WO2015068171A1 - Novel oxazolidinone compounds - Google Patents
Novel oxazolidinone compounds Download PDFInfo
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- WO2015068171A1 WO2015068171A1 PCT/IN2014/000018 IN2014000018W WO2015068171A1 WO 2015068171 A1 WO2015068171 A1 WO 2015068171A1 IN 2014000018 W IN2014000018 W IN 2014000018W WO 2015068171 A1 WO2015068171 A1 WO 2015068171A1
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- compound
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- methyl
- oxooxazolidin
- acetamide
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- AXNUZKSSQHTNPZ-UHFFFAOYSA-N Nc(cc1F)ccc1F Chemical compound Nc(cc1F)ccc1F AXNUZKSSQHTNPZ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
Abstract
A novel oxazolidinone compound (S)-N-((3-(4-fluoro-3-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide of formula -I and a process for the preparation thereof. Compound-I.
Description
NOVEL OXAZOLIDINONE COMPOUNDS
FIELD OF THE INVENTION
The invention relates to novel Oxazolidinone compounds. More particularly, the invention relates to novel oxazolidinone compound [(S)- N- [[3-[4-fluoro-3-morpholino phenyl]-2- oxooxazolidin-5-yl] methyl] acetamide] of Formula-I. The invention also relates to a process for preparation of the compound and its key intermediates.
Compound-I BACKGROUND OF THE INVENTION The oxazolidinones class of drugs are novel synthetic class of drugs having potent antimicrobial activity against a number of human and veterinary pathogens, including anaerobic organisms such as bacteroides and Clostridia species and acid fast organisms such as mycobacterium tuberculosis and mycobacterium avium, multi-drug resistant Gram-positive bacteria, including methicillin resistant Staphylococcus aureus (MRSA), Staphylococcus epidermitis (MRSE), penicillin-resistant Streptococcus pneunoniae (PRSP) and vancomycin-resistant enterococci (VRE).
Other than potent antimicrobial activity, this class of drugs also show other biological activities such as anti-coagulant, antidepressant and anti-thyroid activities.
Oxazolidinone is a five-membered heterocyclic ring exhibiting potential medicinal properties having preferential antibacterial activity. The oxazolidinone derivatives contain 2-oxazolidone in the structure having following general structure
A large number of oxazolidinone compounds with different structures and different biological activities have been developed so far. The oxazolidinones class of antibacterials possess a unique mechanism of inhibiting bacterial protein synthesis. Linezolid is one of the most important oxazolidinone class of drug having potent antibacterial activity and was first oxazolidinone to be approved for clinical use with potential antibacterial activity against many important resistant pathogens.
OBJECT OF THE INVENTION
The primary object of the invention is to provide a novel oxazolidinone compound.
Another object of the invention is to provide a novel oxazolidinone compound with potential biological activities.
Another object of the invention is to provide a process for synthesis of such novel oxazolidinone compound.
A further object of the invention is to provide novel intermediates for synthesis of the oxazolidinone compound. A further object of the invention is to provide a process for synthesis of the key intermediates for the novel oxazolidinone compound.
SUMMARY OF THE INVENTION
Accordingly the present invention provides a novel oxazolidinone compound [(S)- N- [[3- [4-fluoro-3-morpholino phenyl]-2-oxooxazolidin-5-yl] methyl] acetamide] of formula-1 and its key intermediates.
