Improved Process For Preparing Linezolid
Abstract:
ABSTRACT
TITLE: "AN IMPROVED PROCESSES FOR PREPARING LINEZOLID"
The present invention provides simple, environmental friendly improved process for the preparation of Linezolid. The present invention also provides an alternate improved process for preparing Linezolid with good yield.
Specification
AN IMPROVED PROCESSES FOR PREPARING LINEZOLID
This application claims priority to this Indian patent application numbers 3963/CHE/2013 filed on September 4, 2013.
FIELD OF THE INVENTION
The present invention provides an improved process for preparing Linezolid and the present is also provides Linezolid with substantially free of impurities.
BACKGROUND OF THE INVENTION
Linezolid is a synthetic antibiotic used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics. Linezolid is a synthetic antibiotic, the first of the oxazolidinone class, used for the treatment of infections caused by multi-resistant bacteria including streptococcus and methicillin-resistant Staphylococcus aureus (MRSA).
Chemically, Linezolid is (5)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-
oxazolidinyl]methyl] acetamide. The empirical formula is C16H20FN3O4. Its molecular weight is 337.35, and its chemical structure is represented below:
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).
Linezolid is first discloses in US 5688792 (Barbachyn et al, 1997) and the process of US '792 patent describes the usage of R -glycidylbutyrate which results in the formation of (R) - N-
[[3-[3-fiuoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methanol which in the subsequent stages has to be converted to various intermediary compounds to finally form Linezolid. The said process also encompasses intermediary azide compound, which is difficult and harmful to handle at an industrial level.
WO 2012/114355 (Alia, Raghu Mitra et al, 2010), discloses a process for preparing Linezolid as described in the following scheme:
The disadvantages of the process covered under WO '355 are that it is a cumbersome process that may not be cost effective and being a lengthy process, the productivity will be affected.
WO 2012/019632 (Bartos Petr, et al, 2010) appears to cover a process for preparing 3-(3-fluoro-4-(morpholin-4-yl)phenyl)-2-oxo oxazolidin-5(S)-yl methyl)amine and/or an acid addition salt,
an intermediate used in the preparation of Linezolid, as shown below
The drawbacks of WO '632 are the use of metal salt of diformylamide, which is commercially unavailable and therefore increases the cost of API. Also, the disadvantages of using metal salt of diformylamide, is that it is sensitive to water and it may require special storage conditions like dehumidifier.
US 20070021417 (Serguei Fine et al, 2005) appears to cover a process for preparation of S-N-(4-morpholinyl-3 -fluorophenyl)-2-oxo-5 -oxazolidinyl-methyl amine
from R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III)
by catalytic hydrogenation comprising combining R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) with an organic solvent other than ethyl acetate.
In the above described process, the drawbacks are the use of azide intermediate which is industrially not preferred, catalytic hydrogenation requires special facility which increases the project cost and is environmentally hazardous. The use of catalyst can increase the analysis cost for heavy metal.
The inventors of the present invention have developed cost-effective, simple and environmental friendly processes for the preparation of Linezolid. The inventors have worked towards providing an operational friendly and cost effective process, wherein the formation of impurities is minimized and the yields are good.
The inventors have developed improved processes for preparing Linezolid using raw materials that are commercially available and it don't require special storage conditions or any special equipments like autoclave.
