WO2016113751A1 - Procédé de préparation de linézolide cristallin de forme iii - Google Patents

Procédé de préparation de linézolide cristallin de forme iii Download PDF

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Publication number
WO2016113751A1
WO2016113751A1 PCT/IN2015/050016 IN2015050016W WO2016113751A1 WO 2016113751 A1 WO2016113751 A1 WO 2016113751A1 IN 2015050016 W IN2015050016 W IN 2015050016W WO 2016113751 A1 WO2016113751 A1 WO 2016113751A1
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Prior art keywords
dioxane
solution
form iii
reaction mass
solvent
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PCT/IN2015/050016
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English (en)
Inventor
Satyanarayana Reddy BHEMIREDDY
V. Vara Prasada Reddy Paidimarla
Venkat Reddy YARAPATHI
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Nosch Labs Private Limited
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Publication of WO2016113751A1 publication Critical patent/WO2016113751A1/fr

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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

Definitions

  • the invention relates to novel process for preparing crystalline Linezolid Form III. BACKGROUND OF THE INVENTION:
  • Linezolid is an oxazolidinone compound chemically known as (S)-N-[[3-[3-fluoro-4- (4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide.
  • Linezolid 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 multocida. It is mostly active against streptococci, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant enterococci
  • Linezolid is represented by the following structure:
  • Linezolid is known to exhibit different polymorphic forms. Linezolid described in J. of Med. Chem. 39(3), 673-679 is reported as Form I which is characterized by having melting point of 181.5-182.5°C and by IR spectrum having bands at 3284, 3092, 1753, 1728, 1649, 1565, 1519, 1447, 1435 cm “1 .
  • US Patent No. 6,559,305 discloses crystalline Linezolid Form II characterized by powder X-ray diffraction spectrum having 2 ⁇ values at 7.10, 9.54, 13.88, 14.23, 16.18, 16.79, 17.69, 19.41, 19.69, 19.93, 21.61, 22.39, 22.84, 23.52, 24.16, 25.28, 26.66, 27.01 and 27.77 degrees and IR spectrum having bands at 3364, 1748, 1675, 1537, 1517, 1445, 1410, 1401, 1358, 1329, 1287, 1274, 1253, 1237, 1221, 1145, 1130, 1123, 1116, 1078, 1066, 1049, 907, 852 and 758 cm "1 .
  • WO2005/035530 discloses crystalline Linezolid Form III characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 7.6, 9.6, 13.6, 14.9, 18.2, 18.9, 21.2, 22.3, 25.6, 26.9, 27.9 and 29.9 degrees; and characterized by IR spectrum having main bands at about 3338, 1741, 1662, 1544, 1517, 1471, 1452, 1425, 1400, 1381, 1334, 1273, 1255, 1228, 1213, 1197, 1176, 1116, 1082, 1051, 937, 923, 904, 869, 825 and 756 cm "1 .
  • Linezolid Form III possesses good thermal stability favouring its utility for preparation of solid dosage forms.
  • crystalline Linezolid Form III is prepared by directly heating Linezolid at 90°C -200°C.
  • Solvents are selected from toluene, xylene, chloroform, methylene dichloride, acetonitrile, water, methanol, ethanol, propanol, isopropyl alcohol, ter- butyl alcohol, acetone, mehyl ethyl ketone, ethyl acetate, diethyl ether and methyl tert.
  • Butyl ether This document preferably uses toluene, xylene and isopropyl alcohol.
  • US Pat. No. 7,989,618 claims a process for the preparation of Linezolid in crystalline Form III, which comprises treating an first aqueous solution of a Linezolid addition salt with an alkali metal carbonate, in the presence of a low-boiling organic solvent, having a boiling point below 85° C, separating phases of the first solution after treatment with the alkali metal carbonate, to provide an organic second solution, treating the organic second solution with toluene to obtain Linezolid crystalline Form III.
  • the addition salt is selected from Linezolid dihydrochloride, Linezolid sulfate and Linezolid camphorsulfonate.
  • WO 2011051384 [(family WO2011050826 and WO2011050865 (all from Synthon B.V)] discloses process for preparation of Crystalline Linezolid designated as Form A (Corresponds to Linezolid Form I or Form III) comprising a step of dissolving linezolid in an organic solvent at an enhanced temperature (at reflux) to obtain a solution followed by a step of adding the obtained solution into an antisolvent kept at a pre- selected temperature and, optionally, seeded with crystals of the desired crystalline form of linezolid.
  • the primary object of the present invention is to provide novel process for preparation of crystalline Linezolid Form III.
  • the present invention provides novel process for the preparation of Linezolid Crystalline Form III.
  • step (b) heating the solution obtained in step (a) to 75-80° C and stirring;
  • step (c) slowly cooling the whole reaction mass obtained in step (b) to 25-30° C and stirring to cause the crystallization;
  • step (d) recovering the crystalline Linezolid Form- III from the reaction mass of step (c) and washing with fresh solvent to obtain highly pure crystalline Form-Ill of Linezolid.