Compound-I
The invention also provides a process for synthesis of the novel oxazolidinone compound [(S)- N- [[3-[4-fluoro-3-morpholino phenyl]-2-oxooxazolidin-5-yl] methyl] acetamide] (formula-I) comprising the steps of: a) reduction of 3, 4 -difluoro nitrobenzene compound of formula-11
Compound-II
to give 3,4-difluoro-aniline compound of formula-Ill;
Compound-Ill b) reacting compound-ill with (R) epichlorohydrin to give (R)- l -chloro-3-((3,4- difluorophenyl)amino)propan-2-ol compound of formula -IV;
Compound-IV
c) coupling (R)- l -chloro-3-((3,4-difluorophenyl)amino)propan-2-ol compound of formula- IV with Potassium phthalimide to obtain (R)-2-(3-((3,4- difluorophenyl)amino)-2- hydroxy! propyl)isoindoline- l ,3-dione compound of formula- V;
d) cyclization of (R)-2-(3-((3,4-difluorophenyl)amino)-2- hydroxy! propyl) isoindoline- 1 ,3-dione compound of formula- V with CDI to obtain (S)-2-((3-(3,4- difIuorophenyl)-2-oxooxazolidin-5-yl)methyi)isoindoline-l ,3-dione compound of formula-VI;
Compound-VI e) opening of phthalimide ring of compound-VI by reacting with Hydrazine hydrate to obtain (S)-5-(amino methyl)-3-(3,4-difluorophenyl)oxazolidin-2-one compound of formula-VII;
Compound-VII
f) acylation of compound-VII with Acetic anhydride to obtain the corresponding (S)-N- ((3-(3,4-difluorophenyl)-2-oxooxazolidin-5-yl)methyI)acetamide compound of formula-VHI;
Compound-VIII nitration of compound VIII with nitrating reagents (nitric acid & sulphuric acid ) to give (S)-M-((3-(4,5-difluoro-2-nitrophenyl)-2-oxooxazolidin-5-yl) methyl)acetamide compound of formula IX;
Compound-IX reacting (S)- -((3-(4,5-d fluoro-2-nitrophenyl)-2-oxooxazol'idin-5-yl) methyl) acetamide compound-IX with morpholine to give (S)-N-((3-(4-fluoro-5-morpholino- 2-nitrophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide compound formula -X;
Compound-X
i) reduction of (S)-N-((3-(4-fluoro-5-rriorpholino-2-nitrophenyl)-2-oxooxazolidin-5- yl)methyl)acetamide compound of formula-X to obtain (S)-N-((3-(2-amino-4-fluoro-5- morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide formula XI;
Compound-XI j) deamination of (S)-N-((3-(2-amino-4-fluoro-5-morpholinophenyl)-2-oxooxazolidin-5- yl)methyl)acetamide (compound-XI) to obtain (S)-N-((3-(4-fluoro-3- morpholinophenyI)-2-oxooxazolidin-5-yl)methyl)acetamide compound of formula -1.
Compound-I
The novel compound of formula-1 is characterized by following 1 H-NMR, C 13-NMR, Mass and IR spectral data.
IR spectral data:
3335,3085,2984,2900,2743,2697, 1 736, 1671 , 1609, 1597, 1 542, 1512, 1474, 1420, 1369, 1348, 1318, 1285,1231 , 1 142, 1 1 14, 1083. ( As shown in Figure-1)
(H-NMR.CDC-3 : 6 2.0Hs,3H), 3.06(t,4H), 3.60-3.78(m,4H),3.85-3.86(t,2H), 4.03(t,2H) ,4.78 (m, 1 H), 6. 12(s, 1 H),6.82-6.85(m, 1 H),6.98-7.03(q, 1 H),7.32-7.34(dd, 1 H) (As shown in Figure-2)
13C-NMR:CDC13:22.7,41.7,47.7,50.5,66.6,71.8, 109.6, 1 1 1.9, 1 16.2, 134.3, 139.9, 140.0, 150.8, 1 53.2, 154.6, 171.2. (As shown in Figure-3)
ESI-MS (m/z) :338.37(M+1) (As shown in Figure-4)
In another embodiment, the invention provides an efficient, convenient and commercially viable process for the preparation enantiomerically pure compound of formula-!.
In another embodiment, the invention provides (S)-N-((3-(4-fluoro-3-morpholinophenyl)- 2-oxooxazolidin-5-yl)methyl)acetamide (compound-I) having purity greater than about 98% specifically greater than 99 % and more specifically greater than 99.5 %.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure-1 is IP Spectral data of Oxazolidinone compound of formula-I.
Figure-2 is H-NMR Spectral data of Oxazolidinone compound of formula-I. Figure-3 is '3C-NMR Spectral data of Oxazolidinone compound of formula-I.
Figure-4 is ESI-MS (m/z) spectral data of Oxazolidinone compound of formula-I.
DETAILLED DESCRIPTION OF THE INVENTIO
Detailed embodiments of the present invention are disclosed herein below. However, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which can be embodied in various forms. The scope of the invention is not limited to the disclosed embodiments and terms and phrases used herein are not intended to be limiting but rather to provide an understandable description of the invention. The invention is defined by claims appended hereto.
In one preferred embodiment the invention provides a novel oxazolidinone compound [(S)- N- [[3-[4-fiuoro-3-morpholino phenyl]-2-oxooxazolidin-5-yl] methyl] acetamide] of formula-I.
Compound-I
The novel compound of formula-1 is characterized by following Ή-NMR, C 13-NMR, Mass and IR spectral data.
