CN103130733B - Method for preparing linezolid - Google Patents
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- CN103130733B CN103130733B CN201110394359.8A CN201110394359A CN103130733B CN 103130733 B CN103130733 B CN 103130733B CN 201110394359 A CN201110394359 A CN 201110394359A CN 103130733 B CN103130733 B CN 103130733B
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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 and N-[the fluoro-4-morpholino phenyl of 3-] amino formate compounds and (S)-N-[2-acetoxy-3-substituted propyl] ethanamide cyclization are prepared improving one's methods of Linezolid.
Background technology
Bacterial resistance is one of most serious problems of facing of the clinical and public health in the whole world, and Linezolid novel structure, mechanism of action is unique, to drug tolerant bacteria, particularly has good killing action to vancomycin-resistant bacterium.Linezolid (Linezolid), chemical name (S)-N-[[3-[the fluoro-4-of 3-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide, be the mono-oxazolidinone antimicrobial drug that Pfizer releases for 2000, be mainly used in treatment drug resistant bacterial infections and surgical infection.
World patent WO2002085849 and Org. Proce. Res. Dev 2003; 7:533 reports the convergence type operational path prepared for Linezolid, and syntheti c route is as follows.
This operational path has obvious advantage in numerous Linezolid syntheti c routes: first, and highway route design has fully demonstrated best " convergence type " principle; Secondly, in reaction process, avoid using the phosgene of severe toxicity to carry out the carbamate precursor of oxazolidinones ring processed (as WO9924393, CN1772750 etc.), also avoid using the sodiumazide being easy to explode that the methylol functional groups on 5, oxazolidone ring is converted to aminomethyl (as US5688792, WO9507271, CN1673224 etc.).
But still there are the following problems for this operational path, seriously constrain its suitability for industrialized production:
(1) in S-halogen Propanolamine preparation process, difficult crystallization, yield is low, affects whole process costs;
(2) when Linezolid is prepared in cyclization, employ the tetrahydrofuran solution of condensing agent trimethyl carbinol lithium, high to the requirement of tetrahydrofuran (THF), expensive during this preparation of reagents, transport difficult simultaneously, is easy to blast, is not easy to suitability for industrialized production in using;
(3) when Linezolid is prepared in cyclization, reaction is thorough, and 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 2,4-dichloro) and CN102153521 (R=methyl, ethyl or sec.-propyl) above-mentioned technique is improved, report the operational path that another prepares Linezolid, referred to as imidohydrine technique, syntheti c route is as follows.
Although this route avoids the problem of S-halogen Propanolamine crystallization purifying difficulty, in this route, the advantage of convergence type synthesis can not get fully demonstrating, and when preparing compound 1, the reaction times is oversize, and aftertreatment is very loaded down with trivial details, and total recovery also has no and obviously increases.
Afterwards, West China pharmaceutical journal 2007; 22:179 reports improving one's methods of preparation S-halogen Propanolamine, namely uses the mixed solvent crystallization of ethyl acetate and sherwood oil, solves the problem of the difficult crystallization of S-halogen Propanolamine.
For above-mentioned problem (2), patent application CN102206194 reports and directly uses solid t-butyl alcohol lithium catalyzed cyclization to prepare the method for Linezolid in containing the mixed solvent of dimethyl formamide, methylene dichloride and methyl alcohol.We find through repetition test, and when when directly adding solid t-butyl alcohol lithium during reaction, trimethyl carbinol lithium and N-[the fluoro-4-morpholino phenyl of 3-] benzyl carbamate and methyl alcohol react, heat release is very violent, very easily rushes material, and reduces yield, be unfavorable for suitability for industrialized production.
Therefore, realize the industrialization of this convergence type route, solve foregoing problem (2) and (3) in the urgent need to a kind of method that is safe, practical, low cost, the present invention is just providing such method.
Summary of the invention
In view of the above-mentioned problems, the present invention prepares expensive reagents in Linezolid ring and reactions steps in order to avoid existing, 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 defects such as suitability for industrialized production, and provides a kind of ring and prepare improving one's methods of Linezolid.
