CN103130733A - Method for preparing linezolid - Google Patents
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- CN103130733A CN103130733A CN2011103943598A CN201110394359A CN103130733A CN 103130733 A CN103130733 A CN 103130733A CN 2011103943598 A CN2011103943598 A CN 2011103943598A CN 201110394359 A CN201110394359 A CN 201110394359A CN 103130733 A CN103130733 A CN 103130733A
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Abstract
The invention provides an improved method for preparing linezolid. Specifically, after N-[3-fluorine-4-morpholinyl phenyl] carbamice ster is mixed with protic solvents and dipole solvents, under existing of condensating agent lithium t-butoxide, the N-[3-fluorine-4-morpholinyl phenyl] carbamice ster is in cyclization with (S)-N-[2-acetoxyl group-3-replacing propyl group] to obtain the linezolid. Compared with an original method, the method for preparing the linezolid is temperate in reaction condition, short in reaction time, simple and convenient in operation, low in cost, high in yield and prone to industrialization.
Description
Technical field
The present invention relates to N-[3-fluoro-4-morpholinyl phenyl] amino formate compounds and (S)-N-[2-acetoxy-3-substituted propyl] the ethanamide cyclization prepares improving one's methods of Linezolid.
Background technology
Bacterial resistance is one of serious problems of facing of the clinical and public health in the whole world, the Linezolid novel structure, and mechanism of action is unique, to drug tolerant bacteria, particularly the drug resistance of vancomycin bacterium is had killing action preferably.Linezolid (Linezolid), chemical name (S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide, be the one the oxazolidine ketone antimicrobial drug that Pfizer released in 2000, be mainly used in treating drug resistant bacterial infections and surgical infection.
World patent WO2002085849 and Org. Proce. Res. Dev 2003; 7:533 has reported the convergence type operational path that is used for the Linezolid preparation, and syntheti c route is as follows.
This operational path has obvious advantage in numerous Linezolid syntheti c routes: at first, demonstrated fully best " convergence type " principle on highway route design; Secondly, in reaction process, avoid the carbamate precursor of phosgene oxazolidinones ring processed with severe toxicity (as WO9924393, CN1772750 etc.), also avoid with the sodiumazide that is easy to explode, the methylol functional group on 5, oxazolidone ring being converted to aminomethyl (as US5688792, WO9507271, CN1673224 etc.).
But still there are the following problems for this operational path, seriously restricted its suitability for industrialized production:
(1) in S-halogen Propanolamine preparation process, difficult crystallization, yield is low, affects whole process costs;
When (2) cyclization prepares Linezolid, used the tetrahydrofuran solution of condensing agent trimethyl carbinol lithium, during the preparation of this reagent to tetrahydrofuran (THF) require highly, expensive, transportation difficulty simultaneously is easy to blast in use, be not easy to suitability for industrialized production;
When (3) cyclization prepares Linezolid, react not thorough, the reaction times reaches 21 hours, and with the prolongation in reaction times, impurity increases, and yield reduces.
For above-mentioned problem (1), patent WO2007116284 (CN200780012580.4) (R=chlorine, bromine or 2, the 4-dichloro) and CN102153521 (R=methyl, ethyl or sec.-propyl) above-mentioned technique is improved, reported the operational path of another preparation Linezolid, referred to as imidohydrine technique, syntheti c route is as follows.
Although this route has been avoided S-halogen Propanolamine crystallization purifying hard problem, in this route, the synthetic advantage of convergence type can not get demonstrating fully, and during preparation compound 1, the reaction times is oversize, and aftertreatment is very loaded down with trivial details, and total recovery also has no obviously and increases.
Afterwards, the West China pharmaceutical journal 2007; 22:179 has reported improving one's methods of preparation S-halogen Propanolamine, namely uses the mixed solvent crystallization of ethyl acetate and sherwood oil, has solved the problem of the difficult crystallization of S-halogen Propanolamine.
