[go: up one dir, main page]

WO2015162622A1 - Procédé de préparation de linézolide - Google Patents

Procédé de préparation de linézolide Download PDF

Info

Publication number
WO2015162622A1
WO2015162622A1 PCT/IN2015/000020 IN2015000020W WO2015162622A1 WO 2015162622 A1 WO2015162622 A1 WO 2015162622A1 IN 2015000020 W IN2015000020 W IN 2015000020W WO 2015162622 A1 WO2015162622 A1 WO 2015162622A1
Authority
WO
WIPO (PCT)
Prior art keywords
linezolid
reaction
mass
compound
formula
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IN2015/000020
Other languages
English (en)
Inventor
Dharmesh Mahendra Shah
Viral Narenda JARIWALA
Sanjay Amratlal Solanki
Ashok Vasantray Vyas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Virdev Intermediates PVT Ltd
Original Assignee
Virdev Intermediates PVT Ltd
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 Virdev Intermediates PVT Ltd filed Critical Virdev Intermediates PVT Ltd
Publication of WO2015162622A1 publication Critical patent/WO2015162622A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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 present invention relates to an in-situ process for preparation of Linezolid polymorphic Form II free from specified and unspecified pharmacopoeal impurities.
  • Linezolid is an antimicrobial agent and first disclosed in US5688792 among a list of oxazine and thiazine oxazolidinone derivatives.
  • Linezolid is the first antibacterial agent belonging to oxazolidinone class, invented by US Pharmacia & Upjohn Corporation. It is significantly useful in treatment of infections of soft tissues, skin as well as pneumonia.
  • Linezolid chemically known as N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]acetamide and represented by the following structure:
  • IN229267 discloses linezolid polymorphic form III and process for preparation thereof. I '267 is granted for process for preparation of polymorphic form III of Linezolid, however, the claim for polymorphic form III is refused under section 3(d) of IPA, 1970.
  • Linezolid polymorphic Form II and process for preparation thereof is disclosed in Indian patent application No. 623/MUMNP/2004, however, only process claims were granted and the claims for polymorphic form II was refused under section 3(d).
  • the present inventors have come up with a novel process starting from much basic and easily available starting material and at the same time involving much fewer operational steps.
  • the key reaction is an inventive process which involves an in- situ process for synthesis of linezolid starting from Phenyl amine compound of formula II to (S)-N-[3-[3-fluro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxozolidinyl]methyl]phthalimide of formula III.
  • the instant process is cost-effective and industrially scalable. Summary of the invention
  • the present invention provides an in-situ process for preparation of Linezolid polymorphic Form II free from specified and unspecified pharmacopoeal impurities.
  • in-situ process for preparation of linezolid polymorphic Form II comprises: a) Condensing 3,4-Diflouronitrobenzene with Morpholine in ethyl acetate at room temperature followed by addition of a base, raising the temperature to 78-80°C followed by distillation of Ethyl Acetate to obtain compound of formula I;
  • Fig 1 depicts XRD data of the linezolid polymorphic Form II prepared according to example 8 which matches with the XRD described in 623/MUMNP/2004.
  • Fig 2 depicts DSC of linezolid polymorphic Form II prepared according to example 8.
  • Fig 3 depicts HPLC chromatogram of Linezolid finished product according to example
  • Fig 4 depicts HPLC chromatogram of Linezolid polymorphic Form II according to example 8. Detailed description of the invention:
  • the present invention describes an in-situ process for preparation of linezolid polymorphic Form II free from specified and unspecified pharmacopoeal impurities that is easier to carry on industrial scale.