The method that the present invention prepares Linezolid relates to following steps:
Can refer to WO2002085849 or West China pharmaceutical journal 2007; 22:179 prepares N-[the fluoro-4-morpholino phenyl of 3-] amino formate compounds and (S)-N-[2-acetoxy-3-substituted propyl] ethanamide.
After N-[the fluoro-4-morpholino phenyl of 3-] amino formate compounds is mixed with protonic solvent and dipole solvent, 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-morpholino phenyl] the preferred N-of amino formate compounds [3-fluoro-4-morpholino phenyl] phenyl carbamate or N-[the fluoro-4-morpholino phenyl of 3-] benzyl carbamate, particularly preferably N-[the fluoro-4-morpholino phenyl of 3-] phenyl carbamate; (S)-N-[2-acetoxy-3-substituted propyl] ethanamide preferably (S)-N-[2-acetoxy-3-chloropropyl] ethanamide.
The above-mentioned protonic solvent mentioned is C
2-
4one in straight or branched fatty alcohol, hexalin, preferred Virahol; Dipole solvent is acetonitrile, N, N ,-dimethyl formamide, N, N, the one in-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), preferred N, N ,-dimethyl formamide.The former with the latter consumption volume ratio is 1: 5-15, preferably 1: 8-12.
N-[the fluoro-4-morpholino phenyl of 3-] amino formate compounds, (S)-N-[2-acetoxy-3-substituted propyl] ethanamide, trimethyl carbinol lithium and protonic solvent consumption mol ratio are 1-1.2: 1.5-2.5: 3-3.5: 2-5.5.The temperature of ring and reaction is 15 DEG C-45 DEG C, preferably 20 DEG C-30 DEG C.Condensing agent trimethyl carbinol lithium used is domestic industrial rank goods, and in use directly solid use.
React complete, in the Linezolid obtained, add saturated NH successively
4the Cl aqueous solution, water, saturated aqueous common salt and methylene dichloride, stratification, separates organic layer, and dry, solvent evaporated, obtains oily matter, and oily matter, through isopropyl ether crystallization, obtains off-white color Linezolid solid.
In patent application CN102206194, when preparing Linezolid by N-[the fluoro-4-morpholino phenyl of 3-] benzyl carbamate and (S)-N-[2-acetoxy-3-chloropropyl] ethanamide cyclization, select the mixed solvent system containing protonic solvent methyl alcohol, trimethyl carbinol lithium is added the heat release that in the solvent containing methyl alcohol, meeting is violent, very easily rush material, even and if be warmed up to 35 DEG C-45 DEG C and also need insulation reaction 8-14 hour.Again due to trimethyl carbinol lithium add containing methyl alcohol solvent in the violent methanol lithium simultaneously of heat release, lithium methoxide is highly basic, and raised temperature can cause other active hydrogen site in reaction substrate that side reaction occurs, and reduces yield further.Known by embodiment, its yield preparing 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, hexalin, significantly can reduce the reactive behavior of trimethyl carbinol lithium and alcohol, thus make heat release gentle, can directly use solid t-butyl alcohol lithium and avoid costliness and the trimethyl carbinol lithium tetrahydrofuran solution of danger in the process that feeds intake, the alcohol lithium compound generated can catalyzing N-[the fluoro-4-morpholino phenyl of 3-] amino formate compounds and (S)-N-[2-acetoxy-3-substituted propyl] ethanamide cyclization be prepared Linezolid, and not have racemization phenomenon better faster.Improve through this, the reaction times is stable shortens to 6-12 hour.In addition, to the reactive behavior of N-[the fluoro-4-morpholino phenyl of 3-] amino formate compounds relatively in find, the phenoxy group leaving capability in the benzyloxy in N-[3-fluoro-4-morpholino phenyl] benzyl carbamate and N-[the fluoro-4-morpholino phenyl of 3-] phenyl carbamate is better than the C in similar compound
1-8alkoxyl group, when reaction substrate made by preferred N-[3-fluoro-4-morpholino phenyl] benzyl carbamate or N-[the fluoro-4-morpholino phenyl of 3-] phenyl carbamate, the reaction times can be stablized and shortened to 6-8 hour.
