WO2018055499A1 - One pot synthesis for the preparation of substituted phthalimido oxazolidinone antibacterials and oxazolidinone antiharombotics compounds by using recyclable heterogeneous catalyst - Google Patents

One pot synthesis for the preparation of substituted phthalimido oxazolidinone antibacterials and oxazolidinone antiharombotics compounds by using recyclable heterogeneous catalyst Download PDF

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WO2018055499A1
WO2018055499A1 PCT/IB2017/055620 IB2017055620W WO2018055499A1 WO 2018055499 A1 WO2018055499 A1 WO 2018055499A1 IB 2017055620 W IB2017055620 W IB 2017055620W WO 2018055499 A1 WO2018055499 A1 WO 2018055499A1
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compound
formula
oxazolidinone
preparation
substituted
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PCT/IB2017/055620
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French (fr)
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Srirama Krishna AVIRNENI
Venkata Srihari Tadimalla
Venkata Mallaparaju GOTTIMUKKULA
N.V. Suryanarayana Murthy MOTAMARRI
Yesubabu KOTICHUKKALA
Prakash M.S.S.
Suribabu SABBAVARAPU
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Phalanx Labs Private Limited
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    • 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
    • C07D413/06—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 only aliphatic 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
    • C07D413/14—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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

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  • the present invention provides a novel and high yield processfor preparation of substitutedphthalimidoOxazolidinone compoundof Formula-I by using recyclable heterogeneous catalyst. More particularly this substitutedphthalimidoOxazolidinone compound of Formula-I is keyintermediate in manufacturing of many Active Pharmaceutical ingredients such asanti bacterial such as Linezolid and antithrombotic compounds such as Rivaroxaban.
  • oxazolidinone compounds are not products of fermentation, but chemically synthesized ones, and various structures of their derivatives are known.
  • 3-phenyl-2-oxazolidinone derivatives having one, two or three substituents are Linezolid and Rivaroxaban, whoseprior art is stated as follows;
  • Linezolid also known as (S)-N-[[3-[3-iluoro-4-(4-morpholinyl)phenyl]-2-oxo-5- oxa.zolidinyl]rnethyi]a.cetarnide, can be represented by the structure of general Formula-IVa.
  • Linezolid has the following chemical structure:
  • Linezolid is a synthetic antibacterial agent, of the oxazolidinone class.
  • Linezolid has clinical utility in the treatment of infections caused by aerobic Gram- positive bacteria.
  • the in vitro spectrum of activity of Linezolid also includes certain Gram- negative bacteria and anaerobic bacteria.
  • Linezolid inhibits bacterial protein synthesis through, a mechanism of action different from that of other antibacterial agents, therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely.
  • Linezolid is marketed by Pfizer under the trade names Zyvox (in the United States, United Kingdom, Australia, and. several other countries), Zyvoxid (in Europe), and Zyvoxam (in Canada, and Mexico) .
  • Rivaroxaban is an orally active factor Xa inhibitor developed by Bayer Healthcare, for the prevention and treatment of deep vein thrombosis and pulmonary embolism, in patients under going knee and hip replacement surgery. Rivaroxaban has an oxazolidinone nucleus and chemically is known as 5-ChIoro ⁇ N-(((5S)-2-oxo-3-(4-(3-oxo ⁇ 4-morpholinyl)phenyl]-- l ,3--oxa2olidin-5- yl)methyl)-2-thiophenecarboxamide, represented by the following structural formula compound of Formula-lVb.
  • Rivaroxaban is marketed under trade name XARELTG ® by Janssen Pharmaceuticals, Inc.
  • phthalimidooxazolidinone is prepared by a process as depicted in Scheme-IX.
  • the present novel process is easier to carry on Industrial scalewith high yields, less expensive and short process time.
