WO2014170908A1 - Procédé de préparation de dérivés oxazolidinone - Google Patents

Procédé de préparation de dérivés oxazolidinone Download PDF

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WO2014170908A1
WO2014170908A1 PCT/IN2013/000761 IN2013000761W WO2014170908A1 WO 2014170908 A1 WO2014170908 A1 WO 2014170908A1 IN 2013000761 W IN2013000761 W IN 2013000761W WO 2014170908 A1 WO2014170908 A1 WO 2014170908A1
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compound
solvent
azide
alcohol
azido
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PCT/IN2013/000761
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English (en)
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Satyanarayana Reddy BHEMIREDDY
V. Vara Prasada Reddy PAIDIMARLA
Venkat Reddy YARAPATHI
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Nosch Labs Private Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic 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
    • C07D295/04—Heterocyclic 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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic 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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic 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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to a process for preparation of oxazolidinone derivatives. More particularly, the invention relates to a novel combined process for preparation of Linezoiid and Rivaroxaban using (5)-Epich.lorohydrin.
  • Oxazolidinones are a class of compounds containing 2-oxazolidone in the structure.
  • the general structure of oxazolidinone is given below:-
  • oxazolidinone derivatives show a number of biological activities such as antibacterial, anticoagulant, anti-tubercular, antidepressant, anti-thyroid, agriculture fungicide etc.
  • Some of the oxazolidinone derivatives include Linezoiid, Torezolid, Radezolid, Eperezolid and Rivaroxaban.
  • Linezoiid is a potent antibacterial agent whereas; Rivaroxaban is an important antithrombotic agent.
  • both Linezoiid and Rivaroxaban are oxazolidinone derivatives but both exhibit different biological activities and different pharmaceutical use.
  • Linezoiid is chemically known as (5)-N-[[3-[3-fIuoro-4-(4-morpholinyl)phenyl]-2-oxo-5- oxazo!idinyl] methyl] acetamide and is a synthetic antibacterial agent of oxazolidinone class.
  • Linezoiid is used for the treatment of serious infections caused by Gram positive bacteria that are resistant to other antibiotics and also gram-negative microorganism such as Pasteurella muliocida. It is mostly active against streptococci, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).
  • Rivaroxaban has chemical formula of (5-chloro-N-( ⁇ 5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)- phenyl]-l,3-oxazolidin-5-yl ⁇ -methyl)-2-thiophene carboxainide and is an orally active anticoagu lant used for prophylaxis and/or treatment of thromboembolic disorders especially angina pectoris, myocardial infarction, stroke, ischemic attacks, pulmonary embolism (PE) and deep vein thrombosis (VTE).
  • U.S Patent No. 5,688,792 ( WO 95/0727 1 , EP07 1 7738) first disclosed Linezol id and related compounds, its therapeutic uses as well as a process for its preparation and is represented by fol lowing structure (I).
  • WO 2001/47919 also describes a process for preparation of Rivaroxaban from the starting compounds 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3(2H)-dione, 4-(4-aminophenyl)-3- morpholinone and 5-chlorothiophene-2-carbonyl chloride as given in Scheme-Ill below:
  • WO 2004/060887 relates to a method producing 5-chloro-N-( ⁇ 55)-2-oxo-3-[4-(3-oxo-4- ⁇ morpholinyl)-phenyl]-l,3-oxazolidin-5-yl ⁇ -methyl)-2-thiophenecarboxamide involving starting compound 5-chlorothiophene-2-carbonyl chloride, (2 1 S -3 i amino-p!Opane-l,2-diol and 4-(4-amtnophenyl)-3-morpholinone.
  • the staring materials are prepared by reaction of (5)-Epicholorohydrin with NaN 3 in presence of AcOH and H 2 0, in ambient temperature for 5 h or with Phthal imide in presence of K 2 C0 3 (cat.), !PA, with reflux for 5 h and further treating the corresponding product with triphosgene in presence of Et 3 N and THF.
  • Reagents and conditions (a) NaN 3 , AcOH, H 2 0, ambient temperature, 5 h, 80%; (b) Phthalimide, 2 C0 3 (cat.), I PA, reflux, 5 h, 75%; (c) Triphosgene, Et 3 N, THF, 0 °C to r.t. 2-3 h,72-89%. '
  • CN 102321041 describes a reaction of (S')-epichloiOhydrin and sodium azide to obtain l-azido-3-chloro-2-propanol; cyclizing l-azido-3-chloro-2-propanol with N-(3-fluoro-4-morpholinophenyl)amine; and finally, reducing and acetylizing to obtain the linezolid as shown below in scheme-Vlll:
  • R 2 is (Ci-Cis)alkyl, aryl, aryl (C1-C4) alkyl, hetroaryl or heteroaryl-(Ci-Ci)alkyl.
