lot of 1 (R═PO3Na2) are shown in Table 1.
Preparation of Purified R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate, 1 (R═PO(OH)22)
The disodium salt 1 (R═PO3Na2) was re-dissolved in water (1 L, 10 vol) and then was filtered through Whatman #1 filter paper when black flecks were observed in the solution. The filtrate was diluted with THF (1 L, 10 vol). The pH of the aqueous THF solution was 9.57. Freshly prepared 2 M hydrochloric acid solution (222 mL, 0.444 mol, 2 eq.) was added dropwise to pH 1.34. The product did not precipitate until approximately 170 mL of the 2 M HCl solution was added. The yellow slurry was filtered and rinsed with water (500 mL, 5 vol) and methanol (500 mL, 5 vol). The filter cake cracked as it dried, so it was smoothed out before adding the rinse solvents. The product was dried in a vacuum oven at 60° C. for 19.5 hours to give 79.3 g of 1 (R═P(OH)2) (80% yield). HPLC analysis (Method B): 99.5% (AUC) tR=5.6 min. 1H and 31P NMR analyses were consistent with the assigned structure. The level of residual THF by NMR analysis was 1600 ppm, and the palladium level was 11 ppm. Since extended drying did not remove the THF, future batches were made with use of ethanol as the antisolvent.
Isolation of bis{[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl}dihydrogen diphosphate (the dimer of 1)
Crude 1 from example 8 was dissolved in phosphate buffer and chromatographed on a Gilson preparative HPLC system The mobile phase was a linear gradient of water and acetonitrile t+0 was 100 5 H2O and T=20 was 100% acetonitrile. Fractions were analyzed using analytical HPLC. Those fractions found to be enriched in the Dimer were pooled providing a solution containing over 60% Dimer. Further purification of the Dimer enriched fractions was accomplished on a semi preparative HPLC. This yielded pure dimer: accurate mass (m/z 883; calcd. For C34H31F2N12O11P2=883.1679. found 883.1658, Δ=2.4 ppm m/z 905 calcd. for C34H30F2N1O11P2Na=905.1498. found 905.1484, Δ=1.6 ppm) confirming the formula for this compound.
Analysis of TR-701 (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-
yl)-3-fruorophenyl)-5-hydroxymethyl oxazolidin-2-one, 1 (R = PO3Na2)
<- Previous Patent (Substituted bipyridi...) | Next Patent (Luminescent probes f...) ->