  • the hydrogenation of compound of formula I using 5% Pd/C was conducted in methanol.
  • the catalytic hydrogenation process was carried out with hydrogen pressure (0.3 kg/cm2 — 2.0 kg/cm2) and temperature (28°-35°C) for a period of 2-4 hrs while monitoring reaction progress by TLC. After completion of reaction, the reaction mass was cooled, filtered to remove the catalyst, methanol was distilled out, water was added, cooled and filtered to get compound of formula II.
  • reaction of compound of formula II to compound III was carried in-situ, wherein compound II was reacted with R (-) Epichlorohydrin in Isopropyl alcohol at 80- 88°C and progress of reaction was monitored by TLC. After completion of reaction, IPA was distilled out and the reaction mass was treated with Potassium Phthalamide in DMF. After the completion of reaction, the reaction mass was quenched with ice water, extracted with MDC and back extracted with water. The MDC layer was partially distilled off to remove the traces of water azeotropically, and the reaction mass was reacted with carbonyl diimidazole to obtain compound III.
  • the carbonylation was undertaken in THF solvent. After completion of reaction, THF was recovered by distillation, the mass was treated with water and ethyl acetate, cooled and filtered the solids to isolate compound III.
  • the Crude Linezolid of formula IV was purified in methanol to get pure crystalline Linezolid in Polymorph Form-II. Accordingly, the solution of crude linezolid of formula (IV) in methanol was refluxed until dissolution followed by addition of active carbon. The mixture was further refluxed for about an hour at same temperature; the mass was filtered and concentrated by distillation. This was followed by seeding the mass under cooling with linezolid polymorphic form II to isolate the pure crystals of linezolid polymorphic Form II.
  • the present invention provides a process for synthesis of linezolid as provided in example below and further purification in methanol to obtain polymorphic Form II .
  • the polymorph Form II was characterized by XRD and DSC data that match with the XRD values disclosed in Indian patent application No. 623/MUMNP/2004.
  • the Linezolid polymorphic Form II obtained in the present process is substantially free of the specified pharmacopoeal impurities and unspecified impurities such as N-[3-chloro-2 (R)-hydroxypropyl]-3-fluoro-4-mo holinylaniline (D) and N-[3-Phthalimido-2(R)- hydroxy propoyl-3-fluoro-4-morpholinylaniline (E) as depicted in HPLC chromatogram.(fig 3 and fig 4 respectively).
  • the limits may vary with change in analytical instrument / lab / operating analyst / sensitivity of detection etc. and the total impurities do not exceed 0.5%.
  • the acceptance limit for any single impurity is Not More Than 0.5 % and for total impurities is Not More Than 1.0%
  • the specified and unspecified impurities in form of compounds A, B, C and additional impurities D and E are as follows:
  • Impurity A (R)-5-(Azidomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one
  • ImpurityB (S)-N- ⁇ [3-(3-Fluoro-4-mo ⁇ holinophenyl)-2-oxooxazolidin-5-yl]methyl ⁇ thio- acetamide.
  • Impurity C (S)-5-(Aminomethyl)-3-(3-fluoro-4-mo ⁇ holinophenyl)oxazolidin-2-one.
  • Impurity D N-[3-chloro-2 ( R)-hydroxypropyl]-3-fluoro-4-nK ⁇ holinylaniline
  • Impurity E N-[3-Phthalimide-2( R)-hydroxy propoyl-3fluoro-4-mo holinylaniline.
  • Linezolid polymorphic Form II obtained from the process of instant invention not only comply with the limit/absence of the specified and unspecified impurities A, B, C of USP's pending monograph but also is free of additional impurities such as D and E.
  • Example-I The process was carried out as in Example-I with reactants quantities as 3,4- Difluoronitrobenzene (220 gms), morpholine (142 gms) and triethylamine (43 gms). Yield of compound-I was observed to be 298 gms.
