CN103965183B - Fluorine-containingoxazolidinonecompound as well as preparation method and application thereof - Google Patents
Fluorine-containingoxazolidinonecompound as well as preparation method and application thereof Download PDFInfo
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- CN103965183B CN103965183B CN201410096495.2A CN201410096495A CN103965183B CN 103965183 B CN103965183 B CN 103965183B CN 201410096495 A CN201410096495 A CN 201410096495A CN 103965183 B CN103965183 B CN 103965183B
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- trifluoromethyl
- difluoromethyl
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- 0 CCC1C2(CC)C1CC(*C)C2 Chemical compound CCC1C2(CC)C1CC(*C)C2 0.000 description 5
- DFLQSWWWQUZULQ-HNNXBMFYSA-N CC(C)(C)OC(NC[C@@H](CN1c(cc2)ccc2-[n]2c(C(F)(F)F)ccc2)OC1=O)=O Chemical compound CC(C)(C)OC(NC[C@@H](CN1c(cc2)ccc2-[n]2c(C(F)(F)F)ccc2)OC1=O)=O DFLQSWWWQUZULQ-HNNXBMFYSA-N 0.000 description 1
- BRWBVEXFPXNDLF-XVNBXDOJSA-N CC(C)C/C(/C(F)(F)F)=C\CN Chemical compound CC(C)C/C(/C(F)(F)F)=C\CN BRWBVEXFPXNDLF-XVNBXDOJSA-N 0.000 description 1
- ISOWCHKKGIELKR-SNAWJCMRSA-N CC[O](C)/C=C/C(C(F)(F)F)=O Chemical compound CC[O](C)/C=C/C(C(F)(F)F)=O ISOWCHKKGIELKR-SNAWJCMRSA-N 0.000 description 1
- BKPVGIAXVCFLSN-UHFFFAOYSA-N Cc1ccn[n]1-c(cc1)ccc1[N+]([O-])=O Chemical compound Cc1ccn[n]1-c(cc1)ccc1[N+]([O-])=O BKPVGIAXVCFLSN-UHFFFAOYSA-N 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Nc1ccccc1 Chemical compound Nc1ccccc1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Technical field
The invention belongs to pesticide field, and in particular to a class is containing different fluoro-containing group oxazolidinone compounds and its system
Preparation Method sterilizes to watermelon anthrax bacteria or botrytis cinerea pers as disinfectant use in agriculture with which.
Background technology
Disinfectant use in agriculture has irreplaceable important function at the aspect such as pathogenic bacteria prevention and control, is agricultural foison and grain
The important guarantee of food safety.In recent years, on global agrochemical market, antibacterial selling market shows a rising trend always.But, sterilization
The resistance of agent occurs comparatively fast, and the pesticide new variety that will be listed is being researched and developed in the whole world at present, and antibacterial ranks the 1st.Therefore,
Exploitation just seems extremely important with novel mechanism, environment amenable antibacterial new varieties.
Oxazole heterocyclic compound is a kind of five-membered azole heterocycle compound of important oxygen-containing nitrogen, is particularly in multiple fields
Medicine has broad application prospects.Wherein ， oxazolidinone compounds are listed after sulfonamides and Comprecin
The complete synthesis antibacterials of another class, its mechanism of action is unique, all has extremely strong resisting gram-positive bacteria (G in vivo and in vitro+
Bacterium) activity, to there is preferable therapeutical effect, such as methicillin-resistant Staphylococcus by the microbial infection of most of Grain-positives
(MRSA), vancomycin resistance staphylococcuses, vancomycin-resistant enterococcus (VRE), Penicillin-resistant Pneumococci and anaerobe etc..Remove
Outside this, some seminars also prepare new different oxazolidinone compounds, and screen these compound anti thrombotic actions
Medicinal activity.
But up to the present, yet there are no the preparation of the fluorine-containing oxazolidinone compounds of system, and which is carried out
The report of agricultural bactericidal activity research.
The content of the invention
An object of the present invention is to provide a kind of fluorine-containing oxazolidinone compounds.
