CN101948442A - Preparation method of linezolid and preparation thereof - Google Patents
Preparation method of linezolid and preparation thereof Download PDFInfo
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- CN101948442A CN101948442A CN2009101607400A CN200910160740A CN101948442A CN 101948442 A CN101948442 A CN 101948442A CN 2009101607400 A CN2009101607400 A CN 2009101607400A CN 200910160740 A CN200910160740 A CN 200910160740A CN 101948442 A CN101948442 A CN 101948442A
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- 0 CCCc1cc(*(C[C@](C)(C*C(C)=O)O2)C2=O)ccc1C1=CCCOCC1 Chemical compound CCCc1cc(*(C[C@](C)(C*C(C)=O)O2)C2=O)ccc1C1=CCCOCC1 0.000 description 1
Abstract
The invention relates to a preparation method of linezolid and a preparation thereof, in particular to a preparation method of a linezolid raw material and a freeze-dried powder injection thereof. The preparation method mainly comprises the following steps: (1) synthesizing 2(S)-1-amino-3-chloro-2-propanol hydrochloride; (2) synthesizing (S)-N-[2-acetoxyl-3-chloropropyl] acetamide; (3) synthesizing 3-fluoro-4-morpholinyl nitrobenzene; (4) synthesizing N-carbobenzoxy-3-fluoro-4-morpholinyl aniline; (5) synthesizing the linezolid; and (6) preparing the linezolid preparation. The freeze-dried powder injection of the linezolid for injection, which is prepared by the invention, effectively improves the stability of medicines so that the medicines have longer shelf life, can be transported more conveniently and are more favorable for clinical applications. Moreover, the method of the invention for preparing the raw material linezolid and the freeze-dried powder injection thereof is simple and effective and is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to field of medicaments, relate in particular to the preparation method of Linezolid and freeze-dried powder thereof.
Background technology
Linezolid (Linezolid) has another name called linezolid, the morpholine oxazolone, and commodity are called Zyvox.Its chemistry (S)-N-((3-(3-4-(4-morpholinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl) ethanamide by name.The molecular formula of Linezolid is C
16H
20FN
3O
4, molecular weight is 337.35, and it is a white solid, and fusing point is 181.5 ℃～182.5 ℃, and its structural formula is as follows:
Linezolid is a novel oxazolidinone class antimicrobial drug, it is the microbiotic that the first kind stops early stage gram positive organism protein synthesis, vast potential for future development is arranged, the faecalis that is applicable to treatment skin and soft tissue infection, hospital and community acquired pneumonia and drug resistance of vancomycin infects, and comprises microbemia.
At present, Linezolid has only injection liquid, tablet, because Chinese distant territory is wide, injection liquid easily freezes winter, influences its stability, brings the safety issue of drug use, and there is the situation of transportation inconvenience in injection liquid, and its shelf lives is short.Therefore, exploitation Linezolid freeze-dried powder is necessary at present, also do not have the report of injection Linezolid freeze-dried powder very much.
