CN102516191B - Method for preparing Linezolid - Google Patents

Method for preparing Linezolid Download PDF

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CN102516191B
CN102516191B CN201110431242.2A CN201110431242A CN102516191B CN 102516191 B CN102516191 B CN 102516191B CN 201110431242 A CN201110431242 A CN 201110431242A CN 102516191 B CN102516191 B CN 102516191B
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formula
reaction
preparation
linezolid
milliliters
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CN102516191A (en
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李宏武
李晓东
谢文博
张莉
王龙兴
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JILIN BROADWELL PHARMACEUTICAL CO Ltd
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Abstract

The invention provides a method for preparing Linezolid. The preparation method has the advantages of few total reaction steps of the synthetic route, high yield, mild reaction of each step of the synthesis, no need of special reagent and device, and simple operation, and is suitable for large scale industrial production. High-purity of Linezolid can be prepared by the method, and medicinal requirements can be satisfied.

Description

A kind of preparation method of Linezolid
Technical field
The invention provides a kind of preparation method of Linezolid, the synthetic and purification process of this preparation method's intermediate is also provided, belong to medical science pharmaceutical technology field.
Background technology
Linezolid (the formula the present invention relates to
Figure 154902DEST_PATH_IMAGE001
) structure is as follows:
Figure 371120DEST_PATH_IMAGE002
。
Linezolid is the novel oxazolidinones antiseptic-germicide of Pharmacia S.P.A. research and development, is the antiseptic-germicide of the brand new of unique listing in the last thirty years, is clinically mainly used in treating the severe infection that resistance gram-positive microorganism causes.
Gram positive organism is clinical common pathogenic bacteria, is widely used the positive fast rise of its resistance due to antibiotic; Methicillin-resistant Staphylococci, glycopeptide class resistance faecalis, Penicillin-resistant Streptococcus proportion rising, the responsive staphylococcus of glycopeptide class intermediary also occurs.In institute, vancomycin-resistant enterococcus segregation ratio is greater than 20% according to statistics, and in intensive care unit(ICU), methicillin-resistant Staphylococcus surpasses 50%.The treatment of the pathogenic microbial infectious diseases of resistance is faced with formidable challenges.
The novel oxazolidinones antimicrobial drug of Linezolid one class, its Linezolid combines with 23S ribosome-RNA(rRNA) (23S rRNA) site of bacterium 50S subunit; Stop the formation of the initiating mixture 70S of protein synthesis, and then block the synthetic of bacterioprotein, given play to the antibacterial of Linezolid.Because the Antibacterial mechanism of this product is unique, be not easy to other medicines and produce cross resistance, to the equal tool anti-microbial activity of all kinds of resistance gram-positive coccis, so this product provides sound assurance for the infection that clinical treatment resistance gram-positive microorganism causes.
? j.M.C, 1996,39 (3), the preparation method of Linezolid has been described in 673-679.
This method has been used active especially n-Butyl Lithium in the preparation process of key intermediate 2, and this reaction need be at low temperature (78 oc) under, carry out this severe reaction conditions; In the preparation process of intermediate 5, use catalytic hydrogenation reduction nitrine, needed special equipment, be not suitable for industrialization raw.
the preparation method of following Linezolid has been described in WO2005099353
Figure 481476DEST_PATH_IMAGE004
While preparing intermediate (3), be to carry out at the temperature refluxing at Virahol, the temperature of reaction is higher, and chloro nucleophilic substitution reaction and ring-opening reaction exist competitive relation, and the specificity of reaction is poor, in building-up process, can introduce multiple its impurity.The condition of preparing intermediate (5) is that DMF is solvent refluxing reaction 5 hours, and reaction conditions is also comparatively harsh, the quality of wayward product.
Organic process research & development 2003,7, has described the preparation method of following Linezolid in 533-546
Figure 424024DEST_PATH_IMAGE005
This synthetic method is in the end prepared Linezolid step by amino ionization, nucleophilic substitution reaction, four reaction compositions of deacetylate and transesterify, and reaction mechanism is complicated; intermediate 1-7 reaction does not complete, and yield is lower, and the purity difference of the product obtaining; refining difficulty, is difficult for fulfilling medicinal requirements.
Summary of the invention
