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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

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WO2005051933A1
WO2005051933A1 PCT/IB2004/003829 IB2004003829W WO2005051933A1 WO 2005051933 A1 WO2005051933 A1 WO 2005051933A1 IB 2004003829 W IB2004003829 W IB 2004003829W WO 2005051933 A1 WO2005051933 A1 WO 2005051933A1
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formula
compound
ch
form
alkyl
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PCT/IB2004/003829
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French (fr)
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Yatendra Kumar
Vijay Kumar Kaul
Nitu Singh
Gyan Chand Yadav
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Ranbaxy Laboratories Limited
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08Heterocyclic 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
    • C07D263/16Heterocyclic 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
    • C07D263/18Oxygen atoms
    • C07D263/20Oxygen atoms attached in position 2
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic 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
    • C07D295/16Heterocyclic 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 acylated on ring nitrogen atoms
    • C07D295/20Heterocyclic 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 acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205Radicals derived from carbonic acid

Abstract

Provided herein are process for the synthesis of the 4-(4-benzyloxy-carbonylamino-2-fluorophenyl)-piperazine-1-carboxylic acid tert-butyl ester, which is a key intermediate in the synthesis of oxazolidinone compounds having antibacterial activity. Also provided herein are processes for preparing oxazolidinone compounds. In addition, compounds prepared by the processes provided herein are also encompassed. Formula (I) and Formula (II).

Description

AN IMPROVED PROCESS FOR THE SYNTHESIS OF 4- (4-BENZYL0XY-CARB0NYLAMIN0-2-FLU0R0PH ENYD -PIPΞRAZINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER, A KEY INTERMEDIATE FOR OXAZOLIDINONE ANTIMICROBIALS AND COMPOUNDS PREPARED THEREBY

Field of the Invention The present invention relates to processes for the synthesis of the 4-(4-benzyloxy- carbonylamino-2-fluorophenyl)-piperazine-l-carboxylic acid tert-butyl ester of Formula I,

Formula I which is a key intermediate in the synthesis of oxazolidinone compounds having antibacterial 10 activity.

Background of the Invention

Oxazolidinones are a new class of synthetic antimicrobial agents, which kill gram- positive pathogens by inhibiting a very early stage of protein synthesis. Oxazolidinones inhibit the formation of ribosomal initiation complex involving 30S and 50S ribosomes 15 leading to prevention of initiation complex formation. Due to their novel mechanism of action, these compounds are active against pathogens resistant to other clinically useful antibiotics. For example, phenyloxazolodinones and phenyl piperazinyl oxazolidinones have been disclosed as being useful antimicrobial agents effective against human and veterinary pathogens including gram positive and acid-fast organisms. 0 A previosly known general method for the synthesis of the intermediate 4-(4- benzyloxy-carbonylamino-2-fluorophenyl)-piperazine-l-carboxylic acid tert-butyl ester of Formula I has been reported, which comprises reacting piperazine with l,2-difluoro-4- nitrobenzene in acetonitrile to form l-(2-fluoro-4-nitrophenyl)-piρerazine, which is reacted further with di-tert-butoxycarbonyl anhydride in tetrahydrofuran to form 4-(2-fluoro-4- 5 nitrophenyl) piperazin-l-carboxylic acid tert-butyl ester. The resulting nitro compound is reduced with palladium on carbon in methanol and reacted with benzylchloroformate in tetrahydrofuran to form 4-(4-benzyloxycarbonyl amino-2-fluorophenyl)-piperazin-l- carboxylic acid tert-butyl ester of Formula I.