Summary of the invention
The object of the invention has been to provide the preparation method of a kind of Linezolid and preparation thereof, it is characterized in that: this method may further comprise the steps:
(1) 2 (S)-1-amino-3-chloro-2-propylate hydrochlorate synthetic each composition weight proportioning and preparation:
10～20 parts of 10～20 parts of (S)-epoxy chloropropane of phenyl aldehyde
10～20 parts of the HCl that ethanol is 20～35 part 37%
10～20 parts in 10～20 parts of water of 25% ammoniacal liquor
By the weight proportion of each component, phenyl aldehyde, ethanol, 25% ammoniacal liquor are mixed in the adding bottle, slowly splash into (S)-epoxy chloropropane again, stirring at room 15～25h after concentrating, adds 37% HCl and water, stir 2～4h down at 35 ℃～45 ℃, divide water-yielding stratum, concentrate ethanol-sherwood oil crystallization, suction filtration, washing, drying gets white solid;
(2) (S)-and N-[2-acetoxy-3-chloropropyl] ethanamide synthetic each composition weight proportioning and preparation:
2 (2～10 parts of 2 (S)-1-amino-3-chloro-2-propylate hydrochlorate
CH
2Cl
210～30 parts
Ac
25～15 parts of O
2～8 parts of pyridines
K
2CO
35～10 parts of the aqueous solution
By the weight proportion of each component, with compound 2 (2 (S)-1-amino-3-chloro-2-propylate hydrochlorate, CH
2Cl
2, gAc
2O adds in the bottle, in the time of 30 ℃ pyridine is splashed into wherein, dropwises insulation reaction 15～25h; In the time of 6 ℃, slowly add and contain K
2CO
3The aqueous solution, tell organic layer, water layer CH
2Cl
2Extract, merge organic layer, the saturated common salt water washing, solvent evaporated, an amount of methylbenzene azeotropic band water twice, the sherwood oil crystallization, ethyl acetate-sherwood oil is refining, and oven dry gets the off-white color solid;
(3) each composition weight proportioning and preparation of the synthetic of 3-fluoro-4-morpholinyl oil of mirbane:
2～8 parts of 10～35 parts of morpholines of ethyl acetate
3～7 part 3 of triethylamine, 5～10 parts of 4-difluoro nitrobenzenes
By the weight proportion of each component, ethyl acetate, morpholine, triethylamine are added in the bottle, stirring at room slowly drips 3,4-difluoro nitrobenzene, room temperature left standstill 24 hours, ethyl acetate extraction, saturated common salt water washing, anhydrous magnesium sulfate drying boils off solvent, filter yellow solid;
(4) N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl aniline synthetic each composition weight proportioning and preparation:
7～13 parts in 3-fluoro-4-morpholinyl oil of mirbane
0.5～1.0 part of 10%Pd/C (palladium carbon catalyst)
5～10 parts of formic acid ammonia
140～320 parts in acetone
NaHCO
32～15 parts
2～10 parts of CBZ-Cl (chlorination benzyl formate)
Weight proportion by each component, compound 3-fluoro-4-morpholinyl oil of mirbane, 10%Pd/C (palladium carbon catalyst), formic acid ammonia, acetone (70～160 parts) are added in the bottle, and 45 ℃～50 ℃ reaction 2～4h are chilled to room temperature, suction filtration adds acetone (70-160 part) and NaHCO
3, 0 ℃ slowly drips CBZ-Cl (chlorination benzyl formate), dropwise, and stirring at normal temperature 1～3h, in the impouring frozen water, suction filtration, washing, drying gets the off-white color solid;
(5) each composition weight proportioning and preparation of Linezolid synthetic:
1～5 part of N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl aniline
2～6 parts of DMF (dimethyl formamide)
MeOH 0.2～0.5g part
1molL
-110～25 parts of the THF of LiOt-Bu (tetrahydrofuran (THF)) solution
(S)-and N-[2-acetoxy-3-chloropropyl] 1～3 part of ethanamide
Saturated NH
41.5～6.5 parts of Cl
20～40 parts of saturated aqueous common salts