  • Compound of Formula-IIreacted with (R)-Epichlorohydrin in solvents include cvclic esters such as tetrahvdrofuran, amides such as N.N-Dimethvlformamide, ⁇ , ⁇ -Dimethylacetamide, and alcohols such as methanol, ethanol, n-butanol, t- amyl alcohol, t-butyl alcohol, isopropyl alcohol and hexanol; and a mixture thereof.
  • the most preferable solvent is n-butanol.
  • the catalyst preferred mole ratio is 1 :0.05- 1. Time required for completion of reaction to higher yields depends upon the factors those are solvent, catalyst and temperature. Wherein the catalyst reduces the time cycle, enable to complete the condensation at mild temperatures with Formula-Ill and carbonylationinsitu. Wherein carbonylation was performed by using alkylchloro formates such methylchloro formate, ethylchloro formate, etc., the preferable alkylchloroformate is methylchloro formate.
  • reaction mass was treated with Potassium phthalimide in N,N-Dimethylformamide after worked up to get compound of Formula-I.
  • the theoritieal yield from the aniline compound of Formula--ll to substituted phthalimidooxazolidinone compound of Formula.-l is above 80% of theory.
  • the compound of Formula-I was further converted to Linezolid or Rivaroxaban as per the known Inventors processes.
  • Example 1 Preparation of (S) - N - [ [3 - [3 --Fluoro-4 - [4 -morpholinyl]phenyl] -2 -oxo - 5 -oxazolidiny 1] me thy 1] ph thalim ide 3-Fluoro-4-morpholinoaniline (100 gm) was added in n-butanol (300 ml) and charged Alumia sulfonic acid at ambient temperature. Cool the mass, added(R)-Epichlorohydrin (72 gm) and maintain the reaction mass at below 20°C. Confirmed the completion of reaction, separated the catalyst.
  • Linezolid was having the HPLC purity >99.5% and FTIR in KBrvalues in cm -1 are: 3364, 1748, 1675, 1537, 1517, 1445, 1410, 1400, 1358, 1329, 1287, 1273, 1252, 1237, 122 1 , 1 144, 1 130, 1 123, 1 1 16, 1078, 1065, 1049, 906, 851 and 757.
  • Example 2 was repeated with same quantities and process except the material was isolated in ethyl acetate to obtain Linezolid having HPLC purity > 99.5% and the melting range was matching Inventors Form-I. The melting range obtained was 180.0- 182.5°C.
  • Example 4 Preparation of 2 - ( ⁇ (5 S) -2 -Oxo-3 - [4- (3 -oxo-4-morpholinyl) phenyl] - l ,3-oxazolidin-5-34 ⁇ metliyl)- IH-isoindole- l ,3(2H)-dione

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

Abstract

A novel one pot and high yield process for the preparation of substituted phthalimidooxazolidinone compounds by using recyclable heterogeneous catalyst and preparation of oxazolidinoneantibacterials and oxazolidinoneantithrombotics thereof.

Description

Title:
ONE POT SYNTHESIS FOR THE PREPARATION OF SUBSTITUTED PHTHALIMIDO OXAZOLIDINONE ANTIBACTERIALS AND OXAZOLIDINONE ANTI HAROMBOTICS COMPOUNDS BY USING RECYCLABLE HETEROGENEOUS CATALYST
Field of the invention:
The present invention provides a novel and high yield processfor preparation of substitutedphthalimidoOxazolidinone compoundof Formula-I by using recyclable heterogeneous catalyst. More particularly this substitutedphthalimidoOxazolidinone compound of Formula-I is keyintermediate in manufacturing of many Active Pharmaceutical ingredients such asanti bacterialsuch as Linezolid and antithrombotic compounds such as Rivaroxaban.