The invention provides a kind of preparation method of Linezolid, for a kind of new preparation technology, there is technological reaction mild condition, easy and simple to handle, be applicable to suitability for industrialized production.
Linezolid (the formula the present invention relates to
Figure 799641DEST_PATH_IMAGE001
) structure is as follows:
Figure 157942DEST_PATH_IMAGE002
Comprise the following steps:
(a), formula
Figure 630511DEST_PATH_IMAGE006
middle nitro reacts with ammonium formiate under the katalysis of palladium carbon, is converted into amino.
Figure 436572DEST_PATH_IMAGE007
(b), by formula
Figure 299486DEST_PATH_IMAGE008
middle hydroxyl and amino change respectively acetonyl ester and ethanamide into
Figure 523794DEST_PATH_IMAGE009
(c), formula
Figure 788553DEST_PATH_IMAGE010
with formula
Figure 10587DEST_PATH_IMAGE011
amalgamation production under sodium hydride effect
Figure 423114DEST_PATH_IMAGE012
Figure 123217DEST_PATH_IMAGE013
(d), in acid alcohol solution by formula
Figure 304799DEST_PATH_IMAGE012
in acetyl ester group remove and change free hydroxyl group into
Figure 697735DEST_PATH_IMAGE014
(e), formula under carbonyl dimidazoles effect, target compound Linezolid is prepared in cyclization
。
In step (c), intermediate formula
Figure 75123DEST_PATH_IMAGE010
be dissolved in non-protonic solvent toluene production under the effect of sodium hydride
Figure 701277DEST_PATH_IMAGE010
disodium iminodiacetic active to increase nucleophilic reaction, the latter and formula
Figure 23149DEST_PATH_IMAGE011
there is nucleophilic substitution reaction, generate key intermediate formula
Figure 65055DEST_PATH_IMAGE012
.Control formula in this step synthetic method
Figure 221229DEST_PATH_IMAGE011
with formula
Figure 955967DEST_PATH_IMAGE012
molar feed ratio be 0.95-1.05, to avoid di-substituted generation; Reaction medium is for selecting non-protonic solvent toluene; Temperature of reaction is controlled at 80-130 ℃., this step product directly carries out the next step without treating process.
In step (d), intermediate
Figure 564803DEST_PATH_IMAGE012
in the alcoholic solvent of 1-6 mol/L hydrogenchloride, transesterification reaction occurs, remove ester bond ethanoyl protecting group, hydroxyl dissociates.Alcohols is as the deprotection solvent reagent of holding concurrently, R 1for methyl, ethyl, sec.-propyl, butyl, isobutyl-or its mixture; This step reaction control temperature is 10-40 ℃.Because hydrogenchloride alcohol liquid is as selectivity deprotection agent, its reaction conditions is gentle, and selectivity is good, has avoided other alkaline deprotecting regent to generate removing on amido linkage ethanoyl and remove fluorine by product when removing ester bond ethanoyl.
In step (e), intermediate
Figure 675979DEST_PATH_IMAGE015
be methylene dichloride, chloroform, 1, the halogenated alkanes such as 2-ethylene dichloride are done under solvent to close ring with carbonyl dimidazoles, prepare target compound Linezolid.This step temperature of reaction is 10-40 ℃, and carbonyl dimidazoles is gentle as the reaction conditions of coupling reagent, and specificity is good, can reduce the generation of the intermolecular coupling by product of phosgene; Simultaneously also relatively friendly to environment.
Linezolid purity prepared by the present invention is greater than 99.5%.
positively effect of the present invention is:the total reactions steps of preparation method's synthetic route is less, and yield is higher, and it is all comparatively gentle that each walks building-up reactions, without special reagent and equipment, simple to operate, is applicable to large-scale industrial production; By this processing method, can prepare high purity Linezolid, can fulfilling medicinal requirements.
Accompanying drawing explanation
Fig. 1 is the fluoro-4-morpholine of 3-aniline hydrogen spectrogram;
Fig. 2 is the chloro-2-acetoxyl group of (S)-3-acetyl propylamine hydrogen spectrogram;
Fig. 3 is (R)-3-acetylaminohydroxyphenylarsonic acid 1-(the fluoro-4-morpholine of 3-phenylamino)-2-propyl alcohol acetic ester hydrogen spectrogram;
Fig. 4 is Linezolid hydrogen spectrogram.
Embodiment
embodiment 1:
The fluoro-4-morpholine of 3-aniline
Figure 686660DEST_PATH_IMAGE007
By the 40.23 grams of fluoro-4-morpholine of 3-oil of mirbane in be dissolved in 100 milliliters of tetrahydrofuran (THF)s with containing in 400 ml methanol liquid of 44.28 grams of ammonium formiates; Reaction solution is down to 0 ℃, and nitrogen is taken a breath 3 times, adds the palladium carbon of 1.02 gram 10%, reaction system nitrogen protection, stirring reaction 2 hours.Reaction is finished, reacting liquid filtering, and filter cake is successively with 40 milliliters of tetrahydrofuran (THF)s and 80 milliliters of ethyl acetate washings, and filtrate is concentrated into 400 milliliters, adds 400 milliliters of ethyl acetate and 300 ml waters, extraction separatory; Water extracts with 2 * 100 milliliters of ethyl acetate with 1 * 200 milliliter, merges organic phase, with 300 milliliters of saturated common salt water washings; Anhydrous magnesium sulfate drying, filtering siccative, evaporate to dryness, obtains 30.41 grams of brown products, yield: 87%. 1h NMR (DMSO-d 6, 600MHz): 6.77 (t, 1H) 6.36 (m, 2H) 4.98 (s, 2H) 3.69 (br s, 4H) be 81 (br s, 4H) 2., referring to Fig. 1.