15～45 parts in water
CH
2Cl
225～45 parts
By the weight proportion of each component, in bottle, add compound N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl aniline, DMF (dimethyl formamide), MeOH, in the time of 20 ℃, drip 1molL
-1The THF of LiOt-Bu (tetrahydrofuran (THF)) solution, in the time of 5 ℃ with compound (S)-N-[2-acetoxy-3-chloropropyl] ethanamide adds wherein stirring at room 10～30h; Reaction finishes, and adds saturated NH successively
4Cl, water, saturated aqueous common salt, CH
2Cl
2, tell organic layer, water layer CH
2Cl
2Extraction merges organic layer, anhydrous MgSO
4Drying, solvent evaporated, ethyl acetate-sherwood oil crystallization gets off-white color solid Linezolid;
(6) each set of dispense of Linezolid formulation preparation when prepares
10～50 parts of Linezolids
5～60 parts of solubilizing agent
PH value conditioning agent is an amount of
Get the Linezolid raw material and put adding water for injection stirring in the container, add pH value conditioning agent and regulate pH value to 5.0～7.0, add the solubilizing agent stirring and make dissolving fully, regulate pH value to 5.5～6.5 with pH value conditioning agent again, add an amount of water for injection, obtain every milliliter of solution that contains Linezolid 10～50mg, solubilizing agent 50～80mg; Add Medicinal Charcoal by 2～8g/l in the gained solution, 20～30 ℃ were stirred 20-60 minute down, filtering decarbonization, and filtration sterilization quantitatively divides pack into antibiotic bottle and false add plug, and putting into the freeze drying equipment casing carries out lyophilize; Described lyophilize is carried out in accordance with the following methods: 1. pre-freeze: freeze-drying solution is put into carries out pre-freeze on the dividing plate of lyophilize casing treating of installing of branch, is cooled to-45～35 ℃, freezing insulation 2-5 hour; 2. sublimation drying: condenser temperature is dropped to-40 ℃ earlier, per hour carry out desorption with average 4-6 ℃ heat-up rate, total time in this stage was controlled at 12-17 hour; 3. redrying: at 30-40 ℃, products temperature reaches 30-40 ℃ and kept 3-8 hour with the temperature control of moisture eliminator box plate; Tamponade, roll lid sealing, promptly get injection Linezolid powder injection of the present invention.Wherein the solubilizing agent described in the step (six) is lactose, sodium-chlor, dextran, glucose, amino acid, N.F,USP MANNITOL or the mixture between them, preferred N.F,USP MANNITOL, and described pH value conditioning agent is basic cpd, buffering system or acid.
The invention has the beneficial effects as follows: 1, the injection Linezolid freeze-dried powder of the present invention's preparation improves stability of drug, makes that the quality guaranteed period of medicine is longer, the transportation is more convenient, more helps its clinical application; 2, the present invention simple on the method for preparing raw material Linezolid and freeze-dried powder thereof, effectively, be applicable to industrialized production.
Embodiment
The present invention is described in further detail below by embodiments of the invention, but protection of the present invention does not mean that and only is confined to following examples:
Embodiment 1
Step 1: 2 (S)-1-amino-3-chloro-2-propylate hydrochlorate synthetic: in the 100ml there-necked flask, add the 10.07g phenyl aldehyde, 30ml ethanol, 10.26g 25% ammoniacal liquor slowly splashes into 10.19g (S)-epoxy chloropropane, stirring at room 15h again, concentrate, add 37% HCl 10.84g and 10ml water, 35 ℃～45 ℃ are stirred 2h, divide water-yielding stratum, concentrate ethanol-sherwood oil crystallization, suction filtration, washing, drying gets white solid 3.67g;