IR spectral data:
3335,3085,2984,2900,2743,2697, 1736, 1671 , 1609, 1597, 1542, 1512, 1474, 1420, 1369, 1348, 13 1 8, 1285, 123 1 , 1 142, 1 1 14, 1083. ( As shown in Figure- 1 )
(H-NMR:CDC13 : δ 2.01 (s,3H), 3.06(t,4H), 3.60-3.78(m,4H),3.85-3.86(t,2H), 4.03(t,2H) ,4.78 (m, 1 H), 6. 12(s, 1 H),6.82-6.85(m, 1 H),6.98-7.03(q, 1 H),7.32-7.34(dd, 1 H) (As shown in Figure-2)
,3C-NMR:CDC13:22.7,41.7,47.7,50.5,66.6,71 .8, 109.6, 1 1 1 .9, l 'l 6.2, 134.3, 139.9, 140.0, 150.8, 153.2, 154.6, 171.2. (As shown in Figure-3)
ESI-MS (m/z) :338.37(M+1 ) (As shown in Figure-4)
The process of synthesis of the novel oxazolidinone compound of formula-1 is illustrated in below scheme-1:
Scheme-I
The process for synthesis of the novel oxazolidinone compound [(S)- N- [[3-[4-fluoro-3- morpholino phenyl]-2-oxoox.azolidtn-5-yl] methyl] acetamide] (formula-I) comprises the following steps:
a) reduction of 3, 4 -difluoro nitrobenzene compound of formula-II
Compound-II
to give 3,4-difluoro-aniline compound of formula-Ill;
Compound-Ill b) reacting compound-Ill with (R) epichlorohydrin to obtain (R)- l -chloro-3-((3,4- difluorophenyl)amino)propan-2-ol compound of formula -IV;
Compound-IV
c) coupling the (R)- l -chloro-3-((3,4-difIuorophenyl)amino)propan-2-ol compound of formula- IV with Potassium phthalimide to obtain (R)-2-(3-((3,4-difluorophenyI)amino)- 2- hydroxyl propyl)isoindoline-l ,3-dione compound of formula- V;
Compound-V
d) cyclization of (R)-2-(3-((3,4-difluorophenyl)amino)-2- hydroxyl propyl) isoindoline- 1 ,3-dione compound of formula- V with CDI to obtain (S)-2-((3-(3,4-difIuorophenyl)-2- oxooxazolidin-5-yl)methyl)isoindoline-l ,3-dione compound of formula-VI;
Compound-VI e) opening of phthalimide ring of compound-VI by reacting with Hydrazine hydrate to obtain (S)-5-(amino methyl)-3-(3,4-difluorophenyl)oxazolidin-2-one compound of formula-VII;
Compound-VII
f) acylation of compound-VII with Acetic anhydride to obtain the corresponding (S)-N- ((3-(3,4-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide compound of formula-VIII;
Compound-VIII
g) nitration of compound VIII with nitrating reagents (nitric acid & sulphuric acid ) to give (S)-N-((3-(4,5-difluoro-2-nitrophenyl)-2-oxooxazolidin-5-yl) methy!)acetamide compound of formula IX;
Compound-IX h) reacting (S)-N-((3-(4,5-difluoro-2-nitroph6ny!)-2-oxooxazolidin-5-yl) methyl) acetamide compound-IX with morpholine to give (S)-N-((3-(4-fluoro-5-morpholino-2- nitrophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide compound formula -X;
Compound-X i) reduction of (S)-N-((3-(4-fluoro-5-morpholino-2-nitrophenyl)-2-oxooxazolidin-5 yl)methyl)acetamide compound of formula-X to obtain (S)-N-((3-(2-amino-4-fluoro-5 morpholinophenyI)-2-oxooxazolidin-5-yl)methyl)acetamide formula XI;
Compound-XI j) deamination of (S)-N-((3-(2-amino-4-fluoro-5-morpholinophenyl.)-2-oxooxazolidin-5- yl)methyl)acetamide (compound-XI) to obtain (S)-N-((3-(4-fluoro-3-morpholinophenyl)- 2-oxooxazolidin-5-yl)methyl)acetamide compound of formula -I.
Compound-I Each step of the above process is further elaborated herein below.
Step-a: Reduction of 3, 4 -difluoro nitrobenzene to give 3,4-difluoro-aniIene.
In this step 3, 4 -difluoro nitrobenzene of formula-1 is reduced with pd/C in autoclave, applying Hydrogen gas and maintaining the reaction for 3-4 hrs. After completion of reaction filtered and distilled to obtain compound of formula-Ill. Step-b: Reaction of 3,4-difluoro-anilene with (R) epichlorohydrin to yield (R)-l- chIoro-3-((3,4-difluorophenyI)amino)propan-2-ol of formula -IV.
This step involves reacting 3,4-Difluoro aniline with (R) epichlorohydrin, heating at 50°C- 55°C 5.0-6.0 hrs and after completion of reaction distilled under vaccum to obtain (R)- l - chloro-3-((3,4 difluorophenyl)amino)propan-2-ol of formula -IV.