  • the primary object of the invention is to provide a combined process for preparation of more than one oxazolidinone derivative compounds using (5)- Epichlorohydrin .
  • Another object of the invention is to provide a novel combined process for preparation of Linezol id and Rivaroxaban using (£)- Epichlorohydrin.
  • Another object of the invention is to provide a novel process for preparation of Linezol id compounds using (S)- Epich lorohydrin.
  • Another object of the invention is to provide a novel process for preparation of Ri varoxaban compounds using (S)- Epichlorohydrin .
  • novel process of the invention is suitable for preparation of more than one oxazolid inone derivatives, more particularly Linezol id compounds and Rivaroxaban compounds.
  • the novel process uses (S)-Epich!orohydrin as the starting material which reacts with a metal azide to give an azido alcohol compound (Compound- 1 ), subsequently cycl izing compound-I to an oxirane compound (Compound-2) in presence of an inorgan ic base as fol lows:
  • Compound-1 Compound-2
  • the novel process comprises the steps of: reacting (5)-Epich lorohydrin with a metal azide to give an azido alcohol compound- 1
  • step (i) cycl izing the azido alcohol compound- 1 obtained in step (i) above to an- oxirane compound-2 in organic solvents in presence of an inorganic base;
  • step (i ii) reacting oxirane compound-2 obtained in step (i i) above with a compound-3 in presence of solvents;
  • step (iv) converting azido alcohol compound-4 obtained in step (i i i) above to an xazol idinone com pound of formula (Compund-5);
  • R 2 -CH 3 or R 7
  • R -o-e-cn 3 o
  • R -OH or -CI
  • the invention provides a process for preparation of more than one oxazol id i none derivatives using (5)-Epichlorohydrin. More particularly, the invention specifically provides a process which can be used for the preparation of Linezolid as well as Rivaroxaban compounds using (S)-Epich lorohydrin.
  • scheme-A i l lustrates a common process for preparation of oxazolidinone derivatives, more specifical ly, Linezolid and Rivaroxaban starting from reaction of (S)-Epich lorohydrin and a metal azide as fol lows: — NH,
  • Step-i -Reacting (S ⁇ -Epichlorohydrin with a metal azide to give an azido alcohol
  • This step comprises dissolving metal azide in water at room temperature and adding (5)- Epichlorohydrin in a suitable organic solvent. Stir the reaction mixture at 5- 10°C for l hour and allowing the reaction mixture to reach to room'temperature for 3-4 hrs.
  • the metal azide may be selected from l ithium azide (LiNj j , sodium azide (NaN 3 ) and potassium azide (K.N 3 ). In one preferred embodiment the metal azide is sodium azide (NaN 3 ).
  • the su itable organ ic solvent may be selected from methanol, ethanol, propano l, acetone , dimethyl formamide and butanol.
  • the organic solvent is methanol.
  • Step-II -Cyclizing the azido alcohol compound-1 obtained in Step-(I) above to an oxirane compound-2 in presence of an inorganic base o,
  • Th is step com prises cyclizing the compound- 1 in presence of an inorganic base in a suitabl organic solvent .
  • the inorgan ic base is potassium carbonate.
  • Step-HI Reacting the oxirane compound-2 obtained in Step-II above with compound-3
  • Th is step involves addition of compound-3 to a solution of compound-2 in alcoholic solvent at room temperature.
  • the reaction can be carried out in any suitable alcohol ic solvent selected from methanol, ethanol, isopropyl alcohol (1 PA), propanol and butanol. I n one preferred embodiment, isopropyl alcohol is used.
  • Step-IV -Converting azido alcohol compound-4 obtained in Step-III above to an
  • the step-I V comprises d issolving azide compound-4 in a su itable organic solvent and carbonylating using carbonylating reagents to obtain compound-5.
  • the carbonylation reaction is carried out by using any carbonylating reagents such as carbonyldii m idazole (CD1), diethyl carbonate, methyl chloroformate, benzyl chloroformate, phenyl chloroformate and triphosgene, preferably carbonyldi im idazole or d iethyl carbonate.
  • carbonylation should be carried out in presence of inorgan ic bases such as metal carbonates, metal bicarbonates and metal hydroxides.