Step 2: (S)-N-[2-acetoxy-3-chloropropyl] ethanamide synthetic: in the 50ml there-necked flask, add the CH of 2.08g compound 2 (S)-1-amino-3-chloro-2-propylate hydrochlorate, 10ml
2Cl
2, the Ac of 5.37g
2O splashes into the 2.61g pyridine wherein in the time of 30 ℃, dropwises insulation reaction 15h; In the time of 6 ℃, slowly add the K that contains 5.27g
2CO
3Aqueous solution 20ml tells organic layer, water layer CH
2Cl
2Extract, merge organic layer, the saturated common salt water washing, solvent evaporated, an amount of methylbenzene azeotropic band water twice, the sherwood oil crystallization, ethyl acetate-sherwood oil is refining, and oven dry gets off-white color solid 2.07g;
Step 3: 3-fluoro-4-morpholinyl oil of mirbane synthetic: in the 100ml there-necked flask, add ethyl acetate 15ml, morpholine 2.61g, triethylamine 3.08g, stirring at room slowly drips 3,4-difluoro nitrobenzene 5.02g, room temperature left standstill 24 hours, ethyl acetate extraction, saturated common salt water washing, anhydrous magnesium sulfate drying, boil off solvent, filter yellow solid 8.73g;
Step 4: N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl aniline synthetic
In the 250ml there-necked flask, add 7.02g 3-fluoro-4-morpholinyl oil of mirbane, 10%Pd/C (palladium carbon catalyst) 0.51g, formic acid ammonia 5.87g, acetone 100ml, 45 ℃～50 ℃ reaction 2h are chilled to room temperature, suction filtration, solution are transferred in another 500ml there-necked flask, add acetone 100ml and contain NaHCO
32.19g aqueous solution 100ml, 0 ℃ slowly drips CBZ-Cl (chlorination benzyl formate) 3.76g, dropwise, stirring at normal temperature 1h, in the impouring 200ml frozen water, suction filtration, washing, drying, off-white color solid 5.27g;
Step 5: Linezolid synthetic: in the 25ml there-necked flask, add N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl aniline of 1.09g, the DMF of 3ml (dimethyl formamide), the MeOH of 0.29g in the time of 20 ℃, drips 11.84ml, 1molL
-1The THF of LiOt-Bu (tetrahydrofuran (THF)) solution, in the time of 5 ℃ with (S)-N-[2-acetoxy-3-chloropropyl of 1.16g] ethanamide adds wherein stirring at room 15h; Reaction finishes, and adds the saturated NH of 2ml successively
4The CH of Cl, 28ml water, 30ml saturated aqueous common salt, 25ml
2Cl
2, tell organic layer, water layer CH
2Cl
2Extraction merges organic layer, anhydrous MgSO
4Drying, solvent evaporated, ethyl acetate-sherwood oil crystallization gets off-white color solid Linezolid 0.96g;
Step 6: the Linezolid raw material 0.9g that gets above-mentioned preparation, put and add water for injection 45ml in the container, stirring makes dissolving, adding sodium hydroxide solution regulates about pH value to 6.9, adding N.F,USP MANNITOL, lactose stir and make dissolving fully, be adjusted to about 6.0 with hydrochloric acid soln again, add an amount of water for injection, obtain every milliliter of solution that contains Linezolid 20mg, N.F,USP MANNITOL 35mg and lactose 25mg; Consumption according to 5g/l adds charcoal absorption, stirred 30 minutes, after the decarburization with 0.22 μ m millipore filtration sterile filtration, quantitatively divide to be filled to and carry out lyophilize in the antibiotic bottle, goods are chilled to about-40 ℃, be incubated 4 hours, condenser is chilled to-40 ℃ and vacuumizes loft drier vacuum tightness is reached below the 50Pa, allow product heat up gradually during primary drying, time control 13 hours, product temperature is set in 36 ℃ of insulations 4 hours during redrying, tamponade, rolls lid sealing, promptly gets injection Linezolid powder injection of the present invention.
