CN103965183A - Fluorine-containingoxazolidinonecompound as well as preparation method and application thereof - Google Patents

Fluorine-containingoxazolidinonecompound as well as preparation method and application thereof Download PDF

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CN103965183A
CN103965183A CN201410096495.2A CN201410096495A CN103965183A CN 103965183 A CN103965183 A CN 103965183A CN 201410096495 A CN201410096495 A CN 201410096495A CN 103965183 A CN103965183 A CN 103965183A
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fluorine
oxazolidinone compounds
magnetic resonance
trifluoromethyl
methyl
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CN103965183B (en
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吴晶晶
颜莉莉
吴范宏
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Shanghai Institute of Technology
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Shanghai Institute of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/76—1,3-Oxazoles; Hydrogenated 1,3-oxazoles

Abstract

The invention discloses a fluorine-containingoxazolidinonecompound as well as a preparation method and an application thereof. The structural formula of the fluorine-containingoxazolidinonecompound is as follows, wherein Rf refers to a trifluoromethyl group, a difluoromethyl group, a fluorine atom or perfluoralkane, R<1> and R<2>independently refer to H, C1-C6 straight-chain or branchedalkyl groups, C1-C6 straight-chain or branchedperfluoroalkyl groups, C1-C6 straight-chain or branchedalkoxygroups, a halogen such as F, Cl, Br or I, a nitro group, a cyano group or a phenyl group; R<3>, R<4>, R<5> and R<6>independently refer to H, F, Cl, Br, I or C1-C3 alkyl groups. The fluorine-containingoxazolidinonecompound has the better antimicrobial activity on watermelonanthracnose and cucumber grey mold and is particularly good in inhibitory activity on phytopathogencucumber grey mold of imperfect fungihyphomycetes, and a new choice is provided for development and utilization of new sterilization pesticides.

Description

A kind of Han Fu oxazolidinone compounds and its preparation method and application
Technical field
The invention belongs to pesticide field, be specifically related to a class and as disinfectant use in agriculture, watermelon anthrax bacteria or botrytis cinerea pers carried out to sterilization with it containing different fluoro-containing group oxazolidinone compounds and preparation method thereof.
Background technology
Disinfectant use in agriculture has irreplaceable vital role at aspects such as germ prevention and controls, is the important guarantee of agricultural foison and grain security.In recent years, on global agrochemical market, sterilant selling market showed a rising trend always.But the resistance of sterilant occurs comparatively fast, the pesticide new variety that is about to listing being is is being researched and developed in the whole world at present, and sterilant ranks the 1st.Therefore, exploitation has novel mechanism, environment amenable sterilant new variety just seem extremely important.
Oxazole heterogeneous ring compound is a kind of important five-membered azole heterocycle compound containing oxygen nitrogen, and in multiple fields, particularly medicine has broad application prospects.Wherein ， oxazolidinone compounds is the complete synthesis antibacterials of another class of going on the market after sulfamido and Comprecin, and its mechanism of action uniqueness, all has extremely strong resisting gram-positive bacteria (G in vivo and in vitro +bacterium) activity, to thering is good therapeutic action by the microbial infection of most of gram-positives, as methicillin-resistant Staphylococcus (MRSA), vancomycin resistance staphylococcus, vancomycin-resistant enterococcus (VRE), Penicillin-resistant Pneumococci and anerobe etc.In addition, new different oxazolidinone compounds is also prepared by some seminars, and screens the medicinal activity of these compound anti thrombotic actions.
But up to the present, yet there are no the preparation of the fluorine-containing oxazolidinone compounds of system, and it is carried out to the report of agricultural bactericidal activity research.
Summary of the invention
One of object of the present invention is to provide a kind of fluorine-containing oxazolidinone compounds.
Two of object of the present invention is the preparation method of a kind of fluorine-containing oxazolidinone compounds that provides above-mentioned.
Three of object of the present invention is above-mentioned a kind of fluorine-containing oxazolidinone compounds as disinfectant use in agriculture.
Technical scheme of the present invention
A fluorine-containing oxazolidinone compounds, its structural formula is as follows:
Wherein, R 1, R 2be independently H, C 1～C 6straight or branched alkyl, C 1～C 6straight or branched perfluoroalkyl, C 1～C 6straight or branched alkoxyl group, halogen, nitro, cyano group or phenyl, described halogen is F, Cl, Br or I;
R 3, R 4, R 5, R 6be independently H, F, Cl, Br, I or C 1～C 3alkyl;
R ffor trifluoromethyl, difluoromethyl, fluorine atom or perfluoro alkane.
Preferred: R 1, R 2be independently H, methyl, ethyl, methoxyl group, F, Cl, B, r cyano group or phenyl;
R 3, R 4, R 5, R 6be independently H, F or methyl;
R ffor trifluoromethyl, difluoromethyl or fluorine atom.
The preparation method of above-mentioned a kind of Han Fu oxazolidinone compounds, the chemical equation of its preparation process is as follows:
Specifically comprise 11 steps reactions, i.e. the ammoniacal liquor that (S)-epoxy chloropropane 1 of the first step: 1N and the phenyl aldehyde of 1N are 25% at the mass percent concentration of 16N after 35-40 DEG C of stirring reaction 6h again at 18-25 DEG C stirring reaction 14h obtain the reaction solution that contains imine intermediate;
Second step: toward the hydrochloric acid that adds 1.5N in the reaction solution that contains imine intermediate of above-mentioned gained, reaction generates the chloro-2-propylate of (S)-1-amino-3-hydrochlorate 2 at 35-45 DEG C;
The chloro-2-propylate of (the S)-1-amino-3-hydrochlorate 2 of the 3rd step: 1N is (Boc) in chemical equation with the two dimethyl dicarbonate butyl esters of 2N 2o at room temperature reacts generation (S)-tertiary butyl-(3-chlorine-2-hydroxyl propyl group) t-butyl carbamate 3;
The diacetyl oxide that the different fluoro-containing groups of the alkene ether 4 of the 4th step: 1.1N and 1N replace, under the pyridine effect of 1N, successively after 0 DEG C of reaction 3h, is controlled and at 25 DEG C of normal temperature, is reacted 12h and generate intermediate 5 in dichloromethane solvent;
The diacetyl oxide that described different fluoro-containing groups replace is trifluoroacetic anhydride, difluoroacetic acid acid anhydride or single gifblaar poison acid anhydride;
The paranitrophenylhydrazine 6 that the intermediate 5 of the 5th step: 1N replaces from the different groups of 1N obtains intermediate 7 through alcohol reflux reaction; The paranitrophenylhydrazine (6) that described different groups replace is the fluoro-4-nitrophenyl hydrazine of 4-nitrophenyl hydrazine or 2-;
The intermediate 7 of the 6th step: 1N at room temperature reacts dehydroxylation with the trifluoroacetic acid (TFA) of 2N and generates intermediate 8;
The 7th step: intermediate 8 obtains intermediate 9 through Pd/C catalytic hydrogenation;
The intermediate 9 of the 8th step: 1N reacts and generates intermediate 10 with the intermediate 3 of 1.6N under microwave condition;
The intermediate 10 of the 9th step: 1N obtains disliking intermediate 11 through carbonyl dimidazoles (CDI) cyclisation of 2N at room temperature;
The intermediate 11 of the tenth step: 1N obtains containing fluorine oxazolidine ketoamine intermediate 12 after the de-tertbutyloxycarbonyl protection of trifluoroacetic acid of 2N;
The intermediate 12 of the 11 step: 1N again with the diacetyl oxide of 2N under the triethylamine effect of 3N, finally obtain Han Fu oxazolidinone compounds 13.