For above-mentioned problem (2), patent application CN102206194 has reported the method for directly using solid trimethyl carbinol lithium catalyzed cyclization to prepare Linezolid in the mixed solvent that contains dimethyl formamide, methylene dichloride and methyl alcohol.We find through repetition test, trimethyl carbinol lithium and N-[3-fluoro-4-morpholinyl phenyl when directly adding the solid trimethyl carbinol lithium during reaction] during the reaction of benzyl carbamate and methyl alcohol heat release very violent, punching material very easily, and reduced yield is unfavorable for suitability for industrialized production.
Therefore, realize the industrialization of this convergence type route, in the urgent need to a kind of safe, practical, method solves foregoing problem (2) and (3) cheaply, the present invention just provides such method.
Summary of the invention
In view of the above-mentioned problems, the present invention is for fear of having reagent costliness in preparation Linezolid ring and reactions steps now, operational condition is harsh, potential safety hazard is large, long reaction time, yield is low, and technique is loaded down with trivial details is not easy to the defective such as suitability for industrialized production, and improving one's methods of a kind of ring and preparation Linezolid is provided.
The method that the present invention prepares Linezolid relates to following steps:
Can be with reference to WO2002085849 or West China pharmaceutical journal 2007; 22:179 prepares N-[3-fluoro-4-morpholinyl phenyl] amino formate compounds and (S)-N-[2-acetoxy-3-substituted propyl] ethanamide.
With N-[3-fluoro-4-morpholinyl phenyl] amino formate compounds is with after protonic solvent and dipole solvent mix, under the existence of condensing agent trimethyl carbinol lithium, with (S)-N-[2-acetoxy-3-substituted propyl] ethanamide ring and obtain Linezolid, syntheti c route is as follows:
Wherein, X is chlorine, bromine, iodine or sulphonate; R is benzyl, phenyl or C
1-8Alkyl.
In this preparation method, N-[3-fluoro-4-morpholinyl phenyl] the preferred N-[3-fluoro-of amino formate compounds 4-morpholinyl phenyl] phenyl carbamate or N-[3-fluoro-4-morpholinyl phenyl] benzyl carbamate, particularly preferably N-[3-fluoro-4-morpholinyl phenyl] phenyl carbamate; (S)-N-[2-acetoxy-3-substituted propyl] preferred (the S)-N-[2-acetoxy-3-chloropropyl of ethanamide] ethanamide.
The above-mentioned protonic solvent of mentioning is C
2-
4A kind of in straight or branched Fatty Alcohol(C12-C14 and C12-C18), hexalin, preferred Virahol; Dipole solvent is acetonitrile, N, N ,-dimethyl formamide, N, N, a kind of in-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), preferred N, N ,-dimethyl formamide.The former with the latter consumption volume ratio is 1: 5-15, preferred 1: 8-12.
N-[3-fluoro-4-morpholinyl phenyl] amino formate compounds, (S)-N-[2-acetoxy-3-substituted propyl] ethanamide, trimethyl carbinol lithium and protonic solvent consumption mol ratio be 1-1.2: 1.5-2.5: 3-3.5: 2-5.5.The temperature of ring and reaction is 15 ℃-45 ℃, preferred 20 ℃-30 ℃.Condensing agent trimethyl carbinol lithium used is domestic industrial rank goods, and in use directly solid use.
React complete, add successively saturated NH in the Linezolid that obtains
4The Cl aqueous solution, water, saturated aqueous common salt and methylene dichloride, standing demix is told organic layer, drying, solvent evaporated gets oily matter, and oily matter gets off-white color Linezolid solid through the isopropyl ether crystallization.
