CN102516191B - Method for preparing Linezolid - Google Patents
Method for preparing Linezolid Download PDFInfo
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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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- 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 24
- 229960003907 linezolid Drugs 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- -1 acetonyl ester Chemical class 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 238000005267 amalgamation Methods 0.000 claims description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 1
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 3
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical class NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 241000191940 Staphylococcus Species 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical class CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 230000014616 translation Effects 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
- 238000010792 warming Methods 0.000 description 1
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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
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
) structure is as follows:
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
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
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
) structure is as follows:
Comprise the following steps:
(a), formula
middle nitro reacts with ammonium formiate under the katalysis of palladium carbon, is converted into amino.
(b), by formula
middle hydroxyl and amino change respectively acetonyl ester and ethanamide into
(c), formula
with formula
amalgamation production under sodium hydride effect
(d), in acid alcohol solution by formula
in acetyl ester group remove and change free hydroxyl group into
(e), formula
under carbonyl dimidazoles effect, target compound Linezolid is prepared in cyclization
。
In step (c), intermediate formula
be dissolved in non-protonic solvent toluene production under the effect of sodium hydride
disodium iminodiacetic active to increase nucleophilic reaction, the latter and formula
there is nucleophilic substitution reaction, generate key intermediate formula
.Control formula in this step synthetic method
with formula
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
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
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
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
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
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
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
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
Comprise the following steps:
(a), formula
middle nitro reacts with ammonium formiate under the katalysis of palladium carbon, is converted into amino;
?(b), by formula
middle hydroxyl and amino change respectively acetonyl ester and ethanamide into
(c), formula
with formula
amalgamation production under sodium hydride effect
(d), in acid alcohol solution by formula
in acetyl ester group remove and change free hydroxyl group into
(e), formula
under carbonyl dimidazoles effect, target compound Linezolid is prepared in cyclization
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
with formula
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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| Development》.2003,第7卷第533-546页. * |
| William R. Perrault et al..The Synthesis of N-Aryl-5(S)-aminomethyl-2-oxazolidinone Antibacterials and Derivatives in One Step from Aryl Carbamates.《Organic Process Research & Development》.2003,第7卷第533-546页. |
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