The preparation method of above-mentioned Han Fu oxazolidinone compounds is applicable to the general step of all Han Fu oxazolidinone compounds.With Han Fu oxazolidinone compounds 13a(S)-N-((2-oxo-3-(4-(5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl) oxazolidine-5-yl) methyl) ethanamide be prepared as example, specifically comprise following reactions steps:
(1),intermediate (S)-tertiary butyl (3-chlorine-2-hydroxyl propyl group) t-butyl carbamate 3preparation
In 100ml round-bottomed flask, add successively 13.89g (131.2mmol) phenyl aldehyde, 35ml ethanol, 13.62g mass percent concentration is 25% ammoniacal liquor (200.8mmol), under room temperature, stir, more slowly drip 11.79g (the S)-epoxy chloropropane of (127.7mmol) 1, 35-40 DEG C is stirred 6h, and 18-25 DEG C is stirred 14h, be spin-dried for solvent, add toluene 15ml, then add aqueous hydrochloric acid and 18ml water that people 19.10g mass percent concentration is 37%, 35-45 DEG C is stirred 3h, and point water-yielding stratum is concentrated, ethyl alcohol recrystallization, insert refrigerator crystallisation by cooling, next day, suction filtration, washed, dry, obtain 13.98g white crystalline solid 2the i.e. chloro-2-propylate of (S)-1-amino-3-hydrochlorate ;
Claim 4.70g (32mmol) white crystalline solid 2the i.e. chloro-2-propylate of (S)-1-amino-3-hydrochlorate, adds 35ml methylene dichloride and 9.71g triethylamine (96mmol), slowly drips i.e. (Boc) of 13.97g (64mmol) two dimethyl dicarbonate butyl esters under ice bath 2o, after dropwising, normal-temperature reaction is spent the night, and is spin-dried for solvent, carries out post separate to obtain i.e. (S)-tertiary butyl (the 3-chlorine-2-hydroxyl propyl group) t-butyl carbamate of the transparent thick liquid of 6.42g by sherwood oil and ethyl acetate 3,it is with respect to (S)-epoxy chloropropane 1reaction yield 95.60%;
(2),intermediate 5ai.e. (E)-4-oxyethyl group-1, the preparation of the fluoro-3-alkene-2-of 1,1-tri-ketone
In 100ml round-bottomed flask, add 1.73g (22mmol) ethyl vinyl ether 4a, with the dissolving of 35ml methylene dichloride, and add 1.58g (20mmol) pyridine, under cryosel is bathed, slowly drip 4.20g (20mmol) trifluoroacetic anhydride, after dropwising, react 3h at 0 DEG C, remove ice bath, normal-temperature reaction 12h, after completion of the reaction, adds saturated NaHCO 3solution 35ml stirs 10 minutes, separates organic layer, and water layer dichloromethane extraction merges organic layer, uses anhydrous Na 2sO 4dry, be spin-dried for solvent and obtain 3.21g yellow transparent liquid-intermediate 5ai.e. (E)-4-oxyethyl group-1, the fluoro-3-alkene-2-of 1,1-tri-ketone, it is with respect to ethyl vinyl ether 4ayield be 95.50%;
(3),4-(5-(Trifluoromethyl-1 H-pyrazol-1-yl) aniline 9apreparation
In 100ml round-bottomed flask, get the intermediate of the above-mentioned gained of 3.21g (19.1mmol) 5a, use 35ml dissolve with ethanol, and add 2.92g (19mmol) 4-nitrophenyl hydrazine 6a, be heated to the 20h that refluxes, be spin-dried for ethanol, add ethyl acetate and water, extract 3 times, merge organic layer, be spin-dried for solvent, obtain intermediate 7abe 1-(4-nitrophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-5-pyrazoles alcohol, is directly used in the next step;
Get 4.70g (17.1mmol) intermediate 7a1-(4-nitrophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-5-pyrazoles alcohol, dissolve with 35ml methylene dichloride, add 3.90g (34.2mmol) trifluoroacetic acid, stirring at normal temperature is spent the night, add saturated aqueous common salt extraction, merge organic layer, be spin-dried for solvent, carry out post by sherwood oil and ethyl acetate and separate to such an extent that 4.10 g brown color solid-intermediate 8a are 1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-pyrazoles, it is with respect to intermediate 7ayield be 93.40%.
In 100ml round-bottomed flask, get 4.10g (16mmol) intermediate 8ait is 1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-pyrazoles, use 35ml dissolve with methanol, take the Pd/C that 0.45 g mass percent is 5% and add round-bottomed flask, fill hydrogen exchange 3 times, stirring at normal temperature reaction 4h, suction filtration, methanol wash, be spin-dried for filtrate, carry out post by sherwood oil and ethyl acetate and separate to obtain 3.55g brown color liquid-intermediate 9abe 4-(5-(trifluoromethyl)-1H-pyrazol-1-yl) aniline, it is with respect to intermediate 8ayield be 97.60%;
(4),(S)-tertiary butyl (2-methyl-3-((4-(5-(Trifluoromethyl-1 H-pyrazol-1-yl) phenyl) amino) propyl group) t-butyl carbamate 10apreparation
In tube sealing, get the intermediate of the above-mentioned gained of 2.84g (11mmol) 9abe 4-(5-(trifluoromethyl)-1H-pyrazol-1-yl) aniline, and 3.79g (18mmol) (S)-tertiary butyl (3-chlorine-2-hydroxyl propyl group) t-butyl carbamate 3, temperature is arranged on 150 DEG C, and reaction is spent the night, and finishes reaction, and the reaction solution of gained carries out post by sherwood oil and ethyl acetate and separates to obtain 3.79g intermediate 10a(2-methyl-3-((4-(5-(Trifluoromethyl-1 H-pyrazol-1-yl) phenyl) amino) propyl group) t-butyl carbamate, it is with respect to intermediate for (S)-tertiary butyl 9aproductive rate be 86.30%.
(5),(S)-5-(amino methyl)-3-(4-(5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl) oxazolidine-2-ketone ( 12a) preparation
In 100ml round-bottomed flask, get the intermediate of the above-mentioned gained of 3.19g (8mmol) 10ai.e. (S)-tertiary butyl (2-methyl-3-((4-(5-(Trifluoromethyl-1 H-pyrazol-1-yl) phenyl) amino) propyl group) t-butyl carbamate, after dissolving with 30ml tetrahydrofuran (THF), add 1.62g (16mmol) triethylamine, and 2.59g (16mmol) carbonyl dimidazoles, normal-temperature reaction is spent the night, be spin-dried for solvent, ethyl acetate extraction, merge organic layer, be spin-dried for solvent, carry out post by sherwood oil and ethyl acetate and separate to obtain intermediate 11a2.91g, yield: 85.32%.