  • the solvent used in step (a) and in step (d) is an organic solvent selected from a cyclic ether, e.g. 1,4-dioxane; an aliphatic ether e.g. diethyl ether, methyl tert-butyl ether; an aliphatic ester, e.g. ethyl acetate; an aliphatic alcohol, e.g.
  • step (a) and step (d) is 1,4-dioxane.
  • step (b) The stirring in step (b) is done for about 50-60 minutes at 75-80° C.
  • step (c) is done for about 50-60 minutes at 25-30° C.
  • the invention provides a process for preparation of Crystalline Linezolid Form III comprising the steps of:
  • step (b) cooling the reaction mass obtained in step (a) to 10-15°C and slowly adding a reducing agent at the same temperature;
  • step (c) heating the whole content obtained in step (b) to 85-90°C for 2-3 hrs;
  • step (d) cooling the content of step (c) to 25-30°C and adjusting the pH to 1.0 with dil
  • step (i) heating the reaction mass of step (h) to reflux temp, for 30-40 min;
  • step (j) recovering the pure crystalline Linezolid Form III from the reaction mass of step (i) with 1,4-dioxane or ethyl acetate.
  • the organic solvent in step (a) used to obtain the solution of ( ?)-5-azidomethyl-3-(3- fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one may be selected from cyclic ether, e.g. 1,4-dioxane, toluene, tetrahydrofuran, alcoholic solvents such as methanol, ethanol, isopropyl alcohol, and mixtures thereof.
  • the organic solvent is either 1,4-dioxane or toluene.
  • the reducing agent used in step (b) is selected from Pd-C/H 2 , trialkyl and triaryl phosphine.
  • the reducing agent is triphenyl phosphine (TPP).
  • the invention provides a process for preparation of Crystalline Linezolid Form III comprising the steps of:
  • step (b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
  • step (d) distilling the reaction mass of step (c) and recovering pure crystalline Linezolid Form III either in 1,4-dioxane or ethyl acetate.
  • the solvent used in above step (a) is an organic solvent selected from methylene dichloride, 1,4-dioxane and ethyl acetate.
  • the organic solvent selected in step (a) is methylene dichloride.
  • the invention provides a process for preparation of crystalline Linezolid Form III comprising the steps of: (a) providing a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl- phenyl)-oxazolidin-2-one in a solvent;
  • step (b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
  • the solvent used in above step (a) is an organic solvent selected from methylene dichloride , 1,4-dioxane and ethyl acetate. In one preferred embodiment the organic solvent selected in step (a) is 1,4-dioxane.
  • Linezolid is chemically N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl] methyl] acetamide and is represented by following structure
  • Crystalline Linezolid Form III prepared in the present invention corresponds to Linezolid Form III disclosed in International Publication No. WO2005/035530.
  • WO2005/035530 discloses Linezolid Form III characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 7.6, 9.6, 13.6, 14.9, 18.2, 18.9, 21.2, 22.3, 25.6, 26.9, 27.9 and 29.9 degrees; and characterized by IR spectrum having main bands at about 3338, 1741, 1662, 1544, 1517, 1471, 1452, 1425, 1400, 1381, 1334, 1273, 1255, 1228, 1213, 1197, 1176, 1116, 1082, 1051, 937, 923, 904, 869, 825 and 756 cm "1 .
  • Crystalline Linezolid Form III is prepared by a process comprising the steps of:
  • step (b) heating the solution obtained in step (a) to 75-80° C and stirring;
  • step (c) slowly cooling the whole reaction mass obtained in step (b) to 25-30° C and stirring to cause the crystallization;
  • step (d) recovering the crystalline Linezolid Form-Ill from the reaction mass of step (c) and washing with fresh solvent to obtain highly pure crystalline Form- III of Linezolid.
  • the crystalline Linezolid used in step (a) may be obtained by any viable process known in the prior art.
  • the solvent used in steps (a) and (d) is an organic solvent selected from cyclic ether, e.g. 1,4-dioxane; an aliphatic ether e.g. diethyl ether, methyl tert-butyl ether; an aliphatic ester, e.g.
  • step (d) is the same organic solvent as used in step (a).
  • the solvent used in step (a) and step (d) is 1,4-dioxane.
  • step (b) the contents obtained after step (a) is then heated to temperature 75-80° C and stirred for 50-60 minutes at same temperature i.e. 75-80° C.
  • step (b) The stirring in step (b) is done for about 50-60 minutes at 75-80° C.
  • step (c) is done for about 50-60 minutes at25-30° C.
  • the Crystalline Linezolid Form III obtained in step (d) is further dried at temperature 70-75° C.
  • the process for preparation of Crystalline Linezolid Form III comprises:
  • step (b) heating the solution obtained in step (a) to 75-80° C and stirring for 50-60 minutes at the same temperature;
  • Crystalline Linezolid Form III is prepared by a process comprising the steps of:
  • step (b) cooling the reaction mass obtained in step (a) to 10-15°C and slowly adding a reducing agent at the same temperature;
  • step (c) heating the whole content obtained in step (b) to 85-90°C for 2-3 hrs;
  • step (d) cooling the content of step (c) to 25-30°C and adjusting the pH to 1.0 with dil HC1;
  • step (i) heating the reaction mass of step (h) to reflux temp for 30-40 min;
