CN103864707B - (S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine preparation method - Google Patents
(S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine preparation method Download PDFInfo
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- 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
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Abstract
The present invention relates to the preparation method of a kind of linezolid intermediate (S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine, comprise the following steps: 1) (R)-N-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol is joined in water-miscible organic solvent, the haloid acid being 30 ~ 35% with mass concentration carries out first time and heats in reaction vessel, and reaction generates (R)-5-halogenated methyl-3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxazolidone; 2) (R)-5-halogenated methyl-3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxazolidone is joined in water-miscible organic solvent, the ammoniacal liquor being 25 ~ 29% with mass concentration carries out second time and heats in reaction vessel, and reaction generates described linezolid intermediate (S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine.The present invention two step total recovery is that 76 ~ 80%, HPLC purity can reach more than 99.5%.
Description
Technical field
The present invention relates to the preparation method of a kind of linezolid intermediate (S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine, belong to pharmacy field.
Background technology
Linezolid, chemical name is (S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylacetamide, and molecular formula is C
16h
20fN
3o
4, there is following structural formula:
Linezolid is the mono-oxazolidinone antimicrobial drug developed by Pfizer (Pfizer) company, commodity are called ZYVOX (Si Wo), be mainly used in treating pneumonia and comprehensive skin infections that microbemia, methicillin-resistant staphylococcus aureus (MRSA) that vancomycin-resistant enterococcus (VRE) causes cause and the microbemia that penicillin resistance pneumococcus (PRSP) causes, be considered to the novel antibacterial medicine having clinical value.
In the Merck index (13th edition, Monograph number:05526, CAS RegistryNumber:165800-03-3), describe Linezolid, it is white crystal, and fusing point is 181.5 ~ 182.5 DEG C.Linezolid and preparation method thereof is disclosed in U.S. Patent No. 5688792, European patent No.717738, Israel patent No.110802, Canadian Patent No.2168560 and international monopoly WO9507271.
(S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine (compound III) prepares the important intermediate of Linezolid, and this intermediate and diacetyl oxide or Acetyl Chloride 98Min. can obtain Linezolid through acetylizing.Relevant report both at home and abroad about this intermediate of synthesis is more:
US5688792, US6107519, US7291614, WO2009063505, CN200910101973.3, J.Med.Chem.1996, Vol39 (3): 673 ~ 679, Chinese Journal of New Drugs 2002; 11:378, Chinese pharmaceutical chemistry 2005; 15:89 etc. report and for starting raw material, prepare compound III through Mesylation, azide, catalytic hydrogenation with key intermediate (R)-N-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol (Compound I).Employ hazardous explosion prone thing sodium azide (NaN3) in this route as reaction raw materials, greatly reduce the security of whole piece synthetic route, be unsuitable for Workshop Production and amplify; In catalytic hydrogenation, need the catalyst P d/C using price more expensive, cause production cost to improve.
Sodium azide synthesis technique
Document J.Med.Chem.1996; Vol39 (3): 673 ~ 679 have reported with key intermediate (R)-N-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol (Compound I) as starting raw material; through steps such as Mesylation, Gabriel reaction, hydrazine hydrate ammonia solutions, obtain compound III.This method is when carrying out Gabriel reaction preparation compound III, and because temperature of reaction is higher, the sylvite alkalescence of phthalic imidine is comparatively strong, is easy to the open loop of Shi oxazolidone and produces impurity, causing product yield to reduce.
Gabriel synthesis technique
Summary of the invention
Technical problem to be solved by this invention is to provide the preparation method of a kind of purity and all higher linezolid intermediate (S)-[3-(the fluoro-4-morpholinyl of the 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine of yield.