In 100ml round-bottomed flask, get the above-mentioned intermediate of 2.56g (6mmol) 11a, with the dissolving of 35ml methylene dichloride, adding 1.37g (12mmol) trifluoroacetic acid, stirring at normal temperature is spent the night, and is spin-dried for solvent and obtains intermediate 12a, be directly used in the next step;
(6),(S)-N-((2-oxo-3-(4-(5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl) oxazolidine-5-yl) methyl) ethanamide ( 13a) preparation
In 100ml round-bottomed flask, get (6mmol) above-mentioned intermediate 12adissolve with 35ml methylene dichloride, add 1.82g (18mmol) triethylamine, add 1.23g (12mmol) diacetyl oxide, stirring at normal temperature, spends the night again, with dichloromethane extraction 3 times, merge organic layer, be spin-dried for solvent, carry out post by sherwood oil and ethyl acetate and separate to obtain 1.89g faint yellow solid 13ai.e. (S)-N-((2-oxo-3-(4-(5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl) oxazolidine-5-yl) methyl) ethanamide, yield: 85.49%.
Above-mentioned a kind of Han Fu oxazolidinone compounds has good restraining effect to watermelon anthrax and gray mold of cucumber, therefore can be used for disinfectant use in agriculture.As disinfectant use in agriculture, watermelon anthrax bacteria or botrytis cinerea pers are carried out to sterilization by a kind of Han Fu oxazolidinone compounds of the present invention.
Useful technique effect of the present invention
A kind of fluorine-containing oxazolidinone compounds of the present invention, has different fluoro-containing groups, comprises trifluoromethyl, difluoro methylene, fluorine atom etc., and compared with Xian You oxazolidinone compounds, structure has novelty.The invention provides the preparation method of Han Fu oxazolidinone compounds, compared with the preparation method of Xian You oxazolidinone compounds, preparing intermediate 10time standby microwave method react, greatly shortened the reaction times, improved reaction yield.Meanwhile, be different from Xian You oxazolidinone compounds and be applied to the screening of medical fungicidal activity, this series compound has carried out the screening ， Shi oxazolidinone compounds first Application of agricultural bactericidal activity in the report of disinfectant use in agriculture exploitation.
A kind of fluorine-containing oxazolidinone compounds of the present invention, experimental result shows that it has good restraining effect to watermelon anthrax and gray mold of cucumber, therefore, fluorine-containing oxazolidinone compounds of the present invention can be used for agricultural bactericide.
Embodiment
Below by specific embodiment, the present invention is further elaborated, and its object is only better to understand content of the present invention.Therefore, protection scope of the present invention is not limited by the cases cited.
In various embodiments of the present invention, detect model and manufacturer's information of instrument used:
High resolution mass spectrum is measured by MicroMass GCT CA055 mass spectrograph, EI source;
1h NMR, 13c NMR is by Brucker AM-400(400MHz, 100MHz) nmr determination (TMS is interior mark);
19f NMR is by Brucker AM-400(376MHz) nmr determination;
Fusing point is measured by B ü chi Melting Point B-540 melting point apparatus, does not proofread and correct.
embodiment 1
A fluorine-containing oxazolidinone compounds, its structural formula is as follows:
Wherein, R 1for H, R 2for H;
R 3, R 4, R 5, R 6be respectively H;
R ffor trifluoromethyl.
The preparation method of above-mentioned a kind of Han Fu oxazolidinone compounds, specifically comprises the steps:
(1), (S)-tertiary butyl (3-chlorine-2-hydroxyl propyl group) t-butyl carbamate 3preparation
In 100ml round-bottomed flask, add successively 13.89g (131.2mmol) phenyl aldehyde, 35ml ethanol, 13.62g mass percent concentration is 25% ammoniacal liquor (200.8mmol), under room temperature, stir, more slowly drip 11.79g (the S)-epoxy chloropropane of (127.7mmol) 1, 35-40 DEG C is stirred 6h, and 18-25 DEG C is stirred 14h, be spin-dried for solvent, add toluene 15ml, then add aqueous hydrochloric acid and 18ml water that people 19.10g mass percent concentration is 37%, 35-45 DEG C is stirred 3h, and point water-yielding stratum is concentrated, ethyl alcohol recrystallization, insert refrigerator crystallisation by cooling, next day, suction filtration, washed, dry, obtain 13.98g white crystalline solid 2the i.e. chloro-2-propylate of (S)-1-amino-3-hydrochlorate ;
Claim 4.70g (32mmol) white crystalline solid 2the i.e. chloro-2-propylate of (S)-1-amino-3-hydrochlorate, adds 35ml methylene dichloride and 9.71g triethylamine (96mmol), slowly drips 13.97g (64mmol) two dimethyl dicarbonate butyl esters (Boc) under ice bath 2o, after dropwising, normal-temperature reaction is spent the night, and is spin-dried for solvent, carries out post separate to obtain i.e. (S)-tertiary butyl (the 3-chlorine-2-hydroxyl propyl group) t-butyl carbamate of the transparent thick liquid of 6.42g by sherwood oil and ethyl acetate 3,it is with respect to (S)-epoxy chloropropane 1reaction yield 95.60%;
The transparent thick liquid warp of above-mentioned gained 1h magnetic resonance detection and high resolution mass spectrum detect, and its data are as follows respectively:
1H-NMR(CDCl 3, 400MHz): δ3.85-3.83 (m, 1H), 3.60 (dd, J=5Hz, 1H), 3.50 (dd, J=5Hz, 1H), 3.26 (dd, J=5Hz, 1H), 3.14 (dd, J=5Hz, 1H), 1.46 (s, 1H).
HR-MS: measured value is 209.0814; Theoretical value is 209.0819.
Above-mentioned 1the data results that H magnetic resonance detection and high resolution mass spectrum detect shows, the transparent thick liquid of above-mentioned gained is (S)-tertiary butyl (3-chlorine-2-hydroxyl propyl group) t-butyl carbamate 3;
(2),intermediate 5ai.e. (E)-4-oxyethyl group-1, the preparation of the fluoro-3-alkene-2-of 1,1-tri-ketone
In 100ml round-bottomed flask, add 1.73g (22mmol) ethyl vinyl ether 4a, with the dissolving of 35ml methylene dichloride, and add 1.58g (20mmol) pyridine, under cryosel is bathed, slowly drip 4.20g (20mmol) trifluoroacetic anhydride, after dropwising, react 3h at 0 DEG C, remove ice bath, normal-temperature reaction 12h, after completion of the reaction, adds the saturated NaHCO of 35ml 3solution stirring 10 minutes, separates organic layer, and water layer dichloromethane extraction merges organic layer, uses anhydrous Na 2SO 4dry, be spin-dried for solvent and obtain 3.21g yellow transparent liquid-intermediate 5ai.e. (E)-4-oxyethyl group-1, the fluoro-3-alkene-2-of 1,1-tri-ketone, it is with respect to ethyl vinyl ether 4ayield be 95.50%;
Yellow transparent liquid-the intermediate of above-mentioned gained 5awarp 1h magnetic resonance detection, 19f magnetic resonance detection and high resolution mass spectrum detect, and its data are as follows respectively:
1H-NMR(CDCl 3, 400MHz): δ7.86 (d, 1H), 5.83 (d, 1H), 4.12 (d, 2H), 1.39 (t, 3H).