Available methods for the synthesis of compounds of Formula I suffer from a number of limitations and accordingly, are not suitable for commercial production. For example, known methods require the use of acetonitrile, which is highly toxic, inflammable and difficult to handle at commercial scales; and tetrahydrofuran, which is unsafe and burdened with the risk of explosion and fire due to peroxide formation, as well as being an expensive solvent and adds significant factor in the overall cost of preparation of final product. Further, the nitro group reduction is carried out in methanol and tetrahydrofuran and in the presence of ammonium formate-Pd/C catalyst, which is a highly exothermic reaction. This sudden rise in temperature increases the formation of by-products and thereby decreases the overall product yield. In addition, purification of the compound involves column chromatography, which is cumbersome, tedious and not practicable on an industrial scale; the synthesis of the pure compound involves more steps; and the overall yield of the pure compound is poor. Accordingly, there remains a need for an improved, commercially viable process to synthesize oxazolidinones. Summary of the Invention

The process provided herein encompass novel methods for the synthesis of the 4-(4- benzyloxy-carbonylamino-2-fluorophenyl)-piperazine-l-carboxylic acid tert-butyl ester of Formula I, which provides improvements over prior methods of synthesis. In one aspect, there is provided a process for the synthesis of highly pure 4-(4- benzyloxy-carbonylamino-2-fluorophenyl)-piperazine-l-carboxylic acid tert-butyl ester of Formula I,

Formula I comprising the steps of: condensing piperazine with l,2-difluoro-4-nitrobenzene to form l-(2-fluoro-4-nitro-phenyl)- piperazine of Formula II,

contacting the compound of Formula II with di-tert-butoxycarbonyl anhydride to form 4- (2- fluoro-4-nitrophenyl)-piperazine 1-carboxylic acid tert-butyl ester of Formula III,

reducing the compound of Formula III to form 4-(4-amino-2-fluorophenyl)-piperazin-l- carboxylic acid tert-butyl ester of Formula IV,

Formula IV and reacting the compound of Formula IN with benzylchloroformate to form 4-(4-benzyloxy- carbonylamino-2-fluorophenyl)-piperazine- 1-carboxylic acid tert-butyl ester of Formula I. In one aspect, the step of condensing piperazine with l,2-difluoro-4-nitrobenzene is carried out in an aromatic hydrocarbon, such as toluene, xylene and the like, or mixtures thereof, and at a temperature of, for example, about 40 °C to about 90 °C, or from about 80 °C to about 90 °C.

In another aspect, the step of contacting the compound of Formula II with di-tert- butoxycarbonyl anhydride is carried out in an aromatic hydrocarbon, such as toluene, xylene and the like, or mixtures thereof.

In yet another aspect, the step of reducing the compound of Formula III is carried out in the presence of a reducing agent, such as palladium on carbon, and in an aromatic hydrocarbon, such as toluene, xylene and the like, or mixtures thereof. In another aspect, the reaction of the compound of Formula IN with benzylchloroformate is carried out in the presence of an inorganic base, such as sodium bicarbonate, potassium carbonate or potassium bicarbonate, in an organic solvent, such as toluene, and at a temperature of about 20 °C to about 40 °C. Processes provided herein are advantageous over prior methods because, among other reasons, involve fewer steps, as some steps are carried out in situ; the purification of compound need not involve column chromatography, which thus makes the processes convenient to operate at commercial scale; the reduction may be carried out in toluene in the presence of Pd/C, avoiding the exothermicity of the reaction and by-product formation; and the processes need not involve the use of tetrahydrofuran, a material associated with a high risk of fire and explosion. Oxazolidinone compounds can be prepared from compounds of Formula I using, for example, using methods disclosed in U.S. Patent No. 6,734,307 and PCT Publication Nos. WO 02/06278, WO 03/007870, WO 03/097059, WO04/089944 and WO04/14392, which are incorporated herein by reference. Scheme I below shows a synthetic route starting from a compound of Formula I to oxazolidinone compounds.

Formula lb

Formula lc

Formula Id Scheme I A compound of Formula I

Formula I can be reacted with a base, e.g., butyl lithium, and glycidyl butyrate to form a compound of

Formula la.

Formula la

The compound of Formula la can be reacted with methane sulphonyl chloride, followed by ammonium hydroxide, and finally acetyl halide of Formula CH3CO-hal (wherein hal is Br, CI or I) to form a compound of Formula lb.

Formula lb

The compound of Formula lb can be deprotected to form a compound of Formula Ic.