  • the inorgan ic base is metal carbonate selected from potassium carbonate and sod ium carbonate.
  • the metal carbonate is potassium carbonate.
  • Step-V -Reducing the compound-5 obtained in Step-IV above to an amine compound-6
  • the compound-5 is dissolved in an organic solvent and reduced to am ine compound-6 using a reducing agent.
  • the reducing agent may be selected from Pd-C/H and triphenyl phosph ine (TPP).
  • TPP triphenyl phosph ine
  • the reduction reaction is carried out in solvent selected from protic and aprotic solvents or mixtures thereof.
  • the solvents are toluene, tetrahydrofuran and alcoholic solvents.
  • Step-VI -reacting the amine compound-6 obtained in Step-V above with a compoii
  • This step comprises reacting compound (6) with compound (7) in an organic solvent under suitable conditions to get the crude oxazolidinone derivative compound (8). Crystallizing the crude compound (8) in suitable solvent to get pure compound (8).
  • vvhen- The-obtained oxazolidinone derivative is Rivaroxaban com ound.
  • the oxazol idinone derivatives compound of formula (Com pound-8) is Linezol id or Rivaroxaban.
  • scheme-A is further described herein after separately for Linezol id as scheme-B and for Rivaroxaban as scheme-C.
  • Scheme-B The process for preparation of Linezolid il lustrated in Scheme-B comprises the steps of.
  • Step-I Reacting (5 -Epichlorohydrin with a metal azide to give (S)- ⁇ -azido-3-chloro- propan-2-ol (Compound- 1 );
  • Step-II Cyclizing the compound- 1 obtained in step (I) above to (S)-2- azidomethyl-oxirane (Compound-2) in presence of an inorganic base;
  • Step-III Reacting compound-2 obtained in step (I I) above with 3-fluoro-4-morpholin-4- yl-pheny!amine (Compou of organic solvents;
  • Step-V Reducing compound-5a obtained in step (IV) above to (5)-5-aminomethyl-3-(3- fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (Compound-6a);
  • Step- VI Reacting compound-6a obtained in step (V) above with acetic anhydride
  • the Step (I) in above described Scheme-B comprises reacting (S)-Epichlorohydrin with a metal azide in a suitable organic solvent at ambient temperature to give (5)- l -azido-3-chloro- propan-2-ol (Compound- ! ), wherein the metal azide may be selected from lithium azide (LiN 3) , sodium azide (NaN 3 ) and potassium azide ( N 3 ). In one preferred embodiment the metal azide is sodium azide (NaN 3 ).
  • the suitable organic solvent may be selected from methanol, ethanol, propanol, acetone , dimethyl formamide and butanol. In one preferred embodiment the organic solvent is methanol.
  • the step-ll in above Scheme-B comprises dissolving (Syi-azido ⁇ -chloro-propan ⁇ -ol (Compound- 1) in suitable organic solvent in presence of an inorganic base and refluxing for 3-4 hr at reflux temperature. Distilling and dissolving the residue in water and ethyl acetate at room temperature with stir for 5-10 minutes and separating and distill out organic solvent to get crude (5)-2-azidomethyl-oxirane (Compound-2).
  • the organic solvent may be ketonic solvent, alcoholic solvent or a mixture thereof.
  • the ketonic solvent may be selected from acetone, methyl isobutyl ketone, methyl isopropyl ketone .
  • the alcohiic solvent may be selected from methanol, ethanol, propanol, isopropanol, n-butanol.
  • ketonic solvent is acetone and alcohiic solvent is isopropyl alcohol.
  • the inorganic base may be selected from potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate In one preferred embodiment the inorganic base is • potassium carbonate.
  • step-Ill in above described scheme-B involves addition of 3-fluoro-4-morpholin-4 yl- phenylamine (Compound-3a) to a solution of (5")-2-azidomethyl-oxirane compound-2 in an alcoholic solvent at room temperature. Heating the reaction mass to reflux temperature for 10-12 hrs, distilling the solvent under vacuum to obtain the crude (R)-l -azido-3-(3-fluoro-4- morpholin-4-yl-phenylamino)-propan-2-ol (Compound-4a).
  • the reaction can be carried out in any suitable alcoholic solvent selected from isopropyl alcohol (IPA), methanol, ethanol, propanol and butanol.
  • IPA isopropyl alcohol
  • isopropyl alcohol is used.