19F NMR (CDCl 3, 376MHz): δ-73.8 (s, 3F).
HR-MS: measured value is 168.0399; Theoretical value is 168.0398.
From above-mentioned 1h magnetic resonance detection, 19the data results that F magnetic resonance detection and high resolution mass spectrum detect can be found out, the yellow transparent liquid-intermediate of above-mentioned gained 5afor (E)-4-oxyethyl group-1, the fluoro-3-alkene-2-of 1,1-tri-ketone;
(3),4-(5-(Trifluoromethyl-1 H-pyrazol-1-yl) aniline 9apreparation
In 100ml round-bottomed flask, get the intermediate of the above-mentioned gained of 3.21g (19.1mmol) 5a, use 35ml dissolve with ethanol, and add 2.92g (19mmol) 4-nitrophenyl hydrazine 6a, be heated to the 20h that refluxes, be spin-dried for ethanol, add ethyl acetate and water, extract 3 times, merge organic layer, be spin-dried for solvent, obtain intermediate 7abe 1-(4-nitrophenyl)-5-(trifluoromethyl)-4,5-dihydro-1H-5-pyrazoles alcohol, is directly used in the next step;
Get 4.70g (17.1mmol) intermediate 7adissolve with 35ml methylene dichloride, add 3.90g (34.2mmol) trifluoroacetic acid, stirring at normal temperature is spent the night, add saturated aqueous common salt extraction, merge organic layer, be spin-dried for solvent, carry out post by sherwood oil and ethyl acetate and separate to such an extent that 4.10 g brown color solid-intermediate 8a are 1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-pyrazoles, it is with respect to intermediate 7ayield be 93.40%.
Yellow solid-the intermediate of above-mentioned gained 8awarp 1h magnetic resonance detection, 19f magnetic resonance detection and high resolution mass spectrum detect, and its data are as follows respectively:
1H-NMR(CDCl 3, 400MHz): δ8.14 (m, 2H), 7.61 (m, J=5Hz, 1H), 7.35 (m, 2H), 6.37 (m, 1H).
19F NMR (CDCl 3, 376MHz): δ-62.8 (s, 3F).
HR-MS: measured value is 257.0416; Theoretical value is 257.0412.
From above-mentioned 1h magnetic resonance detection, 19the data results that F magnetic resonance detection and high resolution mass spectrum detect can be found out, the yellow transparent solid-intermediate of above-mentioned gained 8afor 1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-pyrazoles;
In 100ml round-bottomed flask, get 4.10g (16mmol) intermediate 8a, use 35ml dissolve with methanol, take 0.45g mass percent and be 5% Pd/C and add round-bottomed flask, fill hydrogen exchange 3 times, stirring at normal temperature reaction 4h, suction filtration, methanol wash, is spin-dried for filtrate, carries out post separate to obtain 3.55g brown color liquid-intermediate by sherwood oil and ethyl acetate 9abe 4-(5-(trifluoromethyl)-1H-pyrazol-1-yl) aniline, it is with respect to intermediate 8ayield be 97.60%.
Brown color liquid-the intermediate of above-mentioned gained 9awarp 1h magnetic resonance detection, 19f magnetic resonance detection and high resolution mass spectrum detect, and its data are as follows respectively:
1H-NMR(CDCl 3, 400MHz): δ7.65 (m, 2H), 7.62 (m, J=5Hz, 1H), 6.95 (m, 2H), 6.25 (m, 1H), 3.26 (br, 2H).
19F NMR (CDCl 3, 376MHz): δ-62.3 (s, 3F) .
HR-MS: measured value is 227.0668; Theoretical value is 227.0670.
From above-mentioned 1h magnetic resonance detection, 19the data results that F magnetic resonance detection and high resolution mass spectrum detect can be found out, the brown color liquid-intermediate of above-mentioned gained 9afor 4-(5-(Trifluoromethyl-1 H-pyrazol-1-yl) aniline.
(4),(S)-tertiary butyl (2-methyl-3-((4-(5-(Trifluoromethyl-1 H-pyrazol-1-yl) phenyl) amino) propyl group) t-butyl carbamate 10apreparation
In tube sealing, add the intermediate of the above-mentioned gained of 2.84g (11mmol) 9aand 3.79g (18mmol) (S)-tertiary butyl (3-chlorine-2-hydroxyl propyl group) t-butyl carbamate 3, control temperature at 150 DEG C, reaction is spent the night, and finishes reaction, and the reaction solution of gained carries out post by sherwood oil and ethyl acetate and separates to obtain 3.79g yellow solid-intermediate 10a(2-methyl-3-((4-(5-(Trifluoromethyl-1 H-pyrazol-1-yl) phenyl) amino) propyl group) t-butyl carbamate, it is with respect to intermediate for (S)-tertiary butyl 9aproductive rate be 86.30%.
Yellow solid-the intermediate of above-mentioned gained 10awarp 1h magnetic resonance detection, 19f magnetic resonance detection and high resolution mass spectrum detect, and its data are as follows respectively:
1H-NMR(CDCl 3, 400MHz): δ7.46 (m, 1H), 7.39 (m, 2H), 6.60 (d, J=5Hz, 2H), 6.27 (d, 1H),4.07-4.19 (m, 3H), 3.80 (m, 1H), 3.34 (m, J=5Hz, 2H), 3.05 (m, J=2.6Hz, 2H), 1.59 (s, 9H).
19F NMR (CDCl 3, 376MHz): δ-63.8 (s, 3F) .
HR-MS: measured value is 400.1726; Theoretical value is 400.1722.
From above-mentioned 1h magnetic resonance detection, 19the data results that F magnetic resonance detection and high resolution mass spectrum detect can be found out, the yellow solid-intermediate of above-mentioned gained 10afor (S)-tertiary butyl (2-methyl-3-((4-(5-(Trifluoromethyl-1 H-pyrazol-1-yl) phenyl) amino) propyl group) t-butyl carbamate;
(5),(S)-5-(amino methyl)-3-(4-(5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl) oxazolidine-2-ketone 12apreparation
In 100ml round-bottomed flask, get the intermediate of the above-mentioned gained of 3.19g (8mmol) 10aafter dissolving with 30ml tetrahydrofuran (THF), add 1.62g (16mmol) triethylamine, and 2.59g (16mmol) carbonyl dimidazoles, normal-temperature reaction is spent the night, and is spin-dried for solvent, ethyl acetate extraction, merge organic layer, be spin-dried for solvent, carry out post by sherwood oil and ethyl acetate and separate to obtain 2.91g yellow solid-intermediate 11ai.e. (S)-tertiary butyl-(2-oxo-3-(4-(5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl) oxazolidine-5-yl) carbamate, yield: 85.32%.
