CN102153521A - Intermediate for preparing linezolid and preparation method thereof - Google Patents
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Abstract
The invention relates to an intermediate compound of a chemical synthetic drug and a preparation method thereof, in particular to an intermediate compound for preparing linezolid and a preparation method thereof. The preparation method has the advantages of cheap and readily-available raw materials, short process route, low cost, mild and safe reaction process condition and no use of device with special requirements, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of field of midbody compound and preparation method thereof of chemical synthetic drug, particularly, the present invention relates to midbody compound for preparing Linezolid (Linezolid) and preparation method thereof.
Background technology
Bacterial resistance is one of serious problems of facing of the clinical and public health in the whole world, and Linezolid is because its unique chemical structure and mechanism of action to drug tolerant bacteria, particularly have good killing effect to resistance of vancomycin property of medicine bacterium.Linezolid (Linezolid, structural formula IV), chemical name (S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxygen-5-oxazolidinyl] methyl] ethanamide, be first oxazolidine ketone antimicrobial drug that Pfizer released in 2000, be mainly used in treatment drug resistant bacterial infections and surgical infection.
Synthesizing of relevant Linezolid, the technology of bibliographical information can be divided into two classes substantially: a class is a sodium azide technology, and a class is non-sodium azide technology.Early stage technology mostly is sodium azide technology greatly, as shown in Figure 1.Different is the technology difference of preparation structural formula V or structural formula VI compound.As US5688792, US6107519, US7291614, WO2009063505, CN200910101973.3, J.Med Chem 1996; 339:673; Chinese Journal of New Drugs 2002; 11:378; China's pharmaceutical chemistry magazine 2005; 15:89 etc.
Sodium azide technology is owing to the sodium azide explosive, and safety in production has a big risk and is not suitable for amplifying and producing.Therefore non-sodium azide technology is the emphasis of research always.Non-sodium azide technology the earliest is the inferior acid amides technology of phthalic acid such as Fig. 2.This technology is with structural formula IX compound, use the hydrazine hydrolysis, obtain structural formula VIII compound, and then acetylize gets Linezolid [US5688792, WO9924393 (CN98810019.3), WO2005099353, US7429661, US2006008754, Chinese pharmaceutical chemistry magazine 2003; 13:28]
The shortcoming of this technology is during by structural formula IX compound structural formula V III compound, and hydrazinolysis needs more violent condition, easily causes the oxazole ring and decomposes, and causes the product Linezolid to be difficult for purifying, and yield is low.
The technology that world patent WO9737980 (CN97193658.7) (G is a hydrogen), WO2010031769 (G is allyl group, substituted allyl or quaternary carbon alkyl) and WO2010084514 (G is benzyl or substituted benzyl) disclose is the non-repeatedly nitrogen technology of another kind of synthetic Linezolid, its reduction is amine foundry skill, as shown in Figure 3.
This technology be structural formula VI compound is carried out that ammonia is separated or with primary amine generation substitution reaction, take off alkyl again and obtain structural formula VIII compound.The shortcoming of this technology be ammonia separate or amine for the time, in secondary amine generation, take place easily, even three amine generations, be difficult to remove, influence quality.
World patent WO9924393 (CN98810019.3), WO2002085849, Org.Proce.Res Dev2003; 7:533, West China pharmaceutical journal 2007; 22:179 etc. have also reported a kind of non-repeatedly nitrogen technology, and this technology is that structural formula II I compound and S-diethyl carboxylic acid halides Propanolamine (structural formula XI compound) direct reaction are obtained Linezolid, are called for short diethyl carboxylic acid halides Propanolamine technology, shown in figure 04.
Because S-diethyl carboxylic acid halides Propanolamine needs by following prepared (Fig. 5), and the difficult crystallization of S-halogen Propanolamine (structural formula XV compound), yield is low, influences whole technology cost, is not suitable for industrial production.
Pfizer improved above-mentioned technology in 2007, had reported the operational path (WO2007116284, CN200780012580.4) of a synthetic Linezolid again, was called for short imidohydrine technology, as shown in Figure 6.