Embodiment 2
Step 1: 2 (S)-1-amino-3-chloro-2-propylate hydrochlorate synthetic
In the 100ml there-necked flask, add the 19.98g phenyl aldehyde, 40ml ethanol, 19.94g 25% ammoniacal liquor slowly splashes into 18.76g (S)-epoxy chloropropane, stirring at room 255h again, concentrate, add 37% HCl19.34g and 20ml water, 35 ℃～45 ℃ are stirred 4h, divide water-yielding stratum, concentrate ethanol-sherwood oil crystallization, suction filtration, washing, drying gets white solid 4.57g;
Step 2: (S)-N-[2-acetoxy-3-chloropropyl] ethanamide synthetic
In the 50ml there-necked flask, add 4.03g compound 2 (S)-1-amino-3-chloro-2-propylate hydrochlorate, 20ml CH
2Cl
2, 14.49g Ac
2O splashes into the 6.73g pyridine wherein in the time of 30 ℃, dropwises insulation reaction 25h; In the time of 6 ℃, slowly add and contain 9.96gK
2CO
3Aqueous solution 40ml, tell organic layer, water layer CH
2Cl
2Extract, merge organic layer, the saturated common salt water washing, solvent evaporated, an amount of methylbenzene azeotropic band water twice, the sherwood oil crystallization, ethyl acetate-sherwood oil is refining, and oven dry gets off-white color solid 3.94g;
Step 3: 3-fluoro-4-morpholinyl oil of mirbane synthetic
In the 100ml there-necked flask, add ethyl acetate 35ml, morpholine 7.94g, triethylamine 6.97g, stirring at room slowly drips 3,4-difluoro nitrobenzene 9.98g, room temperature left standstill 24 hours, ethyl acetate extraction, saturated common salt water washing, anhydrous magnesium sulfate drying, boil off solvent, filter yellow solid 9.67g;
Step 4: N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl aniline synthetic
In the 250ml there-necked flask, add 9.82g 3-fluoro-4-morpholinyl oil of mirbane, 10%Pd/C (palladium carbon catalyst) 0.86g, formic acid ammonia 8.94g, acetone 200ml, 45 ℃～50 ℃ reaction 4h are chilled to room temperature, suction filtration, solution are transferred in another 500ml there-necked flask, add acetone 200ml and contain NaHCO
314.75g aqueous solution 100ml, 0 ℃ slowly drips CBZ-Cl (chlorination benzyl formate) 8.29g, dropwise, stirring at normal temperature 3h, in the impouring 250ml frozen water, suction filtration, washing, drying, off-white color solid 6.18g;
Step 5: Linezolid synthetic
In the 25ml there-necked flask, add N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl aniline of 5.81g, the DMF (dimethyl formamide) of 6ml, the MeOH of 0.51g in the time of 20 ℃, drips the 1molL of 23.64ml
-1The THF of LiOt-Bu (tetrahydrofuran (THF)) solution, in the time of 5 ℃ with (S)-N-[2-acetoxy-3-chloropropyl of 2.96g] ethanamide adds wherein stirring at room 30h; Reaction finishes, and adds the saturated NH of 6.5ml successively
4Cl, 45ml water, 40ml saturated aqueous common salt, 45mlCH
2Cl
2, tell organic layer, water layer CH
2Cl
2Extraction merges organic layer, anhydrous MgSO
4Drying, solvent evaporated, ethyl acetate-sherwood oil crystallization gets off-white color solid Linezolid 1.17g;
Step 6: the Linezolid raw material 0.9g that gets above-mentioned preparation, put and add water for injection 45ml in the container, stirring makes dissolving, adding sodium hydroxide solution regulates about pH value to 7.0, adding N.F,USP MANNITOL, lactose stir and make dissolving fully, be adjusted to about 6.0 with hydrochloric acid soln again, add an amount of water for injection, obtain every milliliter of solution that contains Linezolid 20mg, N.F,USP MANNITOL 55mg and lactose 5mg; The consumption of pressing 2g/l adds charcoal absorption, stirred 30 minutes, after the decarburization with 0.22 μ m millipore filtration sterile filtration, quantitatively divide to be filled to and carry out lyophilize in the antibiotic bottle, goods are chilled to about-40 ℃, be incubated 3 hours, condenser is chilled to-45 ℃ and vacuumizes loft drier vacuum tightness is reached below the 50Pa, allow product heat up gradually during primary drying, time control 14 hours, product temperature is set in 36 ℃ of insulations 4 hours during redrying, tamponade, rolls lid sealing, promptly gets injection Linezolid powder injection of the present invention.