Back ground of the invention:
Usually oxazolidinone compounds are not products of fermentation, but chemically synthesized ones, and various structures of their derivatives are known. For instance 3-phenyl-2-oxazolidinone derivatives having one, two or three substituents are Linezolid and Rivaroxaban, whoseprior art is stated as follows;
Linezolid, also known as (S)-N-[[3-[3-iluoro-4-(4-morpholinyl)phenyl]-2-oxo-5- oxa.zolidinyl]rnethyi]a.cetarnide, can be represented by the structure of general Formula-IVa. Linezolid has the following chemical structure:
Figure imgf000002_0001
Linezolid is a synthetic antibacterial agent, of the oxazolidinone class. Linezolid has clinical utility in the treatment of infections caused by aerobic Gram- positive bacteria. The in vitro spectrum of activity of Linezolid also includes certain Gram- negative bacteria and anaerobic bacteria. Linezolid inhibits bacterial protein synthesis through, a mechanism of action different from that of other antibacterial agents, therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely. Linezolid is marketed by Pfizer under the trade names Zyvox (in the United States, United Kingdom, Australia, and. several other countries), Zyvoxid (in Europe), and Zyvoxam (in Canada, and Mexico) .
Substituted, phthalirnidooxazoliclinone compound i.e., (S)--N--[[3--[3--Fl.uoro--4--[4-- morpholiriyl]phenyl]-2-ox.o-5-oxazolidinyljmethyl]phthalimide is key
Intermediate in the manufacturing of anti bacterial agent such as Linezolid.
The synthesis of (S)-N-[[3-[3 -Fluoro-4-[4-morpholinyl]phenyl]-2 -oxo-5- o.xazolidinyl]methyl]phthalimide was first disclosed in the U.S. Patent No, 5,688,792. This is an Intermediate in the synthesis of Linezolid. According to thePatent the substituted phthalimiclooxazolidinoneis prepared by a process as depicted in Scheme -I.
Figure imgf000003_0001
The synthesis of (S) -N - [[3 - [3 -Pluoro-4- [4-morpholinyl] phenyl] -2 -oxo-5- oxazolidinyl]methyl]phthalimide was disclosed in the Patent No. WO 2012/ 1 14355. This is an Intermediate in the synthesis of Linezolid. According to the Patent the substituted phthalirnidooxazalidinone is prepared by a process as depicted in Scheme-IP The theoretical yield from the aniline compound to substituted phtha.limid.ooxazolidmone compound is 17%.
Figure imgf000003_0002
The synthesis of (S) -N - [[3 - [3 -Fluoro-4- [4-morpholinyl] phenyl] -2 -oxo-5- oxazolidinyl]methyl]phthalrmide was disclosed, in the US Patent No. 7,307, 163, This is an Intermediate in the synthesis of Linezolid, According to the Patent the substituted phthalimidooxazolidinone is prepared by a process as depicted in Scheme-ill. The. theoritical yield from the aniline, compound to substituted phthalimidooxazolidinone compound is 47.3%.
Figure imgf000004_0001
The svnthesis of (S) -N - [[3 - [3 -Fluoro-4- [4-morpholinyl] phenyl] oxazolidinyl]methyl]phthalimide was disclosed in the US Patent No, 7,429,661 B2. This is an Intermedicite in the synthesis of Linezolid. According to the Patent the substituted phthalimidooxazolidinone is prepared by a process as depicted in Scheme-IV. The theoritical yield from the aniline compound to substituted phthalimidooxazolidinone compound by the A route is 50 % and by the route B is 59%.
Figure imgf000004_0002
The synthesis of (S) -N - [[3 - [3 -Fluoro-4- [4-morpholinyl] phenyl]--2~oxo-5~ oxazolidinyl]met.hyl]phthalmi ide was disclosed in the Patent No. WO 2015/ 162622 A 1. This is an Intermediate in the synthesis of Linezolid. According to the Patent the substituted phthalimidooxazolidinone is prepared by a. process as depicted in Scheme-V. The theoritical yield from the aniline compound to substituted phthalimidooxazolidinone compound is 54%.