There is following shortcoming in this technology:
When 1, preparing structural formula XVI compound, the reaction times needs more than 20 hour, and is oversize, is unfavorable for improving producing.Need in addition behind recrystallisation solvents such as reaction solution (methyl tertiary butyl ether is a solvent) adding normal heptane, octane-iso, structural formula XVI compound could be separated out in crystallization.Because mixed solvent reclaims than single solvent difficulty, production cost is higher relatively.And normal heptane, octane-iso, methyl tertiary butyl ether are all inflammable and explosive, and the production safety risk is also big.
2, when isolating construction formula XVII compound, adopt to reaction solution (methylene dichloride is a solvent) to add methyl alcohol or Virahol condensing crystal mode repeatedly.Not only operate loaded down with trivial details, and methyl alcohol and methylene dichloride or Virahol and methylene dichloride ratio, quantity all are subject to the influence of working condition (as temperature, pressure and concentration time), be difficult to stable and consistent, cause the crystallization yield and the difficult quality of structural formula XVII compound stable, do not meet drug quality and guarantee requirement.In addition, adopt mixed solvent crystallization, separated from solvent reclaims also difficulty, produces uneconomical.
3, can by-product chlorobenzaldehyde or bromobenzaldehyde or 2,4 dichloro benzene formaldehyde or 2 during structural formula XVII compound hydrolysis, 6-dichlorobenzaldehyde or paranitrobenzaldehyde etc.These aldehyde are solid aldehyde, and reclaiming purifies needs recrystallization, the cost height, and yield is low.
Adopting methylene dichloride when 4, preparing the finished product Linezolid is reaction solvent, and ethyl acetate is a recrystallisation solvent.Because methylene dichloride belongs to the II kind solvent, toxicity is bigger, and product safety has a big risk.In addition, because solvent residual amount is strictly controlled, production cost is higher relatively.
Therefore, press for a kind of safe, practical, prepare the technology of Linezolid cheaply.
Summary of the invention
The invention provides a kind of intermediate that is used to prepare Linezolid,
R wherein
1Be hydrogen, alkyl or substituted alkyl, preferred R
1Be the alkyl or the substituted alkyl of hydrogen, a 1-5 carbon atom, most preferably R
1Be methyl, ethyl or sec.-propyl.
The present invention also provides a kind of method for preparing structural formula I compound, and this method comprises with the structural formula II compound as reaction raw materials.
Preferably with structural formula II compound and structural formula II I compound
Reaction, generating structure formula I compound.Most preferably in the presence of alkali, structural formula II compound and structural formula II I compound react generating structure formula I compound in organic solvent.
Structural formula II I compound is with reference to West China pharmaceutical journal 2007; 22:179, Tianjin Normal University's journal (natural science edition) 2005; 25:13 and Chinese pharmaceutical chemistry magazine 2003; The preparation of documents such as 13:28.
In this reaction:
The structural formula II compound, R
2Be preferably the alkyl or the substituted alkyl of H, a 1-5 carbon atom, most preferably R
2Be H, methyl, ethyl or sec.-propyl.
The mol ratio of structural formula II compound and structural formula II I compound is 0.1: 1-10: 1, preferred 0.5: 1-2: 1, most preferably 1: 1-1.5: 1
Alkali is metal alkyl compound, metal hydride, metal alkoxide compound and metal hydroxides.Preferred butyllithium, sodium hydride, hydrolith, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide and trimethyl carbinol lithium, most preferably trimethyl carbinol lithium.
Organic solvent is halogenated alkane, ether, ester, nitrile, acid amides, sulfone class etc.Preferred methylene dichloride, chloroform, ether, methyl tertiary butyl ether, tetrahydrofuran (THF), dioxane, ethyl acetate, butylacetate, acetonitrile, N,N-DIMETHYLACETAMIDE or methyl-sulphoxide etc.Most preferably methylene dichloride or methyl tertiary butyl ether or tetrahydrofuran (THF).