(S) the chloro-2-acetoxyl group of-3-acetyl propylamine
Figure 592299DEST_PATH_IMAGE009
By 100.23 grams of (S)-3-chlorine-2-hydroxyl propylamine outstanding being dissolved in 230 milliliters of methylene dichloride under room temperature, add 161.37 grams of diacetyl oxides, be heated to 38 ℃, add 70.21 grams of pyridines, insulation 36-38 ℃, adds 20 milliliters of washed with dichloromethane.At 37-40 ℃, stirring reaction is 5 hours, and 20-25 ℃ is reacted 14 hours.Reaction is finished, and reaction solution is cooled to 25 ℃, adds 150 milliliters of purified water in reaction solution, and reaction temperature is cooled to 6 ℃, in being greater than in 7 minutes, adds the solution of potassium carbonate of 400 gram 47%, keeps temperature 5-7 ℃.Add 300 ml waters and 120 milliliters of methylene dichloride, extraction separatory; 2 * 60 milliliters of dichloromethane extraction for water; Merge organic phase, be evaporated to 270 milliliters, add 2 * 200 milliliters of toluene, after adding, be concentrated into 270 milliliters at every turn, treatment solution is cooled to 28 ℃; Add 450 milliliters of octane-iso, be cooled to 3 ℃, filter, filter cake washs with 140 milliliters of octane-iso, and nitrogen dries up, and obtains 117.56 grams of white solids, yield: 88%. 1h NMR (DMSO-d 6, 600MHz): 7.99 (br s t, 1H) 4.97 (m, 1H) 3.79 (br m, 2H) 3.39 (br m, 1H) 3.22 (br m, 1H) are 1. 81 (s, 3H) of 04 (s, 3H) 2., referring to Fig. 2.
(R)-3-acetylaminohydroxyphenylarsonic acid 1-(the fluoro-4-morpholine of 3-phenylamino)-2-propyl alcohol acetic ester
Figure 626114DEST_PATH_IMAGE013
The 20.35 grams of fluoro-4-morpholine of 3-aniline are dissolved in 200 milliliters of toluene, add 3.76 gram of 70% sodium hydride, stirring at room 15 minutes, is warming up to 120 ℃ by reaction solution; In 2 hours, 20.13 grams of (R)-3-acetylaminohydroxyphenylarsonic acid 1-(the fluoro-4-morpholine of 3-phenylamino)-50 milliliters of toluene solutions of 2-propyl alcohol acetic ester are dropped in reaction solution; Drip and finish, in 120 ℃, continue reaction 1 hour.Reaction is finished, in reaction solution, add 200 milliliters of ethyl acetate and 200 milliliters of purified water, extraction separatory, water extracts by 50 milliliters of ethyl acetate, merges organic phase, with 200 milliliters of saturated common salt water washings, anhydrous sodium sulfate drying, filtering siccative, concentrating under reduced pressure evaporate to dryness, obtain thick liquid, be directly used in the next step.
(R)-N-(3-(the fluoro-4-morpholine of 3-phenylamino)-2-propyl alcohol) ethanamide
Figure 72139DEST_PATH_IMAGE014
Upper step product is dissolved in 200 ml methanol, passes into 14.73 grams of dry hydrogen chloride gas under ice bath, logical finishing, in 25 ℃ of stirring reactions 15 hours.Reaction is finished, reaction solution is in the lower concentrated evaporate to dryness of decompression, in residue, add 200 milliliters of ethyl acetate and 100 milliliters of saturated sodium bicarbonate aqueous solutions, extraction separatory, water extracts by 50 milliliters of ethyl acetate, merge 50 milliliters of saturated aqueous common salt washed twice of nothing for organic phase, anhydrous sodium sulfate drying, filtering siccative, is evaporated to 30 milliliters and adds 100 milliliters of normal hexanes, separate out solid, stir 30 minutes, filter, filter cake washs with 40 milliliters of normal hexanes, obtain 21.61 grams of faint yellow solids, yield 67% (continuous two step yields). 1h NMR (DMSO-d 6, 600MHz): 7.85 (b, 1H) 6.84 (t, 1H) 6.42 (d, 1H) 6.35 (d, 1H), 5.44 (s, 1H) 4.96 (d, 1H) 3.69 (s, 4H), 3.64 (m, 1H) 3.18 (m, 1H) 3.07 (m, 2H), 2.88 (m, 1H) 2.81 (s, 4H) 1.83 (s, 3H), referring to Fig. 3.
linezolid
Figure 140589DEST_PATH_IMAGE016
By 13.21 gram(R)-N-(3-(the fluoro-4-morpholine of 3-phenylamino)-2-propyl alcohol) ethanamide is dissolved in 150 milliliters of methylene dichloride under room temperature, adds 8.26 grams of carbon back diimidazoles, and under room temperature, stirring reaction is 18 hours.Reaction is finished, 100 milliliters of saturated common salt water washings for reaction solution, 100 milliliters of dichloromethane extraction for water, merge organic phase, with 100 milliliters of saturated aqueous common salt washed twice, anhydrous sodium sulfate drying, filtering siccative, in lower concentrated the steaming to 10 milliliters of decompression, add 100 milliliters of normal hexanes, separate out solid, stir 10 minutes, filter, obtain off-white color crystalline powder.With ethyl acetate normal hexane recrystallization, obtain 10.53 grams of off-white color crystalline powders, yield: 74%. 1h NMR (DMSO-d 6, 600MHz): 7.39 (b, 1H) 7.03 (b, 1H) 6.88 (m, 2H) 4.75 (br m, 1H) 3.99 (t, 1H) 3.83 (s, 4H) 3.75 (t, 1H) 3.61 (m, 2H) 3.01 (s, 4H), 1.98 (s, 3H), referring to Fig. 4.