Embodiment 3
Step 1: 2 (S)-1-amino-3-chloro-2-propylate hydrochlorate synthetic
In the 100ml there-necked flask, add the 13.90g phenyl aldehyde, 35ml ethanol, 13.60g 25% ammoniacal liquor slowly splashes into (S)-epoxy chloropropane of 11.80g, stirring at room 20h again, concentrate, add 37% HCl19.10g and 18ml water, 35 ℃～45 ℃ are stirred 3h, divide water-yielding stratum, concentrate ethanol-sherwood oil crystallization, suction filtration, washing, drying gets white solid 14.10g;
Step 2: (S)-N-[2-acetoxy-3-chloropropyl] ethanamide synthetic
In the 50ml there-necked flask, add 5.00g compound 2 (S)-1-amino-3-chloro-2-propylate hydrochlorate, 18mlCH
2Cl
2, 8.00gAc
2O splashes into the 3.40g pyridine wherein in the time of 30 ℃, dropwises insulation reaction 20h.In the time of 6 ℃, slowly add and contain 9.30gK
2CO
3Aqueous solution 30ml, tell organic layer, water layer CH
2Cl
2Extract, merge organic layer, the saturated common salt water washing, solvent evaporated, an amount of methylbenzene azeotropic band water twice, the sherwood oil crystallization, ethyl acetate-sherwood oil is refining, and oven dry gets off-white color solid 5.99g.
Step 3: 3-fluoro-4-morpholinyl oil of mirbane synthetic
In the 100ml there-necked flask, add ethyl acetate 25ml, morpholine 4.79g, triethylamine 5.57g, stirring at room slowly drips 3,4-difluoro nitrobenzene 7.95g, room temperature left standstill 24 hours, ethyl acetate extraction, saturated common salt water washing, anhydrous magnesium sulfate drying, boil off solvent, filter yellow solid 10.87g.
Step 4: N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl aniline synthetic
In the 250ml there-necked flask, add 9.05g 3-fluoro-4-morpholinyl oil of mirbane, 10%Pd/C (palladium carbon catalyst) 0.80g, formic acid ammonia 7.57g, acetone 120ml, 45 ℃～50 ℃ reaction 3h are chilled to room temperature, suction filtration, solution are transferred in another 500ml there-necked flask, add acetone 120ml and contain NaHCO
35.88g aqueous solution 100ml, 0 ℃ slowly drips CBZ-Cl (chlorination benzyl formate) 7.85g, dropwise, stirring at normal temperature 2h, in the impouring 200ml frozen water, suction filtration, washing, drying, off-white color solid 11.83g.
Step 5: Linezolid synthetic: in the 25ml there-necked flask, add 2.05g compound 6 (N-carbobenzoxy-(Cbz)s-3-fluoro-4-morpholinyl aniline), the DMF of 4ml (dimethyl formamide), the MeOH of 0.4g in the time of 20 ℃, drips the 1molL of 18.75ml
-1The THF of LiOt-Bu (tetrahydrofuran (THF)) solution adds 1.94g compound 3 ((S)-N-[2-acetoxy-3-chloropropyl] ethanamide) wherein stirring at room 21h in the time of 5 ℃; Reaction finishes, and adds the saturated NH of 4ml successively
4Cl, 35ml water, 30ml saturated aqueous common salt, 35mlCH
2Cl
2, tell organic layer, water layer CH
2Cl
2Extraction merges organic layer, anhydrous MgSO
4Drying, solvent evaporated, ethyl acetate-sherwood oil crystallization gets off-white color solid Linezolid 1.59g.
Step 6: the Linezolid raw material 0.9g that gets above-mentioned preparation, put and add water for injection 45ml in the container, stirring makes dissolving, adding sodium hydroxide solution regulates about pH value to 7.1, regulate about pH value to 6.0 with the hydrochloric acid hydrogen solution again, add an amount of water for injection, obtain every milliliter of solution that contains Linezolid 20mg, N.F,USP MANNITOL 25mg and lactose 35mg; Consumption according to 8g/l adds charcoal absorption, stirred 20 minutes, after the decarburization with 0.22 μ m millipore filtration sterile filtration, quantitatively divide to be filled to and carry out lyophilize in the antibiotic bottle, goods are chilled to about-40 ℃, be incubated 3 hours, condenser is chilled to-45 ℃ and vacuumizes loft drier vacuum tightness is reached below the 50Pa, allow product heat up gradually during primary drying, time control 13 hours, product temperature is set in 36 ℃ of insulations 5 hours during redrying, tamponade, rolls lid sealing, promptly gets injection Linezolid powder injection of the present invention.