Yellow solid-intermediate 11a warp of above-mentioned gained 1h magnetic resonance detection, 19f magnetic resonance detection and high resolution mass spectrum detect, and its data are as follows respectively:
1H-NMR(CDCl 3, 400MHz): δ7.80 (s, 1H), 7.79 (s, 2H), 7.52 (d, J=5Hz, 2H), 6.99 (s, 1H), 4.87-4.85 (m, 1H), 4.26 (t, J=5Hz, 1H), 3.93 (dd, J=5Hz, 1H), 3.61 (d, J=2.5Hz, 2H), 1.51 (s, 9H).
19F NMR (CDCl 3, 376MHz): δ-62.6 (s, 3F) .
HR-MS: measured value is 426.1514; Theoretical value is 426.1515.
From above-mentioned 1h magnetic resonance detection, 19the data results that F magnetic resonance detection and high resolution mass spectrum detect can be found out, the yellow solid-intermediate of above-mentioned gained 11afor (S)-tertiary butyl-(2-oxo-3-(4-(5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl) oxazolidine-5-yl) carbamate;
In 100ml round-bottomed flask, get the above-mentioned intermediate 11a of 2.56g (6mmol), with the dissolving of 35ml methylene dichloride, add 1.37g (12mmol) trifluoroacetic acid, stirring at normal temperature is spent the night, and is spin-dried for solvent and obtains intermediate 12a, be directly used in the next step;
(6),(S)-N-((2-oxo-3-(4-(5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl) oxazolidine-5-yl) methyl) ethanamide 13apreparation
In 100ml round-bottomed flask, get the above-mentioned intermediate of 1.96g (6mmol) 12adissolve with 35ml methylene dichloride, add 1.82g (18mmol) triethylamine, add 1.23g (12mmol) diacetyl oxide, stirring at normal temperature, spends the night again, with dichloromethane extraction 3 times, merge organic layer, be spin-dried for solvent, carry out post by sherwood oil and ethyl acetate and separate to obtain 1.89g faint yellow solid 13a, yield: 85.49%.
The faint yellow solid of above-mentioned gained 13awarp 1h magnetic resonance detection, 13c magnetic resonance detection, 19f magnetic resonance detection and high resolution mass spectrum detect, and its data are as follows respectively:
1H-NMR(CDCl 3, 400MHz): δ7.82 (s, 1H), 7.76 (s, 2H), 7.58 (d, J=5Hz, 2H), 7.01 (s, 1H), 4.89-4.86 (m, 1H), 4.25 (t, J=10Hz, 1H), 3.98 (dd, J=5Hz, 1H), 3.63 (d, J=2.6Hz, 2H), 1.99 (s, 3H).
19F NMR (CDCl 3, 376MHz): δ-62.7 (s, 3F) .
13C NMR (CDCl 3, 100MHz): δ174.9, 152.9, 138.5, 137.6, 137.1, 123.3, 121.2, 120.1, 107.8, 84.3, 47.2, 43.0, 24.3.
HR-MS: measured value is 368.1094; Theoretical value is 368.1096.
From above-mentioned 1h magnetic resonance detection, 13c magnetic resonance detection, 19the data results that F magnetic resonance detection and high resolution mass spectrum detect can be found out, the faint yellow solid of above-mentioned gained 13afor (S)-N-((2-oxo-3-(4-(5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl) oxazolidine-5-yl) methyl) ethanamide.
embodiment 2
A fluorine-containing oxazolidinone compounds, its structural formula is as follows:
Wherein, R 1, R 2independently be respectively methyl, H;
R 3, R 4, R 5, R 6independently be respectively H, H, H, H;
R ffor trifluoromethyl.
Above-mentioned a kind of Han Fu oxazolidinone compounds, i.e. (S)-N-((3-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide 13b, its structural formula is as follows:
Above-mentioned a kind of Han Fu oxazolidinone compounds, i.e. (S)-N-((3-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide 13b'spreparation method, with embodiment 1, is by step (2), ethyl vinyl ether 4areplace with 2-ethoxy propylene, the other the same as in Example 1, the final 1.91g faint yellow solid that obtains, its yield with respect to raw material 2-ethoxy propylene is 45.41%.
The faint yellow solid warp of above-mentioned gained 1h magnetic resonance detection, 13c magnetic resonance detection, 19f magnetic resonance detection and high resolution mass spectrum detect, and its data are as follows respectively:
1H NMR(CDCl 3, 400MHz): δ7.78 (d, J=5Hz, 2H), 7.50 (d, J=5Hz, 2H), 6.79 (s, 1H), 4.89-4.85 (m,1H), 4.25 (t, J=10Hz,1H), 3.92 (dd, J=5Hz, 1H), 3.61 (d, J=2.6Hz, 2H), 2.36 (s, 3H), 1.99 (s, 3H).
13C NMR (CDCl 3, 100MHz): δ174.7, 152.9, 146.5, 137.6, 136.1, 135.2,123.1, 122.2, 120.1, 107.9, 84.3, 48.7, 42.3, 23.3.
19F NMR (CDCl 3, 376MHz): δ-62.4 (s, 3F) .
HR-MS: measured value is 382.125; Theoretical value is 382.1253.
From above-mentioned 1h magnetic resonance detection, 13c magnetic resonance detection, 19the data results that F magnetic resonance detection and high resolution mass spectrum detect can find out, the faint yellow solid of above-mentioned gained is (S)-N-((3-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide.
embodiment 3
A fluorine-containing oxazolidinone compounds, its structural formula is as follows:
Wherein, R 1, R 2independently be respectively H, H;
R 3, R 4, R 5, R 6independently be respectively F, H, H, H;
R ffor trifluoromethyl.
Above-mentioned a kind of Han Fu oxazolidinone compounds, i.e. (S)-N-((3-(the fluoro-4-of 3-(5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide 13c, its structural formula is as follows:
Above-mentioned a kind of Han Fu oxazolidinone compounds, i.e. (S)-N-((3-(the fluoro-4-of 3-(5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide 13cpreparation method with embodiment 1, just by 4-nitrophenyl hydrazine in step (3) 6areplace with the fluoro-4-nitrophenyl hydrazine of 2-, the other the same as in Example 1, obtains 1.87g faint yellow solid, and its yield with respect to raw material ethyl vinyl ether is 42.60%.
The faint yellow solid warp of above-mentioned gained 1h magnetic resonance detection, 13c magnetic resonance detection, 19f magnetic resonance detection and high resolution mass spectrum detect, and its data are as follows respectively:
1H-NMR(CDCl3, 400MHz): δ7.82 (s, 1H), 7.69 (t, J=2.6Hz, 1H), 7.60 (s, 1H), 7.53 (d, J=2.6Hz,2H), 6.97 (s, 1H), 4.89-4.86 (m, 1H), 4.25 (t, J=10Hz, 1H), 3.98 (dd, J=5Hz, 1H), 3.63(d, J=2.6Hz,2H)，1.99 (s, 3H).
13C NMR (CDCl 3, 100MHz): δ174.5, 156.7, 153.5, 137.6, 137.1, 135.2,123.1, 122.2, 120.1, 117.9, 110.4,107.1,84.3, 48.7, 45.3, 24.3.