In patent application CN102206194, by N-[3-fluoro-4-morpholinyl phenyl] benzyl carbamate and (S)-N-[2-acetoxy-3-chloropropyl] when the ethanamide cyclization prepares Linezolid, select the mixed solvent system that contains protonic solvent methyl alcohol, trimethyl carbinol lithium is added the violent heat release of meeting in the solvent that contains methyl alcohol, punching material very easily is even and be warmed up to 35 ℃-45 ℃ and also need insulation reaction 8-14 hour.Because trimethyl carbinol lithium adds the violent methanol lithium simultaneously of heat release in the solvent that contains methyl alcohol, lithium methoxide is highly basic again, and the rising temperature can cause other active hydrogen site generation side reaction in reaction substrate, further reduces yield.By embodiment as can be known, the yield of its preparation Linezolid is no more than 60%.
Find after deliberation, protonic solvent methyl alcohol is replaced by acid more weak C
2-
4The protonic solvent of straight or branched Fatty Alcohol(C12-C14 and C12-C18), hexalin, can significantly reduce the reactive behavior of trimethyl carbinol lithium and alcohol, thereby make heat release gentle, can directly use solid trimethyl carbinol lithium in the process that feeds intake and avoid costliness and dangerous trimethyl carbinol lithium tetrahydrofuran solution, the pure lithium compound that generates is catalyzing N-[3-fluoro-4-morpholinyl phenyl] amino formate compounds and (S)-N-[2-acetoxy-3-substituted propyl better faster] the ethanamide cyclization prepares Linezolid, and there is no the racemization phenomenon.Through this improvement, the reaction times is stable shortens to 6-12 hour.In addition, to N-[3-fluoro-4-morpholinyl phenyl] reactive behavior of amino formate compounds finds in relatively, N-[3-fluoro-4-morpholinyl phenyl] benzyloxy and N-[3-fluoro-4-morpholinyl phenyl in benzyl carbamate] the phenoxy group ability of leaving away in phenyl carbamate is better than the C in similar compound
1-8Alkoxyl group, preferred N-[3-fluoro-4-morpholinyl phenyl] benzyl carbamate or N-[3-fluoro-4-morpholinyl phenyl] when phenyl carbamate was made reaction substrate, the reaction times can be stablized and shortened to 6-8 hour.
Simultaneously, show by embodiments of the invention, the method for preparing Linezolid with WO2002085849 compares, and molar yield is by 72% stable being increased to more than 80%.
To sum up, the improving one's methods of preparation Linezolid of the present invention, reaction conditions is gentle, and the reaction times is short, and is easy and simple to handle, and cost is low, and yield is high, is easy to industrialization.
Below continue by reference example and embodiment that the present invention will be described, various replacements or combination according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
Reference example 1 (S)-N-[2-acetoxy-3-chloropropyl] preparation of ethanamide is (with reference to West China pharmacy impurity 2007; The 22:179 preparation)
2 (S)-1-amino-3-chloro-2-propylate hydrochlorates (50g, 0.342mol), diacetyl oxide (80g, 0.786mol) add in methylene dichloride (180mL), drip pyridine (34g, 0.341mol), drip and finish, and 30 ℃ were reacted 20 hours.Be cooled to 6 ℃, slowly add the aqueous solution (300mL) of salt of wormwood (93g, 0.68mol), tell organic layer, the water layer dichloromethane extraction merges organic layer, the saturated common salt water washing, solvent evaporated, the sherwood oil crystallization, ethyl acetate-sherwood oil is refining, oven dry, get off-white color solid 58.8g, yield 89.8%.m.p.：71-73℃，MS[MH+](m/z)：192。
Reference example 2 N-[3-fluoro-4-morpholinyl phenyl] preparation of benzyl carbamate is (with reference to West China pharmacy impurity 2007; The 22:179 preparation)