The compound of Formula Ic can be reacted with R-T-(W)0-ι-R12 to form a compound of Formula Id

Formula Id wherein T can be a five- to seven-membered heterocyclic ring, aryl or substituted aryl, bound to the piperazinyl ring via linker W, wherein the heterocyclic ring can have at least one heteroatom selected from oxygen, nitrogen and sulfur. Preferred forms of T can be aryl and five-membered heteroaryl, which can be further substituted by a group represented by R, wherein R can be H, CHO, (Cι-C6)-alkyl, F, CI, Br, I, -CN, COR5, COOR5, N(R6R7), CON(RδR7), CH2NO2, NO2, CH2R8, CHR9, -CH=N-ORιo, -C=CH-R5, NHCOC(R8R9), NHCOOR10, CH(OAc)2, OR5, SR5, -C(R9)NO2, (C Ci^-alkyl substituted with one or more of F, CI, Br, I, OR4 or SR4, wherein R5 can be H, optionally substituted (C1-C1 )-alkyl, (C3-Cι2)-cycloalkyl, aryl, heteroaryl, ( -C^-alkoxy, or (C1-C6)-alkyl substituted with one or more of F, CI, Br, I or OH; R6 and R7 can be independently selected from H, optionally substituted (CVC1 )-alkyl, (C3-C12)-cycloalkyl, or ( -C^-alkoxy; R8 and R9 can be independently selected from H, (Cι-C6)-alkyl, F, CI, Br, (C1-C12)- alkyl substituted with one or more of F, CI, Br, I, OR5, SR5, N(R6R7) wherein R5, Re and R7 can be the same as defined earlier, R10 is H, optionally substituted ( -Cn)- alkyl, (C3-C12)-cycloalkyl, (C!-C6)-alkoxy, (Cι-C6)-alkyl, aryl, or heteroaryl; W can be selected from CH2, CO, -CH2 NH-, -NHCH2-, -CH2NHCH2-, -CH2-N(Rι ι)CH2-, -CH2(Rn)N-, CH(Rπ), S, CH2(CO), NH, wherein Rπ can be optionally substituted (C1-C12)-alkyl, (C3-C12)-cycloalkyl, (Cι-C6)- alkoxy, ( -C^-alkyl, aryl or heteroaryl; and R12 can be a suitable leaving group well known to one of ordinary skill in the art, for example, fluoro, chloro, bromo, SCH3, -SO2CH3, -SO2CF3 or OC6H5 and the like. Another aspect encompasses compounds prepared by processes provided herein. Detailed Description of the Invention

In the following section preferred embodiments are described in a way to illustrate the disclosure. However, this does not limit the scope of the present invention.

EXAMPLE Preparation of 4-(4-benzyloxy-carbonylamino-2-fluorophenyl -piperazine- 1 - carboxylic acid tert-butyl ester of Formula I

Piperazine (0.77 mol, 66.2 g) was mixed with toluene (500 mL) and stirred at room temperature and subsequently stirred at 50 °C until a homogenous solution was obtained. 1,2- difluoro-4-nitrobenzene (0.314 mol, 50 g) was added to the piperazine/toluene solution and the reaction mixture was stirred at 80-90 °C for 3-6 hours. The reaction mixture then was cooled to 40-45 °C and diluted with deionized water. The organic layer was separated and about 250-350 mL of toluene was evaporated off under reduced pressure at 40 °C. Di-tert- butoxycarbonyl anhydride (0.334mol, 75 g) was then added dropwise to the reaction mixture at room temperature. The resulting reaction mixture was stirred at room temperature for 1-2 hours and then further diluted with hexane (200 mL) and stirred for 15-20 minutes at room temperature. The solid product formed in the reaction mixture was filtered, washed with hexane (150 mL), and dried under reduced pressure at 60-70°C to yield 4-(2-fluoro-4- nitrophenyl)-piperazine- 1-carboxylic acid tert butyl ester of Formula III. Yield = 1.8-1.9 (w\w); Purity = 96-98% by HPLC.