Claims (4)

1. the preparation method of a Linezolid
Figure 662551DEST_PATH_IMAGE001
Comprise the following steps:
(a), formula
Figure 799134DEST_PATH_IMAGE002
middle nitro reacts with ammonium formiate under the katalysis of palladium carbon, is converted into amino;
Figure 202433DEST_PATH_IMAGE003
?(b), by formula
Figure 399059DEST_PATH_IMAGE004
middle hydroxyl and amino change respectively acetonyl ester and ethanamide into
Figure 890739DEST_PATH_IMAGE002
(c), formula
Figure 650885DEST_PATH_IMAGE004
with formula amalgamation production under sodium hydride effect
Figure 992184DEST_PATH_IMAGE008
Figure 567479DEST_PATH_IMAGE008
(d), in acid alcohol solution by formula
Figure 598746DEST_PATH_IMAGE008
in acetyl ester group remove and change free hydroxyl group into
Figure 689336DEST_PATH_IMAGE009
(e), formula
Figure 2011104312422100001DEST_PATH_IMAGE010
under carbonyl dimidazoles effect, target compound Linezolid is prepared in cyclization
Figure 691107DEST_PATH_IMAGE010
Wherein, R 1-OH is methyl alcohol, ethanol, Virahol, butanols, isopropylcarbinol or its mixture.
2. preparation method as claimed in claim 1, is characterized in that: the dehydrogenating agent that step (c) is selected is sodium hydride, formula
Figure 458687DEST_PATH_IMAGE004
with formula
Figure 150699DEST_PATH_IMAGE006
molar feed ratio is 0.95-1.05, and reaction solvent is toluene, and temperature of reaction is 80-130 ℃, and this step product directly carries out the next step without treating process.
3. preparation method as claimed in claim 1, is characterized in that: step (d) is selected R 1-OH is as the deprotection solvent reagent of holding concurrently; In alcohol liquid, hydrogen cloride concentration is 1-6 mol/L, and temperature of reaction is 10-40 ℃.
4. preparation method as claimed in claim 1, is characterized in that: step (e) is selected methylene dichloride, chloroform, 1, and 2-ethylene dichloride or its mixture, as solvent, select carbonyl dimidazoles to supply base as carbonyl, and temperature of reaction is 10-50 ℃.
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CN104370854B (en) * 2013-08-12 2016-07-06 四川大学 3-halogen-2-hydroxypropyl-1-anilid compounds Preparation Method And The Use
CN104513211B (en) * 2013-09-29 2017-01-04 丹阳恒安化学科技研究所有限公司 A kind of method preparing linezolid
CN103554058B (en) * 2013-11-08 2015-06-24 南京靖龙药物研发有限公司 Preparation method of linezolid derivative
CN104262280B (en) * 2014-09-22 2016-07-20 山东华生化学股份有限公司 A kind of preparation method of linezolid
CN108299329A (en) * 2018-03-28 2018-07-20 许传森 An oxazole ketones derivant and its application in antibacterials

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