CN102174043B - Method for preparing linezolid intermediate - Google Patents
Method for preparing linezolid intermediate Download PDFInfo
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- CN102174043B CN102174043B CN2011100532724A CN201110053272A CN102174043B CN 102174043 B CN102174043 B CN 102174043B CN 2011100532724 A CN2011100532724 A CN 2011100532724A CN 201110053272 A CN201110053272 A CN 201110053272A CN 102174043 B CN102174043 B CN 102174043B
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- 0 *C[C@@](CN1c(cc2)cc(F)c2N2CCOCC2)OC1=O Chemical compound *C[C@@](CN1c(cc2)cc(F)c2N2CCOCC2)OC1=O 0.000 description 1
- OIIATKPAHNLEAI-RDJZCZTQSA-N CC(N[C@@H](C1)[C@]1(CN1c(cc2F)ccc2N2CCNCC2)OC1=O)=O Chemical compound CC(N[C@@H](C1)[C@]1(CN1c(cc2F)ccc2N2CCNCC2)OC1=O)=O OIIATKPAHNLEAI-RDJZCZTQSA-N 0.000 description 1
- FKZUTWSVQLXKQE-OAHLLOKOSA-N O=C(c1c2cccc1)N(C[C@@H](CN1c(cc3)cc(F)c3N3CCOCC3)OC1=O)C2=O Chemical compound O=C(c1c2cccc1)N(C[C@@H](CN1c(cc3)cc(F)c3N3CCOCC3)OC1=O)C2=O FKZUTWSVQLXKQE-OAHLLOKOSA-N 0.000 description 1
Abstract
The invention relates to a method for preparing linezolid intermediate which is (R)-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazoline alkyl] methyl phthalimide (compound 2) from (R)-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazoline alkyl] methanol methanesulfonate ester (compound 1). In the process of preparing the compound 2, a mixed organic solvent system containing organic esters is adopted, and no base is added to catalyze, thus the ring opening of oxazolidinone and the generation of impurities due to the increase of the alkalinity of reaction solution because of the existence of water is avoided, the product is improved in properties, is easy to filter and has high yield, and the reaction time is shortened to 2 hours. The method is more suitable for industrial production and ensures that the HPLC (high-performance liquid chromatography) purity of the compound 2 is over 98.5%.
Description
Technical field
The present invention relates to the preparation method of the Linezolid intermediate of a kind of utilization (R)-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates (compound 1) preparation (R)-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl phthalimide (compound 2).
Background technology
Linezolid (s)-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methylacetamide ， is oxazolidinone compounds, and molecular formula is C
16H
20FN
3O
4, have following structural formula
Linezolid is by Pfizer, and Inc., as injection liquid, tablet and oral administration mixed suspension listing, is called ZYVOX in the U.S..It is mainly used in treating, and nosocomial pneumonia, skin and skin histology infect and the drug resistance of vancomycin enterococcus faecalis infects.Described Linezolid in the Merck index (13th edition, Monograph number:05526, CASRegistry Number:165800-03-3), be white crystal, fusing point is 181.5 ℃～182.5 ℃.Linezolid and preparation method thereof is disclosed in the open WO95/07271 of U.S. Patent No. 5688792 (embodiment 5), European patent No.717738, Israel patent No.110802, Canadian Patent No.2168560 and international monopoly.
in prior art and above-mentioned preparation method, it prepares adopt by (R)-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates (compound 1) of Linezolid more and prepares the intermediate (R) of Linezolid-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl phthalimide (compound 2), and then utilize the intermediate (R) of Linezolid-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl phthalimide (compound 2) to prepare the precursor (S) of Linezolid-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methylamine (compound 3), finally to prepare Linezolid.Therefore, the process that is prepared compound 2 by compound 1 is whole preparation technology's basic link, and the quality of its effect directly affects compound 3 and final Linezolid quality.