The compound of Formula III (0.246 mol, 80 g) was added to toluene (800 mL) followed by the addition of palladium on carbon (4 g) at room temperature with continuous stirring. Hydrogen gas was bubbled into the resulting reaction mixture at a pressure of 72 psi. The reaction mixture was stirred for 12-16 hours and then diluted with toluene (150 mL). The reaction mixture was filtered through a celite pad and washed with toluene (200 mL). Sodium bicarbonate solution was added to the reaction mixture at room temperature with continuous stirring. Benzyl chloroformate (0.310 mol, 103 g) was added dropwise to the reaction mixture with continuous stirring for 2-3 hours. Ethyl acetate (1600 mL) was added to the reaction mixture and stirred for about 30 minutes followed by addition of deionized water (400 mL). The organic layer was separated and the solvent was removed under reduced pressure. The semi-solid product was washed with hexane (350 mL) to obtain 4-(4-benzyloxy- carbonylamino-2-fluorophenyl)-piperazine- 1-carboxylic acid tert-butyl ester of Formula I as a solid. Yield = 1.16-1.23 (w/w); Purity = 97-99% by HPLC.

Claims

We Claim: A process for the preparation of 4-(4-benzyloxy-carbonylamino-2- fluorophenyl)-piperazin- 1 -carboxylic acid tert butyl ester of Formula I,
Formula I comprising the steps of: condensing piperazine with l,2-difluoro-4-nitrobenzene to form a 4-(2-fluoro-4- nitropheyι)-piperazine of Formula II,
Formula II contacting the compound of Formula II with di-tert-butyl carboxylic anhydride to form 4-(2- fluoro-4-nitrophenyl)-piperazine- 1 -carboxylic acid butyl ester of Formula III,
reducing the compound of Formula III to form 4-(4-amino-2-fluorophenyl)-piperazin- 1- carboxylic acid tert-butyl ester of Formula IV,
and reacting the compound of Formula TV with benzylchloroformate to form a compound 4-(4-benzyloxy-carbonylamino-2-fluorophenyl)-piperazin- 1 -carboxylic acid tert butyl ester of Formula I. 2. The process of claim 1, wherein the reaction of piperazine with l,
2-difluoro-4- nitrobenzene to form Formula II is earned out in an aromatic hydrocarbon.
3. The process of claim 2, wherein the aromatic hydrocarbon is selected from toluene, xylene, and mixtures thereof.
4. The process of claim 2, wherein the aromatic hydrocarbon is toluene.
5. The process of claim 1, wherein the reaction of piperazine with l,2-difluoro-4- nitrobenzene is carried out at a temperature of about 40 °C to about 90 °C.
6. The process of claim 5, wherein the reaction of piperazine with l,2-difluoro-4- nitrobenzene is carried out at a temperature of about 80 °C to about 90 °C.
7. The process of claim 1 , wherein the reaction of a compound of Formula II with di-tert-butoxycarbonyl anhydride to form a compound of Formula III is carried out in an aromatic hydrocarbon.
8. The process of claim 7, wherein the aromatic hydrocarbon is selected from toluene, xylene, and mixtures thereof.
9. The process of claim 8, wherein the aromatic hydrocarbon is toluene.
10. The process of claim 1 , wherein the reduction of a compound of Formula III to form a compound of Formula TV is carried out in an aromatic hydrocarbon.
11. The process of claim 10, wherein the aromatic hydrocarbon is selected from toluene, xylene, and mixtures thereof.
12. The process of claim 11, wherein the aromatic hydrocarbon is toluene.
13. The process of claim 1 wherein the reduction of a compound of Formula III to form a compound of Formula TV is carried out in the presence of a reducing agent.
14. The process of claim 13, wherein the reducing agent is palladium on carbon.
15. The process of claim 1 , wherein the reaction of a compound of Formula IV with benzylchloroformate to form a compound of Formula I is carried out in an organic solvent.
16. The process of claim 15, wherein the organic solvent is toluene.
17. The process of claim 1 , wherein the reaction of a compound of Formula IV with benzylchloroformate is carried out in the presence of an inorganic base.
18. The process of claim 17, wherein the inorganic base is selected from sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
19. The process of claim 18, wherein the inorganic base is sodium bicarbonate.
20. A process for the preparation of oxazolidinone compounds of Formula Id
Formula Id comprising the steps of: a. reacting a compound of Formula I
Formula I with butyl lithium and glycidyl butyrate to form a compound of Formula la, Formula la b. reacting the compound of Formula la with methane sulphonyl chloride, ammonium hydroxide and an acetyl halide of Formula CH3CO-hal, wherein hal is Br, CI or I, to form a compound of Formula lb,
Formula lb c. deprotecting the compound of Formula lb to form a compound of Formula Ic, and