  • the step-IV in above described scheme-B comprises d issolving (7?)- l -azido-3-(3-fIuoro-4- morpholin-4-yl-phenylam ino)-propan-2-ol (Compound-4a) in a suitable organic solvent and carbonylati ng using carbonylating reagents to obtain (./?)-5-azidomethyl-3-(3-fl uoro-4- morpholin-4-y)-phenyl)-oxazol idin-2-one (Compund-5a).
  • the carbonylation reaction is carried out by using any carbonylating reagents such as carbonyldiimidazole, diethyl carbonate, methyl ch loro formate, benzyl ch loroform ate, phenyl chloroformate and triphosgene, preferably carbonyldiimidazole , or diethyl carbonate.
  • carbonylating reagents such as carbonyldiimidazole, diethyl carbonate, methyl ch loro formate, benzyl ch loroform ate, phenyl chloroformate and triphosgene, preferably carbonyldiimidazole , or diethyl carbonate.
  • the carbonylation should. be carried out in presence of inorgan ic bases such as metal carbonates, metal bicarbonates and metal hydroxides.
  • inorganic bases such as metal carbonates, metal bicarbonates and metal hydroxides.
  • the inorganic base is metal carbonate selected from potassium carbonate and sod ium carbonate.
  • the metal carbonate is potassium carbonate.
  • the step-V in above described scheme-B comprises dissolving (7?)-5-azidomethyl-3-(3- fluoro-4-morphol in-4-yl-phenyl)-oxazol idin-2-one (Compund-5a) in an organic solvent and reduced to (5)-5-am inomethyl-3-(3-fluoro-4-morphol in-4-yl-phenyl)-oxazol id in-2-one (Compound-6a) using a reducing agent.
  • the reducing agent may be selected from Pd-C/H 2 and triphenyl phosphine. I n one preferred embodiment, triphenyl phosph ine (TPP) is used as reducing agent.
  • the reduction reaction is carried out in solvent selected from protic and aprotic solvents or m ixtures thereof.
  • solvents are toluene,tetrahydrofuran, isopropyl alcohol (IP A) and mixture thereof.
  • the step-VI in above described scheme-B comprises adding acetic anhydride (com pound-7a) at 0-5°C to a solution of (5)-5-am inomethyl-3-(3-fluoro-4-morphol in-4-yl-phenyl)- oxazol idin-2-one (Compound-6a) in an organic solvent either using base or in absence of the base and slowly raising the temperature to room temperature and heating up to 70°C based on choosen solvent and stirring for 1 -2 hrs. Cooling the reaction mass to room temperature, fi ltering and washi ng the mass to get crude oxazol idinone derivative Linezol id (compound- 8a).
  • the suitable solvent is used methanol.
  • the organic solvent may be selected from methylene dichloride (MDC), toluene, tetrahydrofuran, acetonitrile, chloroform .
  • MDC methylene dichloride
  • toluene tetrahydrofuran
  • acetonitrile chloroform
  • chloroform a preferred embodiment the organic solvent methylene dichloride is used.
  • Step-I Reacting (5)-epichlorohydrin with a metal azide to give (5)-l -azido-3-chloro- propan-2-ol (Compound- 1 )
  • Step-III Reacting compound-2 obtained in step (I I) above with 4-(4-am inophenyI)-3- morphol inone (Compou of alcohol ic solvents;
  • Step-IV Converting compound-4b obtained in step (H I) above to ( ?)-4-[4-(5-azidomethyl- 2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (Compund-5 b);
  • Step-V Reducing compound-5b obtained in step (IV) above to (5)-4-[4-(5-aminomethyl- 2-oxo-oxazolidin-3-yl)-phenyl]-morphol in-3-one (Compound-6b);
  • Step- VI Reacting compound-6b obtained in step (v) above with a compound of formula
  • Step (I) in above described Scheme-B comprises reacting (5)-Epich lorohydrin with a metal azide in a suitable organ ic solvent at am bient temperature to give (S - l -azido-3-chloro- propan-2-ol (Compound- 1 ), vvherein the metal azide may be selected from lithium azide (LiN 3) , sod ium azide ( aN 3 ) and potassi um azide ( N 3 ). In one preferred embodiment the metal azide is sodium azide (MaN 3 ).
  • the suitable organic solvent may be selected from methanol, ethanol, propanol, acetone , dimethyl formam ide and butanol. In one preferred embod iment the organic solvent is methanol.
  • the step- l l in above Scheme-B comprises d issolvi ng (5)- 1 -azido-3-ch loro-propan-2-ol (Compound- 1 ) in suitable organic solvent in presence of an inorganic base and refluxing for 3-4 hr at reflux temperature.