Figure imgf000005_0001
Rivaroxaban is an orally active factor Xa inhibitor developed by Bayer Healthcare, for the prevention and treatment of deep vein thrombosis and pulmonary embolism, in patients under going knee and hip replacement surgery. Rivaroxaban has an oxazolidinone nucleus and chemically is known as 5-ChIoro~N-(((5S)-2-oxo-3-(4-(3-oxo~4-morpholinyl)phenyl]-- l ,3--oxa2olidin-5- yl)methyl)-2-thiophenecarboxamide, represented by the following structural formula compound of Formula-lVb.
Currently, Rivaroxaban is marketed under trade name XARELTG® by Janssen Pharmaceuticals, Inc.
Figure imgf000005_0002
The synthesis of 2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl|-l ,3- oxazoliclin-5~yI}methyIj- lH-isoindole- l ,3(2H)-dione was first disclosed in the U .S. Patent No, 7, 157,456. This is an Intermediate in the synthesis of Riva.roxa.han, According to the Patent the substituted, phthalimidooxazolidinone is prepared by a process as depicted in Scheme- VI.
Figure imgf000006_0001
The synthesis of 2-({(5S) -·2··Οχο-3- [4-(3-oxo-4-morpholinyl)phenyl]- 1 ,3- oxazolidin-5-yl}methyl)- lH-isoindole- l ,3(2H)-dione was disclosed in the Patent No. WO 2013/ 120464 A 1. This is an Intermediate in the synthesis of Rivaroxahan. According to the Patent the substituted phthalimidooxazolidinone is prepared by a. process as depicted in Scheme-- VII.
Figure imgf000006_0002
The synthesis of 2 - ({(5S) -2 - Oxo-3 - [4-(3 -oxo-4-morpholinyl) phenyl] - 1 ,3- oxazolidin-5-yl}methyl)- lH-isoindoIe- l ,3(2H)--dione was disclosed in the Patent No. US 2014/0142303 A1. This is an Intermediate in the synthesis of Rivaroxaban. According to the Patent the substituted phthalimidooxazolidinone is prepared by a process as depicted in Scheme-VIII.
Figure imgf000007_0001
The synthesis of 2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l -1,3- oxazolidlin-5~yl}methyl)- lH-isoindole- l ,3(2H)-dione was disclosed in the Patent No. US 2015/001 1756 A 1. This is an Intermediate in the synthesis of
Riva.roxa.han. According to the Patent the substituted.
phthalimidooxazolidinone is prepared by a process as depicted in Scheme-IX.
Figure imgf000007_0002
The synthesis of 2 - ({(5 S) -2 - Oxo-3 - [4-(3 -oxo-4-morphoIinyl) phenyl] - 1 ,3- oxazolidin-5-yl}methyl)- 1H-isoindole- l ,3(2H)-dione was disclosed in the Patents US 2014/ 0378682, US 2015/0038704, US 2015/ 0299175, US 2016/0052919, US 9079892 B2, US 9394292 B2, WO 201 1 /012321 AL WO 2013 / 120465 AL WO 2015/ 198259 A l , WO 2016 /030669 Al .
However these process for the synthesis of phthalimidooxazolidinone compound of Formula-I were associated with many draw backs in commercialization such as lower yields, usage of many solvents, using of n- Butyllithium at very lower temperature and using of Phosgene are very difficult in the commercialization process. In another invention expensive chiral resolution reagents are used. In another Invention (R)-Epichlorohydrin condensed with substituted aniline compound in Isopropyl alcohol at reflux temperature wherein the condensation is leading many impurities and isolation of hydroxy 1 compound Intermediate in the process of purification is leading to the process lengthy and expensive. In the prior art process expensivecarbonylating agents are used like l , l '-Carbonyldiimidazole, Phosgene, butylchloroformate, phenylchloroformate, tertiary butylchloro formate.
In the prior art processes, the chloro derivate obtaining from the aniline derivative treating with (R)-Epichlorohydrin in Isopropyl alcohol, tertiary Butanol at boiling temperatures. Impurities are forming by these processes hence shows the result on low yield around 50% of theory.
