CN102491954B - Preparation method of linezolid - Google Patents
Preparation method of linezolid Download PDFInfo
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- CN102491954B CN102491954B CN201110401106.9A CN201110401106A CN102491954B CN 102491954 B CN102491954 B CN 102491954B CN 201110401106 A CN201110401106 A CN 201110401106A CN 102491954 B CN102491954 B CN 102491954B
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- TYZROVQLWOKYKF-ZDUSSCGKSA-N CC(NC[C@@H](CN1c(cc2)cc(F)c2N2CCOCC2)OC1=O)=O Chemical compound CC(NC[C@@H](CN1c(cc2)cc(F)c2N2CCOCC2)OC1=O)=O TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a preparation method of linezolid, which comprises the following steps of: reacting a formula (II) compound with a formula (V) compound to obtain a formula (III) compound or acid salt thereof; then removing a protecting group to obtain a formula (IV) compound or acid salt thereof; and finally carrying out aminoacylation reaction to prepare the formula (I) linezolid. The preparation method has the advantages of simple and convenient process and easiness for industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, be specifically related to a kind of (S)-N-[[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] methyl] preparation method of ethanamide.
Background technology
Linezolid, chemical name (S)-N-[[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide, it is a kind of oxazolidine ketone antiseptic-germicide of synthetic, within 2000, obtain U.S. FDA approval, be used for the treatment of the coccigenic infection of gram-positive (G+), comprise caused by MRSA doubtful or make a definite diagnosis nosocomial pneumonia (HAP), community acquired pneumonia (CAP), complicacy skin or skin soft-tissue infection (SSTI) and vancomycin-resistant enterococcus (VRE) infects.As injection, tablet and the listing of the oral suspension Ji U.S., Linezolid structural formula is suc as formula I:
WO 95/07271 discloses Linezolid and preparation method thereof: (R)-N-[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] methyl alcohol reacts with Methanesulfonyl chloride, make (R)-N-[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] methylmethanesulfonate ester, again with reaction of sodium azide, make trinitride, under Pd/C exists, pass into hydrogenation, hydrogenation makes (S)-N-[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] methylamine, under alkali exists, carry out amino acetylization reaction with acetic anhydride, make Linezolid (I).
This method has been used a kind of explosive reagent sodiumazide; there is potential safety hazard; be not suitable for suitability for industrialized production; and WO 2006091731 and WO 2006091848 have reported that trinitride is under Pd/C exists; hydro-reduction preparation (S)-N-[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] methylamine; side reaction is many, when making Linezolid (I) after acetylize, can produce a large amount of two Linezolids (VI).
CN 1355165 has described a kind of preparation method of Linezolid: (R)-N-[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] methyl alcohol reacts with Methanesulfonyl chloride; make (R)-N-[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] methylmethanesulfonate ester; react with the sylvite of phthalic imidine again; with aqueous methylamine solution, be hydrolyzed; make (S)-N-[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] methylamine; under alkali exists; carry out amino acetylization reaction with acetic anhydride, make Linezolid (I).This route is carrying out Gabriel when reaction, because the sylvite alkalescence of phthalic imidine is too strong, is easy to the open loop of Shi oxazolidone and produces impurity.
CN 101415694 has described a kind of preparation method of Linezolid: morpholinyl fluorophenyl carbamate reacts with the chloro-3-of (S)-1-(benzylidene is amino)-propyl-2-alcohol; to make protected imine intermediate, this intermediate through hydrolysis, acetylize to generate Linezolid (I).The method chiral raw material is not easy to obtain, and needs fabricated material, and reaction scheme is long, needs extraction, the operating unit such as concentrated to be unsuitable for suitability for industrialized production.
WO 2010/084514 has described a kind of preparation method of Linezolid: (R)-N-[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] Methanol must be with the intermediate of leavings group L; make again the intermediate with halogen group; by intermediate, reacted with the benzylamine of replacement; through Pd/C catalytic hydrogenation reduction deprotection base; make (S)-N-[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] methylamine; carry out amino acetylization reaction with acetic anhydride, make Linezolid (I).The intermediate that the method makes need be under Pd/C exists, react 8～10h under the hydrogen pressure of 5～12kg just can react completely, and side reaction is many, and compressive reaction is high to equipment requirements, has potential safety hazard, is not suitable for suitability for industrialized production.
Summary of the invention
The preparation method who the object of this invention is to provide a kind of Linezolid.