  • step (j) recovering the pure crystalline Linezolid Form III from the reaction mass of step (i) with 1,4-dioxane or ethyl acetate.
  • Crystalline Linezolid Form III is prepared starting from intermediate (R)-5- azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one.
  • the organic solvent in step (a) used to obtain the solution of ( ?)-5-azidomethyl-3-(3- fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one may be selected from cyclic ether e.g. 1,4-dioxane, toluene, tetrahydrofuran, alcoholic solvents such as methanol, ethanol, isopropyl alcohol, and mixtures thereof.
  • the organic solvent is either 1,4-dioxane or toluene.
  • the reducing agent used in step (b) is selected from Pd-C/H 2 , trialkyl and triaryl phosphine.
  • the reducing agent is triphenyl phosphine (TPP).
  • TPP triphenyl phosphine
  • step (b) the mass obtained in step (a) is cooled to 10-15°C and reducing agent is added portions wise at the same temperature.
  • the reducing agent in step (b) may be selected from Pd-C/H 2 , trialkyl and triaryl phosphine.
  • the reducing agent is triphenyl phosphine (TPP).
  • step (c) the whole reaction contents of step (b) is heated to 85-90°C for 2-3 hours and after that cooled to 25-30°C.
  • step (d) the pH is adjusted to 1.0 with dilute HC1 (Hydrochloric acid) and stirred for 10-15 min.
  • step (e) comprises separation of aqueous layer and organic layer.
  • step (f) the aqueous layer obtained in step (e) is washed with methylene dichloride.
  • the step (g) comprises addition of fresh methylene dichloride to aqueous layer and the pH is adjusted to 13-14 with 10% sodium hydroxide solution.
  • step (h) comprises separation of the organic layer and the aqueous layer and treating the organic layer with acetic anhydride.
  • step (i) the reaction mass of step (h) is heated to reflux temperature for 30-40 min.
  • step (j) the organic layer is distilled and isolated Crystalline Linezolid Form III either in 1,4-dioxane or ethyl acetate.
  • the process for preparation of Crystalline Linezolid Form III comprises: (a) providing a solution of ( ?)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl- phenyl)-oxazolidin-2-one either in 1, 4-dioxane or toluene and adding water to the solution at temperature 25-30°C;
  • step (b) cooling the reaction mass obtained in step (a) to 10-15°C and slowly adding triphenyl phosphine at the same temperature;
  • step (c) heating the whole content obtained in step (b) to 85-90°C for 2-3 hrs;
  • step (d) cooling the content of step (c) to 25-30°C and adjusting the pH to 1.0 with dilute HC1 and stirring for 10-15 min;
  • step (i) heating the reaction mass of step (h) to reflux temp for 30-40 min;
  • step (j) recovering the pure crystalline Linezolid Form III from the reaction mass of step (i) with 1, 4-dioxane or ethyl acetate.
  • the invention provides a process for preparation of Crystalline Linezolid Form III starting with (S)-5-aminomethyl-3-(3-fluoro-4- morpholin-4-yl-phenyl)-oxazolidin-2-one.
  • the process comprises:
  • step (b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
  • step (d) distilling the reaction mass of step (c) and recovering pure crystalline Linezolid Form III in 1, 4-dioxane or ethyl acetate.
  • the solvent used in above step (a) is an organic solvent selected from methylene dichloride, ethyl acetate and 1, 4-dioxane.
  • the organic solvent selected in step (a) is methylene dichloride.
  • the step (b) comprises addition of acetic anhydride to the intermediate solution obtained in step (a). The addition of acetic anhydride takes place at temperature 25- 30°C. Then the temperature is raised slowly to 35-40°C followed by stirring for 1-2 hrs.
  • step (d) The recovery of pure crystalline Linezolid Form III in step (d) is done either in 1,4- dioxane or ethyl acetate.
  • step (b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
  • step (d) distilling the reaction mass of step (c) and recovering pure crystalline
  • the invention provides a process for preparation of Crystalline Linezolid Form III comprising the steps of:
  • step (b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
  • the solvent used in above step (a) is an organic solvent selected from ethyl acetate and 1,4-dioxane. In one preferred embodiment the solvent used in step (a) is 1,4- dioxane.
  • the step (b) comprises addition of acetic anhydride to the intermediate solution obtained in step (a).
  • the addition of acetic anhydride takes place at temperature 25- 30°C. Then the temperature is raised slowly to 65-70°C followed by stirring for 1-2 hrs. Then further cooled to 25-30°C followed by stirring for 25-30 min.
  • step (d) The recovery of pure crystalline Linezolid Form III in step (d) is done either in 1,4- dioxane or ethyl acetate.
  • step (b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
  • 1,4-Dioxane 500.0 mL was added to crystalline Linezolid (100.0 gr) at 25-30°C. The total contents were heated to 75-80°C and stirred for 50-60 min at same temperature. Then the whole reaction mass was cooled to 25-30°C and stirred for 50- 60 min at same temperature. The precipitated solid was filtered and washed with fresh 1,4-dioxane (100.0 mL). The filtered solid was dried at 70-75°C to get Crystalline Linezolid Form III.