SUMMARY OF THE INVENTION
Leading to the present invention, the intensive and thorough research on oxazoliclinone derivatives, conducted, by the present inventors aiming to overcome the above problems encountered in prior arts, resulted in inventing a novel, economic, single pot and high yield process for the preparation of substituted phthalimidooxazolidinone compounda key Intermediate by treating the aniline derivative in an alcoholic solvent with pseudo acidic metal heterogeneous recyclable catalyst at lower temperature. The novel process solve the drawbacks associated with the prior art processes such as formation of impurities, lower yield, higher temperature and process time.
In the prior art process, the condensation reaction of (R)-Epichlorohydrin processed in one solvent and carbonylation reaction processed in other solvent. The invented novel process avoiding the usage more solvents and reactions are conducting in one solvent by in-situ process.
Therefore, it is an object of the present invention to provide a simple process by using less number of solvents and less expensive reagents to enhance the efficiency of the reaction at mild temperatures. Another object of the present invention to provide a process at lower
temperatures and. shorter reaction time to avoid impurities thus achieving higher yields.
It is a further object of the present invention to provide a process with less number of solvent evaporations thus avoid exposure to the higher
temperatures and isolations.
In accordance with, an aspect of the present invention., the process for
substituted phthalimidooxazolidinonecompound of Formuia-I to fulfill the above said objects was invented as follows:
Aniline derivative compound of Formula-II
Figure imgf000009_0001
in n-Butanol at low temperature in the presence of pseudo acidic metal heterogeneous catalyst, followed by alkyl chloroformate, further treated with Potassium phthalimide in N,N-Dimeth.yiformam.ide to get compound of Formula-I. The yield from the aniline compound of Formula-II to substituted pbthalimidooxazolidinone compound of Formula-I is above 80% of theory.
Figure imgf000009_0002
Detailed description of the invention:
The present invention describes an one pot process for preparation of compound of Formula-I which are the Intermediates for Linezolid where R=Morpholineand X=Flouorine whereas for Rivaroxaban R=Morpholinone and X=Hydrogen.
The present novel process is easier to carry on Industrial scalewith high yields, less expensive and short process time.
Figure imgf000010_0001
in n-Butanol using Pseudo acidic metal heterogeneous catalyst and carbonylation with Methylchloroformate further evaporating the n-butanol and reacting with Potassium phthalimide in Ν,Ν-Dimethylformamide in -situ and quenching in water provides compound of Formula-I.
Figure imgf000010_0002
Compound of Formula-IIreacting with (R)-Epichlorohydrin, the (R)- Epichlorohydrin mole ratio is 1 : 1.0- 1.5. The most preferable mole ratio of Compound of Formula-II and (R)-Epichlorohydrin is 1.5. Compound of Formula-IIreacted with (R)-Epichlorohydrin in solvents include cvclic esters such as tetrahvdrofuran, amides such as N.N-Dimethvlformamide, Ν,Ν-Dimethylacetamide, and alcohols such as methanol, ethanol, n-butanol, t- amyl alcohol, t-butyl alcohol, isopropyl alcohol and hexanol; and a mixture thereof. The most preferable solvent is n-butanol.
Compound of Formula-IIreacted with (R)-Epichlorohydrin in n-butanol at 0- 40°C. The most preferable temperature is 10-20°C.
Compound of Formula-IIreacted with (R)-Epichlorohydrin in n-Butanol at 0- 40°C in the presence of Pseudo acedicmetal heterogenius catalyst such as Alumina sulfonic acid. Silica sulfonic acid, Alumina and Aluminium.