Object of the present invention can reach by following measures:
A preparation method for Linezolid, it comprises the steps:
(a) formula (II) compound reacts with formula (V) compound, obtains formula (III) compound or its acid group salt;
Wherein R is C
1-C
4alkyl, C
1-C
4alkyl phenyl, nitrophenyl or C
1-C
4chloro alkyl; R
1, R
2, R
3, R
4or R
5be H, C independently respectively
1-C
4alkyl, C
1-C
4alkoxyl group, nitro or halogen, and R
1, R
2, R
3, R
4and R
5when different, be H;
(b) formula (III) compound or its acid group salt deprotection base, obtain formula (IV) compound or its acid group salt;
(c) formula (IV) compound or its acid group salt are carried out to glycyl reaction, prepare formula (I) Linezolid;
The method can further include step (d): the formula preparing (I) Linezolid is carried out to recrystallization, make Linezolid finished product.
Step in the present invention (a) can be further: in solvent orange 2 A or do not using under the condition of solvent, formula (II) compound reacts at 80～160 ℃ with formula (V) compound; Cooling after reaction, add solvent B, or also add sour A, solid-liquid separation after crystallization, obtains formula (III) compound or its acid group salt.
Wherein solvent orange 2 A adopts high boiling solvent, and concrete can be selected from DMF, N, one or more in N-N,N-DIMETHYLACETAMIDE or dimethyl sulfoxide (DMSO), solvent orange 2 A is preferably DMF or dimethyl sulfoxide (DMSO), solvent orange 2 A most preferably is DMF.
The temperature of reaction of formula (II) compound and formula (V) compound is preferably 120～150 ℃, and further preferable reaction temperature is 130～140 ℃; The mol ratio of formula (II) compound and formula (V) compound can be 1: 1～6, be preferably 1: 2～and 5, most preferably be 1: 2.5～3.5.
Solvent B can be selected from methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, n-butyl alcohol, 2-butanols, the trimethyl carbinol, acetone, acetonitrile, ethyl acetate or 1, one or more in 4-dioxane, solvent B is preferably one or more in ethanol, 2-propyl alcohol, acetone or ethyl acetate, and solvent B most preferably is ethanol, ethyl acetate or its mixture.
Acid A can be selected from one or more in formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid or sulfuric acid, preferably adopts hydrochloric acid or sulfuric acid, further preferably adopts concentrated hydrochloric acid (massfraction 36-37%).
Solvent B or sour A can wait system to add in the time of 70 ℃～80 ℃ again; After adding, can continue cooling reaction system to room temperature or lower temperature, be beneficial to separating out of formula (III) compound or its acid group salt.
It is foundation that the consumption of solvent orange 2 A and solvent B be take the solvent conventional amount used of this area, and generally speaking the consumption of solvent B can be 1～5 times of solvent orange 2 A volume, preferably 2～3 times; The consumption of solvent orange 2 A, in formula II compound, can be 0.1～10ml/g, is preferably 0.5～5ml/g, most preferably is 1～2ml/g.The consumption of acid A is so that formula (III) compound is converted into acid group salt or excessive in a little foundation.
The reaction times of formula (II) compound and formula (V) compound be take concrete extent of reaction as foundation, and it is generally 2～4 hours, is further about 3 hours or 3 hours.
In each group in formula (II) compound and formula (V) compound, R is preferably C
1-C
4alkyl, C
1-C
4alkyl phenyl, nitrophenyl or trifluoromethyl, R is C more preferably
1-C
4alkyl; R
1, R
2, R
3, R
4or R
5be preferably H, C independently respectively
1-C
4alkyl, C
1-C
4alkoxyl group, nitro or halogen, and R
1, R
2, R
3, R
4and R
5when different, be H.
Step in the present invention (b) can be specially: in solvent C, under catalyzer exists, when sour B exists or do not exist, under normal pressure, pass into hydrogen, make formula (III) compound or its acid group salt deprotection base, make compounds Ⅳ or its acid group salt.
Solvent C can be selected from one or more in methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, n-butyl alcohol, 2-butanols, the trimethyl carbinol, acetone, acetonitrile, ethyl acetate, toluene, acetic acid or water, solvent C is preferably one or more in methyl alcohol, ethanol, acetone, ethyl acetate or water, and solvent C most preferably is one or more in methyl alcohol, ethanol or water.It is foundation that the consumption of solvent C be take the solvent conventional amount used of this area, and generally speaking the consumption of solvent B, counts 0.5～20ml/g with formula (III) compound, preferred 5～20ml/g, further preferred 8～15ml/g.