The technical scheme that the present invention solves the problems of the technologies described above is as follows: the preparation method of a kind of linezolid intermediate (S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine, comprises the following steps:
1) (R)-N-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol is joined in water-miscible organic solvent, the haloid acid being 30 ~ 35% with mass concentration carries out first time and heats in reaction vessel, and reaction generates (R)-5-halogenated methyl-3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxazolidone; Wherein,
The structure of described (R)-N-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol
The structural formula of described (R)-5-halogenated methyl-3-(3-fluoro-4-morpholinyl) phenyl-2-oxazolidone is as follows:
Wherein, described R is halogen;
The mass ratio of described water-miscible organic solvent and described (R)-N-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol is 4 ~ 6:1, and the mol ratio of described haloid acid and described (R)-N-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol is 2 ~ 4:1;
2) (R)-5-halogenated methyl-3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxazolidone described in generating in step 1) is joined in water-miscible organic solvent, the ammoniacal liquor being 25 ~ 29% with mass concentration carries out second time and heats in reaction vessel, and reaction generates described linezolid intermediate (S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine; Wherein,
The structural formula of described linezolid intermediate (S)-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methylamine is as follows:
The mol ratio of described ammoniacal liquor and described (R)-5-halogenated methyl-3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxazolidone is 2 ~ 4:1;
The mass ratio of described water-miscible organic solvent and described (R)-5-halogenated methyl-3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxazolidone is 6 ~ 8:1.
The invention has the beneficial effects as follows: the linezolid intermediate (S) that preparation method of the present invention obtains-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine, two step total recoverys are that 76 ~ 80%, HPLC purity can reach more than 99.5%.Adopt the linezolid intermediate of technical scheme gained of the present invention, with diacetyl oxide or Acetyl Chloride 98Min. after acetylize, do not need complicated last handling process can obtain high purity Linezolid, yield is higher, is more applicable to suitability for industrialized production.
On the basis of technique scheme, the present invention can also do following improvement.
Further, described halogen is any one in Cl, Br or I.
Further, described water-miscible organic solvent comprises acetonitrile, acetone, tetrahydrofuran (THF), dioxane, diglyme, any one or two or more mixing in DMF, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO) or glacial acetic acid.
Further, described haloid acid is any one in spirit of salt (HCl), Hydrogen bromide (HBr) or hydroiodic acid HI (HI).
Further, in step 1), described in carry out first time heating processing condition be: at the temperature of 45 ~ 55 DEG C heat 5 ~ 10 hours.
Further, in step 2) in, described in carry out second time heating processing condition be: at the temperature of 40 ~ 45 DEG C heat 10 ~ 15 hours.
Embodiment
Be described principle of the present invention and feature below, example, only for explaining the present invention, is not intended to limit scope of the present invention.
Embodiment 1:
The preparation of Compound I (R)-N-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol:
By the fluoro-4-morpholinyl phenylamine of N-carbobenzoxy-(Cbz)-3-(84.00g, 0.255mol) be dissolved in 500mL tetrahydrofuran (THF), be cooled to-70 ~-80 DEG C, drip 2.2mol/L n-Butyl Lithium hexane solution (123.3mL, 0.272mol), continuation reaction 2 hours are dropwised.Drip (R)-Glycidyl butyrate (37.60g, 0.255mol), after being naturally warming up to room temperature, reaction 8 ~ 10h.TLC monitors, and raw material reaction is complete, in reaction solution, add saturated NH
4cl solution and each 300mL of methylene dichloride, stir 20 minutes, separatory, aqueous phase CH
2cl
2(300mL × 2) extract, and merge organic phase, use the saturated NaCl solution washing of 400mL water, 400mL successively, and washing is finished, and adds 150g anhydrous Na
2sO
4drying, decompression desolventizing, obtains faint yellow solid crude product 126.50g.Obtain white powder 63.20g after crude product re-crystallizing in ethyl acetate, yield is 85.3%, purity 99.2% (HPLC).
Embodiment 2:
The preparation of Compound II per (R)-5-chloromethyl-3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxazolidone:
Be dissolved in 360mL THF by the Compound I (60.00g, 0.203mol) prepared by embodiment 1, dripping 89.81g massfraction is the aqueous hydrochloric acid solution of 33%, and hierarchy of control temperature is at 20 ~ 30 DEG C.Drip after finishing, be heated to 45 ~ 55 DEG C, stirring reaction 10h at this temperature.TLC monitors, and Compound I reacts completely.Remove THF under reduced pressure, obtain yellow oil (lower floor) and the mixing solutions of water (upper strata), add 200mL water, stirring and evenly mixing, extract with methylene dichloride (200mL × 3).Merge organic phase, successively with 300mL tap water and the washing of 300mL saturated sodium-chloride water solution.Washing is finished, and adds 100g anhydrous sodium sulfate drying 2h, and decompression desolventizing, obtains pale solid 57.50g, yield 90.0%, purity 92.2% (HPLC).