Temperature of reaction: 0-100 ℃, preferred reflux temperature.
The mol ratio of alkali and structural formula II I compound is 0.1: 1-10: 1, preferred 0.5: 1-2: 1, most preferably 1: 1-2: 1.
The weight ratio of organic solvent and structural formula II I compound is 1: 1-100: 1, preferred 2: 1-20: 1, most preferably 3: 1-10: 1.
After reaction finishes, structural formula I compound or obtain through extraction or through recrystallization or through chromatography or by above-mentioned one or more purification process combined utilization.
In this preparation method, the structural formula II compound removes R
2Outside hydrogen, all the other also all are new compounds.Therefore, the present invention also provides a class new compound, its structure shown in structural formula II, R wherein
2Be alkyl or substituted alkyl, preferred R
2Be the alkyl or the substituted alkyl of 1-5 carbon atom, most preferably R
2Be methyl, ethyl or sec.-propyl.
The present invention also provides a kind of method for preparing the structural formula II compound, it is characterized in that with S-epoxy chloropropane (structural formula XVIII) be reaction raw materials.Preferably with the S-epoxy chloropropane with to alkylbenzene formaldehyde (structural formula XIX compound) reaction, generating structure formula II compound, most preferably with the S-epoxy chloropropane with alkylbenzene formaldehyde and ammoniacal liquor are reacted in organic solvent, obtain the structural formula II compound.
Wherein:
To alkylbenzene formaldehyde R
2Be alkyl or substituted alkyl, preferred R
2Be the alkyl or the substituted alkyl of 1-5 carbon atom, most preferably R
2Be methyl, ethyl or sec.-propyl.
All can be purchased alkylbenzene formaldehyde and S-epoxy chloropropane.
Mol ratio to alkylbenzene formaldehyde and S-epoxy chloropropane is 0.1: 1-10: 1, preferred 0.5: 1-2: 1, and most preferably 1: 1.
Ammoniacal liquor is preferably commercially available strong aqua, wherein NH
3With the mol ratio of S-epoxy chloropropane be 0.1: 1-10: 1, preferred 0.5: 1-4: 1, most preferably 1: 1-2: 1
Reaction solvent is alcohol, ether, halogenated alkane, nitrile, acid amides, sulfone class etc.Particular methanol, ethanol, ether, methyl tertiary butyl ether, tetrahydrofuran (THF), dioxane, acetonitrile, N,N-DIMETHYLACETAMIDE or methyl-sulphoxide etc.Most preferably methyl alcohol, ethanol, methyl tertiary butyl ether, tetrahydrofuran (THF).
Temperature of reaction: 0-100 ℃, preferred reflux temperature.
With the acid hydrolysis of structural formula II compound, with aceticanhydride or Acetyl Chloride 98Min. acetylize, can obtain Linezolid again.
Advantage of the present invention:
When 1, preparing the structural formula II compound, the reaction times only needs 6-8 hour, shortens half during than the R=halogen.And the structural formula II compound is a direct crystallization from reaction solution, need not to resemble to add inflammable and explosive recrystallisation solvent the R=halogen, and is simple to operate, produces safer.Because recrystallisation solvent is a single solvent, than the easier recovery of mixed solvent, production cost is low, and is little to environmental influence.
2, structural formula I compound of the present invention crystallization in single Virahol, its advantage are the amount may command that Virahol adds, and the crystallization yield and the steady quality of structural formula I compound are simple to operate, the yield height, and cost is low, meets quality assurance requirements.On the contrary, when the R=halogen, WO2007116284 adopts to reaction solution (methylene dichloride is a solvent) and adds methyl alcohol or Virahol condensing crystal mode isolating construction formula I compound repeatedly, not only operate loaded down with trivial details, and the influence of temperature, pressure and distillation time when being subjected to concentrate, methyl alcohol and methylene dichloride or Virahol and methylene dichloride ratio and numbers of poles are difficult stable, and then the yield of structural formula I compound crystal and quality are also unstable, do not meet drug quality and guarantee requirement.