The catalyzer of deprotection radical reaction can be Pd/C, Pt/C or Pd (OH)
2/ C, the catalytic amount that consumption can select this area to adopt.Hydrogen passes under normal pressure.
Acid B can be one or more in formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid or sulfuric acid, is preferably acetic acid, hydrochloric acid or its mixture, and most preferred acid is acetic acid.It can be 0.1～10ml/g that the consumption of acid B be take formula (III) compound, preferred 0.5～5ml/g, further preferred 0.8～3ml/g.
The temperature of reaction of formula (III) compound or its acid group salt deprotection base can be 20 ℃～60 ℃, is preferably 30 ℃～50 ℃.It is foundation that reaction times be take the concrete extent of reaction that ordinary method detects, and it is generally 1～4 hour, is further about 2 hours.
The operation of step in the present invention (c) can be specially: in solvent D, under alkali exists, compounds Ⅳ or its acid group salt and acetic anhydride or halogenation acetic acid (halogenide of acetic acid) carry out acetylization reaction, prepare formula I Linezolid.
Wherein solvent D can be selected from one or more in methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, n-butyl alcohol, 2-butanols, the trimethyl carbinol, methyl tertiary butyl ether, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, tetrahydrofuran (THF), toluene, normal hexane or water, solvent D is preferably one or more in methyl alcohol, ethanol, acetone, methyl tertiary butyl ether or normal hexane, and solvent D most preferably is one or more in ethanol, methyl tertiary butyl ether or normal hexane.It is foundation that the consumption of solvent D be take the solvent conventional amount used of this area, and generally speaking the consumption of solvent D, counts 0.5～20ml/g with formula IV compound, preferably 1～10ml/g.
Acetylization reaction alkali used can be selected from ammoniacal liquor, triethylamine, N; one or more in N-diisopropylethylamine, pyridine, DMAP, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus; be preferably one or more in ammoniacal liquor, triethylamine, DMAP or sodium bicarbonate, most preferably be ammoniacal liquor or triethylamine.The mol ratio of compounds Ⅳ or its acid group salt and alkali is 1: 1～5, be preferably 1: 1～and 3, more preferably 1: 1～2.The mol ratio of compounds Ⅳ or its acid group salt and acetic anhydride or halogenation acetic acid is 1: 1～5, be preferably 1: 1～and 3, more preferably 1: 1～2.
The temperature of acetylization reaction can be 30 ℃～70 ℃, is preferably 40 ℃～60 ℃, most preferably is 45 ℃～50 ℃.It is foundation that reaction times be take the concrete extent of reaction that ordinary method detects, and it is generally 20～100 minutes, is further about 1 hour.
After acetylization reaction finishes, can reduce the temperature of system, be beneficial to separating out of Linezolid, generally can be down to-5 ℃～10 ℃, preferably 0 ℃ of left and right.
In a kind of technical scheme, reaction scheme of the present invention is as follows:
The operation of step in the present invention (d) can be specially: the formula preparing (I) Linezolid is carried out to recrystallization in solvent E, make Linezolid finished product.Solvent E can be one or more in methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, n-butyl alcohol, 2-butanols, the trimethyl carbinol, methyl tertiary butyl ether, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, tetrahydrofuran (THF) or normal hexane, be preferably one or more in methyl alcohol, ethanol, ethyl acetate, methyl tertiary butyl ether or normal hexane, optimum is one or more in ethanol, ethyl acetate or methyl tertiary butyl ether.It is foundation that the consumption of solvent E be take the consumption of general recrystallization solvent.
The present invention also provides (S)-N-[[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] methyl] preparation method of alkyl substituted benzyl amine compound (III), this compound is the important intermediate of preparing Linezolid (I) medicine.
(S)-N-[[[3-prepared by the present invention (the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] methyl] alkyl substituted benzyl amine compound (III), having overcome in existing Linezolid preparation method, there is high-pressure hydrogenation, long reaction time, the many problems of side reaction in hydrogenation Deprotection process; Solved in existing preparation method operational condition harsh, high to equipment requirements, there is potential safety hazard, be unfavorable for suitability for industrialized production, yield is low, by product is many, purification difficult, chiral raw material is not easy to obtain and the problem such as technique is loaded down with trivial details.Preparation method of the present invention adopts normal pressure Deprotection can reach reaction requirement; advantage is that the reaction times is short, chiral raw material is easy to get and low price; technique is simple, by product is few, total recovery high (more than 78%, can reach 85%), product is easy to purifying and purity is high, low for equipment requirements, safe, be easy to realize suitability for industrialized production.