The second object of the present invention is the preparation method of a kind of fluorine-containing oxazolidinone compounds for providing above-mentioned.
The third object of the present invention is that above-mentioned a kind of fluorine-containing oxazolidinone compounds are used as disinfectant use in agriculture.
Technical scheme
A kind of fluorine-containing oxazolidinone compounds, its structural formula are as follows：
Wherein, R1、R2It is independently H, C1～C6Straight or branched alkyl, C1～C6Straight or branched perfluoroalkyl, C1～C6
Straight or branched alkoxyl, halogen, nitro, cyano group or phenyl, described halogen are F, Cl, Br or I；
R3、R4、R5、R6It is independently H, F, Cl, Br, I or C1～C3Alkyl；
RfFor trifluoromethyl, difluoromethyl, fluorine atom or perfluoro alkane.
It is preferred that：R1、R2It is independently H, methyl, ethyl, methoxyl group, F, Cl, B, r cyano group or phenyl；
R3、R4、R5、R6It is independently H, F or methyl；
RfFor trifluoromethyl, difluoromethyl or fluorine atom.
A kind of preparation method of above-mentioned Han Fu oxazolidinone compounds, the chemical equation of its preparation process is such as
Shown in lower：
Specifically include the reaction of 11 steps, the i.e. first step：Quality of the benzaldehyde of (the S)-epoxychloropropane 1 and 1N of 1N in 16N
Percent concentration is that at 18-25 DEG C, stirring reaction 14h is obtained containing Asia again after 35-40 DEG C of stirring reaction 6h for 25% ammonia
The reactant liquor of amine intermediate；
Second step：The hydrochloric acid of 1.5N is added toward the reactant liquor containing imine intermediate of above-mentioned gained, at 35-45 DEG C
Reaction generates the chloro- 2- propanol hydrochlorides of (S) -1- amino -3- 2；
3rd step：The chloro- 2- propanol hydrochlorides 2 of (S) -1- amino -3- of 1N and the two dimethyl dicarbonate butyl esters of 2N are chemistry
(Boc) in reaction equation2O reacts generation (the S)-tert-butyl group-(3- chlorine-2-hydroxyl propyl group) the tertiary fourth of carbamic acid at room temperature
Ester 3；
4th step：The acetic anhydride that the alkene ether 4 of 1.1N fluoro-containing group different from 1N replaces under the pyridine effect of 1N, two
After 3h being reacted in 0 DEG C successively in chloromethane alkane solvents, react 12h at 25 DEG C of room temperature of control and generate intermediate 5；
The acetic anhydride that described different fluoro-containing groups replace is trifluoroacetic anhydride, difluoroacetic acid acid anhydride or single Fluoroethanoic acid acid anhydride；
5th step：During the intermediate 5 of 1N is obtained from 6 Jing alcohol refluxs of the paranitrophenylhydrazine reaction of the different substituent groups of 1N
Mesosome 7；The paranitrophenylhydrazine (6) of described different substituent groups is 4- nitrophenyl hydrazines or the fluoro- 4- nitrophenyl hydrazines of 2-；
6th step：The intermediate 7 of 1N reacts dehydroxylation at room temperature with the trifluoroacetic acid (TFA) of 2N and generates intermediate 8；
7th step：8 Jing Pd/C catalytic hydrogenations of intermediate obtain intermediate 9；
8th step：The intermediate 9 of 1N reacts generation intermediate 10 under microwave condition with the intermediate 3 of 1.6N；
9th step：The intermediate 10 of 1N at room temperature middle Jing 2N carbonyl dimidazoles (CDI) cyclisation obtain dislike intermediate 11；
Tenth step：The intermediate 11 of 1N obtains the ketoamine of oxazolidine containing fluorine Jing after the trifluoroacetic acid of 2N takes off tertbutyloxycarbonyl protection
Intermediate 12；
11st step：The intermediate 12 of 1N finally gives Han Fu Evil again with the acetic anhydride of 2N under the triethylamine effect of 3N
Oxazolidinones 13.