The catalyst preferred mole ratio is 1 :0.05- 1. Time required for completion of reaction to higher yields depends upon the factors those are solvent, catalyst and temperature. Wherein the catalyst reduces the time cycle, enable to complete the condensation at mild temperatures with Formula-Ill and carbonylationinsitu. Wherein carbonylation was performed by using alkylchloro formates such methylchloro formate, ethylchloro formate, etc., the preferable alkylchloroformate is methylchloro formate. The reaction mass was treated with Potassium phthalimide in N,N-Dimethylformamide after worked up to get compound of Formula-I.The theoritieal yield from the aniline compound of Formula--ll to substituted phthalimidooxazolidinone compound of Formula.-l is above 80% of theory.
The embodiments and illustrated examples are set forth to aid in understanding the invention but are not intended to, and should not be constructed to limit its scope any way.
The compound of Formula-Iwas further converted to Linezolid or Rivaroxaban as per the known Inventors processes.
Examples;
Example 1 : Preparation of (S) - N - [ [3 - [3 --Fluoro-4 - [4 -morpholinyl]phenyl] -2 -oxo - 5 -oxazolidiny 1] me thy 1] ph thalim ide 3-Fluoro-4-morpholinoaniline (100 gm) was added in n-butanol (300 ml) and charged Alumia sulfonic acid at ambient temperature. Cool the mass, added(R)-Epichlorohydrin (72 gm) and maintain the reaction mass at below 20°C. Confirmed the completion of reaction, separated the catalyst. Added sodiumbicarbonate, cool the mass temperature to 0-5°C and added methylchloro formate (56 gm) . After completion of reaction, evaporated the n- butanol and charged Ν,Ν-dimethylformamide (500 ml), potassium phthalimide (122 gm). The reaction temperature maintained at 95- 100°C for 3 hours. Cool the mass temperature to ambient temperature, quenched the mass into water. Filtered the mass and washed the product with water. Dried the material up to get constant weight .The obtained (S)-N- [[3-[3-FIuoro-4--[4---morphoIi.nyI]phenyl.]-- 2--oxo-H5--oxazoliclinyl]methyl] phthalimide was 180 gm (83% yield) .
Example 2% Preparation of Linezolid Form-II
Methanol (1000 ml) and hydrazine hydrate ( 1 15 gm) was taken into flask containing (S) -N- [[3 - [3 -Fluoro-4- [4-morpholinyl] phenyl] -2 -oxo-5- oxazolidinyl]methyl]phthalimide obtained in example- 1 and heated to reflux, maintained the reflux for a period of 2 hrs. Evaporated the solvent under reduced pressure. Cool the mass to ambient temperature, water (900 ml) is added to the reaction mass and extracted into methylene chloride ( .1.500 ml) . Dried the organic layer over sodium sulphate. Take the organic layer cool to 0- 10°C. Added acetic anhydride (35 gm). After completion of reaction, distil out under reduced pressure. Isolated the Linezolid in toluene. The material was dried at 60°C. The Linezolid recrystallized in methanol to get pure Linezolid. IR values matched with Linezolid polymorph Form-II. The obtained Linezolid was having the HPLC purity >99.5% and FTIR in KBrvalues in cm-1 are: 3364, 1748, 1675, 1537, 1517, 1445, 1410, 1400, 1358, 1329, 1287, 1273, 1252, 1237, 122 1 , 1 144, 1 130, 1 123, 1 1 16, 1078, 1065, 1049, 906, 851 and 757.