Embodiment
In the present invention, described room temperature is 20～30 ℃, and described normal pressure is 0.8atm～1.2atm, in following embodiment, if not otherwise specified, is synthesis under normal pressure.
Embodiment 1:(S)-3-(the fluoro-4-morpholino of 3-phenyl)-5-(preparation of ((3-methylbenzene methyl) amino) methyl) oxazolidine-2-ketone
In the there-necked flask of 250mL, add (R)-N-[3-(3-fluoro-(4-morpholinyl) phenyl)-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates 10g (0.0267mol), 3-methylbenzylamine 9.71g (0.0801mol), N, dinethylformamide 20mL, nitrogen protection, be heated to 140 ℃, reaction 3h reacts completely, be cooled to 70～80 ℃, add ethyl acetate 50mL, stirring is cooled to room temperature, 0 ℃ of stirring and crystallizing 1h, filter, 20mL ethyl acetate washing leaching cake, 50 ℃ of drying under reduced pressure 3h, obtain white crystalline solid 9.83g, yield 92.1%, HPLC purity (normalization method): 98.69%, ee%:99.43%.
1H-NMR(500MHz，CDCl
3)δ(ppm)：7.33(d，1H)，7.13(s，1H)，7.08(t，1H)，6.95(m，2H)，6.81(s，1H)，6.69(d，1H)4.66(m，1H)，4.06(t，1H)，3.77(m，4H)，3.61(m，3H)，3.05(t，4H)，2.91(m，1H)，2.83(m，1H)，2.35(s，3H)。
13C-NMR(125MHz，CDCl
3)δ(ppm)：156.16，153.87，136.94，136.36，135.78，133.12，129.67，127.83，117.25，114.77，107.11，72.55，66.32，54.34，52.68，50.45，48.74，23.78。MS(ESI+)：400[M+H]
+，422[M+Na]
+。
Embodiment 2:(S)-3-(the fluoro-4-morpholino of 3-phenyl)-5-(preparation of ((4-methylbenzene methyl) amino) methyl) oxazolidine-2-keto hydrochloride
In the there-necked flask of 2L, add (R)-N-[3-(3-fluoro-(4-morpholinyl) phenyl)-2-oxo-5-oxazolidinyl] methyl alcohol methanesulfonates 100g (0.267mol), 4-methylbenzylamine 97.1g (0.801mol), N, dinethylformamide 100mL, nitrogen protection, be heated to 150 ℃, 3h reacts completely, be cooled to 70～80 ℃, add dehydrated alcohol 200mL and ethyl acetate 400mL, add concentrated hydrochloric acid 54.2g, stirring is cooled to room temperature, 0 ℃ of stirring and crystallizing 1h, filter, use successively 200mL ethyl acetate, 200mL absolute ethanol washing filter cake, 50 ℃ of drying under reduced pressure 3h, obtain white crystalline solid 108.59g, yield 96.8%, HPLC purity (normalization method): 99.33%, ee%:99.54%.
1H-NMR(500MHz，CDCl
3)δ(ppm)：7.43(d，1H)，7.19(d，2H)，7.12(m，3H)，6.92(t，1H)，4.72(m，1H)，3.95(t，1H)，3.86(m，4H)，3.78(m，3H)，3.04(t，4H)，2.97(m，1H)，2.89(m，1H)，2.33(s，3H)。
13C-NMR(125MHz，CDCl
3)δ(ppm)：156.52，154.56，136.88，136.54，136.28，133.51，129.18，128.10，118.83，113.83，107.49，72.32，66.95，53.49，51.42，51.05，48.19，21.04。
MS(ESI+)：400[M+H]
+，422[M+Na]
+。
Embodiment 3:(S)-N-[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] preparation of methylamine (IV)
In the there-necked flask of 250mL, add (S)-3-(the fluoro-4-morpholino of 3-phenyl)-5-(((3-methylbenzene methyl) amino) methyl) oxazolidine-2-ketone 9.83g (0.0246mol), methyl alcohol 98mL, acetic acid 9.8mL, 10%Pd/C 0.49g, normal pressure passes into hydrogen, is heated to 35～40 ℃, and reaction 2h reacts completely, boil off solvent, 50 ℃ of drying under reduced pressure, obtain white solid 7.18g, yield 98.8%.