3, during structural formula I compound hydrolysis the aldehyde of by-product be phenyl aldehyde, p-tolyl aldehyde, to ethylbenzene formaldehyde or cumic aldehyde.These aldehyde all are liquid aldehydes, can directly apply mechanically after the alkali cleaning dehydration.On the contrary, when the R=halogen, by-product be chlorobenzaldehyde, bromobenzaldehyde, 2,4 dichloro benzene formaldehyde, 2,6-dichlorobenzaldehyde or paranitrobenzaldehyde etc.These aldehyde are solid aldehyde.The solid aldin does not wash clean, and needs recrystallization, needs baking, the cost recovery height, and yield is low, complex operation.
4, when preparation finished product Linezolid, reaction solvent of the present invention and recrystallisation solvent all are ethyl acetate.What its advantage was not only the present invention's use is single solvent, the solvent recovering rate height, and cost is low.The more important thing is that ethyl acetate is the reaction solvent methylene dichloride (II kind solvent) that the III kind solvent need be used during than the R=halogen, toxicity is little, and product is safer, and is also little to environmental influence.
Embodiment
The first step
Embodiment 1:(S)-and 1-chloro-3-[(phenyl methyne) amino] propan-2-ol (structural formula II, R
2=H) preparation
In the 500ml reaction flask, add the 53.1g phenyl aldehyde, 175ml 95% ethanol and 45.7g ammoniacal liquor (28.8%) stirred 10 minutes, added S-epoxy chloropropane 46.3g, and exothermic heat of reaction stirred 1 hour, and temperature rises to about 40 ℃ voluntarily.The heating, be incubated 35-40 ℃, reacted 6 hours, stirring at room is 13.5 hours again, is concentrated into about 50ml, crystallisation by cooling leaches solid, dry (S)-1-chloro-3-[(phenyl methyne) amino] propan-2-ol (structural formula II, R
2=H).
1H NMR (400MHz, CDCl
3): 2.80 (bs, 1H, OH), 3.67-3.69 (m, 2H, NCH
2), 3.76-3.87 (m, 2H, ClCH
2), 4.13-4.17 (m, 1H, OCH), 7.43-7.76 (m, 5H, phenyl ring H), 8.36 (S, 1H, N=CH).
Embodiment 2:(S)-and 1-chloro-3-[[(4-aminomethyl phenyl) methyne] amino] propan-2-ol (structural formula II, R
2=CH
3) preparation substitute the 53.1g phenyl aldehyde with the 60g p-tolyl aldehyde, all the other are constant, press embodiment 1 and operate, and can make
(S)-and 1-chloro-3-[[(4-aminomethyl phenyl) methyne] amino] propan-2-ol (structural formula II, R
2=CH
3).
1H NMR (400MHz, CDCl
3): 2.39 (s, 3H, CH
3), 2.88 (bs, 1H, OH), 3.64-3.67 (m, 2H, NCH
2), 3.75-3.82 (m, 2H, ClCH
2), 4.10-4.13 (m, 1H, OCH), 7.21-7.64 (dd, 4H, phenyl ring H), 8.31 (S, 1H, N=CH).
Embodiment 3:(S)-and 1-chloro-3-[[(4-ethylphenyl) methyne] amino] propan-2-ol (structural formula II, R
2=CH
2CH
3) preparation
With 67.1g ethylbenzene formaldehyde is substituted the 53.1g phenyl aldehyde, all the other are constant, press embodiment 1 operation, can make (S)-1-chloro-3-[[(4-ethylphenyl) methyne] amino] propan-2-ol (structural formula II, R
2=CH
2CH
3).
1H NMR (400MHz, CDCl
3): 1.10 (T, 3H, CH
3), 2.56 (Q, 2H, CH
2), 2.87 (bs, 1H, OH), 3.64-3.67 (m, 2H, NCH
2), 3.75-3.84 (m, 2H, ClCH
2), 4.10-4.14 (m, 1H, OCH), 7.22-7.64 (dd, 4H, phenyl ring H), 8.32 (S, 1H, N=CH).