3-fluoro-4-morpholinyl oil of mirbane (90.5g, 0.4mol), 10% palladium carbon (8g), ammonium formiate (75.7g, 1.2mol) add in acetone (1200mL), 45 ℃-50 ℃ were reacted 3 hours, be cooled to room temperature, suction filtration, filtrate is transferred to acetone (1200mL) and sodium bicarbonate (58.8g, 0.7mol) the aqueous solution (1000mL) in, 0 ℃ slowly drips chloroformic acid benzyl ester (78.5g, 0.46mol), stirring at normal temperature 2 hours, in impouring frozen water (2000mL), suction filtration, the filter cake washing and drying gets off-white color solid 121.1g, yield 92%.m.p.：123-124℃，MS[MH+](m/z)：331，332。
Reference example 3 N-[3-fluoro-4-morpholinyl phenyl] preparation of phenyl carbamate is (with reference to West China pharmacy impurity 2007; The 22:179 preparation)
3-fluoro-4-morpholinyl oil of mirbane (90.5g, 0.4mol), 10% palladium carbon (8g), ammonium formiate (75.7g, 1200mmol) add in acetone (1200mL), 45 ℃-50 ℃ were reacted 3 hours, be cooled to room temperature, suction filtration, filtrate is transferred to acetone (1200mL) and sodium bicarbonate (58.8g, 0.7mol) the aqueous solution (1000mL) in, 0 ℃ slowly drips phenyl chloroformate (72g, 0.46mol), stirring at normal temperature 2 hours, in impouring frozen water (2000mL), suction filtration, the filter cake washing and drying gets off-white color solid 117.6g, yield 93%.m.p.：160-162℃，MS[MH+](m/z)：317，318。
The preparation of reference example 4 Linezolids---comparing embodiment (with reference to the WO2002085849 preparation)
N-[3-fluoro-4-morpholinyl phenyl] benzyl carbamate (20.6g, 62.5mmol), methyl alcohol (5.1mL, 126.4mmol) add N, N, in-dimethyl formamide (40mL), drip trimethyl carbinol lithium (83.2g, 187.8mmol) tetrahydrofuran solution (23%), temperature control is below 24 ℃, drip and finish, be cooled to 5 ℃, add (S)-N-[2-acetoxy-3-chloropropyl] ethanamide (24.1g, 124.68mmol), 21 ℃ were reacted 21 hours, after add successively saturated aqueous ammonium chloride (100mL), water (600mL), saturated aqueous common salt (400mL) and methylene dichloride (400mL), tell organic layer, anhydrous magnesium sulfate drying, the evaporate to dryness methylene dichloride, the dimethylbenzene crystallization, get off-white color solid 15.2g, yield 72%.
The preparation of embodiment 1 Linezolid
N-[3-fluoro-4-morpholinyl phenyl] benzyl carbamate (93.7g, 0.284mol) add ethanol (33.4mL, 0.568mol) and acetonitrile (215mL) in, stirring at room adds trimethyl carbinol lithium (68.7g to entirely molten, 0.852mol), stirring at room 20min is cooled to 5 ℃, adds (S)-N-[2-acetoxy-3-chloropropyl] ethanamide (110.0g, 0.568mol), be warming up to 22 ℃ of reactions 8 hours.Reaction is finished, add successively saturated aqueous ammonium chloride (210mL), water (1200mL), saturated aqueous common salt (1000mL) and methylene dichloride (1300mL) stir 15min, tell organic layer, anhydrous sodium sulfate drying, solvent evaporated, isopropyl ether crystallization, get off-white color solid 78g, yield 81%.m.p.：181-182℃，MS[MH+](m/z)：337,338,339,340。
The preparation of embodiment 2 Linezolids
N-[3-fluoro-4-morpholinyl phenyl] benzyl carbamate (140.6g, 0.426mol) adds n-propyl alcohol (80mL, 1.065mol) and N, N, in-N,N-DIMETHYLACETAMIDE (1200mL), stirring at room adds trimethyl carbinol lithium (119.3g to entirely molten, 1.491mol), stirring at room 20min is cooled to 5 ℃, adds (S)-N-[2-acetoxy-3-chloropropyl] ethanamide (123.6g, 0.639mol), be warming up to 22 ℃ of reactions 7 hours.Reaction is finished, add successively saturated aqueous ammonium chloride (315mL), water (1800mL), saturated aqueous common salt (1500mL) and methylene dichloride (1950mL) stir 15min, tell organic layer, anhydrous sodium sulfate drying, solvent evaporated, isopropyl ether crystallization, get off-white color solid 118g, yield 82%.m.p.：181-182℃，MS[MH+](m/z)：337,338,339,340。