, shown by embodiments of the invention meanwhile, prepare the Measures compare of Linezolid with WO2002085849, molar yield stable is increased to more than 80% by 72%.
To sum up, of the present inventionly prepare improving one's methods of Linezolid, reaction conditions is gentle, and the reaction times is short, easy and simple to handle, and cost is low, and yield is high, is easy to industrialization.
Continue below by way of reference example and embodiment that the present invention will be described, the various replacement made according to ordinary skill knowledge and customary means or combination, all should comprise within the scope of the invention.
The preparation of reference example 1 (S)-N-[2-acetoxy-3-chloropropyl] ethanamide is (with reference to West China pharmacy impurity 2007; Prepared by 22:179)
The chloro-2-propanol hydrochloride (50g, 0.342mol) of 2 (S)-1-amino-3-, diacetyl oxide (80g, 0.786mol) add in methylene dichloride (180mL), drip pyridine (34g, 0.341mol), drip and finish, 30 DEG C are reacted 20 hours.Be cooled to 6 DEG C, slowly add the aqueous solution (300mL) of salt of wormwood (93g, 0.68mol), separate organic layer, water layer dichloromethane extraction, merges organic layer, saturated common salt water washing, solvent evaporated, sherwood oil crystallization, ethyl acetate-light petrol is refined, and dries, obtain off-white color solid 58.8g, yield 89.8%.m.p.：71-73℃，MS[MH+](m/z)：192。
The preparation of reference example 2 N-[the fluoro-4-morpholino phenyl of 3-] benzyl carbamate is (with reference to West China pharmacy impurity 2007; Prepared by 22:179)
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 DEG C-50 DEG C are reacted 3 hours, be cooled to room temperature, suction filtration, filtrate is transferred to acetone (1200mL) and sodium bicarbonate (58.8g, in the aqueous solution (1000mL) 0.7mol), 0 DEG C slowly drips chloroformic acid benzyl ester (78.5g, 0.46mol), stirring at normal temperature 2 hours, in impouring frozen water (2000mL), suction filtration, filter cake washing and drying obtains off-white color solid 121.1g, yield 92%.m.p.：123-124℃，MS[MH+](m/z)：331，332。
The preparation of reference example 3 N-[the fluoro-4-morpholino phenyl of 3-] phenyl carbamate is (with reference to West China pharmacy impurity 2007; Prepared by 22:179)
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 DEG C-50 DEG C are reacted 3 hours, be cooled to room temperature, suction filtration, filtrate is transferred to acetone (1200mL) and sodium bicarbonate (58.8g, in the aqueous solution (1000mL) 0.7mol), 0 DEG C slowly drips phenyl chloroformate (72g, 0.46mol), stirring at normal temperature 2 hours, in impouring frozen water (2000mL), suction filtration, filter cake washing and drying obtains off-white color solid 117.6g, yield 93%.m.p.：160-162℃，MS[MH+](m/z)：317，318。
The preparation of reference example 4 Linezolid---comparing embodiment (with reference to WO2002085849 preparation)
N-[the fluoro-4-morpholino phenyl of 3-] 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, tetrahydrofuran solution (23%) 187.8mmol), temperature control less than 24 DEG C, drip and finish, be cooled to 5 DEG C, add (S)-N-[2-acetoxy-3-chloropropyl] ethanamide (24.1g, 124.68mmol), 21 DEG C are reacted 21 hours, after add saturated aqueous ammonium chloride (100mL) successively, water (600mL), saturated aqueous common salt (400mL) and methylene dichloride (400mL), separate organic layer, anhydrous magnesium sulfate drying, evaporate to dryness methylene dichloride, dimethylbenzene crystallization, obtain off-white color solid 15.2g, yield 72%.