Embodiment 4:(S)-and 1-chloro-3-[[(4-isopropyl phenyl) methyne] amino] propan-2-ol (structural formula II, R
2=CH
3CHCH
3) preparation
Substitute the 53.1g phenyl aldehyde with the 74.1g cumic aldehyde, all the other are constant, press embodiment 1 operation, can make (S)-1-chloro-3-[[(4-isopropyl phenyl) methyne] amino] propan-2-ol (structural formula II, R
2=CH3CHCH3).
1H NMR (400MHz, CDCl
3): 1.13 (d, 6H, CH (CH
3)
2), 2.84 (bs, 1H, OH), 2.88-2.92 (m, 1H, (CH
3)
2CH), 3.65-3.69 (m, 2H, NCH
2), 3.75-3.84 (m, 2H, ClCH
2), 4.11-4.14 (m, 1H, OCH), 7.20-7.64 (dd, 4H, phenyl ring H), 8.33 (S, 1H, N=CH).
Second step
Embodiment 5:(S)-[[(phenyl methyne) amino] methyl]-3-(3-fluoro-4-morpholine-4-base phenyl) oxazolidine-2-ketone (structural formula I, R
1=H) preparation
With (S)-1-chloro-3-[(phenyl methyne) amino] (structural formula 16, R2=H) 17.79g dissolve among the methylene dichloride 40ml standby propan-2-ol.
With carbobenzoxy-(Cbz)-3-fluoro-4-morpholine aniline 19.82g, trimethyl carbinol lithium 12.01g and methylene dichloride 80ml, put in the reaction flask, stirring at room, above-mentioned (the S)-1-of disposable adding chloro-3-[(phenyl methyne) amino] propan-2-ol (structural formula 16, R2=H) dichloromethane solution, stir, heating refluxed 10 hours.Reaction solution is cooled to room temperature.Water 100ml, 50ml washing reaction liquid successively.With the organic phase anhydrous magnesium sulfate drying, to filter, filtrate is concentrated into dried.Add Virahol, stir, crystallization under the-20--10 ℃ of condition leaches crystallization, and 50 ℃ of vacuum-dryings get (S)-[[(phenyl methyne) amino] methyl]-3-(3-fluoro-4-morpholine-4-base phenyl) oxazolidine-2-ketone (structural formula I, R
1=H).
1H NMR (400MHz, CDCl
3): 3.06 (t, 4H, 2NCH
2), 3.88 (t, 4H, 2OCH
2), 3.90-3.99 (m, 2H ,=NCH
2), 4.06-4.12 (m, 2H, OCNCH
2), 4.93-4.97 (m, 1H, HOCH), 6.90-7.70 (m, 8H, phenyl ring hydrogen), 8.40 (s, 1H, N=CH).
Embodiment 6:(S)-[[[(4-aminomethyl phenyl) methyne] amino] methyl]-3-(3-fluoro-4-morpholine-4-base phenyl) oxazolidine-2-ketone (structural formula I, R
1=CH
3) preparation
With (S)-1-chloro-3-[[(4-aminomethyl phenyl) methyne] amino] propan-2-ol (structural formula II, R
2=CH
3) alternative (the S)-1-chloro-3-[(phenyl methyne of 19.05g) amino] propan-2-ol (structural formula II, R2=H) 17.79g, all the other are constant, press embodiment 5 operations, can make (S)-[[[(4-aminomethyl phenyl) methyne] amino] methyl]-3-(3-fluoro-4-morpholine-4-base phenyl) oxazolidine-2-ketone (structural formula I, R
1=CH
3).
1H NMR (400MHz, CDCl
3): 2.38 (s, 3H, CH
3), 3.06 (t, 4H, 2NCH
2), 3.87 (t, 4H, 2OCH
2), 3.85-4.01 (m, 2H ,=NCH
2), 4.02-4.14 (m, 2H, OCNCH
2), 4.92-4.96 (m, 1H, HOCH), 6.90-7.60 (m, 7H, phenyl ring hydrogen), 8.35 (s, 1H, N=CH).