Step-c: Coupling (R)-l-chloro-3-((3,4-difluorophenyl)amino)propan-2-oI of formula- IV with Potassium phthalimide to yield (R)-2-(3-((3,4-difluorophenyl)amino)-2- hydroxyl propyl)isoindoline-l,3-dione of formula- V.
In this step (R)- l -chloro-3-((3,4-difluorophenyl)amino)propan-2-ol of formula- IV is treated with Potassium phthalimide in DMF at 140- 1 50°C for 5.0-6.0hrs. Then cooled, filtered and washed with mixture of water and methanol to yield (R)-2-(3-((3,4- difluorophenyl)amino)-2- hydroxyl propyl)isoindoline- l ,3-dione of formula- V.
Step-d: Cyclization of (R)-2-(3-((3,4-difluorophenyl)amino)-2- hydroxyl propyl) isoindo!ine-l,3-dione of formula- V with CDI to yield (S)-2-((3-(3,4-difluorophenyl)- 2-oxooxazolidin-5-yl)methyl)isoindoline-l,3-dione of formula- VI.
In this step (R)-2-(3-((3,4-difluorophenyl)amino)-2-hydroxypropyl) isoindoline-1 ,3- dione(formula-V) in ethyl acetate is cyclized with CDI, stirred for 3.0-4. Ohrs at room temperature. After completion of reaction washed with ethyl acetate followed by washed with water to get (S)-2-((3-(3,4-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)isoindoline- 1 ,3-dione of formula- VI.
Step-e: Opening of phthalimide ring of (S)-2-((3-(3,4 difluorophenyl)-2- oxooxazolidin-5-yl)methyl)isoindoline-l,3-dione by reacting with Hydrazine hydrate to yield (S)-5-(amino methyl)-3-(3,4 difluorophenyI)oxazolidin-2-one.of formula- VII.
This step involves reaction of (S)-2-((3-(3,4-difluorophenyI)-2-oxooxazolidin-5- yl)methyl)isoindoline- l ,3-dione with Hydrazine hydrate in methanol and water at room temperature and heated to 65-70°C, stirred for 2.0-3.0 hrs same temperature. After completion of reaction extracted with dichloromethane and distilled to obtain (S)-5-(amino methyl)-3-(3,4 difluorophenyl)oxazolidin-2-one.of formula-VII.
Step-f: Acyclation of (S)-5-(amino methyl)-3-(3,4-difluorophenyI)oxazolidin-2-one of formula-VII with Acetic anhydride yield the corresponding (S)-N-((3-(3,4- difluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide of formula- VIII.
In this step (S)-5-(amino methyl)-3-(3,4-difluorophenyl)oxazolidin-2-one of formula-VIl reacted with acetic anhydride in dichloromethane at 25-30°C, stirred for 3.0-4. Ohrs. After the completion of the reaction, organic layer is distilled and washed with water to obtain (S)-N-((3-(3,4-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide of formula-VIH. Step-g: Nitration of (S)-N-((3-(3,4-difluorophenyI)-2-oxooxazoIidin-5- yl)methyl)acetamide withnitrating reagent (nitric acid & sulphuric acid ) to give (S)- N-((3-(4,5-difluoro-2-nitrophenyI)-2-oxooxazolidin-5-yl) methyl)acetamide of formula IX.
This step involves addition of (S)-N-((3-(3,4-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)acetamide to a solution of sulphuric acid and nitric acid in dichloromethane, stirred for 30.0 min at 0-5°C, stirred for 3.0-4. Ohrs. Then raised the temperature, separated organic layer and extracted with dichloromethane to obtain (S)-N-((3-(4,5-difluoro-2- nitrophenyl)-2-oxooxazolidin-5-yl) methyl)acetamide.
Step-h: (S)-N-((3-(4,5-difluoro-2-nitrophenyl)-2-oxooxazolidin-5-yl) methyl)acetamide reacts with morpholine to give (S)-N-((3-(4-fluoro-5-morphoIino- 2-nitrophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide formula X.
In this step to a solution of (S)-N-((3-(4,5-difluoro-2-nitrophenyl)-2-oxooxazolidin-5-yl) methyl)acetamide in isopropyl alcohol, added morpholine, stirred for 1.0-2. Ohrs at 70- 75°C. Then'added water, separated and washed with water to obtain (S)-N-((3-(4-fluoro-5- morpholino-2-nitrophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide.