The preparation of embodiment 1 Linezolid
N-[the fluoro-4-morpholino phenyl of 3-] benzyl carbamate (93.7g, 0.284mol) add ethanol (33.4mL, 0.568mol) with in acetonitrile (215mL), stirring at room temperature, to entirely molten, adds trimethyl carbinol lithium (68.7g, 0.852mol), stirring at room temperature 20min, is cooled to 5 DEG C, adds (S)-N-[2-acetoxy-3-chloropropyl] ethanamide (110.0g, 0.568mol), 22 DEG C of reactions 8 hours are warming up to.Reaction is finished, add saturated aqueous ammonium chloride (210mL) successively, water (1200mL), saturated aqueous common salt (1000mL) and methylene dichloride (1300mL), stir 15min, separate organic layer, anhydrous sodium sulfate drying, solvent evaporated, isopropyl ether crystallization, obtain off-white color solid 78g, yield 81%.m.p.：181-182℃，MS[MH+](m/z)：337,338,339,340。
The preparation of embodiment 2 Linezolid
N-[the fluoro-4-morpholino phenyl of 3-] benzyl carbamate (140.6g, 0.426mol) add n-propyl alcohol (80mL, 1.065mol) and N, N, in-N,N-DIMETHYLACETAMIDE (1200mL), stirring at room temperature is to entirely molten, add trimethyl carbinol lithium (119.3g, 1.491mol), stirring at room temperature 20min, is cooled to 5 DEG C, adds (S)-N-[2-acetoxy-3-chloropropyl] ethanamide (123.6g, 0.639mol), 22 DEG C of reactions 7 hours are warming up to.Reaction is finished, add saturated aqueous ammonium chloride (315mL) successively, water (1800mL), saturated aqueous common salt (1500mL) and methylene dichloride (1950mL), stir 15min, separate organic layer, anhydrous sodium sulfate drying, solvent evaporated, isopropyl ether crystallization, obtain off-white color solid 118g, yield 82%.m.p.：181-182℃，MS[MH+](m/z)：337,338,339,340。
The preparation of embodiment 3 Linezolid
N-[the fluoro-4-morpholino phenyl of 3-] phenyl carbamate (45g, 0.142mol) add Virahol (27mL, 0.356mol) and N, N, in-dimethyl formamide (324mL), stirring at room temperature is to entirely molten, add trimethyl carbinol lithium (40g, 0.497mol), stirring at room temperature 30min, is cooled to 5 DEG C, adds (S)-N-[2-acetoxy-3-chloropropyl] ethanamide (55.0g, 0.284mol), 20 DEG C of reactions 6 hours are warming up to.Reaction is finished, add saturated aqueous ammonium chloride (120mL) successively, water (600mL), saturated aqueous common salt (500mL) and methylene dichloride (600mL), stir 15min, separate organic layer, anhydrous sodium sulfate drying, solvent evaporated, isopropyl ether crystallization, obtain off-white color solid 41g, yield 86%.m.p.：181-182℃，MS[MH+](m/z)：337,338,339,340。
The preparation of embodiment 4 Linezolid
N-[the fluoro-4-morpholino phenyl of 3-] phenyl carbamate (22.5g, 0.071mol) add hexalin (37mL, 0.355mol) and N, N, in-dimethyl formamide (300mL), stirring at room temperature is to entirely molten, add trimethyl carbinol lithium (17g, 0.213mol), stirring at room temperature 15min, is cooled to 5 DEG C, adds (S)-N-[2-acetoxy-3-chloropropyl] ethanamide (27.5g, 0.142mol), 25 DEG C of reactions 8 hours are warming up to.Reaction is finished, add saturated aqueous ammonium chloride (60mL) successively, water (300mL), saturated aqueous common salt (250mL) and methylene dichloride (300mL), stir 15min, separate organic layer, anhydrous sodium sulfate drying, solvent evaporated, isopropyl ether crystallization, obtain 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 Linezolid