The preparation method of above-mentioned Han Fu oxazolidinone compounds is adapted to all of Han Fu oxazolidinone compounds
General step.It is (S)-N- ((2- oxo -3- (4- (5- (trifluoromethyl) -1H- pyrroles with Han Fu oxazolidinone compounds 13a
Azoles -1- bases) phenyl) oxazolidine -5- bases) methyl) acetamide preparation as a example by, specifically include following reactions steps：
(1), the preparation of intermediate (S)-tert-butyl group (3- chlorine-2-hydroxyl propyl group) t-butyl carbamate 3
In 100ml round-bottomed flasks, 13.89g (131.2mmol) benzaldehyde, 35ml ethanol, 13.62g mass are sequentially added
Percent concentration is 25% ammonia (200.8mmol), stirs, then be slowly added dropwise 11.79g's (127.7mmol) under room temperature
(S)-epoxychloropropane 1,35-40 DEG C of stirring 6h, 18-25 DEG C of stirring 14h, is spin-dried for solvent, adds toluene 15ml, then plus people
19.10g mass percent concentrations are 37% aqueous hydrochloric acid solution and 18ml water, and 35-45 DEG C is stirred 3h, separates water layer, is concentrated, second
Alcohol recrystallization, inserts refrigerator crystallisation by cooling, and next day sucking filtration, washing are dried, obtain 13.98g white crystalline solids 2 i.e. (S) -1- ammonia
The chloro- 2- propanol hydrochlorides of base -3-；
Claim 4.70g (32mmol) white crystalline solid 2 to be the chloro- 2- propanol hydrochlorides of (S) -1- amino -3-, add 35ml bis-
Chloromethanes and 9.71g triethylamines (96mmol), are slowly added dropwise two dimethyl dicarbonate butyl esters of 13.97g (64mmol) i.e. under ice bath
(Boc)2O, after completion of dropping, normal-temperature reaction overnight, is spin-dried for solvent, carries out post separation with petroleum ether and ethyl acetate and obtains 6.42g
Clear viscous liquids are (S)-tert-butyl group (3- chlorine-2-hydroxyl propyl group) t-butyl carbamate 3, and which is relative to (S)-epoxy chloropropionate
The reaction yield 95.60% of alkane 1；
(2), intermediate 5a is the preparation of three fluoro- 3- alkene -2- ketone of (E) -4- ethyoxyls -1,1,1-
In 100ml round-bottomed flasks, 1.73g (22mmol) vinyl ethyl ether 4a is added, dissolved with 35ml dichloromethane, and
1.58g (20mmol) pyridine is added, under ice salt bath, 4.20g (20mmol) trifluoroacetic anhydride, after completion of dropping, 0 DEG C is slowly added dropwise
Lower reaction 3h, removes ice bath, and normal-temperature reaction 12h after completion of the reaction, adds saturation NaHCO3Solution 35ml is stirred 10 minutes, point
Go out organic layer, water layer is extracted with dichloromethane, is merged organic layer, is used anhydrous Na2SO4It is dried, being spin-dried for solvent, to obtain 3.21g yellow saturating
Prescribed liquid-intermediate 5a i.e. (E) -4- ethyoxyl -1,1,1- tri- fluoro- 3- alkene -2- ketone, its yield relative to vinyl ethyl ether 4a
For 95.50%；
(3), the 4- (preparations of 5- (Trifluoromethyl-1 H- pyrazol-1-yls) aniline 9a
The intermediate 5a of the above-mentioned gained of 3.21g (19.1mmol) in 100ml round-bottomed flasks, is taken, is dissolved with 35ml ethanol,
And 2.92g (19mmol) 4- nitrophenyl hydrazine 6a are added, the 20h that flows back is heated to, ethanol is spin-dried for, ethyl acetate and water, extraction 3 is added
It is secondary, merge organic layer, be spin-dried for solvent, obtain intermediate 7a i.e. 1- (4- nitrobenzophenones) -5- (trifluoromethyl) -4,5- dihydro -1H-5-
Pyrazoles alcohol, is directly used in the next step；
Take 4.70g (17.1mmol) the intermediate i.e. 1- of 7a (4- nitrobenzophenones) -5- (trifluoromethyl) -4,5- dihydro -1H-5-
Pyrazoles alcohol, is dissolved with 35ml dichloromethane, adds 3.90g (34.2mmol) trifluoroacetic acid, stirring at normal temperature overnight, to add saturation food
Saline extract, merge organic layer, be spin-dried for solvent, with petroleum ether and ethyl acetate carry out post separation obtain 4.10g yellow-brown solids-in
Mesosome 8a is 1- (4- nitrobenzophenones) -5- (trifluoromethyl) -1H- pyrazoles, and which is 93.40% relative to the yield of intermediate 7a.