1H-NMR(500MHz，DMSO-d
6)δ(ppm)：7.51(dd，1H)，7.21(dd，1H)，7.07(t，1H)，4.79(m，1H)，4.11(t，1H)，3.85(t，1H)，3.75(t，4H)，3.06(m，2H)，2.97(t，4H)。
13C-NMR(125MHz，DMSO-d
6)δ(ppm)：155.48，153.88，135.54，133.40，119.21，114.14，106.77，71.66，66.09，50.66，47.11，42.81。
MS(ESI+)：296[M+H]
+。
Embodiment 4:(S)-N-[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] preparation of methylamine (IV) hydrochloride
In the there-necked flask of 2L, add (S)-3-(the fluoro-4-morpholino of 3-phenyl)-5-(((4-methylbenzene methyl) amino) methyl) oxazolidine-2-keto hydrochloride 108.59g (0.259mol), methyl alcohol 1.09L, water 326mL, 10%Pd/C 5.43g, normal pressure passes into hydrogen, is heated to 45～50 ℃, and reaction 2h reacts completely, boil off solvent, 50 ℃ of drying under reduced pressure, obtain white solid 85.01g, yield 99.1%.
Embodiment 5: the preparation of Linezolid (I)
In the there-necked flask of 100mL, add (S)-N-[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] methylamine 7.18g (0.0243mol), dehydrated alcohol 29mL, triethylamine 1.23g, diacetyl oxide 3.72g, be heated to 45～50 ℃, 1h reacts completely, and 0 ℃ of stirring and crystallizing 3h filters, dehydrated alcohol 7mL * 2 washing leaching cake, 50 ℃ of drying under reduced pressure, obtain white crystalline solid 7.07g, yield 86.3%, HPLC purity (normalization method): 99.78%, ee%:99.81%.
1H-NMR(500MHz，CDCl
3)δ(ppm)：7.41(dd，1H)，7.06(dd，1H)，6.91(t，1H)，4.76(m，1H)，4.01(t，1H)，3.84(t，4H)，3.75(m，1H)，3.03(t，4H)，1.99(s，3H)。
13C-NMR(125MHz，CDCl
3)δ(ppm)：171.15，156.45，154.49，136.61，132.95，118.85，113.99，107.67，71.95，66.91，50.98，47.67，41.93，23.01。
MS(ESI+)：338[M+H]
+，360[M+Na]
+。
Embodiment 6: the preparation of Linezolid (I)
In the there-necked flask of 2L, add (S)-N-[[3-(the fluoro-4-morpholinyl of 3-) phenyl]-2-oxo-5-oxazolidinyl] methylamine hydrochloride 85.01g (0.256mol), dehydrated alcohol 340mL, triethylamine 38.86g, diacetyl oxide 39.20g, be heated to 45～50 ℃, 1h reacts completely, 0 ℃ of stirring and crystallizing 3h, filters dehydrated alcohol 85mL * 2 washing leaching cake, 50 ℃ of drying under reduced pressure, obtain white crystalline solid 76.08g, yield 88.1%, HPLC purity (normalization method): 99.72%.ee％：99.83％。
Embodiment 7: refining
In 500mL there-necked flask, add Linezolid crude product 76.08g, dehydrated alcohol 228mL, heating for dissolving, cool to 0～5 ℃, stirring and crystallizing 3h, filters dehydrated alcohol 10mL * 3 washing leaching cake, 50 ℃ of drying under reduced pressure, obtain white crystalline solid 65.73g, yield 86.4%, HPLC purity (normalization method): 99.95%.ee％：99.98％。
Claims (12)
1. a preparation method for Linezolid, is characterized in that comprising the steps:
(a), in solvent DMF, formula II compound reacts at 120～150 ℃ with formula V compound; While being cooled to 70 ℃～80 ℃ after reaction, adding solvent B, or also add hydrochloric acid, solid-liquid separation after crystallization, obtains formula III compound or its acid group salt; Described solvent B is ethanol, ethyl acetate or its mixture;
Wherein R is C
1-C
4alkyl; R
1, R
2, R
3, R
4or R
5be H, C independently respectively
1-C
4alkyl, C
1-C
4alkoxyl group, nitro or halogen, and R
1, R
2, R
3, R
4and R
5when different, be H;
(b) in solvent methanol and water, under catalyst P d/C exists, pass into hydrogen under normal pressure, make formula III compound or its acid group salt deprotection base, make compounds Ⅳ or its acid group salt;
(c), in etoh solvent, under alkali exists, compounds Ⅳ or its acid group salt and acetic anhydride or halogenation acetic acid carry out acetylization reaction at 45 ℃～50 ℃, prepare formula I Linezolid;
2. preparation method according to claim 1, is characterized in that the method also comprises step (d), and the formula I Linezolid preparing is carried out to recrystallization in solvent E, makes Linezolid finished product; Described solvent E is one or more in methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, n-butyl alcohol, 2-butanols, the trimethyl carbinol, methyl tertiary butyl ether, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, tetrahydrofuran (THF) or normal hexane.
