CN105524009A - Preparation method of linezolid in type B crystal form - Google Patents
Preparation method of linezolid in type B crystal form Download PDFInfo
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- CN105524009A CN105524009A CN201610015921.4A CN201610015921A CN105524009A CN 105524009 A CN105524009 A CN 105524009A CN 201610015921 A CN201610015921 A CN 201610015921A CN 105524009 A CN105524009 A CN 105524009A
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- linezolid
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- organic solvent
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- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 title claims abstract description 62
- 229960003907 linezolid Drugs 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000013078 crystal Substances 0.000 title abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 7
- 239000007789 gas Substances 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 4
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical compound CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 8
- 239000002904 solvent Substances 0.000 abstract description 6
- 239000013557 residual solvent Substances 0.000 abstract description 5
- 238000002425 crystallisation Methods 0.000 abstract description 3
- 230000008025 crystallization Effects 0.000 abstract description 3
- 238000003860 storage Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 238000001228 spectrum Methods 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- -1 azoles amine Chemical class 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010035664 Pneumonia Diseases 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 206010062255 Soft tissue infection Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- 208000008745 Healthcare-Associated Pneumonia Diseases 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a preparation method of linezolid in the type B crystal form. The linezolid is used as a raw material and forms a salt with hydrochloric acid in an organic solvent, which solves the problems that the linezolid hydrochloride is low in yield and inconvenient in storage and transportation. At the same time, during the crystallization process, water is used as a solvent, which effectively solves the problem of excessive residual solvent in the finished product of the linezolid. The obtained product by the method is high in yield and high in purity; the operation is good; the reproducibility is good; and the method is suitable for industrial production.
Description
Technical field
The invention belongs to crystal formation technical field, be specifically related to the preparation method of a kind of linezolid form B.
Background technology
Linezolid (Linezolid), chemical name: (S)-N-[[3-[the fluoro-4-of 3-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide, be first man work synthesis for clinical novel oxazolidinone class antimicrobial drug, be used for the treatment of gram-positive (G+) coccigenic infection, comprise by cause doubtful of MRSA or make a definite diagnosis nosocomial pneumonia (HAP), community acquired pneumonia (CAP) complicacy skin or skin soft-tissue infection (SSTI) and vancomycin-resistant enterococcus (VER) infect, its molecular formula is C
16h
20fN
3o
4, there is the structure as shown in the formula (I):
（I）
Linezolid has now reported multiple crystal formation, document (J.Med.Chem.39(3) 673-679,1996) disclose linezolid form I, its fusing point is 181.5-182.5 DEG C, Infrared spectra adsorption 3284,3092,1753,1728,1649,1565,1519,1447,1435cm
-1.
Patent US6444813 and US6559305 discloses linezolid form II and preparation method thereof, powder X-ray 2 θ value 7.10,9.54,13.88,14.23,16.18,16.79,17.69,19.41,19.69,19.93,21.61,22.39,22.84,23.52,24.16, there is characteristic peak at 25.28,26.66,27.01 and 27.77 places.
WO2005/035530 discloses linezolid form III and preparation method thereof, and powder X-ray 2 θ value has characteristic peak at 7.6,9.6,13.6,14.9,18.2,18.9,21.2,22.3,25.6,26.9,27.9 and 29.9 places.
CN101262853A discloses linezolid form IV and preparation method thereof, and powder X-ray 2 θ value has characteristic peak at 7.4,9.4,13.6,14.8,15.2,15.4,16.3,16.9,18.0,18.8,21.0,22.3 and 29.7 places.
CN102260222B discloses linezolid form V and preparation method thereof, powder X-ray 2 θ value 7.36,9.28,13.44,14.62,16.76,17.94,18.43,18.67,19.77,20.68,20.92,22.14,25.40,26.80,27.67,28.34 there is characteristic peak at 29.68,33.63 and 34.10 places.
