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WO2015068171A1 - Nouveaux composés oxazolidinone - Google Patents

Nouveaux composés oxazolidinone Download PDF

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
compound
formula
methyl
oxooxazolidin
acetamide
Prior art date
Application number
PCT/IN2014/000018
Other languages
English (en)
Inventor
Raghu Mitra ALLA
Ajay Kumar DUBEY
Srinivas Reddy Mallepalli
Ramakrishna Reddy PONGILATI
Original Assignee
Lee Pharma Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lee Pharma Limited filed Critical Lee Pharma Limited
Publication of WO2015068171A1 publication Critical patent/WO2015068171A1/fr

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Classifications

    • 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

Definitions

  • 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.
  • 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).
  • MRSA methicillin resistant Staphylococcus aureus
  • MRSE Staphylococcus epidermitis
  • PRSP penicillin-resistant Streptococcus pneunoniae
  • VRE vancomycin-resistant enterococci
  • 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.
  • 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.
  • 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.
  • 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
  • novel compound of formula-1 is characterized by following 1 H-NMR, C 13-NMR, Mass and IR spectral data.
  • the invention provides an efficient, convenient and commercially viable process for the preparation enantiomerically pure compound of formula-!.
  • 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 %.
  • 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 ' 3 C-NMR Spectral data of Oxazolidinone compound of formula-I.
  • Figure-4 is ESI-MS (m/z) spectral data of Oxazolidinone compound of formula-I.
  • the invention provides a novel oxazolidinone compound [(S)- N- [[3-[4-fiuoro-3-morpholino phenyl]-2-oxooxazolidin-5-yl] methyl] acetamide] of formula-I.
  • the novel compound of formula-1 is characterized by following ⁇ -NMR, C 13-NMR, Mass and IR spectral data.
  • Step-a Reduction of 3, 4 -difluoro nitrobenzene to give 3,4-difluoro-aniIene.
  • 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.
  • 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.
  • 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.
  • (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.
  • 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.
  • 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.
  • 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.
  • HCI Hypo phosphorus
  • Example-2 Preparation of (R)-2-(3-((3,4-difluorophenyl)amino)-2-hydroxypropyl) isoindoline-l,3-dione (Formula- V).
  • 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.
  • Example-3 Preparation of (S)-2-((3-(3,4-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)isoindoline-l,3-dione (Formula-VI).
  • Example-4 Preparation of (S)-N-((3-(3,4-difluorophenyl)-2-oxooxazolidin-5- yl)methyl)acetamide (Formula-VIII).
  • Example-5 Preparation of (S)-N-((3-(4-fluoro-5-morpholino-2-nitrophenyl)-2- oxooxazolidin-5-yl)methyl)acetamide (Formula-X).
  • Example-6 Preparation (S)-N-((3-(2-amino-4-fluoro-5-morpholinophenyl)-2- oxooxazolidin-5-yl) methyl) acetamide (Formula-XI).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Nouveau composé oxazolidinone (S)-N-((3-(4-fluoro-3-morpholinophényl)-2-oxooxazolidin-5-yl)méthyl)acétamide de formule-I et procédé pour le préparer. Composé-I
PCT/IN2014/000018 2013-11-08 2014-01-08 Nouveaux composés oxazolidinone WO2015068171A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN5063CH2013 2013-11-08
IN5063/CHE/2013 2013-11-08

Publications (1)

Publication Number Publication Date
WO2015068171A1 true WO2015068171A1 (fr) 2015-05-14

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9573910B2 (en) 2013-11-08 2017-02-21 Lee Pharma Limited Oxazolidinone antibacterial compound
CN108135887A (zh) * 2015-10-22 2018-06-08 默沙东公司 噁唑烷酮化合物及其作为抗菌剂的使用方法
RU2794494C2 (ru) * 2016-10-17 2023-04-19 МЕРК ШАРП И ДОУМ ЭлЭлСи Оксазолидиноновые соединения и способы их применения в качестве противобактериальных средств

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995007271A1 (fr) * 1993-09-09 1995-03-16 The Upjohn Company Agents antimicrobiens oxazolidinone a substitution oxazine et thiazine
WO1999037630A1 (fr) * 1998-01-23 1999-07-29 Versicor, Inc. Banques combinatoires d'oxazolidinones, compositions a base de tels composes et procedes de preparation
WO2003063862A1 (fr) * 2002-01-25 2003-08-07 Pharmacia & Upjohn Company Cotherapie avec une oxazolidinone et une vitamine b

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995007271A1 (fr) * 1993-09-09 1995-03-16 The Upjohn Company Agents antimicrobiens oxazolidinone a substitution oxazine et thiazine
WO1999037630A1 (fr) * 1998-01-23 1999-07-29 Versicor, Inc. Banques combinatoires d'oxazolidinones, compositions a base de tels composes et procedes de preparation
WO2003063862A1 (fr) * 2002-01-25 2003-08-07 Pharmacia & Upjohn Company Cotherapie avec une oxazolidinone et une vitamine b

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9573910B2 (en) 2013-11-08 2017-02-21 Lee Pharma Limited Oxazolidinone antibacterial compound
CN108135887A (zh) * 2015-10-22 2018-06-08 默沙东公司 噁唑烷酮化合物及其作为抗菌剂的使用方法
EP3364968A4 (fr) * 2015-10-22 2019-05-01 Merck Sharp & Dohme Corp. Composés d'oxazolidinone et procédés pour les utiliser comme agents antibactériens
US10947205B2 (en) 2015-10-22 2021-03-16 Merck Sharp & Dohme Corp. Oxazolidinone compounds and methods of use thereof as antibacterial agents
CN108135887B (zh) * 2015-10-22 2021-07-30 默沙东公司 噁唑烷酮化合物及其作为抗菌剂的使用方法
RU2794494C2 (ru) * 2016-10-17 2023-04-19 МЕРК ШАРП И ДОУМ ЭлЭлСи Оксазолидиноновые соединения и способы их применения в качестве противобактериальных средств

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