3. preparation method according to claim 1, is characterized in that the temperature of reaction of formula II compound and formula V compound is 130～140 ℃; The mol ratio of formula II compound and formula V compound is 1:1～6.
4. preparation method according to claim 3, is characterized in that the mol ratio of formula II compound and formula V compound is 1:2～5.
5. preparation method according to claim 4, is characterized in that the mol ratio of formula II compound and formula V compound is 1:2.5～3.5.
6. preparation method according to claim 1, is characterized in that the temperature of reaction of formula III compound or its acid group salt deprotection base is 20 ℃～60 ℃.
7. preparation method according to claim 6, is characterized in that the temperature of reaction of formula III compound or its acid group salt deprotection base is 30 ℃～50 ℃.
8. preparation method according to claim 1, it is characterized in that described alkali is selected from one or more in ammoniacal liquor, triethylamine, DIPEA, pyridine, DMAP, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood or saleratus; The mol ratio of compound IV or its acid group salt and alkali is 1:1～5; The mol ratio of compound IV or its acid group salt and acetic anhydride or halogenation acetic acid is 1:1～5.
9. preparation method according to claim 8, is characterized in that described alkali is selected from one or more in ammoniacal liquor, triethylamine, DMAP or sodium bicarbonate; The mol ratio of compound IV or its acid group salt and alkali is 1:1～3; The mol ratio of compound IV or its acid group salt and acetic anhydride or halogenation acetic acid is 1:1～3.
10. preparation method according to claim 9, is characterized in that described alkali is selected from ammoniacal liquor or triethylamine; The mol ratio of compound IV or its acid group salt and alkali is 1:1～2; The mol ratio of compound IV or its acid group salt and acetic anhydride or halogenation acetic acid is 1:1～2.
11. preparation methods according to claim 2, is characterized in that described solvent E is one or more in methyl alcohol, ethanol, ethyl acetate, methyl tertiary butyl ether or normal hexane.
12. preparation methods according to claim 11, is characterized in that described solvent E is one or more in ethanol, ethyl acetate or methyl tertiary butyl ether.
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| CN201110401106.9A CN102491954B (en) | 2011-12-06 | 2011-12-06 | Preparation method of linezolid |
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| CN102491954B true CN102491954B (en) | 2014-04-23 |
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| CN201110401106.9A Active CN102491954B (en) | 2011-12-06 | 2011-12-06 | Preparation method of linezolid |
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| WO2010084514A2 (en) * | 2009-01-02 | 2010-07-29 | Neuland Laboratories Ltd. | A process for the preparation of (5s)-(n)-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide |
| WO2011077310A1 (en) * | 2009-12-26 | 2011-06-30 | Alembic Limited | Process for the preparation of linezolid |
| WO2011114210A2 (en) * | 2010-03-15 | 2011-09-22 | Jubilant Life Sciences Limited | Processes for the preparation of linezolid |
| 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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| WO2010084514A2 (en) * | 2009-01-02 | 2010-07-29 | Neuland Laboratories Ltd. | A process for the preparation of (5s)-(n)-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide |
| WO2011077310A1 (en) * | 2009-12-26 | 2011-06-30 | Alembic Limited | Process for the preparation of linezolid |
| WO2011114210A2 (en) * | 2010-03-15 | 2011-09-22 | Jubilant Life Sciences Limited | Processes for the preparation of linezolid |
| 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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