N-[the fluoro-4-morpholino phenyl of 3-] phenyl carbamate (40.5g, 0.128mol) add propyl carbinol (64.4mL, 0.704mol) and N, N, in-dimethyl formamide (515mL), stirring at room temperature is to entirely molten, add trimethyl carbinol lithium (30.7g, 0.384mol), stirring at room temperature 15min, is cooled to 5 DEG C, adds (S)-N-[2-acetoxy-3-chloropropyl] ethanamide (61.9g, 0.32mol), 20 DEG C of reactions 7 hours are warming up to.Reaction is finished, add saturated aqueous ammonium chloride (108mL) successively, water (540mL), saturated aqueous common salt (450mL) and methylene dichloride (540mL), stir 15min, separate organic layer, anhydrous sodium sulfate drying, solvent evaporated, isopropyl ether crystallization, obtain 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 Linezolid
N-[the fluoro-4-morpholino phenyl of 3-] benzyl carbamate (100g, 0.303mol) add isopropylcarbinol (138.6mL, 1.515mol) with in dimethyl sulfoxide (DMSO) (693mL), stirring at room temperature is to entirely molten, add trimethyl carbinol lithium (72.7g, 0.909mol), stirring at room temperature 20min, be cooled to 5 DEG C, add (S)-N-[2-acetoxy-3-chloropropyl] ethanamide (105.5g, 0.545mol), 22 DEG C of reactions 7 hours are warming up to.Reaction is finished, add saturated aqueous ammonium chloride (225mL) successively, water (1285mL), saturated aqueous common salt (1100mL) and methylene dichloride (1392mL), stir 15min, separate organic layer, anhydrous sodium sulfate drying, solvent evaporated, isopropyl ether crystallization, obtain off-white color solid 84.8g, yield 83%.m.p.：181-182℃，MS[MH+](m/z)：337,338,339,340。
Claims (8)
1. prepare a method for Linezolid, it is characterized in that comprising the steps: " C in N-[the fluoro-4-morpholino phenyl of 3-] amino formate compounds, protonic solvent
2-4straight or branched fatty alcohol and hexalin " in any one protonic solvent and dipole solvent in " acetonitrile, N, N,-dimethyl formamide, N, N,-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO) " in any one dipole solvent three mixing after; add trimethyl carbinol lithium solid, 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 the alkyl of benzyl, phenyl or C1-8.
2. the method for claim 1, it is characterized in that described N-[3-fluoro-4-morpholino phenyl] the preferred N-of amino formate compounds [3-fluoro-4-morpholino phenyl] phenyl carbamate or N-[the fluoro-4-morpholino phenyl of 3-] benzyl carbamate, (S)-N-[2-acetoxy-3-substituted propyl] ethanamide is (S)-N-[2-acetoxy-3-chloropropyl] ethanamide preferably.
3. method as claimed in claim 1 or 2, is characterized in that described N-[3-fluoro-4-morpholino phenyl] the preferred N-of amino formate compounds [the fluoro-4-morpholino phenyl of 3-] phenyl carbamate.
4. the method for claim 1, is characterized in that the preferred Virahol of protonic solvent, dipole solvent preferred N, N ,-dimethyl formamide.
5. the method for claim 1, is characterized in that protonic solvent and dipole solvent consumption volume ratio are 1:5-15.
6. the method as described in claim 1 or 5, is characterized in that protonic solvent and the preferred 1:8-12 of dipole solvent consumption volume ratio.
7. the method for claim 1, is characterized in that N-[the fluoro-4-morpholino phenyl of 3-] amino formate compounds, (S)-N-[2-acetoxy-3-substituted propyl] ethanamide, trimethyl carbinol lithium and protonic solvent consumption mol ratio are 1-1.2:1.5-2.5:3-3.5:2-5.5.
8. the method for claim 1, is characterized in that the temperature of ring and reaction is 20 DEG C-30 DEG C.
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Citations (2)
| 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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| 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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