, Formula Ic d. reacting the compound of Formula ic with R-T-(W)o-ι-R12 to form the compound of Formula Id, wherein T is a five- to seven-membered heterocyclic ring, aryl or substituted aryl, bound to the piperazinyl ring via linker W, wherein the heterocyclic ring has at least one heteroatom selected from oxygen, nitrogen and sulfur, and T is further substituted by a group represented by R, wherein R is H, CHO, (Ci-QO-alkyl, F, CI, Br, I, -CN, COR5, COOR5, N(R6R7), CON(R6R7), CH2NO2, NO2, CH2R8, CHR9, -CH=N-OR10, -C=CH-R5, NHCOC(R8R9), NHCOOR10, CH(OAc)2, OR5, SR5, -C(R9)NO2, (Cι-C12)-alkyl substituted with one or more of F, CI, Br, I, OR or SRf, wherein R5 is H, optionally substituted (Cι-C12)-alkyl, (C3-C12)-cycloall yl, aryl, heteroaryl, (Cι-C6)-alkoxy, or (Cι-C6)-alkyl substituted with one or more ofF, Cl, Br, I or OH; R6 and R7 is independently selected from H, optionally substituted (C1- 2)- alkyl, (C3-C12)-cycloalkyl, or (Cι-C6)-alkoxy; R8 and R9 is independently selected from H, (C1-C6)-alkyl, F, CI, Br, (C1.-C12)- alkyl substituted with one or more of F, CI, Br, I, OR5, SR5, N(R6R ) wherein R5, Rό and R7 is the same as defined earlier, R10 is H, optionally substituted (C1-C12)-alkyl, (C3-C12)-cycloalkyl, (C1-C6)-alkoxy, (Cι-C6)-alkyl, aryl, or heteroaryl; and W is CH2, CO, -CH2 NH-, -NHCH2-, -CH2NHCH2-, -CH2-N(RU)CH2-, -CH2(Rn)N-, CH(Rι 1), S, CH2(CO), NH, wherein Rπ is optionally substituted (C1-C12)-alkyl, (C3-Ci2)-cycloalkyl, (C\- C6)-alkoxy, (Cι-C6)-alkyl, aryl or heteroaryl; and R12 is a leaving group.
21. The process of claim 20, wherein the leaving group is fluoro, chloro, bromo, SCH3, -SO2CH3, -SO2CF3 or OC6H5.
22. The process of claim 20, wherein the compound of Formula I is prepared by a process comprising the steps of: a. condensing piperazine with l,2-difluoro-4-nitrobenzene to form a 4-(2-fluoro- 4-nitropheyl)-piperazine of Formula II,
Formula II b. contacting the compound of Formula II with di-tert-butyl carboxylic anhydride to form 4-(2-fluoro-4-nitrophenyl)-piperazine- 1-carboxylic acid butyl ester of Formula III,
c. reducing the compound of Formula III to form 4-(4-amino-2-fiuorophenyl)- piperazin-l-carboxylic acid tert-butyl ester of Formula IN, and
Formula TV d. reacting the compound of Formula TV with benzylchloroformate to form a compound 4-(4-benzyloxy-carbonylamino-2-fluorophenyl)-piperazin-l-carboxylic acid tert butyl ester of Formula I.
Formula I 23. A compound prepared by a process comprising the steps of: condensing piperazine with l,2-difluoro-4-nitrobenzene to form a 4-(2-fluoro-4- nitropheyl)-piperazine of Formula II,
Formula II contacting the compound of Formula II with di-tert-butyl carboxylic anhydride to form 4-(2- fluoro-4-nitrophenyl)-piperazine- 1 -carboxylic acid butyl ester of Formula III,
Formula III reducing the compound of Formula III to form 4-(4-amino-2-fluorophenyl)-piperazin- 1 - carboxylic acid tert-butyl ester of Formula IN, Formula IN and reacting the compound of Formula TV with benzylchloroformate. 24. A compound prepared by a process comprising the steps of: a. reacting a compound of Formula I
Formula I with butyl lithium and glycidyl butyrate to form a compound of Formula la,
Formula la b. reacting the compound of Formula la with methane sulphonyl chloride, ammonium hydroxide and an acetyl halide of Formula CH3CO-hal, wherein hal is Br, CI or I, to form a compound of Formula lb,
Formula lb deprotecting the compound of Formula lb to form a compound of Formula Ic, and
Formula Ic d. reacting the compound ofFormula lc with R-T-(W)0-ι-Ri2, wherein T is a five- to seven-membered heterocyclic ring, aryl or substituted aryl, bound to the piperazinyl ring via linker W, wherein the heterocyclic ring has at least one heteroatom selected from oxygen, nitrogen and sulfur, and T is further substituted by a group represented by R, wherein R is H, CHO, (C1-C6)-alkyl, F, CI, Br, I, -CN, COR5, COOR5, N(R6R7), CON(R6R7), CH2NO2, NO2, CH2R8, CHR9, -CH=N-OR10, -C=CH-R5, NHCOC(R8R9), NHCOOR10, CH(OAc)2, OR5, SR5, -C(R9)NO2, (C1-C12)-alkyl substituted with one or more of F, CI, Br, I, OR4 or SR4, wherein R5 is H, optionally substituted (C3-Ci2)-cycloalkyl, aryl, heteroaryl, (C1-C6)-alkoxy, or ( -C^-alkyl substituted with one or more ofF, Cl, Br, I or OH; R6 and R7 is independently selected from H, optionally substituted ( -C12)- alkyl, (C3-C12)-cycloalkyl, or (C1-C6)-alkoxy; R8 and R9 is independently selected from H, (Cι-C6)-alkyl, F, CI, Br, ( -Cπ)- alkyl substituted with one or more of F, CI, Br, I, OR5, SR5, N(R6R7) wherein R5, R6 and R is the same as defined earlier, R10 is H, optionally substituted (Cι-Cι2)-alkyl, (C3-Cι2)-cycloalkyl, (Cι-C6)-alkoxy, (Cι-C6)-alkyl, aryl, or heteroaryl; and W is CH2, CO, -CH2 NH-, -NHCH2-, -CH2NHCH2-, -CH2-N(RU)CH2-, -CH2(Rπ)N-, CH(R, 1), S, CH2(CO), NH, wherein Rπ is optionally substituted (Cι-C12)-alkyl, (C3-Ci2)-cycloalkyl, (Ci- C6)-alkoxy, (C1-C6)-alkyl, aryl or heteroaryl; and R12 is a leaving group.
PCT/IB2004/003829 2003-11-28 2004-11-23 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 WO2005051933A1 (en)