(R)-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates (compound 1) has following structural formula:
The intermediate of Linezolid (R)-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl phthalimide (compound 2) has following structural formula:
It is existing that to prepare the method kind of compound 2 by compound 1 a lot, a kind of preparation method of compound 2 is disclosed as Chinese invention patent application CN01144613.7, it is in aprotic polar solvent such as DMF, DMSO, acetonitrile, propionitrile etc. or their any mixture, (R)-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates (compound 1) and phthalic imidine salt carry out substitution reaction in 60～100 ℃ and prepare compound 2, add alkali (as salt of wormwood, sodium bicarbonate, triethylamine etc.) catalysis in reaction process.The problem that the method exists is that reaction need add base catalysis, otherwise the reaction times is longer, but, due to the existence of alkaline matter, causes the reaction environment neutral and alkali stronger, be easy to open loop occurs and produce impurity, so compound 2 yields is lower, and purity is lower.
Bricher, et al., J.Med.Chem., reported a kind of method in 39673～679 (1996): in the system of acetonitrile and water, compound 1 and potassium phthalimide effect, under reflux conditions, reaction is 48 hours, concentrating under reduced pressure obtains light yellow gluey thing, and jelly is ground dissolving, concentrating under reduced pressure in ethyl acetate and normal hexane (1: 1), the cooling crystallization, filter and obtain white solid compound 2.Although the method has been avoided use explosive raw material sodiumazide, long reaction time, yield is low, and aftertreatment need to be smashed grinding to pieces, and complex operation is not suitable for suitability for industrialized production.
Summary of the invention
For solving the deficiencies in the prior art, the invention provides the preparation method of the Linezolid intermediate that can improve compound 2 purity, it is simple and easy to do.
For achieving the above object, the preparation method of Linezolid intermediate of the present invention, comprise the steps:
A, compound 1 is added in the mixed solvent that contains aprotic polar solvent,, with the phthalic imidine reactant salt, is heated to back flow reaction, obtain reaction solution X;
B, the reaction solution X of A step gained is purified, dries, obtain compound 2;
Wherein:
Compound 1 is (R)-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates, has following structural formula:
Compound 2 is (R)-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl phthalimide, has following structural formula:
Described high boiling point aprotic polar solvent is at least a in DMF, N,N-dimethylacetamide or dimethyl sulfoxide (DMSO); Mixed solvent described in steps A comprises organic esters solvent, and it is 5%-50% that described organosilane ester solvent accounts for the mixed solvent volume ratio, preferred 15%-30%.
As the restriction to aforesaid way, above-mentioned organosilane ester solvent is ethyl acetate, ethyl formate, at least a in ethyl propionate, methyl-formiate, butylacetate.
Best, above-mentioned organosilane ester solvent is at least a in ethyl acetate, butylacetate.
As the restriction to aforesaid way, above-mentioned aprotic polar solvent is the high boiling point aprotic polar solvent.
Concrete, the above-mentioned preferred DMF of high boiling point aprotic polar solvent (DMF).
As the further restriction to aforesaid way, the mol ratio of described phthalic imidine salt and compound 1 is 1～4: 1, preferred 1.5～2.5: 1.
In addition, in above-mentioned steps A, Heating temperature is 75-85 ℃, and reflux time is 2h.
As the further restriction to aforesaid way, step B is specially: add organosilane ester solvent and purified water in the reaction solution X of A step gained, after being stirred to the crystallization body, filtration, oven dry obtain compound 2.
Further, above-mentioned organosilane ester solvent to adding in reaction solution X is ethyl acetate, ethyl formate, at least a in ethyl propionate, methyl-formiate, butylacetate.
Adopt technique scheme, in the preparation process at compound 2, employing contains the mixed organic solvents system of organosilane ester, need not to add base catalysis, avoided making reaction solution alkalescence strengthen the short generation that makes oxazolidone open loop impurity that brings because of the existence of water, improved the proterties of product, and be easy to filter, simultaneously also will foreshorten to 2 hours the reaction times, its yield is high, is more suitable for suitability for industrialized production.The HPLC purity is more than 98.5%.
Description of drawings
Fig. 1 is the HPLC collection of illustrative plates of the embodiment of the present invention one.
Embodiment
Below by concrete embodiment and embodiment, the present invention is done further and describes in detail, but the present invention is not limited to the restriction of following manner.