In 100ml round-bottomed flasks, 4.10g (16mmol) the intermediate i.e. 1- of 8a (4- nitrobenzophenones) -5- (fluoroforms are taken
Base) -1H- pyrazoles, is dissolved with 35ml methanol, weighs the Pd/C that 0.45g mass percents are 5% and add round-bottomed flask, be flushed with hydrogen gas
Displacement 3 times, stirring at normal temperature reaction 4h, sucking filtration, methanol washing are spin-dried for filtrate, carry out post separation with petroleum ether and ethyl acetate and obtain
3.55g brown colors liquid-intermediate 9a is 4- (5- (trifluoromethyl) -1H- pyrazol-1-yls) aniline, and which is relative to intermediate 8a
Yield be 97.60%；
(4), (S)-tert-butyl group (2- methyl -3- ((4- (5- (Trifluoromethyl-1 H- pyrazol-1-yls) phenyl) amino) propyl group)
The preparation of t-butyl carbamate 10a
In tube sealing, take the above-mentioned gained of 2.84g (11mmol) intermediate 9a i.e. 4- (5- (trifluoromethyl) -1H- pyrazoles -
1- yls) aniline, and 3.79g (18mmol) (S)-tert-butyl group (3- chlorine-2-hydroxyl propyl group) t-butyl carbamate 3, temperature sets
Put at 150 DEG C, reaction overnight, terminates reaction, and the reactant liquor of gained carries out post separation with petroleum ether and ethyl acetate and obtains in 3.79g
Mesosome 10a is (S)-tert-butyl group (2- methyl -3- ((4- (5- (Trifluoromethyl-1 H- pyrazol-1-yls) phenyl) amino) propyl group) ammonia
Base t-butyl formate, which is 86.30% relative to the yield of intermediate 9a.
(5), (S) -5- (amino methyl) -3- (4- (5- (trifluoromethyl) -1H- pyrazol-1-yls) phenyl) oxazolidine -2- ketone
(12a) preparation
In 100ml round-bottomed flasks, intermediate 10a i.e. (S)-tert-butyl group (2- first of the above-mentioned gained of 3.19g (8mmol) is taken
Base -3- ((4- (5- (Trifluoromethyl-1 H- pyrazol-1-yls) phenyl) amino) propyl group) t-butyl carbamate, with 30ml tetrahydrochysene furans
Mutter after dissolving, add 1.62g (16mmol) triethylamine, and 2.59g (16mmol) carbonyl dimidazoles, normal-temperature reaction overnight, to revolve
Dry solvent, ethyl acetate extraction, merges organic layer, is spin-dried for solvent, carries out post separation with petroleum ether and ethyl acetate and obtain intermediate
11a 2.91g, yield：85.32%.
In 100ml round-bottomed flasks, the above-mentioned intermediate 11a of 2.56g (6mmol) are taken, dissolved with 35ml dichloromethane, added
1.37g (12mmol) trifluoroacetic acid, stirring at normal temperature overnight, are spin-dried for solvent and obtain intermediate 12a, be directly used in the next step；
(6), (S)-N- ((2- oxo -3- (4- (5- (trifluoromethyl) -1H- pyrazol-1-yls) phenyl) oxazolidine -5- bases)
Methyl) acetamide (13a) preparation
In 100ml round-bottomed flasks, (6mmol) above-mentioned intermediate 12a is taken, dissolved with 35ml dichloromethane, add 1.82g
(18mmol) triethylamine, adds 1.23g (12mmol) acetic anhydride, and stirring at normal temperature overnight, is extracted 3 times with dichloromethane, merged
Organic layer, is spin-dried for solvent, post separation is carried out with petroleum ether and ethyl acetate and obtains 1.89g faint yellow solids 13a i.e. (S)-N- ((2-
Oxo -3- (4- (5- (trifluoromethyl) -1H- pyrazol-1-yls) phenyl) oxazolidine -5- bases) methyl) acetamide, yield：
85.49%.