SUMMARY OF THE INVENTION
In one aspect of the present invention, a process for the preparation of N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-2-oxo-l, 3-oxazolidin-5-yl}methyl)acetamide (Linezolid) of formula (I), comprises the following steps:
a) pyrrolidine-2,5-dione (II) reacted with ((S)-2-(chloromethyl) oxirane) (III) in
presence of phase transfer catalyst in organic solvent and a base (S)-l-(oxiran-2-
ylmethyl)pyrrolidine-2,5-dione(IV)
b) (S)-l-(oxiran-2-ylmethyl)pyrrolidine-2,5-dione (IV) is reacted with 3-fluoro-4-morpholinoaniline (V) in presence of polar solvent to give (•S)-l-(3-((3-fluoro-4-morpholinophenyl)amino)-2-hydroxypropyl)pyrrolidine-2,5-dione (VI)
c) (S)-l-(3-((3-fluoro-4-morpholinophenyl) amino)-2-hydroxypropyl)pyrrolidine-2,5-dione (VI) is reacted with carbonyl diimidazole in presence of polar organic solvent to produce (5)-l-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl) pyrrolidine -2,5-dione (VII) a
d) (5)-1 -((3 -(3 -fluoro-4-morpholinophenyl)-2-oxooxazolidin-5 -yl)methyl) pyrrolidine -2,5-dione (VI) in organic solvent is reacted with hydrazine hydrate or methylamine to provide (5iS)-5-(aminomethyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-l,3-oxazolidin-2-one (VII), which is not isolated and in-situ treated with acetic anhydride in presence of organic solvent to produce N-({(5
Documents
Application Documents
| # |
Name |
Date |
| 1 |
3963-CHE-2013 FORM-2 04-09-2013.pdf |
2013-09-04 |
| 1 |
3963-CHE-2013-AbandonedLetter.pdf |
2019-03-05 |
| 2 |
3963-CHE-2013 FORM-1 04-09-2013.pdf |
2013-09-04 |
| 2 |
3963-CHE-2013-FORM 13 [28-12-2018(online)].pdf |
2018-12-28 |
| 3 |
3963-CHE-2013-FER.pdf |
2018-08-31 |
| 3 |
3963-CHE-2013 DESCRIPTION(PROVISIONAL) 04-09-2013.pdf |
2013-09-04 |
| 4 |
Correspondence By Agent_Form7a,Power Of Attorney_11-10-2017.pdf |
2017-10-11 |
| 4 |
3963-CHE-2013 CORRESPONDENCE OTHERS 04-09-2013.pdf |
2013-09-04 |
| 5 |
3963-CHE-2013-OTHERS [10-10-2017(online)].pdf |
2017-10-10 |
| 5 |
3963-CHE-2013 FORM-5 01-09-2014.pdf |
2014-09-01 |
| 6 |
3963-CHE-2013-PRE GRANT OPPOSITION DOCUMENT [10-10-2017(online)].pdf |
2017-10-10 |
| 6 |
3963-CHE-2013 FORM-2 01-09-2014.pdf |
2014-09-01 |
| 7 |
3963-CHE-2013-PRE GRANT OPPOSITION FORM [10-10-2017(online)].pdf |
2017-10-10 |
| 7 |
3963-CHE-2013 DESCRIPTION(COMPLETE) 01-09-2014.pdf |
2014-09-01 |
| 8 |
Form 18 [09-12-2016(online)].pdf |
2016-12-09 |
| 8 |
3963-CHE-2013 CORRESPONDENCE OTHERS 01-09-2014.pdf |
2014-09-01 |
| 9 |
3963-CHE-2013 ABSTRACT 01-09-2014.pdf |
2014-09-01 |
| 9 |
3963-CHE-2013 CLAIMS 01-09-2014.pdf |
2014-09-01 |
| 10 |
3963-CHE-2013 ABSTRACT 01-09-2014.pdf |
2014-09-01 |
| 10 |
3963-CHE-2013 CLAIMS 01-09-2014.pdf |
2014-09-01 |
| 11 |
3963-CHE-2013 CORRESPONDENCE OTHERS 01-09-2014.pdf |
2014-09-01 |
| 11 |
Form 18 [09-12-2016(online)].pdf |
2016-12-09 |
| 12 |
3963-CHE-2013 DESCRIPTION(COMPLETE) 01-09-2014.pdf |
2014-09-01 |
| 12 |
3963-CHE-2013-PRE GRANT OPPOSITION FORM [10-10-2017(online)].pdf |
2017-10-10 |
| 13 |
3963-CHE-2013 FORM-2 01-09-2014.pdf |
2014-09-01 |
| 13 |
3963-CHE-2013-PRE GRANT OPPOSITION DOCUMENT [10-10-2017(online)].pdf |
2017-10-10 |
| 14 |
3963-CHE-2013 FORM-5 01-09-2014.pdf |
2014-09-01 |
| 14 |
3963-CHE-2013-OTHERS [10-10-2017(online)].pdf |
2017-10-10 |
| 15 |
3963-CHE-2013 CORRESPONDENCE OTHERS 04-09-2013.pdf |
2013-09-04 |
| 15 |
Correspondence By Agent_Form7a,Power Of Attorney_11-10-2017.pdf |
2017-10-11 |
| 16 |
3963-CHE-2013 DESCRIPTION(PROVISIONAL) 04-09-2013.pdf |
2013-09-04 |
| 16 |
3963-CHE-2013-FER.pdf |
2018-08-31 |
| 17 |
3963-CHE-2013 FORM-1 04-09-2013.pdf |
2013-09-04 |
| 17 |
3963-CHE-2013-FORM 13 [28-12-2018(online)].pdf |
2018-12-28 |
| 18 |
3963-CHE-2013-AbandonedLetter.pdf |
2019-03-05 |
| 18 |
3963-CHE-2013 FORM-2 04-09-2013.pdf |
2013-09-04 |
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