  • reaction mass was cooled to 20°-25°C, filtered to remove the catalyst and concentrated to remove methanol partially (580 ml - 630 ml) at 45°-52°C. Reaction mass turned into thick slurry. It was added with water (390 ml), stirred for half an hour, cooled to 20°-25°C, filtered, washed with cold water (120-150 ml), and finally dried at 60°-65°C in a tray drier to obtain compound-II (92 gms).
  • Example-3 The process was carried out as in Example-3, with adopting modifications as under: Compound-I (80 gms), methanol (900 ml), palladium-carbon catalyst (5%, 1.35 gm), hydrogen gas pressure (0.6 kg/cm 2 - 2.8 kg/cm 2 ). The reaction, was observed to be completed in 3.5 hrs and yield of compound-II was found to be 61.0 gms.
  • Catalytic hydrogenation process was performed in a similar way as described in Example- 3, and quantities of reactants as described in Example-4, but hydrogen pressure was restricted to 0.1 kg/cm 2 -0.2 kg/cm 2 .
  • the reaction was monitored by TLC for completion over a period of eight hours. Yield of compound-II was found to be 64 gms.
  • reaction mass was heated to reflux and was maintained for about 20-24 hrs at 80°- 88°C.
  • the progress of reaction was monitored by TLC at periodic intervals after 16 hrs.
  • Isopropanol was distilled out from the reaction mass after completion of the reaction and then ⁇ , ⁇ -dimethyl forrmamide (DMF) was gradually added (540 ml).
  • the reaction mass was cooled to 35°-38°C and stirred for 15-20 minutes.
  • Potassium phthalamide 222 gms
  • the reaction mass was maintained further at 35°-40°C for 15-20 minutes and then slowly heated to 94°-98°C with careful control on temperature. Heating was stopped and the temperature of reaction mass rose to 122°-130°C.
  • reaction progress was quickly monitored by TLC and reaction was completed in 15-30 minutes period.
  • Reaction mass was cooled to 45°-50° and then slowly poured in to a vessel containing ice (1.4 kg), water (3.8 lit) and methylene dichloride solvent (1.6 lit), with vigorous stirring. After 15-20 minutes of stirring, the organic layer was separated. The aqueous layer was extracted further with MDC (500 ml x 3 times). Combined MDC layer was repeatedly extracted with water (350 ml x 4 times), dried over anhydrous sodium sulphate, filtered and partially concentrated to remove water azeotropically. Fresh MDC was added equal to the quantity of solvent removed by distillation (approximately 600-700 ml). Moisture content of the reaction mass was observed to be 0.1%.
  • reaction mass was next cooled to 30°C and carbonyl diimidazole (146 gm) was added to it over a period of half an hour.
  • the reaction mass temperature was then raised to 35°-37°C and maintained for 20-26 hrs under monitoring by TLC. Reaction was completed in 22 hrs.
  • Water (290 ml) was added in the reaction mass and organic layer was separated. The organic layer was re-extracted with water (250 ml x 3 times), all aqueous layer pooled up and extracted with MDC (220 ml ⁇ 1), MDC extracts pooled up and dried over anhydrous sodium sulphate and filtered MDC extracts was then treated with active carbon (6 gms), filtered and concentrated to remove solvent in vacuo.
  • MDC extract was washed with water (0.45 lit ⁇ 2), dried over anhydrous sodium sulphate, filtered and concentrated partially to remove 0.8 lit MDC.
  • the reaction mass was cooled to 10°-12°C, and acetic anhydride (122 gms) was added in about an hour while maintaining the temperature at 10°-12°C. Reaction mass temperature was then raised to 28°-30°C and maintained for 2 hrs. Reaction completion was ascertained by TLC and solvent was distilled off completely. Two lots of IP A were added in succession (60 ml ⁇ 2) and the mass was stripped off to remove the solvent completely. Third lot of IPA (235 ml) was added followed by cooling the mass to 25°-30°C and then to 2°-5°C.