Embodiment one:
Add successively compound 1 (1kg, 2.67mol) in the 50L reactor, potassium phthalimide (750g, 4.0mol), DMF (11.2L), ethyl acetate (4.0L), stir.Heating in water bath to 80 ℃, insulation 2h, stopped reaction; Add successively the 10L ethyl acetate under agitation condition in above-mentioned reaction solution, the 12.5L purified water, continue to stir 1h, filter, and with appropriate purified water washing leaching cake, oven dry.The 943g that weighs, yield 83.0%.
Adopt acidproof octadecyl silane chromatographic column, gradient program wash-out is measured the HPLC purity of compound 2, and HPLC purity is 99.05%.
The method that following embodiment and embodiment one adopt is basic identical, difference is each component proportions of mixed solvent and the ratio between compound 1 and potassium phthalimide, purity and yield measuring method to each embodiment are identical with embodiment one, do not repeat them here.
As seen from the above embodiment, when compound 1 is prepared compound 2 by method of the present invention, the HPLC purity of its compound 2 is more than 98.5%, especially adopt the DMF/ ethyl acetate as mixed solvent, and when the volume ratio of the shared mixed solvent of ethyl acetate is 25% (embodiment five), the purity of its compound 2 can be up to 99.43%, and yield can reach 83.8%.
Claims (8)
1. the preparation method of a Linezolid intermediate, the method comprises the steps:
A, compound 1 is added in the mixed solvent that contains the high boiling point aprotic polar solvent,, with the phthalic imidine reactant salt, is heated to back flow reaction, obtain reaction solution X;
B, the reaction solution X of A step gained is purified, dries, obtain compound 2;
Wherein:
Compound 1 is (R)-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates, has following structural formula:
Compound 2 is (R)-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl phthalimide, has following structural formula:
It is characterized in that: described high boiling point aprotic polar solvent is at least a in DMF, N,N-dimethylacetamide or dimethyl sulfoxide (DMSO); Mixed solvent described in steps A also comprises organic esters solvent, described organosilane ester solvent is ethyl acetate, ethyl formate, at least a in ethyl propionate, methyl-formiate, butylacetate, it is 5%-50% that described organosilane ester solvent accounts for the mixed solvent volume ratio.
2. the preparation method of Linezolid intermediate according to claim 1, it is characterized in that: it is 15%-30% that described organosilane ester solvent accounts for the mixed solvent volume ratio.
3. the preparation method of Linezolid intermediate according to claim 1 is characterized in that: described organosilane ester solvent is at least a in ethyl acetate, butylacetate.
4. the preparation method of Linezolid intermediate according to claim 1, it is characterized in that: described high boiling point aprotic polar solvent is DMF.
5. the preparation method of Linezolid intermediate according to claim 1, it is characterized in that: the mol ratio of described phthalic imidine salt and compound 1 is 1～4: 1.
6. the preparation method of Linezolid intermediate according to claim 5, it is characterized in that: the mol ratio of described phthalic imidine salt and compound 1 is 1.5～2.5: 1.
7. the preparation method of Linezolid intermediate according to claim 1, it is characterized in that: in steps A, Heating temperature is 75-85 ℃, reflux time is 2h.
8. the preparation method of Linezolid intermediate according to claim 1, it is characterized in that: described step B is specially in the reaction solution X of A step gained and adds organosilane ester solvent and purified water, after being stirred to the crystallization body, filtration, oven dry obtain compound 2; Described organosilane ester solvent is ethyl acetate, ethyl formate, at least a in ethyl propionate, methyl-formiate, butylacetate.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005099353A2 (en) * | 2004-04-19 | 2005-10-27 | Symed Labs Limited | A novel process for the preparation of linezolid and related compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1155585C (en) * | 2001-12-19 | 2004-06-30 | 中国医学科学院医药生物技术研究所 | 3,5-substituted oxazolidinone derivative and its preparing process and application |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005099353A2 (en) * | 2004-04-19 | 2005-10-27 | Symed Labs Limited | A novel process for the preparation of linezolid and related compounds |
Non-Patent Citations (2)
| Title |
|---|
| 孟庆国，等.利奈唑酮的合成工艺改进.《中国药物化学杂志》.2003,第13卷(第1期),28-30. * |
| 孟庆国,等.新3,5-二取代噁唑烷酮抗菌剂的合成及其体外抑菌活性.《药学学报》.2003,第38卷(第10期),754-759. * |
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