Embodiment 7:(S)-[[[(4-ethylphenyl) methyne] amino] methyl]-3-(3-fluoro-4-morpholine-4-base phenyl) oxazolidine-2-ketone (structural formula I, R
1=CH
2CH
3) preparation
With (S)-1-chloro-3-[[(4-ethylphenyl) methyne] amino] propan-2-ol (structural formula II, R
2=CH
2CH
3) alternative (the S)-1-chloro-3-[(phenyl methyne of 20.31g) amino] propan-2-ol (structural formula II, R2=H) 17.79g, all the other are constant, press embodiment 5 operations, can make (S)-[[[(4-ethylphenyl) methyne] amino] methyl]-3-(3-fluoro-4-morpholine-4-base phenyl) oxazolidine-2-ketone (structural formula I, R
1=CH
2CH
3).
1H NMR (400MHz, CDCl
3): 1.10 (T, 3H, CH
3), 2.57 (Q, 2H, CH
2), 3.06 (t, 4H, 2NCH
2), 3.87 (t, 4H, 2OCH
2), 3.87-4.01 (m, 2H ,=NCH
2), 4.03-4.15 (m, 2H, OCNCH
2), 4.92-4.96 (m, 1H, HOCH), 6.90-7.60 (m, 7H, phenyl ring hydrogen), 8.34 (s, 1H, N=CH).
Embodiment 8:(S)-[[[(4-isopropyl phenyl) methyne] amino] methyl]-3-(3-fluoro-4-morpholine-4-base phenyl) oxazolidine-2-ketone (structural formula I, R
1=CH
3CHCH
3) preparation
With (S)-1-chloro-3-[[(4-isopropyl phenyl) methyne] amino] propan-2-ol (structural formula II, R
2=CH
3CHCH
3) alternative (the S)-1-chloro-3-[(phenyl methyne of 21.58g) amino] propan-2-ol (structural formula II, R
2=H) 17.79g, all the other are constant, press embodiment 5 operations, can make (S)-[[[(4-isopropyl phenyl) methyne] amino] methyl]-3-(3-fluoro-4-morpholine-4-base phenyl) oxazolidine-2-ketone (structural formula I, R
1=CH
3CHCH
3).
1H NMR (400MHz, CDCl
3): 1.12 (d, 6H, CH (CH
3)
2), 2.87-2.92 (m, 1H, (CH
3)
2CH), 3.06 (t, 4H, 2NCH
2), 3.86 (t, 4H, 2OCH
2), 3.85-4.01 (m, 2H ,=NCH
2), 4.04-4.16 (m, 2H, OCNCH
2), 4.92-4.97 (m, 1H, HOCH), 6.90-7.61 (m, 7H, phenyl ring hydrogen), 8.38 (s, 1H, N=CH). the 3rd step
Embodiment 9: the preparation of Linezolid
With (S)-[[(phenyl methyne) amino] methyl]-3-(3-fluoro-4-morpholine-4-base phenyl) oxazolidine-2-ketone (structural formula I, R
1=H) 11.5g, acetate acetate 90ml, water 90ml mixes and stirs, and adds 12M concentrated hydrochloric acid 5.0ml, and behind the several minutes, solid enters solution, continues to stir 2 hours, and HPLC analyzes and shows that hydrolysis reaction is complete.Divide and remove organic phase, water is washed once with ethyl acetate 50ml again, the reject organic phase.Add ethyl acetate 90ml to water, transfer pH value 6.7 (about 4.8g) with 50% sodium hydroxide, tell organic phase, water again with ethyl acetate 50ml extraction once, combining extraction liquid, wash once, anhydrous magnesium sulfate drying filters, filtering sal epsom, add aceticanhydride 6.13g, filtrate is concentrated into 50ml, 0 ℃ of crystallization.Suction filtration leaches crystallization, 50 ℃ of following vacuum-dryings naphthalene azoles amine of getting profit.