  • Linezolid (140 gms) obtained as above was added in a reaction flask containing methanol (1.4 lit) and heated under stirring to achieve slow reflux (68°-72°C). After dissolution, active carbon (7 gms) was added, reflux maintained for 1 hrs, and the mass was filtered hot followed by washing of suspended matter with methanol (100 ml). The clear filtrate was concentrated by distillation to remove approximately 50% of methanol. Resultant mass was slowly cooled to 35°C while adding linezolid polymorph form-II (4.2 gms), and finally to 24°-27°C.
  • Linezolid Purification of Linezolid
  • Process of purification was carried out as per the one described in example-8, and quantities of materials used as: Linezolid (91 gm), methanol (955 ml), active carbon (5.46 gms).
  • Linezolid polymorph form-II seed material (2.73 gms) and methanol for washing (25 ml 4 times).
  • Yield of purified linezolid 75.5 gms, HPLC purity above 99.5%).
  • MDC extract was washed with water (2.83 lit), dried over anhydrous sodium sulphate, filtered and concentrated partially to remove 0.8 lit MDC.
  • the reaction mass was cooled 10°-12°C, and acetic anhydride (132 gms) was added in about an hour while maintaining the temperature at 10°-12°C. Reaction mass temperature was then raised to 28°-30°C and maintained for 2 hrs. Reaction completion was ascertained by TLC and solvent was distilled off completely. Two lots of IPA were added in succession (60 ml ⁇ 2) and the mass was stripped off to remove the solvent completely. Third lot of IPA (235 ml) was added followed by cooling the mass to 25°-30°C and then to 2°-5°C.
  • reaction mass was heated to reflux and was maintained for about 20-24 hrs at 80°- 88°C.
  • the progress of reaction was monitored by TLC at periodic intervals after 16 hrs.
  • Isopropanol was distilled out from the reaction mass after completion of the reaction and then ⁇ , ⁇ -dimethyl formamide (DMF) was gradually added (540 ml).
  • the reaction mass was cooled to 35°-38°C.and stirred for 15-20 minutes.
  • Potassium phthalamide (222 gms) was next added over a period of 1.5 hours under moderate stirring.
  • the reaction mass was maintained further at 35°-40°C for 15-20 minutes and then slowly heated to 94°-98°C with careful control on temperature. Heating was stopped and the temperature of reaction mass rose to 122°-130°C.
  • reaction progress was quickly monitored by TLC and reaction was completed in 15-30 minutes period.
  • Reaction mass was cooled to 45°-50° and then slowly poured in to a vessel containing ice (1.4 kg), water (3.8 lit) and methylene dichloride solvent (1.6 lit), with vigorous stirring. After 15-20 minutes of stirring, the organic layer was separated. The aqueous layer was extracted further with MDC (500 ml x 3 times).
  • Aqueous layer was multiple extracted with MDC (430 ml 1, 215 ml x 3), all MDC extracts pooled up, washed with water (430 ml), dried over anhydrous sodium sulphate, filtered and partially concentrated to remove MDC (150 ml). Resultant solution was cooled to 10°-12°C, added with acetic anhydride (44 gms) over one hour and then stirred at 28°-30°C for 2.5 hrs to complete acetylation. MDC was distilled out and residue was added with two subsequent lots of IPA (40 ml x 2) followed by stripping to remove solvent at 50°-55°C.
  • Linezolid (45 gms) (Compound-IV) isolated in the example- 12 was purified by dissolving in methanol (450 ml), refluxing for 1 hrs with addition of active carbon (2.25 gm), hot filtration of solution, removing partial quantity of methanol (230 ml) by distillation, and gradual cooling to 25°-28°C while adding linezolid polymorph-II (1.35 gm).
  • the purified product was filtered, washed with cold methanol (20 ml ⁇ 3 times) and dried at 40°-45°C for 2 hrs and at 45°-55°C for 3-4 hrs (yield 35.5 gms, HPLC purity 100%, Assay 99.93%, SOR(-)9.69°, IR match value with working standard of linezolid polymorph-II 98.23%).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à un procédé in situ pour la préparation d'une forme polymorphe II de linézolide exempte d'impuretés.
PCT/IN2015/000020 2014-04-25 2015-01-14 Procédé de préparation de linézolide Ceased WO2015162622A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1470/MUM/2014 2014-04-25
IN1470MU2014 2014-04-25