Embodiment 3:
The preparation of Compound II per (R)-5-brooethyl-3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxazolidone:
Be dissolved in 360mL THF by the Compound I (60.00g, 0.203mol) prepared by embodiment 1, dripping 99.54g massfraction is the hydrobromic acid aqueous solution of 33%, and hierarchy of control temperature is at 20 ~ 30 DEG C.Drip after finishing, be heated to 45 ~ 55 DEG C, stirring reaction 8h at this temperature.TLC monitors, and Compound I reacts completely, and removes THF under reduced pressure, obtains yellow oil (lower floor) and the mixing solutions of water (upper strata), adds 200mL water, stirring and evenly mixing, extract with methylene dichloride (200mL × 3).Merge organic phase, successively with 300mL tap water and the washing of 300mL saturated sodium-chloride water solution.Washing is finished, and adds 100g anhydrous sodium sulfate drying 2h, and decompression desolventizing, obtains pale solid 64.23g, yield 88.1%, purity 95.5% (HPLC).
Embodiment 4:
The preparation of Compound II per (R)-5-iodomethyl-3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxazolidone:
Be dissolved in 360mL THF by the Compound I (60.00g, 0.203mol) prepared by embodiment 1, dripping 157.37g massfraction is the hydriodic acid aqueous solution of 33%, and hierarchy of control temperature is at 20 ~ 30 DEG C.Drip after finishing, be heated to 45 ~ 55 DEG C, stirring reaction 5h at this temperature.TLC monitors, and Compound I reacts completely, and removes THF under reduced pressure, obtains yellow oil (lower floor) and the mixing solutions of water (upper strata), adds 200mL water, stirring and evenly mixing, extract with methylene dichloride (200mL × 3).Merge organic phase, successively with 300mL tap water and the washing of 300mL saturated sodium-chloride water solution.Washing is finished, and adds 100g anhydrous sodium sulfate drying 2h, and decompression desolventizing, obtains pale solid 73.39g, yield 89.0%, purity 94.0% (HPLC).
Embodiment 5:
The preparation of compound III (S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine:
By the Compound II per (55.00g, 0.175mol) prepared by embodiment 2,40 ~ 45 DEG C, the mixture heating 15h of 440mL acetonitrile and 87.50g28% ammoniacal liquor.TLC detects, and Compound II per reacts completely, and removes solvent under reduced pressure, and residuum adds 200mL water stirring and evenly mixing, extracts with methylene dichloride (200mL × 3).Merge organic phase, successively with 300mL water and the washing of 300mL saturated sodium-chloride water solution, washing is complete adds anhydrous sodium sulfate drying 2h.Dry complete, remove solvent under reduced pressure, obtain faint yellow solid crude product 49.10g.With the mixed solvent recrystallization of ethyl acetate and normal hexane, obtain compound III white solid fine work 43.93g, yield 85.0%, purity 99.62% (HPLC).
Embodiment 6:
The preparation of compound III (S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine:
By the Compound II per (60.00g, 0.167mol) prepared by embodiment 3,40 ~ 45 DEG C, the mixture heating 13h of 390mL acetonitrile and 62.62g28% ammoniacal liquor.TLC detects, and Compound II per reacts completely, and removes solvent under reduced pressure, and residuum adds 200mL water stirring and evenly mixing, extracts with methylene dichloride (200mL × 3).Merge organic phase, successively with 300mL water and the washing of 300mL saturated sodium-chloride water solution, washing is complete adds anhydrous sodium sulfate drying 2h.Dry complete, remove solvent under reduced pressure, obtain faint yellow solid crude product 50.50g.With the mixed solvent recrystallization of ethyl acetate and normal hexane, obtain compound 3 white solid fine work 42.91g, yield 87.0%, purity 99.57% (HPLC).