Step-i: Reduction of (S)-N-((3-(4-fluoro-5-morpholino-2-nitrophenyl)-2- oxooxazolidin-5-yl)methyl)acetamide of formula X to give (S)-N-((3-(2-amino-4- fluoro-5-morpholinophenyi)-2-oxooxazolidin-5 yl)methyl)acetamide formula XI.
In this step, reduction of (S)-N-((3-(4-fluoro-5-morpholino-2-nitrophenyl)-2- oxooxazolidin-5-yl)methyl)acetamide with Pd/C in methanol and maintaining at 5.0- 6.0Kg/Cm2 of hydrogen gas for 3.0-4. Ohrs at 35-40°C. After completion of reaction filtered catalyst and distilled off solvent completely to obtain (S)-N-((3-(2-amino-4-fluoro- 5-morpholinophenyl)-2-oxooxazoIidin-5 yl)methyl)acetamide.
Step-j: Deamination of (S)-N-((3-(2-amino-4-fluoro-5-morpholinophenyl)-2- oxooxazoIidin-5-yl)methyl)acetamide to yield desired (S)-N-((3-(4-fluoro-3- morpholinophenyI)-2-oxooxazoIidin-5-yl)methyl)acetamide.
This step involves addition of Con. HCI to (S)-N-((3-(2-amino-4-fluoro-5- morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide, maintaining the reaction mass at temperature 0-5°C and then added sodium nitrite in water solution and stirred. After completion of the reaction, added hypo phosphorus (H3PO2) at below 10°C and raised the reaction mass temperature to 30-35°C. After completion of reaction added dichloromethane and extracted with dichloromethane to obtain desired novel (S)-N-((3-(4- fluoro-3-morphoIinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide.
The process described above for the preparation of novel oxazolidinone derivative compound [(S)- N- [[3-[4-fluoro-3-morpho!ino pheny!]-2-oxooxazolidin-5-yl] methyl] acetamide] of formula-I is further illustrated by the bellow given examples.
EXAMPLES: Example-1 -.Preparation of (R)-l-chloro-3-((3,4-difluorophenyl)amino)propan-2-ol of formula -IV.
Taken 200.0g of 3,4-difluoro nitro benzene, 600.0ml of Toluene and 12.0g of pd/C into autoclave at 25°C-35°C. Apply the Hydrogen gas 2.0-6.0Kg/Cm2 and maintained the reaction for 3-4 hrs at 25°C-35°C Check the reaction mass TLC to conform reaction completion. After reaction complies unload the reaction mass and filter through hyflow bed and wash with toluene (200.0ml). Take the filtrate and distilled under vacuum at below 50°C. the obtained 3,4-Difluoro aniline crude weight 152.0g,Yield:93.8%,purity by HPLC:95.85%.
140. Og of the previous step 3,4-Difluoro aniline, 120.4g of (R)-Epichlorohydrine into a clean round bottom flask, slowly heat to 50°C-55°C and maintain the reaction mass for 5.0-6.0 hrs at 50°C-55°C and check the reaction mass TLC to conform reaction completion. After reaction compiles distill off low boilers under vacuum at below 50°C.to yield the crude compound of formula-ni( 170.0g,yield:71.0%,purity:73.29%),
Example-2:Preparation of (R)-2-(3-((3,4-difluorophenyl)amino)-2-hydroxypropyl) isoindoline-l,3-dione (Formula- V).
Crude obtained from example- 1 treated with 156.0g of potassium phtha!imide and 1 70.0ml of DMF at 140- 150°C for 5.0-6.0hrs. the reaction mass checked TLC to conform reaction completion. The reaction mass cooled to Room temperature, added 850.0ml of water and 255.0ml of methanol, stirred for 1.0-2.0hrs at Room temperature. The filtered the solids, washed with mixture of water & methanol( 170.0ml). the dried the solids. The obtained solid weight 206.0g, purity by HPLC:63.1 %.
Example-3:: Preparation of (S)-2-((3-(3,4-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)isoindoline-l,3-dione (Formula-VI).
410.Og of (R)-2-(3-((3,4-difluorophenyl)amino)-2-hydroxypropyl) isoindoline-1 ,3- dione(formula-V), 820.0 ml of ethyl acetate and 210.0g of CDI into Round bottom flask. Stirred for 3.0-4.0hrs at room temperature. Checked reaction mass, TLC to conform reaction completion. After reaction complies, filtered the solids, washed with 205.0 ml of ethyl acetate. Then the wet cake and 1 800.0ml of water taken into a round bottom flask. Stirred for 1 .0-2.0hrs at 40-45°C, filtered the solids, washed with 410.0ml of water. Dried the wet cake, the obtained of (S)-2-((3-(3,4-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)isoindoline-l ,3-dione,. eight :272.0g, yield:57.9%, purity by HPLC:94.22%.