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

Abstract

La présente invention concerne un procédé de préparation de linézolide cristallin de forme III par suspension de linézolide cristallin dans un solvant à 25-30 °C pour obtenir une solution (étape a), suivie du chauffage de la solution obtenue dans l'étape (a) à 75 à 80 °C et de l'agitation (étape b), puis un refroidissement lent de la masse de réaction totale obtenue dans l'étape (b) à 25-30 °C et une agitation pour causer la cristallisation (étape c), et enfin la récupération et le lavage du linézolide cristallin de forme III (étapes d et e).
PCT/IN2015/050016 2015-01-13 2015-03-02 Procédé de préparation de linézolide cristallin de forme iii WO2016113751A1 (fr)

Applications Claiming Priority (2)

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IN214/CHE/2015 2015-01-13
IN214CH2015 IN2015CH00214A (fr) 2015-01-13 2015-03-02

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018051360A1 (fr) * 2016-09-16 2018-03-22 Lee Pharma Limited Nouveau procédé de préparation de linézolide cristallin de forme iii

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005035530A1 (fr) * 2003-10-16 2005-04-21 Symed Labs Limited Nouvelle forme cristalline du linezolid

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005035530A1 (fr) * 2003-10-16 2005-04-21 Symed Labs Limited Nouvelle forme cristalline du linezolid

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018051360A1 (fr) * 2016-09-16 2018-03-22 Lee Pharma Limited Nouveau procédé de préparation de linézolide cristallin de forme iii

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