Publications (1)

Publication Number Publication Date
WO2015162622A1 true WO2015162622A1 (fr) 2015-10-29

Family

ID=54331832

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2015/000020 Ceased WO2015162622A1 (fr) 2014-04-25 2015-01-14 Procédé de préparation de linézolide

Country Status (1)

Country Link
WO (1) WO2015162622A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090093422A1 (en) * 2006-10-23 2009-04-09 Roger Tung Oxazolidinone derivatives and methods of use
WO2009154754A2 (fr) * 2008-06-17 2009-12-23 Concert Pharmaceuticals, Inc. Synthèse de dérivés de morpholine deutérés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090093422A1 (en) * 2006-10-23 2009-04-09 Roger Tung Oxazolidinone derivatives and methods of use
WO2009154754A2 (fr) * 2008-06-17 2009-12-23 Concert Pharmaceuticals, Inc. Synthèse de dérivés de morpholine deutérés

Similar Documents

Publication Publication Date Title
US20130137864A1 (en) Process for the preparation of linezolid
EP2613787A2 (fr) Procédés de préparation de 4-{4-[5(s)-(aminométhyl)-2-oxo-1,3-oxazolidin-3-yl]phényl} morpholin-3-one
EP2753619A2 (fr) Procédés et intermédiaires destinés à la préparation de rivaroxaban
EP2837628B1 (fr) Procédé de préparation d'un intermédiaire de rivaroxaban
CA2761663A1 (fr) Derives de 7-aza-spiro[3.5]nonane-7-carboxylates, leur preparation et leur application en therapeutique
CA2761658C (fr) Derives de cyclopenta[c]pyrrolylalkylcarbamates d'heterocycles a 5 chainons, leur preparation et leur application en therapeutique
CN102206194A (zh) 抗菌药利奈唑胺的制备方法
WO2012146692A1 (fr) Nouveaux intermédiaires pour la préparation d'aprépitant ou de fosaprépitant de pureté élevée
WO2010031769A1 (fr) Procédé pour la préparation d’un agent antibactérien à base d’oxazolidinone et de ses intermédiaires
CN102952025B (zh) 一种(s)-1-氨基-3-氯-2-丙醇盐酸盐的制备方法
WO2013164833A1 (fr) Procédé perfectionné pour la préparation de rivaroxaban utilisant de nouveaux intermédiaires
CN102267956B (zh) 1,3-噁唑烷-2-酮类化合物、其制备方法和用途
WO2015162622A1 (fr) Procédé de préparation de linézolide
JP5938109B2 (ja) リネゾリド中間体の調製方法
WO2012041263A2 (fr) Procédé de fabrication d'une 2-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]- l,3-oxazolidin-5-yl}méthyl)-lh-isoindol-l,3(2h)-dione à la pureté optique élevée
CN111559985A (zh) 具有杀菌作用的噁唑酮类化合物及其制备方法
CN105111160B (zh) 一种利奈唑胺的制备方法
WO2014141067A2 (fr) Procédé pour la préparation de dérivés d'oxazolidinone
CN108610306B (zh) 一种2h-1,4-噻嗪-3(4h)-酮衍生物的合成方法
CN108250193B (zh) 一锅法制备利伐沙班的方法
WO2014170908A1 (fr) Procédé de préparation de dérivés oxazolidinone
US20150025236A1 (en) Process for the preparation of stable crystalline form-i of linezolid, substantially free of residual solvent
WO2015198259A1 (fr) Procédé de synthèse de rivaroxaban et intermédiaire pour la production de celui-ci
WO2013190559A1 (fr) Procédés perfectionnés pour la préparation de forme cristalline iii du linézolide
WO2014045292A1 (fr) Procédé amélioré pour la préparation d'un intermédiaire de linézolide

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15782435

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15782435

Country of ref document: EP

Kind code of ref document: A1