Claims (3)
1. the preparation method of Linezolid and preparation thereof, it is characterized in that: this method may further comprise the steps:
(1) 2 (S)-1-amino-3-chloro-2-propylate hydrochlorate synthetic each composition weight proportioning and preparation:
10～20 parts of 10～20 parts of (S)-epoxy chloropropane of phenyl aldehyde
10～20 parts of the HCl that ethanol is 20～35 part 37%
10～20 parts in 10～20 parts of water of 25% ammoniacal liquor
By the weight proportion of each component, phenyl aldehyde, ethanol, 25% ammoniacal liquor are mixed in the adding bottle, slowly splash into (S)-epoxy chloropropane again, stirring at room 15～25h after concentrating, adds 37% HCl and water, stir 2～4h down at 35 ℃～45 ℃, divide water-yielding stratum, concentrate ethanol-sherwood oil crystallization, suction filtration, washing, drying gets white solid;
(2) (S)-and N-[2-acetoxy-3-chloropropyl] ethanamide synthetic each composition weight proportioning and preparation:
2 (2～10 parts of 2 (S)-1-amino-3-chloro-2-propylate hydrochlorate
CH
2Cl
210～30 parts
Ac
25～15 parts of O
2～8 parts of pyridines
K
2CO
35～10 parts of the aqueous solution
By the weight proportion of each component, with compound 2 (2 (S)-1-amino-3-chloro-2-propylate hydrochlorate, CH
2Cl
2, gAc
2O adds in the bottle, in the time of 30 ℃ pyridine is splashed into wherein, dropwises insulation reaction 15～25h; In the time of 6 ℃, slowly add and contain K
2CO
3The aqueous solution, tell organic layer, water layer CH
2Cl
2Extract, merge organic layer, the saturated common salt water washing, solvent evaporated, an amount of methylbenzene azeotropic band water twice, the sherwood oil crystallization, ethyl acetate-sherwood oil is refining, and oven dry gets the off-white color solid;
(3) each composition weight proportioning and preparation of 3-fluoro-4-morpholinyl oil of mirbane synthetic:
2～8 parts of 10～35 parts of morpholines of ethyl acetate
3～7 part 3 of triethylamine, 4-difluoro nitrobenzene 5～1O part
By the weight proportion of each component, ethyl acetate, morpholine, triethylamine are added in the bottle, stirring at room slowly drips 3,4-difluoro nitrobenzene, room temperature left standstill 24 hours, ethyl acetate extraction, saturated common salt water washing, anhydrous magnesium sulfate drying boils off solvent, filter yellow solid;
(4) N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl aniline synthetic each composition weight proportioning and preparation:
7～13 parts in 3-fluoro-4-morpholinyl oil of mirbane
0.5～1.0 part of 10%Pd/C (palladium carbon catalyst)
5～10 parts of formic acid ammonia
140～320 parts in acetone
NaHCO
32～15 parts
2～10 parts of CBZ-Cl (chlorination benzyl formate)
Weight proportion by each component, compound 3-fluoro-4-morpholinyl oil of mirbane, 10%Pd/C (palladium carbon catalyst), formic acid ammonia, acetone (70～160 parts) are added in the bottle, and 45 ℃～50 ℃ reaction 2～4h are chilled to room temperature, suction filtration adds acetone (70-160 part) and NaHCO
3, 0 ℃ slowly drips CBZ-Cl (chlorination benzyl formate), dropwise, and stirring at normal temperature 1～3h, in the impouring frozen water, suction filtration, washing, drying gets the off-white color solid;
(5) each composition weight proportioning and preparation of Linezolid synthetic:
1～5 part of N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl aniline
2～6 parts of DMF (dimethyl formamide)
MeOH 0.2～0.5g part
1molL