CN102850289B discloses linezolid form VI and preparation method thereof, and powder X-ray 2 θ value has characteristic peak at 11.25,16.27,16.70,18.95,19.69,22.73,25.09,25.31,26.22,26.55,27.54 and 29.60 places.
How azoles amine crystal form B, 2 θ values of its powder x-ray diffraction spectrum have characteristic peak at 9.43,11.29,13.27,15.55,16.69,19.04,21.92 and 22.35 places.It is little how azoles amine crystal form B has particle diameter, is evenly distributed, do not need to mill and sieve, and result of extraction is good, very the exploitation of Suitable pharmaceutical preparations.
Linezolid hydrochloride is the critical materials preparing how azoles amine crystal form B, but Linezolid hydrochloride is unstable, and particularly in the environment having water, the easy moisture absorption goes bad, inconvenient storage and transport.What existing document US2009062534 and WO2008000418 reported prepares Linezolid hydrochloride, carry out at organic solvents such as acetone, acetonitrile, ethyl acetate or tetrahydrofuran (THF)s, the method not only yield is low but also easily cause the residual solvent of finished product linezolid form B to exceed standard, and affects the security that medicine uses.
Therefore, a kind of new preparation high purity, high yield and the method for the linezolid form B of noresidue solvent is new problem urgently to be resolved hurrily is at present developed.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of how azoles amine crystal form B of profit, this preparation method's processing parameter simply, easily controls, and favorable reproducibility, be applicable to industrialized production.
Object of the present invention is achieved by the following technical programs:
The preparation method of linezolid form B, it comprises the steps:
(1) Linezolid crude product is placed in organic solvent, heating for dissolving;
(2) pass into hydrogen chloride gas, regulate reaction solution pH to 1 ~ 3, be cooled to room temperature, stir, collect Linezolid HCl, solid;
(3) step (2) gained Linezolid hydrochloride is placed in water, heating;
(4) use alkali regulating step (3) gained solution to pH >=7, stirring and crystallizing, filtration drying obtains linezolid form B.
Wherein, in step (1), the chemical purity of Linezolid crude product is more than 90%, and preferred chemical purity is more than 95%.The chemical purity of Linezolid crude product is higher, and the chemical purity of gained linezolid form B is also higher.
In step (1), described organic solvent is selected from toluene, o-Xylol, m-xylene, p-Xylol, methyl alcohol, ethanol, Virahol, butanols, preferred toluene, ethanol.
In step (1), described Heating temperature be room temperature to reflux temperature, preferably 60 DEG C ~ 100 DEG C, more preferably 70 DEG C ~ 90 DEG C, most preferably 70 DEG C ~ 80 DEG C.
In step (1), the mass volume ratio (g/ml) of described Linezolid and organic solvent is 1:40 ~ 70, preferred 1:45 ~ 55, more preferably 1:50 ~ 55.
In step (2), pH=1.0 ~ 2.5 of described reaction solution, preferred pH=1.5 ~ 2.0.
In step (2), described churning time, without specific requirement, is generally determined according to the input amount of Linezolid.In order to improve the yield of Linezolid hydrochloride, can proper extension churning time, preferred churning time is 1h ~ 12h, more preferably 2h ~ 6h.
In step (2), the Linezolid hydrochloride obtained is unformed, and its XRD figure spectrum substantially as shown in Figure 2.
In step (3), the volume of water is generally 30 ~ 50 times of the quality of Linezolid hydrochloride, preferably 40 ~ 45 times.
In step (3), described Heating temperature is 30 DEG C ~ 70 DEG C, preferably 40 DEG C ~ 60 DEG C, more preferably 40 DEG C ~ 50 DEG C.
In step (4), described alkali is selected from one or more in sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, sodium hydroxide, potassium hydroxide, ammoniacal liquor with the mixture of arbitrary proportion mixing gained, preferred sodium carbonate or salt of wormwood.
In step (4), pH=8 ~ 10 of described solution, preferred pH=9 ~ 10.
In step (4), after crystallization terminates, generally also carry out natural cooling process, preferably naturally cool to room temperature.