19F NMR (CDCl 3, 376MHz): δ-62.7 (s, 3F), -121.2 (s, 1F).
HR-MS: measured value is 386.1006; Theoretical value is 386.1002.
From above-mentioned 1h magnetic resonance detection, 13c magnetic resonance detection, 19the data results that F magnetic resonance detection and high resolution mass spectrum detect can find out, the faint yellow solid of above-mentioned gained is (S)-N-((3-(the fluoro-4-of 3-(5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide.
embodiment 4
A fluorine-containing oxazolidinone compounds, its structural formula is as follows:
Wherein, R 1, R 2independently be respectively methyl, H;
R 3, R 4, R 5, R 6independently be respectively F, H, H, H;
R ffor trifluoromethyl.
Above-mentioned a kind of Han Fu oxazolidinone compounds, i.e. (S)-N-((3-(the fluoro-4-of 3-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide 13d, its structural formula is as follows:
Above-mentioned a kind of Han Fu oxazolidinone compounds, i.e. (S)-N-((3-(the fluoro-4-of 3-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide 13dpreparation method with embodiment 2, just by 4-nitrophenyl hydrazine in step (3) 6areplace with the fluoro-4-nitrophenyl hydrazine of 2-, the other the same as in Example 2, obtains 1.92g off-white color solid, and its yield with respect to raw material 2-ethoxy propylene is 45.02%.
The faint yellow solid warp of above-mentioned gained 1h magnetic resonance detection, 13c magnetic resonance detection, 19f magnetic resonance detection and high resolution mass spectrum detect, and its data are as follows respectively:
1H-NMR(CDCl 3, 400MHz): δ7.75 (t, J=2.6Hz, 1H), 7.69 (s, 1H), 7.53 (d, J=2.6Hz, 1H), 6.78 (s,1H), 4.91-4.86 (m, 1H), 4.23 (t, J=10Hz, 1H), 3.95 (dd, J=5Hz, 1H), 3.64 (d, , J=2.6Hz, 2H)，2.36 (s, 3H), 1.96 (s, 3H).
13C NMR (CDCl 3, 100MHz): δ174.8, 156.6, 153.5, 148.6, 139.1, 138.2,129.1, 122.2, 120.1, 117.9, 110.4, 107.1, 84.3, 48.7, 47.3, 25.3, 13.6.
19F NMR (CDCl 3, 376MHz): δ-63.9 (s, 3F), -121.2 (s, 1F).
HR-MS: measured value is 400.1156; Theoretical value is 400.1159.
From above-mentioned 1h magnetic resonance detection, 13c magnetic resonance detection, 19the data results that F magnetic resonance detection and high resolution mass spectrum detect can find out, the faint yellow solid of above-mentioned gained is (S)-N-((3-(the fluoro-4-of 3-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide.
embodiment 5
A fluorine-containing oxazolidinone compounds, its structural formula is as follows:
Wherein, R 1, R 2independently be respectively H, H;
R 3, R 4, R 5, R 6independently be respectively H, H, H, H;
R ffor difluoromethyl.
Above-mentioned a kind of Han Fu oxazolidinone compounds, i.e. (S)-N-((3-(4-(5-(difluoromethyl)-1H-pyrazol-1-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide 13e, its structural formula is as follows:
Above-mentioned a kind of Han Fu oxazolidinone compounds, i.e. (S)-N-((3-(4-(5-(difluoromethyl)-1H-pyrazol-1-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide 13epreparation method with embodiment 1, just trifluoroacetic anhydride in step (2) is replaced with to difluoroacetic acid acid anhydride, the other the same as in Example 1, obtains 1.72g faint yellow solid, its yield with respect to raw material ethyl vinyl ether is 41.09%.
The faint yellow solid warp of above-mentioned gained 1h magnetic resonance detection, 13c magnetic resonance detection, 19f magnetic resonance detection and high resolution mass spectrum detect, and its data are as follows respectively:
1H-NMR(CDCl 3, 400MHz): δ7.84 (s, 1H), 7.69 (s, 2H), 7.55 (d, J=5Hz, 2H), 7.12-7.03 (m, 1H), 7.04 (s, 1H), 4.88-4.83 (m,1H), 4.22 (t, J=10Hz, 1H), 4.01 (dd, J=5Hz, 1H), 3.64 (d, J=2.6Hz,2H),2.00 (s, 3H).
13C NMR (CDCl 3, 100MHz): δ174.3, 153.6, 139.5, 137.6, 136.1, 135.2,122.1, 120.2, 107.9, 85.3, 48.7, 42.3, 25.3.
19F NMR (CDCl 3, 376MHz): δ-112.7 (s, 2F).
HR-MS: measured value is 350.1194; Theoretical value is 350.1190.
From above-mentioned 1h magnetic resonance detection, 13c magnetic resonance detection, 19the data results that F magnetic resonance detection and high resolution mass spectrum detect can find out, the faint yellow solid of above-mentioned gained is (S)-N-((3-(4-(5-(difluoromethyl)-1H-pyrazol-1-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide.
embodiment 6
A fluorine-containing oxazolidinone compounds, its structural formula is as follows:
Wherein, R 1, R 2independently be respectively methyl, H;
R 3, R 4, R 5, R 6independently be respectively H, H, H, H;
R ffor difluoromethyl.
Above-mentioned one is containing fluorine oxazolidinone compounds, i.e. (S)-N-((3-(4-(5-(difluoromethyl)-3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide 13f, its structural formula is as follows:
。
Above-mentioned one is containing fluorine oxazolidinone compounds, i.e. (S)-N-((3-(4-(5-(difluoromethyl)-3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide 13f'spreparation method is with embodiment 5, just by step (2) medium vinyl ether 4areplace with 2-ethoxy propylene, the other the same as in Example 5, the final 1.69g off-white color solid that obtains, its yield with respect to raw material 2-ethoxy propylene is 40.05%.
The off-white color solid warp of above-mentioned gained 1h magnetic resonance detection, 13c magnetic resonance detection, 19f magnetic resonance detection and high resolution mass spectrum detect, and its data are as follows respectively:
1H-NMR(CDCl 3, 400MHz): δ7.81 (d, J=5Hz, 2H), 7.54 (d, J=5Hz, 2H), 7.08-7.01 (m, 1H), 6.79 (s, 1H), 4.90-4.86 (m, 1H), 4.24 (t, J=10Hz,1 H), 3.94 (dd, J=5Hz, 1H), 3.62 (d, J=2.6Hz, 2H), 2.35 (s, 3H), 1.97 (s, 3H).
13C NMR (CDCl 3,100MHz): δ174.2, 153.6, 148.5, 139.6, 136.1, 135.2, 122.1, 120.2, 111.9, 107.6,84.7, 48.5, 42.3, 23.8,13.6.
19F NMR (CDCl 3,376MHz): δ-113.9 (s, 2F).
HR-MS: measured value is 364.1346; Theoretical value is 364.1347.