-110～25 parts of the THF of LiOt-Bu (tetrahydrofuran (THF)) solution
(S)-and N-[2-acetoxy-3-chloropropyl] 1～3 part of ethanamide
Saturated NH
41.5～6.5 parts of Cl
20～40 parts of saturated aqueous common salts
15～45 parts in water
CH
2Cl
225～45 parts
By the weight proportion of each component, in bottle, add compound N-carbobenzoxy-(Cbz)-3-fluoro-4-morpholinyl aniline, DMF (dimethyl formamide), MeOH, in the time of 20 ℃, drip 1molL
-1The THF of LiOt-Bu (tetrahydrofuran (THF)) solution, in the time of 5 ℃ with compound (S)-N-[2-acetoxy-3-chloropropyl] ethanamide adds wherein stirring at room 10～30h; Reaction finishes, and adds saturated NH successively
4Cl, water, saturated aqueous common salt, CH
2Cl
2, tell organic layer, water layer CH
2Cl
2Extraction merges organic layer, anhydrous MgSO
4Drying, solvent evaporated, ethyl acetate-sherwood oil crystallization gets off-white color solid Linezolid;
(6) each set of dispense of Linezolid formulation preparation when prepares
10～50 parts of Linezolids
5～60 parts of solubilizing agent
PH value conditioning agent is an amount of
Get the Linezolid raw material and put adding water for injection stirring in the container, add pH value conditioning agent and regulate pH value to 5.0～7.0, add the solubilizing agent stirring and make dissolving fully, regulate pH value to 5.5～6.5 with pH value conditioning agent again, add an amount of water for injection, obtain every milliliter of solution that contains Linezolid 10～50mg, solubilizing agent 50～80mg; Add Medicinal Charcoal by 2～8g/l in the gained solution, 20-30 ℃ was stirred 20-60 minute down, filtering decarbonization, and filtration sterilization quantitatively divides pack into antibiotic bottle and false add plug, and putting into the freeze drying equipment casing carries out lyophilize; Described lyophilize is carried out in accordance with the following methods: 1. pre-freeze: freeze-drying solution is put into carries out pre-freeze on the dividing plate of lyophilize casing treating of installing of branch, is cooled to-45～35 ℃, freezing insulation 2-5 hour; 2. sublimation drying: condenser temperature is dropped to-40 ℃ earlier, per hour carry out desorption with average 4-6 ℃ heat-up rate, total time in this stage was controlled at 12-17 hour; 3. redrying: at 30-40 ℃, products temperature reaches 30-40 ℃ and kept 3-8 hour with the temperature control of moisture eliminator box plate; Tamponade, roll lid sealing, promptly get injection Linezolid powder injection of the present invention.
2. the preparation method of Linezolid according to claim 1 and preparation thereof, it is characterized in that: the solubilizing agent described in the step (six) is lactose, sodium-chlor, dextran, glucose, amino acid, N.F,USP MANNITOL or the mixture between them, preferred N.F,USP MANNITOL.
3. the preparation method of Linezolid according to claim 1 and preparation thereof is characterized in that: the pH value conditioning agent described in the step (six) is basic cpd, buffering system or acid.
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| CN102267955A (en) * | 2011-06-02 | 2011-12-07 | 山东鲁抗医药股份有限公司 | Preparation method of linezolid |
| CN102558085A (en) * | 2011-12-28 | 2012-07-11 | 湖南方盛制药股份有限公司 | Method for preparing inezolid |
| WO2012104874A2 (en) * | 2011-02-02 | 2012-08-09 | Mylan Laboratories Limited. | Aqueous concentrated formulation of linezolid |
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