Embodiment 7:
The preparation of compound III (S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine:
By the Compound II per (65.00g, 0.160mol) prepared by embodiment 4,40 ~ 45 DEG C, the mixture heating 10h of 455mL acetonitrile and 40.00g28% ammoniacal liquor.TLC detects, and Compound II per reacts completely, and removes solvent under reduced pressure, and residuum adds 200mL water stirring and evenly mixing, extracts with methylene dichloride (200mL × 3).Merge organic phase, successively with 300mL water and the washing of 300mL saturated sodium-chloride water solution, washing is complete adds anhydrous sodium sulfate drying 2h.Dry complete, remove solvent under reduced pressure, obtain faint yellow solid crude product 45.50g.With the mixed solvent recrystallization of ethyl acetate and normal hexane, obtain compound 3 white solid fine work 42.29g, yield 89.5%, purity 99.80% (HPLC),
1h-NMR (DMSO): δ 7.55 (1H, dd, J=14.4Hz, J=2.7Hz), 7.15 (1H, dd, J=8.7Hz, J=2.7Hz), 6.95 (1H, t, J=9.5Hz), 4.78 (1H, m), 4.02 (1H, t, J=8.9Hz), 3.85 (1H, dd, J=6.4Hz, J=8.9Hz), 3.73 (4H, t, J=4.6Hz), 2.96 (4H, t, J=4.5Hz), 2.89 (2H, m), 2.05 (2H, t, J=9.0Hz).
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (6)
1. the preparation method of linezolid intermediate (S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine, is characterized in that, comprise the following steps:
1) (R)-N-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol is joined in water-miscible organic solvent, the haloid acid being 30 ~ 35% with mass concentration carries out first time and heats in reaction vessel, and reaction generates (R)-5-halogenated methyl-3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxazolidone; Wherein,
The structure of described (R)-N-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol
The structural formula of described (R)-5-halogenated methyl-3-(3-fluoro-4-morpholinyl) phenyl-2-oxazolidone is as follows:
Wherein, described R is halogen;
The mass ratio of described water-miscible organic solvent and described (R)-N-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol is 4 ~ 6:1, and the mol ratio of described haloid acid and described (R)-N-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methyl alcohol is 2 ~ 4:1;
2) (R)-5-halogenated methyl-3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxazolidone described in generating in step 1) is joined in water-miscible organic solvent, the ammoniacal liquor being 25 ~ 29% with mass concentration carries out second time and heats in reaction vessel, and reaction generates described linezolid intermediate (S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine; Wherein,
The structural formula of described linezolid intermediate (S)-[3-(3-fluoro-4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methylamine is as follows:
The mol ratio of described ammoniacal liquor and described (R)-5-halogenated methyl-3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxazolidone is 2 ~ 4:1;
The mass ratio of described water-miscible organic solvent and described (R)-5-halogenated methyl-3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxazolidone is 6 ~ 8:1.
2. the preparation method of linezolid intermediate according to claim 1 (S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine, it is characterized in that, described halogen is any one in Cl, Br or I.
3. the preparation method of linezolid intermediate according to claim 1 (S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine, it is characterized in that, described water-miscible organic solvent comprises acetonitrile, acetone, tetrahydrofuran (THF), dioxane, diglyme, N, any one or two or more mixing in dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO) or glacial acetic acid.
4. the preparation method of linezolid intermediate according to claim 1 (S)-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine, it is characterized in that, described haloid acid is any one in spirit of salt, Hydrogen bromide or hydroiodic acid HI.
5. the preparation method of the linezolid intermediate (S) according to any one of Claims 1-4-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine, it is characterized in that, in step 1), described in carry out first time heating processing condition be: at the temperature of 45 ~ 55 DEG C heat 5 ~ 10 hours.
6. the preparation method of the linezolid intermediate (S) according to any one of Claims 1-4-[3-(the fluoro-4-morpholinyl of 3-) phenyl-2-oxo-5-oxazolidinyl] methylamine, it is characterized in that, in step 2) in, described in carry out second time heating processing condition be: at the temperature of 40 ~ 45 DEG C heat 10 ~ 15 hours.
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| 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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| 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 |
|---|
| 刑其毅等.基础有机化学(上).《基础有机化学(上)》.高等教育出版社,2005,(第三版),393-394. * |
| 陈荣业.卤代芳烃的胺解.《有机合成工艺优化》.化学工业出版社,2006,(第一版),140-144. * |
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