Example-4: Preparation of (S)-N-((3-(3,4-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)acetamide (Formula-VIII).
370. Og of (S)-2-((3-(3,4-difluorophenyI)-2-oxooxazolidin-5-yl)methyl)isoindoline- l ,3- dione, 370.0ml of methanol and 1480.0ml of water, 216.5g of hydrazine hydrate into a round bottom flask at room temperature. The reaction mass slowly heated to 65-70°C, stirred for 2.0-3.0hrs same temperature. Checked reaction mass TLC to conform reaction completion. After reaction complete, cooled the reaction mass to room temperature, extracted product with dichloromethane. The organic layer distilled off completely to give the crude of formula-VII (208.0g),
Crude obtained above was added 370.0ml of dichloromethane, 147.5g of acetic anhydride added slowly above to the reaction mass at 25-30°C, stirred for 3.0-4.0hrs, checked reaction mass TLC to conform reaction completion. After reaction complies, wash the reaction mass with water. The organic layer distilled off completely to get Obtained crude mass to this mass 370.0ml of water was added under stirring maintain for l hr and filtered
the solid, washed with water. Dried to get the (S)-N-((3-(3,4-difluorophenyl)-2- oxooxazolidin-5-yI)methyl)acetamide Formula-VW ,weight:230.0g, yield:81 .6%, purity by HPLC:95.54%.
Example-5: Preparation of (S)-N-((3-(4-fluoro-5-morpholino-2-nitrophenyl)-2- oxooxazolidin-5-yl)methyl)acetamide (Formula-X).
320.3 g of sulphuric acid into round bottom flask. Cooled to 0-5°C,slowly added 88.7g of nitric acid at 0-5°C, stirred for 30 min, added 850.0ml of dichloromethane. Then added 1 70.0g of (S)-N-((3-(3,4-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide lot wise at 0-5°C. stirred for 30.0 min at 0-5°C. raised the reaction mass temperature to room temperature. Stirred for 3.0-4.0hrs. checked TLC to conform reaction completion. After reaction complies, the reaction quenched into 850.0ml of chilled water, separated organic layer. Extracted aqueous layer with dichloromethane. The combined organic layer distilled off solvent. Crude compound (S)-N-((3-(4,5-difluoro-2-nitrophenyl)-2-oxooxazolidin-5- yl) methyl) acetamide of formula IX. (1 82. Og)
f?
To the crude thus obtained was added 1 82.0ml of isopropyl alcohol and to this 122.4g of Morpholine was added slowly and stirred for 1 .0-2.0hrs at 70-75°C.TLC was checked to conform reaction completion. Once complies, added 340.0ml of water to the reaction mass, then cooled to room temperature. The material thus separated was filtered and washed with 170.0ml of water. Dried to get the product obtained (S)-N-((3-(4-fluoro-5- morpholino-2-nitrophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide of formula-X, weight: 189.0g, yield:78.68%,purity by HPLC:91.12%.
Example-6: Preparation (S)-N-((3-(2-amino-4-fluoro-5-morpholinophenyl)-2- oxooxazolidin-5-yl) methyl) acetamide (Formula-XI).
100. Og of (S)-N-((3-(4-fluoro-5-morpholino-2-nitrophenyl)-2-oxooxazolidin-5- yl)methyl)acetamide, 1500.0ml of methanol and l O.Og of Pd/C are subjected to hydrogenation in an autoclave. At 5.0-6.0Kg/Cm2 of hydrogen gas maintain for 3.0-4.0hrs at 35-40°C. Check for reaction completion by TLC. After reaction complies, filtered the catalyst and distilled off solvent completely. The obtained (S)-N-((3-(2-amino-4-fluoro-5- morpholinophenyl)-2-oxooxazolidin-5-yl)methyl) acetamide formula-XI ,weight:80.0g, yield:86.9%, purity by HPLC:96.32%.
ExampIe-7: Preparation (S)-N-((3-(4-fluoro-3-morpholinophenyI)-2-oxooxazolidin-5- yl)methyl)acetamide (Formula-I).