The preparation of embodiment 3 Linezolids
N-[3-fluoro-4-morpholinyl phenyl] phenyl carbamate (45g, 0.142mol) adds Virahol (27mL, 0.356mol) and N, N, in-dimethyl formamide (324mL), stirring at room adds trimethyl carbinol lithium (40g to entirely molten, 0.497mol), stirring at room 30min is cooled to 5 ℃, adds (S)-N-[2-acetoxy-3-chloropropyl] ethanamide (55.0g, 0.284mol), be warming up to 20 ℃ of reactions 6 hours.Reaction is finished, add successively saturated aqueous ammonium chloride (120mL), water (600mL), saturated aqueous common salt (500mL) and methylene dichloride (600mL) stir 15min, tell organic layer, anhydrous sodium sulfate drying, solvent evaporated, isopropyl ether crystallization, get off-white color solid 41g, yield 86%.m.p.：181-182℃，MS[MH+](m/z)：337,338,339,340。
The preparation of embodiment 4 Linezolids
N-[3-fluoro-4-morpholinyl phenyl] phenyl carbamate (22.5g, 0.071mol) adds hexalin (37mL, 0.355mol) and N, N, in-dimethyl formamide (300mL), stirring at room adds trimethyl carbinol lithium (17g to entirely molten, 0.213mol), stirring at room 15min is cooled to 5 ℃, adds (S)-N-[2-acetoxy-3-chloropropyl] ethanamide (27.5g, 0.142mol), be warming up to 25 ℃ of reactions 8 hours.Reaction is finished, add successively saturated aqueous ammonium chloride (60mL), water (300mL), saturated aqueous common salt (250mL) and methylene dichloride (300mL) stir 15min, tell organic layer, anhydrous sodium sulfate drying, solvent evaporated, isopropyl ether crystallization, get off-white color solid 19.4g, yield 81%.m.p.：181-182℃，MS[MH+](m/z)：337,338,339,340。
The preparation of embodiment 5 Linezolids
N-[3-fluoro-4-morpholinyl phenyl] phenyl carbamate (40.5g, 0.128mol) adds propyl carbinol (64.4mL, 0.704mol) and N, N, in-dimethyl formamide (515mL), stirring at room adds trimethyl carbinol lithium (30.7g to entirely molten, 0.384mol), stirring at room 15min is cooled to 5 ℃, adds (S)-N-[2-acetoxy-3-chloropropyl] ethanamide (61.9g, 0.32mol), be warming up to 20 ℃ of reactions 7 hours.Reaction is finished, add successively saturated aqueous ammonium chloride (108mL), water (540mL), saturated aqueous common salt (450mL) and methylene dichloride (540mL) stir 15min, tell organic layer, anhydrous sodium sulfate drying, solvent evaporated, isopropyl ether crystallization, get off-white color solid 35.4g, yield 82%.m.p.：181-182℃，MS[MH+](m/z)：337,338,339,340。
The preparation of embodiment 6 Linezolids
N-[3-fluoro-4-morpholinyl phenyl] benzyl carbamate (100g, 0.303mol) add isopropylcarbinol (138.6mL, 1.515mol) and dimethyl sulfoxide (DMSO) (693mL) in, stirring at room adds trimethyl carbinol lithium (72.7g to entirely molten, 0.909mol), stirring at room 20min is cooled to 5 ℃, adds (S)-N-[2-acetoxy-3-chloropropyl] ethanamide (105.5g, 0.545mol), be warming up to 22 ℃ of reactions 7 hours.Reaction is finished, add successively saturated aqueous ammonium chloride (225mL), water (1285mL), saturated aqueous common salt (1100mL) and methylene dichloride (1392mL) stir 15min, tell organic layer, anhydrous sodium sulfate drying, solvent evaporated, isopropyl ether crystallization, get off-white color solid 84.8g, yield 83%.m.p.：181-182℃，MS[MH+](m/z)：337,338,339,340。
Claims (10)
1. method for preparing Linezolid, it is characterized in that comprising the steps: with N-[3-fluoro-4-morpholinyl phenyl] amino formate compounds is with after protonic solvent and dipole solvent mix, under the existence of condensing agent trimethyl carbinol lithium, with (S)-N-[2-acetoxy-3-substituted propyl] ethanamide ring and obtain Linezolid, syntheti c route is as follows:
Wherein, X is chlorine, bromine, iodine or sulphonate; R is benzyl, phenyl or C
1-8Alkyl.