Embodiment 10: the preparation of Linezolid
With (S)-[[[(4-aminomethyl phenyl) methyne] amino] methyl]-3-(3-fluoro-4-morpholine-4-base phenyl) oxazolidine-2-ketone (structural formula I, R
1=CH
3) 11.9g replacement (S)-[[(phenyl methyne) amino] methyl]-3-(3-fluoro-4-morpholine-4-base phenyl) oxazolidine-2-ketone (structural formula I, R
1=H) 11.5g, all the other are constant, by implementing 9 operations, can make Linezolid.
Embodiment 11: the preparation of Linezolid
With (S)-[[[(4-ethylphenyl) methyne] amino] methyl]-3-(3-fluoro-4-morpholine-4-base phenyl) oxazolidine-2-ketone (structural formula I, R
1=CH
2CH
3) 12.3g replacement (S)-[[(phenyl methyne) amino] methyl]-3-(3-fluoro-4-morpholine-4-base phenyl) oxazolidine-2-ketone (structural formula I, R
1=H) 11.5g, all the other are constant, by implementing 9 operations, can make Linezolid.
Embodiment 12: the preparation of Linezolid
With (S)-[[[(4-isopropyl phenyl) methyne] amino] methyl]-3-(3-fluoro-4-morpholine-4-base phenyl) oxazolidine-2-ketone (structural formula I, R
1=CH
3CHCH
3) 12.8g replacement (S)-[[(phenyl methyne) amino] methyl]-3-(3-fluoro-4-morpholine-4-base phenyl) oxazolidine-2-ketone (structural formula I, R
1=H) 11.5g, all the other are constant, by implementing 9 operations, can make Linezolid.
Claims (8)
1. compound is characterized in that it is shown in structural formula I:
R wherein
1Be hydrogen, alkyl or substituted alkyl.
2. compound according to claim 1, wherein said R
1Be methyl, ethyl or sec.-propyl.
3. the preparation method of the described compound of structural formula I is characterized in that, comprises structural formula II compound as follows
R wherein
2Be hydrogen, alkyl or substituted alkyl.
With structural formula II I compound
Reaction obtains the step of structural formula I compound.
4. preparation method according to claim 3, the wherein R in the structural formula II
2Be methyl, ethyl or sec.-propyl.
5. compound is characterized in that it is shown in structural formula II:
R wherein
2Be alkyl or substituted alkyl.
6. compound according to claim 5, wherein said R
2Be methyl, ethyl or sec.-propyl.
7. the preparation method of the described compound of structural formula II is characterized in that, comprises S-epoxy chloropropane and structural formula XIX compound reaction as follows, obtains the structural formula II compound
R wherein
2Be alkyl or substituted alkyl.
8. preparation method according to claim 7, wherein R
2Be methyl, ethyl or sec.-propyl.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103626712A (en) * | 2012-08-23 | 2014-03-12 | 重庆药友制药有限责任公司 | Intermediate used for preparing linezolid, and preparation method thereof |
| CN105566242A (en) * | 2016-01-12 | 2016-05-11 | 江苏豪森药业集团有限公司 | Preparing method for linezolid and intermediate thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5837870A (en) * | 1996-04-11 | 1998-11-17 | Pharmacia & Upjohn Company | Process to prepare oxazolidinones |
| CN101415694A (en) * | 2006-04-07 | 2009-04-22 | 辉瑞产品公司 | Process for preparing linezolid |
-
2011
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5837870A (en) * | 1996-04-11 | 1998-11-17 | Pharmacia & Upjohn Company | Process to prepare oxazolidinones |
| CN101415694A (en) * | 2006-04-07 | 2009-04-22 | 辉瑞产品公司 | Process for preparing linezolid |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103626712A (en) * | 2012-08-23 | 2014-03-12 | 重庆药友制药有限责任公司 | Intermediate used for preparing linezolid, and preparation method thereof |
| CN105566242A (en) * | 2016-01-12 | 2016-05-11 | 江苏豪森药业集团有限公司 | Preparing method for linezolid and intermediate thereof |
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| CN102153521B (en) | 2012-09-12 |
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