To 82.0ml of Con.HCI slowly added 80.0g of (S)-N-((3-(2-amino-4-fluoro-5- morpholinophenyl)-2-oxooxazolidin-5-yl)methyl) acetamide (Formula-Xl) maintaining reaction mass temperature 0-5°C . To this were added 23.5g of sodium -nitrite in 125.0ml of water solution at 0-5°C,stirred for 30min,checked TLC to conform reaction completion. Once complies added 22.5g of hypo phosphorus (H3PO2) at below 10°C, then raised the reaction mass temperature to 30-35°C, stirred for 30min and checked TLC to conform reaction completion. After reaction complies, cooled the reaction mass to 0-5°C, added 400.0ml of dichloromethane and adjusted pH to 7.0-8.0 with 48%of caustic lye. Separated organic layer and aqueous layer extracted with dichloromethane.Combined organic layer, was distilled off to get the crude.Which is then purified by column chromatography and further re-crystallized with methanol to give (S)-N-((3-(4-fluoro-3-morpholinophenyl)-2- oxooxazolidin-5-yl)methyl)acetamide formula-!, weight: 10. Og, yield: 13.0%, purity by HPLC :99.5%.The structure conformed by 'H-NMR,C13-NMR, Mass, IR spectra] data.
The structural elucidation of the compound of formula I is con firmed by Ή-NMR, CI 3- NMR, Mass, IR spectral data etc. stated as below:
IR spectral data:
3335,3085,2984,2900,2743,2697,1736,1671,1609,1597,1542,1512,1474,1420,1369,1348, 1318,1285,1231,1142,1114,1083. (Fig .-I)
(H-NMR:CDCb ; δ 2.01(s,3H), 3.06(t,4H), 3.60-3.78(m,4H),3.85-3.86(t,2H), 4.03(t,2H) ,4.78 (m,lH), 6.12(s,lH),6.82-6.85(m,lH),6.98-7.03(q,lH),7.32-7.34(dd,lH) (Fig .-II)
13C-NMR:CDC13:22.7,41.7,47.7,50.5,66.6,71.8,109.6,111.9,116.2,134.3,139.9,
140.0,150.8, 153.2,154.6,171.2. (Fig .-III) ESI-MS(m/z):338.37(M+l);(Fig.-IV)
Claims
1. A novel oxazolidinone compound [(S)- N- [[3-[4-fluoro-3-morpholino phenyl]-2- oxooxazolidin-5-yl] methyl] acetamide] of formula -I.
Compound-I
2. The novel oxazolidinone compound-l as claimed in claim- 1 characterized by IR spectral data: 3335,3085,2984,2900,2743,2697, 1736, 1671 , 1609, 1 597, 1 542, 1512, 1474, 1420, 1369, 1348, 1 3 1 8, 1285, 1231 , 1 142, 1 1 14, 1083.
3. The novel oxazolidinone compound-I as claimed in claim- 1 characterized by H- NMR:CDC13: 52.01 (s,3H), 3.06(t,4H), 3.60-3.78(m,4H),3.853.86(t,2H) ,4.03(t,2H), 4.78(m, 1 H),6.12(s, 1 H),6.82-6.85(m, 1 H),6.98 7.03(q, 1 H),7.32-7.34(dd, 1 H).
4. The novel oxazolidinone compound-l as claimed in claim- 1 characterized by 13C- NMR:CDCI3:22.7,41 .7,47.7,50.5,66.6,71.8, 1 09.6, 1 1 1.9, 1 16.2, 134.3, 1 39.9, 140.0, 150.8 , 153.2, 1 54.6, 171 .2.