2. the method for claim 1, it is characterized in that described N-[3-fluoro-4-morpholinyl phenyl] the preferred N-[3-fluoro-of amino formate compounds 4-morpholinyl phenyl] phenyl carbamate or N-[3-fluoro-4-morpholinyl phenyl] benzyl carbamate, (S)-N-[2-acetoxy-3-substituted propyl] preferred (the S)-N-[2-acetoxy-3-chloropropyl of ethanamide] ethanamide.
3. method as claimed in claim 1 or 2, is characterized in that described N-[3-fluoro-4-morpholinyl phenyl] the preferred N-[3-fluoro-of amino formate compounds 4-morpholinyl phenyl] phenyl carbamate.
4. the method for claim 1, is characterized in that described protonic solvent is C
2-
4A kind of in straight or branched Fatty Alcohol(C12-C14 and C12-C18), hexalin.
5. the method for claim 1, is characterized in that described dipole solvent is acetonitrile, N, N ,-dimethyl formamide, N, N, a kind of in-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO).
6. as claim 1,4 or 5 described methods, it is characterized in that the preferred Virahol of protonic solvent, the preferred N of dipole solvent, N ,-dimethyl formamide.
7. the method for claim 1, is characterized in that protonic solvent and dipole solvent consumption volume ratio are 1: 5-15.
8. method as described in claim 1 or 7, is characterized in that protonic solvent and dipole solvent consumption volume ratio preferred 1: 8-12.
9. the method for claim 1, is characterized in that N-[3-fluoro-4-morpholinyl phenyl] amino formate compounds, (S)-N-[2-acetoxy-3-substituted propyl] ethanamide, trimethyl carbinol lithium and protonic solvent consumption mol ratio be 1-1.2: 1.5-2.5: 3-3.5: 2-5.5.
10. the method for claim 1 is characterized in that encircling and the temperature of reacting is 15 ℃-45 ℃, preferred 20 ℃-30 ℃.
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| US20170217911A1 (en) * | 2015-12-18 | 2017-08-03 | Mankind Research Centre | Process For Preparation Of Linezolid |
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| WO2002085849A2 (en) * | 2001-04-20 | 2002-10-31 | Pharmacia & Upjohn Company | Process to prepare oxazolidinones |
| CN102206194A (en) * | 2011-04-12 | 2011-10-05 | 湖北省医药工业研究院有限公司 | Preparation method for antibacterial drug linezolid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002085849A2 (en) * | 2001-04-20 | 2002-10-31 | Pharmacia & Upjohn Company | Process to prepare oxazolidinones |
| CN102206194A (en) * | 2011-04-12 | 2011-10-05 | 湖北省医药工业研究院有限公司 | Preparation method for antibacterial drug linezolid |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170217911A1 (en) * | 2015-12-18 | 2017-08-03 | Mankind Research Centre | Process For Preparation Of Linezolid |
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