  • the organic solvent may be ketonic solvent, alcohol ic solvent or a mixture thereof.
  • the ketonic solvent may be selected from acetone, methyl isobutyl ketone, methyl isopropyl ketone .
  • the alcohl ic solvent may be selected from methanol, ethanol, propanol, isopropanol, n-butanol.
  • the ketonic solvent is acetone and alcohlic solvent is isopropyl alcohol.
  • the inorganic base may be selected from potassium carbonate, sod ium carbonate, potassium bicarbonate and sodium bicarbonate In one preferred embod iment the inorganic base is potassium carbonate.
  • Step-Ill in the above described scheme-C com prises add ition of 4-(4-am inophenyl)-3- morpho!inone (Compound-3b) to a solution of (5)-azidomethyl-oxirane compound-2 in alcoholic solvent at room temperature. Heating the reaction mass to reflux temperature for 1 0- 12 hrs, distil l ing the solvent under vacuum . to obtain the crude (/?)-4-[4-(3-azido-2- hydroxy-propylam ino) phenyl]-morphol in-3-one (Compound-4b).
  • the reaction can be carried out in any suitable solvent selected from isopropyl alcohol (I PA), methanol, ethanol, propanol and butanol .
  • isopropyl alcohol is used.
  • the step-I V in above descri bed scheme-C com prises d issolving (/?)-4-[4-(3-azido-2-hydroxy- propylam ino) phenyl]-morpholin-3-one (Compound-4b) in a su itable organic solvent and carbonylating using carbonylating reagents to obtain (/?)-4-[4-(5-azidomethyl-2-oxo- oxazol idin-3-y!-phenyl]-morpholin-3-one (Compund-5b).
  • the carbonylation reaction is carried out by using any carbonylating reagents such as carbonyld i i m idazole, diethyl carbonate, methyl chloroformate, benzyl chloroformate, phenyl chloroformate and triphosgene, preferably carbonyldi im idazole or diethyl carbonate.
  • carbonylating reagents such as carbonyld i i m idazole, diethyl carbonate, methyl chloroformate, benzyl chloroformate, phenyl chloroformate and triphosgene, preferably carbonyldi im idazole or diethyl carbonate.
  • the inorgan ic base is metal carbonate selected from potassium carbonate and sodium carbonate.
  • the metal carbonate is potassi um carbonate.
  • the step-V in above described scheme-C comprises dissolving (,R)-4-[4-(5-azidomethyl-2- oxo-oxazol idin-3-yl)-phenyl]-morpholin-3-one (Compund-5b) in an organ ic solvent and reduced to (5)-4-[4-(5-aminomethyl-2-oxo-oxazol idin-3-yl)-phenyl]-morphol in-3-one (Compound-6b) using a reducing agent.
  • the reducing agent may be selected from Pd-C/H 2 and tripheny! phosphine.
  • triphenyl phosphine (TPP) is used as reducing agent.
  • the reduction reaction is carried out in solvent selected from protic and aprotic solvents or m ixtures thereof.
  • solvents are tetrahydrofuran, toluene, isopropyl alcohol (I A), water and mixture thereof.
  • the step-Vl in above described scheme-C comprises dissolving the ( -4-[4-(5-aminomethyl- 2-oxo-oxazo!idin-3-yl)-phenyl]-morpholin-3-one (Compound-6b) in an organic solvent reacted with 5-chlorothiophene-2-carboxylic acid (compotind-7b) using CDI and base or with 5-chlorothiophene-2-carbonyl chloride (compound-7b) in presence of base at suitable temperature.
  • step-Vl in above described scheme-C comprises dissolving the ( -4-[4-(5-aminomethyl- 2-oxo-oxazo!idin-3-yl)-phenyl]-morpholin-3-one (Compound-6b) in an organic solvent reacted with 5-chlorothiophene-2-carboxylic acid (compotind-7b) using CDI and base or with 5-chlorothiophene-2-carbonyl chloride (compound-7b
  • Example-1 Preparation of (5)-l-azido-3-chloro-propan-2-ol (compound-1)
  • Example-3 - Preparation of (?)-l-azido-3-(3-fluoro-4-morpholin-4-yl-phenyIamino)- propan-2-ol (compound 4a) (S")-2-azidomethyl oxirane (compound 2) (50.0 gr, 0.5 mol) was taken in isopropyl alcohol (375.0 mL) and 3-fluoro-4-morphoIin-4-yl-phenylamine (compound 3a) (74.3 gr, 0.378 mol) was added at room temperature. The whole reaction mass was heated to reflux temperature for 10-12 hrs. The progress of the reaction was monitored by TLC. After completion of reaction distil off the solvent under vacuum to get residue.