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US9163043B2 (en) 2003-12-18 2015-10-20 Dong-A St Co., Ltd. Oxazolidinone derivatives
US8604209B2 (en) 2008-10-10 2013-12-10 Trius Therapeutics, Inc. Methods for preparing oxazolidinones and compositions containing them
WO2010042887A3 (en) * 2008-10-10 2010-06-24 Trius Therapeutics Methods for preparing oxazolidinones and compositions containing them
US9328087B2 (en) 2008-10-10 2016-05-03 Merck Sharp & Dohme Corp. Methods for preparing oxazolidinones and compositions containing them
JP2012505252A (en) * 2008-10-10 2012-03-01 トリウス セラピューティクス Methods for preparing oxazolidinone and compositions containing them
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US9624250B2 (en) 2009-02-03 2017-04-18 Merck Sharp & Dohme Corp. Forms of R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate
US8426389B2 (en) 2009-02-03 2013-04-23 Trius Therapeutics, Inc. Crystalline form of R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate
US8580767B2 (en) 2009-05-28 2013-11-12 Trius Therapeutics, Inc. Oxazolidinone containing dimer compounds, compositions and methods to make and use
US8778412B2 (en) * 2009-11-06 2014-07-15 Aerpio Therapeutics Inc. Methods for increasing the stabilization of hypoxia inducible factor-1 alpha
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