In step (4), filter after obtaining linezolid form B, drying treatment can be carried out by this area ordinary method, as vacuum-drying, preferably 40 DEG C of-50 DEG C of vacuum-dryings.
On the basis meeting this area general knowledge, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
The preparation method of linezolid form B provided by the invention, by adopting Linezolid to be raw material, in organic solvent with hydrochloric acid salify, solves Linezolid hydrochloride yield low, the problem of storage and transport inconvenience; In Crystallization Process, use water as solvent simultaneously, efficiently solve the problem that in Linezolid finished product, residual solvent exceeds standard.Gained linezolid form B finished product purity of the present invention is high, and chemical purity reaches more than 99.0%, even reaches more than 99.9%; Yield is high, reaches more than 80%, almost no solvent residue and simple to operate, and favorable reproducibility, is applicable to industrialized production.
Accompanying drawing explanation
The XRD figure spectrum of Fig. 1: linezolid form B
Fig. 2: the XRD figure spectrum of unformed Linezolid hydrochloride.
Embodiment
For embodying technical scheme of the present invention and acquired effect thereof, below in conjunction with specific embodiment, the present invention will be further described, but protection scope of the present invention is not confined to specific embodiment.
Embodiment 1
By Linezolid crude product 10.0g, chemical purity is 96.5%, and toluene 500ml is placed in reaction flask, be heated with stirring to 70 DEG C ~ 80 DEG C, dissolution of solid, passes into hydrogen chloride gas, and reaction solution generates white opacity at once, when reaction solution pH=2.0 ~ 2.5, stop passing into hydrogen chloride gas, reaction solution naturally cools to room temperature, continues stirring 2 hours, filter, washing.Filter cake obtains unformed Linezolid hydrochloride 40 DEG C ~ 50 DEG C vacuum-dryings.
Be transferred in reaction flask by unformed Linezolid hydrochloride, add the water of 40 times of volumes, be heated with stirring to 40 DEG C, drip 10% solution of potassium carbonate, regulate reaction solution pH=9 ~ 10, stirring and crystallizing, naturally cools to room temperature, filters, washing.Gained filter cake is at 40 DEG C ~ 50 DEG C, and vacuum-drying obtains 9.1g linezolid form B for 4 ~ 6 hours, and chemical purity 99.8%, does not detect organic solvent residual, and its XRD figure spectrum substantially as shown in Figure 1.
Embodiment 2
By Linezolid crude product 50g, chemical purity is 96.5%, and ethanol 2.5L is placed in reaction flask, be heated with stirring to 60 DEG C ~ 70 DEG C, dissolution of solid, passes into hydrogen chloride gas, and reaction solution generates white opacity at once, when reaction solution pH=1.5 ~ 2.0, stop passing into hydrogen chloride gas, reaction solution naturally cools to room temperature, continues stirring 2 hours, filter, washing.Filter cake obtains unformed Linezolid hydrochloride 40 DEG C ~ 50 DEG C vacuum-dryings.
Be transferred in reaction flask by unformed Linezolid hydrochloride, add the water of 45 times of volumes, be heated with stirring to 40 DEG C, drip 10% solution of potassium carbonate, regulate reaction solution pH=9 ~ 10, stirring and crystallizing, naturally cools to room temperature, filters, washing.Gained filter cake is at 40 DEG C ~ 50 DEG C, and vacuum-drying obtains 45.6g linezolid form B for 4 ~ 6 hours, and chemical purity 99.9%, does not detect organic solvent residual, and its XRD figure spectrum substantially as shown in Figure 1.
Embodiment 3 processing parameter is investigated
Operation is basic with embodiment 1, the results are shown in Table one, table two, table three.
Table one, investigate the impact on the yield of linezolid form B, purity and residual solvent of different solvents and consumption thereof.
NA: do not detect
Solvent made by table two, use toluene, and investigate after passing into hydrogen chloride gas, the pH value of reaction solution is on the impact of the yield of linezolid form B.
The impact of table three, the yield of consumption on linezolid form B investigating water, purity and residual solvent.