From above-mentioned 1h magnetic resonance detection, 13c magnetic resonance detection, 19the data results that F magnetic resonance detection and high resolution mass spectrum detect can find out, the off-white color solid of above-mentioned gained is (S)-N-((3-(4-(5-(difluoromethyl)-3-methyl isophthalic acid H-pyrazol-1-yl) phenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide.
embodiment 7
A fluorine-containing oxazolidinone compounds, its structural formula is as follows:
Wherein, R 1, R 2independently be respectively H, H;
R 3, R 4, R 5, R 6independently be respectively F, H, H, H;
R ffor difluoromethyl.
Above-mentioned a kind of Han Fu oxazolidinone compounds, i.e. (S)-N-((3-(4-(5-(difluoromethyl)-1H-pyrazol-1-yl)-3-fluorophenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide 13g, its structural formula is as follows:
Above-mentioned a kind of Han Fu oxazolidinone compounds, i.e. (S)-N-((3-(4-(5-(difluoromethyl)-1H-pyrazol-1-yl)-3-fluorophenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide 13gpreparation method with embodiment 5, just by 4-nitrophenyl hydrazine in step (3) 6areplace with the fluoro-4-nitrophenyl hydrazine of 2-, the other the same as in Example 5, final 1, the 76g faint yellow solid that obtains, its yield with respect to raw material ethyl vinyl ether is 43.64%.
The faint yellow solid warp of above-mentioned gained 1h magnetic resonance detection, 13c magnetic resonance detection, 19f magnetic resonance detection and high resolution mass spectrum detect, and its data are as follows respectively:
1H-NMR(CDCl 3, 400MHz): δ7.84 (s, 1H), 7.71 (t, J=2.6Hz, 1H), 7.63 (s, 1H), 7.51 (d, J=2.6Hz, 1H), 7.15-7.08 (m, 1H), 6.92 (s, 1H), 4.89-4.86 (m, 1H), 4.24 (t, J=10Hz, 1H), 3.98 (dd, J=5Hz, 1H), 3.63 (d, J=2.6Hz, 2H), 1.99 (s, 3H).
13C NMR(CDCl 3, 100MHz): δ174.3, 156.6, 153.1,139.5, 138.6, 137.1, 123.5, 121.1, 117.2, 110.9, 110.7, 107.6,84.4, 48.7, 42.3, 23.8.
19F NMR (CDCl 3, 376MHz): δ-115.4 (s, 2F), -117.2 (s, 1F).
HR-MS: measured value is 368.1097; Theoretical value is 368.1096.
From above-mentioned 1h magnetic resonance detection, 13c magnetic resonance detection, 19the data results that F magnetic resonance detection and high resolution mass spectrum detect can find out, the faint yellow solid of above-mentioned gained is (S)-N-((3-(4-(5-(difluoromethyl)-1H-pyrazol-1-yl)-3-fluorophenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide.
embodiment 8
A fluorine-containing oxazolidinone compounds, its structural formula is as follows:
Wherein, R 1, R 2independently be respectively methyl, H;
R 3, R 4, R 5, R 6independently be respectively F, H, H, H;
R ffor difluoromethyl.
Above-mentioned a kind of Han Fu oxazolidinone compounds, i.e. (S)-N-((3-(4-(5-(difluoromethyl)-3-methyl isophthalic acid H-pyrazol-1-yl)-3-fluorophenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide 13h, its structural formula is as follows:
Above-mentioned a kind of Han Fu oxazolidinone compounds, i.e. (S)-N-((3-(4-(5-(difluoromethyl)-3-methyl isophthalic acid H-pyrazol-1-yl)-3-fluorophenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide 13h'spreparation method is with embodiment 6, just by wherein ethyl vinyl ether of step (2) 4areplace with 2-ethoxy propylene, other is with embodiment 6, final 1.77g faint yellow solid, and its yield with respect to raw material 2-ethoxy propylene is 42.29%.
The faint yellow solid warp of above-mentioned gained 1h magnetic resonance detection, 13c magnetic resonance detection, 19f magnetic resonance detection and high resolution mass spectrum detect, and its data are as follows respectively:
1H-NMR(CDCl 3, 400MHz): δ7.74 (t, J=2.6Hz, 1H), 7.68 (s, 1H), 7.53 (d, J=2.6Hz, 1H), 7.19-7.10 (m, 1H), 6.80 (s, 1H), 4.89-4.84 (m, 1H), 4.26 (t, J=10Hz, 1H), 3.94 (dd, J=5Hz, 1H), 3.64(d, J=2.6Hz, 2H), 2.36 (s, 3H), 1.97 (s, 3H).
13C NMR(CDCl 3, 100MHz): δ175.2, 156.3, 153.1, 148.5, 139.6, 137.9, 123.5, 121.1, 117.2, 110.9, 110.7, 107.6, 84.9, 49.7, 42.5, 23.4, 13.2.
19F NMR (CDCl 3, 376MHz): δ-117.6 (s, 2F), -121.4 (s, 1F).
HR-MS: measured value is 382.1257; Theoretical value is 382.1253.
From above-mentioned 1h magnetic resonance detection, 13c magnetic resonance detection, 19the data results that F magnetic resonance detection and high resolution mass spectrum detect can find out, the faint yellow solid of above-mentioned gained is (S)-N-((3-(4-(5-(difluoromethyl)-3-methyl isophthalic acid H-pyrazol-1-yl)-3-fluorophenyl)-2-oxo oxazolidine-5-yl) methyl) ethanamide.
application Example 1
8 kinds of Han Fu oxazolidinone compounds of embodiment 1-8 gained are tested the indoor inhibition activity of cotton standing dead, Phytophthora capsici, tomato late blight, apple wheel line, watermelon anthrax and cucumber grey mold six kind of plant pathogenic bacteria mycelial growth rates, with the former medicine of Azoxystrobin in contrast, concrete steps are as follows:
(1), test materials
Tested target:
A. cotton standing dead disease pathogen Rhizoctonia solani K ü hn. belongs to Deuteromycotina fungi, and without born of the same parents' order, silk core belongs to, dry thread Pyrenomycetes.The Ministry of Agriculture of Plant Protection institute, Chinese Academy of Agricultral Sciences chemistry of pesticide separates with utilisation technology emphasis open laboratory preserves bacterial classification.
B. Phytophthora capsici disease pathogen Phytophthora capsici Leon, Mastigomycotina, Peronosporales, phytophthora, Phytophthora capsici.The Ministry of Agriculture of Plant Protection institute, Chinese Academy of Agricultral Sciences chemistry of pesticide separates with utilisation technology emphasis open laboratory preserves bacterial classification.
C. tomato late blight cause of disease Phytophthora infestans (Mont.) de Bary belongs to fungi Mastigomycotina, Peronosporales, phytophthora, phytophthora infestans.The Ministry of Agriculture of Plant Protection institute, Chinese Academy of Agricultral Sciences chemistry of pesticide separates with utilisation technology emphasis open laboratory preserves bacterial classification.
D. ring rot of apple cause of disease Botryosphaeria dothidea (Moug. Ex Fr) Ces.et de Not. belongs to fungi Ascomycotina, lattice spore chamber Zoopagales, Botryosphaeria.Plant Protection institute, Chinese Academy of Agricultral Sciences's pesticides application process innovation is learned component from preserving bacterial classification.