Example 3; Preparation of Linezolid form-I
The example-2 was repeated with same quantities and process except the material was isolated in ethyl acetate to obtain Linezolid having HPLC purity > 99.5% and the melting range was matching Inventors Form-I. The melting range obtained was 180.0- 182.5°C. Example 4; Preparation of 2 - ({(5 S) -2 -Oxo-3 - [4- (3 -oxo-4-morpholinyl) phenyl] - l ,3-oxazolidin-5-34}metliyl)- IH-isoindole- l ,3(2H)-dione
4-(4-Aminophenyl)morpholin-3-one (100 gm) was added in n-butanol (300 ml) and charged Alumia sulfonic acid at ambient temperature. Cool the mass, added (R)-Epichlorohydrin (72 gm) and maintain the reaction mass at below 20°C. Confirmed the completion of reaction, separated the catalyst. Added sodiumbicarbonate, cool the mass temperature to Q-5°C and added methylchloroformate (56 gm) . After completion of reaction, evaporated the n- butanol and charged N,N-dimethylformamide (500 mi), potassium phthalimide (122 gm). The reaction temperature maintained at 95- 100°C for 3 hours. Cool the mass temperature to ambient temperature, quenched the mass into water. Filtered the mass and washed the product with water. Dried the material up to get constant weight. The obtained 2-({(5Sj-2-Qxo-3-[4-(3-Gxo-4- morpholmyl]phenyl ]-- 1 ,3--oxazol.idm-5--yl}methyl)-- 1 H--isoindole-- 1 ,3(2H)--d.ione was 186 gm (85% yield) .
Example 5;Preparation of Rivaroxaban
2-{{(5S)-2-Oxo-3-(4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-y¾methyr|- lH-isoindole- l ,3(2H)-dione ( 100 gm) and ethanol (1500 ml) charged into flask. Added methylamme (40%) solution (230 ml) at ambient temperature. Refluxed for one hour.After completion of reaction distilled off solvent completely. Charged pyridine ( 3,9 L) to the mass, cooled to 5°C. Added 5'- chlorothiophene-2-carbonyichloride (51.5 gm) . Raise the. temperature to ambient temperature maintained for one hour and further extracted with, methylene chloride. The organic phase dried with sodium sulphate. Concentrated the organic layer under reduced pressure to obtain Rivaroxaban,

Claims

We Claim ,
1. A novel one pot and high yield process for the preparation of substituted phthalimidooxazolidinone compound of formula-i
Figure imgf000014_0001
by using recyclable heterogeneous catalyst and preparation of
oxazolidinoneantibacteriais and oxazolidinoneantithrombotics thereof comprises, a) reacting substituted aniline compound of Formula-II
Figure imgf000014_0002
withepoxy compound of Formula-Ill
Figure imgf000014_0003
andcarbonylating agentin presence of pseudo acidic metal heterogeneous recyclable catalyst in a suitable solvent at suitable temperature in-situ. b) converting into phthalimidooxazolidinone compound of formula-I with alkali metal phthalimide in dipolar aprotic solvent in-situ. c) furtherpreparation of oxazolidinone antibacterial compound and oxazolidinone antithrombotic compound by using compound of Formula--l,
2. As claimed in claim la whereincarbonylating agent is selected from the group of alkylchloroformates, arylchloroformat.es, carbonyldiimidazoles, phosgene.
3. As claimed in claim 2, wherein the alkylchloroformates are
methylchloro formate, ethyl chloroformatepreferably methylchloro formate,
4. As claimed in claim la, wherein the pseudo acidic metal heterogeneous recyclable catalyst are selected from the group of Alumina sulfonic acid, Silica sulfonic acid, Alumina, Aluminium preferably Alumina sulfonic acid,
5. As claimed in claim la, wherein the suitable solvent is selected from the group of solvents acetonitrile, methanol, ethanol, n-butanol, isopropyl alcohol, isopropyl acetate, ethyl acetate, methyl acetate preferably n- butanol.
6. As claimed in claim la, wherein the suitable temperature is below 0- 40°Cpreferably below 20°C.
7. As claimed in claim lb, wherein the conversion is performed in-situ in dipolar aprotic solvent such as Ν,Ν-dimethylformamide and alkali metal phthalimide such as potassium phthalimide.
8. As claimed in claim lb, wherein the compound of formula- 1 as isolated by known techniques,
9. As claimed in claim 1c, wherein the preparation of oxazolidinone
antibacterial compound such as Linezolid is performed by known prior art processes,
10. As claimed in claim lc, wherein the preparation of oxazolidinone antithrombotic compound such as rivaroxoban is performed by known prior art processes.
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