NA: do not detect
Table four, investigation recrystallization temperature are on the impact of the yield of linezolid form B.
。
Claims (10)
1. the preparation method of linezolid form B, comprises the steps:
(1) Linezolid crude product is placed in organic solvent, heating for dissolving;
(2) pass into hydrogen chloride gas, regulate reaction solution pH to 1 ~ 3, be cooled to room temperature, stir, collect Linezolid HCl, solid;
(3) step (2) gained Linezolid hydrochloride is placed in water, heating;
(4) use alkali regulating step (3) gained solution to pH >=7, stirring and crystallizing, filter and obtain linezolid form B.
2. preparation method according to claim 1, is characterized in that, in step (1), the chemical purity of Linezolid crude product is more than 90%, and preferred chemical purity is more than 95%.
3. preparation method according to claim 1, is characterized in that, in step (1), described organic solvent is selected from toluene, o-Xylol, m-xylene, p-Xylol, methyl alcohol, ethanol, Virahol, butanols, preferred toluene, ethanol.
4. preparation method according to claim 1, is characterized in that, in step (1), and described Heating temperature 60 DEG C ~ 100 DEG C, preferably 70 DEG C ~ 90 DEG C, more preferably 70 DEG C ~ 80 DEG C.
5. preparation method according to claim 1, is characterized in that, in step (1), the mass volume ratio (g/ml) of described Linezolid and organic solvent is 1:40 ~ 70, preferred 1:45 ~ 55, more preferably 1:50 ~ 55.
6. preparation method according to claim 1, is characterized in that, in step (2), and pH=1.0 ~ 2.5 of described reaction solution, preferred pH=1.5 ~ 2.0.
7. preparation method according to claim 1, is characterized in that, in step (3), the volume of water is 30 ~ 50 times of Linezolid quality, preferably 40 ~ 45 times.
8. preparation method according to claim 1, is characterized in that, in step (3), described Heating temperature is 30 DEG C ~ 70 DEG C, preferably 40 DEG C ~ 60 DEG C, more preferably 40 DEG C ~ 50 DEG C.
9. preparation method according to claim 1, it is characterized in that, in step (4), described alkali is selected from one or more in sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, sodium hydroxide, potassium hydroxide, ammoniacal liquor with the mixture of arbitrary proportion mixing gained, preferred sodium carbonate or salt of wormwood.
10. preparation method according to claim 1, is characterized in that, in step (4), and pH=8 ~ 10 of described solution, preferred pH=9 ~ 10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610015921.4A CN105524009B (en) | 2016-01-12 | 2016-01-12 | Linezolid form B preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610015921.4A CN105524009B (en) | 2016-01-12 | 2016-01-12 | Linezolid form B preparation method |
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| CN105524009B CN105524009B (en) | 2017-09-19 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006004922A1 (en) * | 2004-06-29 | 2006-01-12 | Teva Pharmaceutical Industries Ltd. | Crystalline form iv of linezolid |
| EP2033960A2 (en) * | 2007-09-04 | 2009-03-11 | Dipharma Francis S.r.l. | Linezolid crystalline hydrate form and linezolid salts |
| CN102850289A (en) * | 2012-09-19 | 2013-01-02 | 成都欣捷高新技术开发有限公司 | Linezolid crystal form VI and preparation method thereof |
-
2016
- 2016-01-12 CN CN201610015921.4A patent/CN105524009B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006004922A1 (en) * | 2004-06-29 | 2006-01-12 | Teva Pharmaceutical Industries Ltd. | Crystalline form iv of linezolid |
| EP2033960A2 (en) * | 2007-09-04 | 2009-03-11 | Dipharma Francis S.r.l. | Linezolid crystalline hydrate form and linezolid salts |
| CN102850289A (en) * | 2012-09-19 | 2013-01-02 | 成都欣捷高新技术开发有限公司 | Linezolid crystal form VI and preparation method thereof |
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| CN105524009B (en) | 2017-09-19 |
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