E. watermelon anthrax cause of disease Colletotrichum orbiculare (Berk.et Mont.) Arx, belongs to Deuteromycotina, Melanconiales, colletotrichum, melon anthrax-bacilus.The Ministry of Agriculture of Plant Protection institute, Chinese Academy of Agricultral Sciences chemistry of pesticide separates with utilisation technology emphasis open laboratory preserves bacterial classification.
F. gray mold of cucumber cause of disease Botrytis cinerea Pers., belongs to Deuteromycotina, hyphomycetales, Staphlosporonites, Botrytis cinerea.The Plant Protection Institute Ministry of Agriculture of Academy of Agricultural Sciences of state chemistry of pesticide separates with utilisation technology emphasis open laboratory preserves bacterial classification.
Tested new compound: the compound of preparing by above-mentioned case method 13a-13l, the former medicine of 93% Azoxystrobin (Syngenta Co., Ltd of Britain)
(2), test method
This test, according to People's Republic of China's agricultural industry criteria (NY/T 1156.2-2006), adopts mycelial growth rate method to measure.
By cultured various pathogenic bacterias, under aseptic technique, with the sterilizing punch tool of diameter 7 mm, cut bacterium cake from colony edge, with inoculator, pure culture biscuits involvng inoculation is dull and stereotyped central in pastille, mycelia faces down, and covers ware lid, is placed in 25 DEG C of incubators and cultivates.
(3), working method
The preparation of mother liquor: take respectively 8 new compound 50 ± 2 mg of embodiment 1-8 gained with ten thousand/electronic balance, dissolve with 5mL DMF the mother liquor that is prepared into 10000 μ g/mL respectively.Take the former medicinal 5mL DMF of 53.8mg Azoxystrobin and dissolve the mother liquor that is prepared into 10000 μ g/mL.
The setting of concentration, under aseptic technique, is diluted to the 10000 μ g/mL mother liquor substratum that prepare the toxic culture medium flat plate of 50 μ g/mL, and the not blank containing chemicals treatment is established in test, and each processing repeated 3 times.
(4), experimental result
8 Han Fu oxazolidinone compounds of the present invention 13a-13hunder 50 μ g/mL concentration, the measurement result of six kind of plant pathogenic bacteria mycelial growth rates inhibition situations is shown in table 1.
As can be seen from Table 1, this toxicity measurement result shows, the Han Fu oxazolidinone compounds in the present invention 13a-13hinhibition to cotton standing dead, Phytophthora capsici, tomato late blight and apple wheel line bacterium is active general, and particularly the inhibition of botrytis cinerea pers is active better to watermelon anthrax, botrytis cinerea pers, the disinfectant use in agriculture that therefore the Han Fu oxazolidinone compounds in the present invention can be used as watermelon anthrax, botrytis cinerea pers uses.
Foregoing is only the basic explanation of the present invention under conceiving, and according to any equivalent transformation that technical scheme of the present invention is done, all should belong to protection scope of the present invention.

Claims (5)

1. a fluorine-containing oxazolidinone compounds, is characterized in that its structural formula is as follows:
Wherein, R ffor trifluoromethyl, difluoromethyl, fluorine atom or perfluoro alkane;
R 1, R 2be independently H, C 1～C 6straight or branched alkyl, C 1～C 6straight or branched perfluoroalkyl, C 1～C 6straight or branched alkoxyl group, halogen F, Cl, Br or I, nitro, cyano group or phenyl ;
R 3, R 4, R 5, R 6be independently H, F, Cl, Br, I or C 1～C 3alkyl.
2. as claim 1 Suo Shu oxazolidinone compounds, it is characterized in that:
Described R 1, R 2be independently H, methyl, ethyl, methoxyl group, F, Cl, Br, cyano group or phenyl;
R ffor trifluoromethyl, difluoromethyl.
3. as claim 1 Suo Shu oxazolidinone compounds, it is characterized in that:
Described R 1for H or methyl;
Described R 2for H;
Described R 3for H or F;
Described R 4, R 5, R 6be H;
Described R ffor trifluoromethyl or difluoromethyl.
4. the preparation method of a kind of Han Fu oxazolidinone compounds as claimed in claim 1, is characterized in that its preparation process specifically comprises following 11 step reactions:
The first step, (S)-epoxy chloropropane of 1N ( 1)with the phenyl aldehyde of the 1N ammoniacal liquor that is 25% at the mass percent concentration of 16 N after 35-40 DEG C of stirring reaction 6h again at 18-25 DEG C stirring reaction 14h obtain the reaction solution that contains imine intermediate;
Second step, toward the hydrochloric acid that adds 1.5N in imine intermediate reaction solution that contains of above-mentioned gained, the chloro-2-propylate of reaction generation (S)-1-amino-3-hydrochlorate at 35-45 DEG C ( 2);
The chloro-2-propylate of (the S)-1-amino-3-hydrochlorate of the 3rd step: 1N ( 2)with the two dimethyl dicarbonate butyl esters of 2N at room temperature react generation (S)-tertiary butyl-(3-chlorine-2-hydroxyl propyl group) t-butyl carbamate ( 3);
The alkene ether of the 4th step: 1.1N ( 4)the diacetyl oxide replacing from the different fluoro-containing groups of 1N under the pyridine effect of 1N, in dichloromethane solvent successively after 0 DEG C of reaction 3h, control at 25 DEG C of normal temperature, react 12h generate intermediate ( 5);
The diacetyl oxide that described different fluoro-containing groups replace is trifluoroacetic anhydride, difluoroacetic acid acid anhydride or single gifblaar poison acid anhydride;
The intermediate of the 5th step: 1N ( 5)the paranitrophenylhydrazine that replaces from the different groups of 1N ( 6)through alcohol reflux reaction obtain intermediate ( 7);
Paranitrophenylhydrazine that described different groups replace ( 6) bethe fluoro-4-nitrophenyl hydrazine of 4-nitrophenyl hydrazine or 2-;
The intermediate of the 6th step: 1N ( 7) with the trifluoroacetic acid of 2N at room temperature react dehydroxylation generate intermediate ( 8);
The 7th step: intermediate ( 8)through Pd/C catalytic hydrogenation obtain intermediate ( 9);
The intermediate of the 8th step: 1N ( 9)with the intermediate of 1.6N ( 3)reaction generation intermediate under microwave condition ( 10);
The intermediate of the 9th step: 1N ( 10)at room temperature through the carbonyl dimidazoles cyclisation of 2N obtain intermediate ( 11);
The tenth step; The intermediate of 1N ( 11)after the de-tertbutyloxycarbonyl protection of the trifluoroacetic acid of 2N, obtain containing fluorine oxazolidine ketoamine intermediate ( 12) ;
The intermediate (12) of the 11 step: 1N again with the diacetyl oxide of 2N under the triethylamine effect of 3N, finally obtain Han Fu oxazolidinone compounds ( 13).
5. a kind of fluorine-containing oxazolidinone compounds as described in claim 1,2 or 3 uses as the disinfectant use in agriculture to watermelon anthrax bacteria or botrytis cinerea pers.
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