5. The novel oxazolidinone compound-I as claimed in claim- 1 characterized by ESI-MS (m/z): 338.37(M+1 ).
6. A process for the preparation of novel oxazolidinone compound (S)-N-((3-(4-fluoro-3- morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide of formula -I
Compound-I comprising the steps of :
a) reduction of 3, 4 -difluoro nitrobenzene compound of formula-II
Compound-II
to give 3,4-difiuoro-aniline compound of formula-Ill;
Compound-Ill b) reacting compound-Il l with (R) epichlorohydrin to obtain (R)- l -chloro-3-((3,4- difluorophenyl)amino)propan-2-ol compound of formul -IV;
Compound-IV
c) coupling the (R)- l -chloro-3-((3,4-difluorophenyl)amino)propan-2-ol compound of formula- IV with Potassium phthalimide to obtain (R)-2-(3-((3,4-difIuorophenyl)amino)- 2- hydroxyl propyl)isoindoline-l ,3-dione compound of formula- V;
Compound-V d) cyclization of (R)-2-(3-((3,4-difluorophenyl)amino)-2- hydroxyl propyl) isoindoline- 1,3-dione compound of formula- V with CDI to obtain (S)-2-((3-(3,4-difJuorophenyl)-2- oxooxazolidin-5-yl)methyl)isoindoline- l ,3-dione compound of formula-Vl;
Compound-VI
e) opening of phthalimide ring of compound-VI by reacting with Hydrazine hydrate to obtain (S)-5-(amino methyl)-3-(3,4-difluorophenyl)oxazolidin-2-one compound of formula-Vll ;
Compound-VTI
f) acylation of compound-Vll with Acetic anhydride to obtain the corresponding (S)-N- ((3-(3,4-difIuorophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide compound of formula-VIII;
Compound- VIII
g) nitration of compound VIII with nitrating reagents (nitric acid & sulphuric acid ) to give (S)-N-((3-(4,5-difluoro-2-nitrophenyl)-2-oxooxazolidin-5-yl) methyl)acetamide compound of formula IX;
Compound-IX h) reacting (S)-N-((3-(4,5-difluoro-2-nitrophenyl)-2-oxooxazolidin-5-yl) methyl) acetamide compound-IX with morpholine to give (S)-N-((3-(4-fluoro-5-morpholino-2- nitrophenyl)-2-oxooxazolidin-5-yl)methyl)acetamtde compound formula -X;
Compound-X
i) reduction of (S)-N-((3-(4-fluoro-5-morpholino-2-nitrophenyl)-2-oxooxazol'idin-5- yl)methyl)acetamide compound of formula-X to obtain (S)-N-((3-(2-amino-4-fluoro-5- morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide formula XI;
Compound-XI
j) deamination of (S)-N-((3-(2-amino-4-fluoro-5-morpholinophenyI)-2-oxooxazolidin-5- yl)methyl)acetamide (compound-XI) to obtain (S)-N-((3-(4-fluoro-3-morpholinophenyl)- 2-oxooxazolidin-5-yl)methyl)acetamide compound of formula -I.
Compound-I
7. A pharmaceutically acceptable salt of the novel oxazolidinone compound-I as claimed in claim- 1 .
8. A pharmaceutical composition comprising the novel oxazolidinone compound-I as claimed in claim- lor its pharmaceutically acceptable salt.
9. An enantiomerically pure compound of formula-I as claimed in claim- 1.
10. An enantiomerically pure compound of formula-I obtained by the process as claimed in claim-6.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9573910B2 (en) | 2013-11-08 | 2017-02-21 | Lee Pharma Limited | Oxazolidinone antibacterial compound |
| CN108135887A (en) * | 2015-10-22 | 2018-06-08 | 默沙东公司 | Oxazolidinone compounds and its application method as antiseptic |
| RU2794494C2 (en) * | 2016-10-17 | 2023-04-19 | МЕРК ШАРП И ДОУМ ЭлЭлСи | Oxazolidinone compounds and methods of their application as antibacterial agents |
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| WO1995007271A1 (en) * | 1993-09-09 | 1995-03-16 | The Upjohn Company | Substituted oxazine and thiazine oxazolidinone antimicrobials |
| WO1999037630A1 (en) * | 1998-01-23 | 1999-07-29 | Versicor, Inc. | Oxazolidinone combinatorial libraries, compositions and methods of preparation |
| WO2003063862A1 (en) * | 2002-01-25 | 2003-08-07 | Pharmacia & Upjohn Company | Cotherapy with an oxazolidinone and a vitamin b |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995007271A1 (en) * | 1993-09-09 | 1995-03-16 | The Upjohn Company | Substituted oxazine and thiazine oxazolidinone antimicrobials |
| WO1999037630A1 (en) * | 1998-01-23 | 1999-07-29 | Versicor, Inc. | Oxazolidinone combinatorial libraries, compositions and methods of preparation |
| WO2003063862A1 (en) * | 2002-01-25 | 2003-08-07 | Pharmacia & Upjohn Company | Cotherapy with an oxazolidinone and a vitamin b |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9573910B2 (en) | 2013-11-08 | 2017-02-21 | Lee Pharma Limited | Oxazolidinone antibacterial compound |
| CN108135887A (en) * | 2015-10-22 | 2018-06-08 | 默沙东公司 | Oxazolidinone compounds and its application method as antiseptic |
| EP3364968A4 (en) * | 2015-10-22 | 2019-05-01 | Merck Sharp & Dohme Corp. | Oxazolidinone compounds and methods of use thereof as antibacterial agents |
| US10947205B2 (en) | 2015-10-22 | 2021-03-16 | Merck Sharp & Dohme Corp. | Oxazolidinone compounds and methods of use thereof as antibacterial agents |
| CN108135887B (en) * | 2015-10-22 | 2021-07-30 | 默沙东公司 | Oxazolidinone compounds and methods of use as antibacterial agents |
| RU2794494C2 (en) * | 2016-10-17 | 2023-04-19 | МЕРК ШАРП И ДОУМ ЭлЭлСи | Oxazolidinone compounds and methods of their application as antibacterial agents |
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