  • the resultant crude product was purified by column chromatography using silica gel eluted with ethyl acetate in petroleum ether. The fractions containing the title compound were combined and concentrated under vacuum; the resulted solid was isolated in isopropyl ether. This stage was purified only for compound identification purpose otherwise without purification it can be converted to next stage.
  • the novel azide compound (/?)-l-azido-3-(3-fIuoro-4-morpholin-4-yl-phenylamino)-propan- 2-ol (4a) is characterized by X-ray power diffraction spectrum with peaks at peaks about 7.016, " 10.33, 15.20, 15.73, 16.35, 18.15, 18.59, 20.09, 20.70, 21.04, 21.34, 22.17, 22.97, 23.36, 24.06, 27.49, 28.45, 28.81, 29.58, 29.95, 32.00 ⁇ 0.2° 2 ⁇ .
  • Example-5 - Preparation of (/?)-l-azido-3-(3-fluoro-4-morpholin-4-yl-phenyIamino) propan-2-ol (compound 4a) from (5)-l-azido-3-chloro-propan-2-ol (compound-1) in single step: (S)- l -azido-3-ch loropropan-2-ol (compound- 1 ) ( 1 00.0 gr, 0.738 mol) dissolved in isopropyl alcohol (500.0 mL) and potassium carbonate (200.0 gr, 1 .45 mol) was added at room temperature. The reaction mixture was heated to reflux and maintained at reflux temperature for 3-4 hr.
  • the organ ic layers were combined and washed with brine •solution ( 100.0 mL) and organic layer was dried with anhydrous a 2 SC>4 and distilled under vacuum to get the crude residue.
  • the resultant crude product was purified by column chromatography using si l ica gel eluted with ethyl acetate in petroleum ether. The fractions containing the title compound were combined and concentrated under vacuum the resulted solid was isolated in isopropyl ether.
  • ExampIe-6 - Preparation of (/?)-5-azidomethyi-3-(3-fluoro-4-morpholin-4-yl-phenyi)- oxazolidin-2-one (compound 5a) from (5)-l-azido-3-chloro-propan-2-ol (compound-1) in single step:
  • Example-13 Preparation of (/?)-4-[4-(3-azido-2-hydroxy-propyIamino) phenylj- morpholin-3-one (compound 4b) from (5 -l-azido-3-chloro-propan-2-ol (compound 1) in single step: (.S)- l -azido-3-chloropiOpan-2-ol (compound 1 ) (50.0 gr, s 0.369 mol) dissolved in isopropyl alcohol (250.0 mL) and potassium carbonate ( 100.0 gr, 0.724 mol) was added at room temperature. The reaction mixture was heated to reflux and maintained at reflux temperature for 3-4 hr.

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Abstract

L'invention concerne un procédé de préparation de dérivés d'oxazolidinone tels que le Linézolid et le Rivaroxaban à l'aide de la (S)-épichlorhydrine.
PCT/IN2013/000761 2013-04-18 2013-12-09 Procédé de préparation de dérivés oxazolidinone WO2014170908A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN1715/CHE/2013 2013-04-18
IN1715CH2013 2013-04-18
IN4377/CHE/2013 2013-09-26
IN4377CH2013 2013-09-26

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WO2014170908A1 true WO2014170908A1 (fr) 2014-10-23

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111606870A (zh) * 2020-05-31 2020-09-01 湖北扬信医药科技有限公司 一种利奈唑胺相关物质及其制备方法和用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070032472A1 (en) * 2004-04-19 2007-02-08 Symed Labs Limited Novel process for the preparation of linezolid and related compounds
WO2011137222A1 (fr) * 2010-04-30 2011-11-03 Indiana University Research And Technology Corporation Procédés de préparation de linézolide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070032472A1 (en) * 2004-04-19 2007-02-08 Symed Labs Limited Novel process for the preparation of linezolid and related compounds
WO2011137222A1 (fr) * 2010-04-30 2011-11-03 Indiana University Research And Technology Corporation Procédés de préparation de linézolide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111606870A (zh) * 2020-05-31 2020-09-01 湖北扬信医药科技有限公司 一种利奈唑胺相关物质及其制备方法和用途

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