A kind of above-mentioned Han Fu oxazolidinone compounds have preferably suppression to watermelon anthrax and gray mold of cucumber
Effect, therefore can be used for disinfectant use in agriculture.A kind of Han Fu oxazolidinone compounds that will be of the invention are used as disinfectant use in agriculture
Watermelon anthrax bacteria or botrytis cinerea pers are sterilized.
The Advantageous Effects of the present invention
A kind of fluorine-containing oxazolidinone compounds of the present invention, with different fluoro-containing groups, including trifluoromethyl, difluoro
Methylene, fluorine atom etc., compared with Xian You oxazolidinone compounds, structure has novelty.The invention provides fluorine-containing
The preparation method of oxazolidinone compounds, compared with the preparation method of Xian You oxazolidinone compounds, in the middle of preparing
Reacted with microwave method when body 10, substantially reduced the response time, improve reaction yield.Meanwhile, different from existing
Oxazolidinone compounds are applied to the screening of medical bactericidal activity, and the series compound has carried out the sieve of agricultural bactericidal activity
The report for selecting ， Shi oxazolidinone compounds first Applications to develop in disinfectant use in agriculture.
A kind of fluorine-containing oxazolidinone compounds of the present invention, experimental result show which to watermelon anthrax and Fructus Cucumidis sativi ash
Mildew has good inhibiting effect, therefore, the fluorine-containing oxazolidinone compounds of the present invention can be used for agriculture chemicals fungicide.
Specific embodiment
Below by specific embodiment, the present invention is further elaborated, and its purpose is only that and is best understood from the interior of the present invention
Hold.Therefore, protection scope of the present invention is not limited by the cases cited.
The model and manufacturer's information of instrument used are detected in various embodiments of the present invention:
High resolution mass spectrum is determined by MicroMass GCT CA055 mass spectrographs, EI sources；
1H NMR,13By Brucker AM-400 (400MHz, 100MHz) nmr determination, (TMS is interior to C NMR
Mark)；
19F NMR are by Brucker AM-400 (376MHz) nmr determination；
Fusing point is determined by B ü chi Melting Point B-540 melting point apparatus, is not corrected.
Embodiment 1
A kind of fluorine-containing oxazolidinone compounds, its structural formula are as follows：
Wherein, R1For H, R2For H；
R3、R4、R5、R6Respectively H；
RfFor trifluoromethyl.
A kind of preparation method of above-mentioned Han Fu oxazolidinone compounds, specifically includes following steps：
(1), the preparation of (S)-tert-butyl group (3- chlorine-2-hydroxyl propyl group) t-butyl carbamate 3
In 100ml round-bottomed flasks, 13.89g (131.2mmol) benzaldehyde, 35ml ethanol, 13.62g mass are sequentially added
Percent concentration is 25% ammonia (200.8mmol), stirs, then be slowly added dropwise 11.79g's (127.7mmol) under room temperature
(S)-epoxychloropropane 1,35-40 DEG C of stirring 6h, 18-25 DEG C of stirring 14h, is spin-dried for solvent, adds toluene 15ml, then plus people
19.10g mass percent concentrations are 37% aqueous hydrochloric acid solution and 18ml water, and 35-45 DEG C is stirred 3h, separates water layer, is concentrated, second
Alcohol recrystallization, inserts refrigerator crystallisation by cooling, and next day sucking filtration, washing are dried, obtain 13.98g white crystalline solids 2 i.e. (S) -1- ammonia
The chloro- 2- propanol hydrochlorides of base -3-；
Claim 4.70g (32mmol) white crystalline solid 2 to be the chloro- 2- propanol hydrochlorides of (S) -1- amino -3-, add 35ml bis-
Chloromethanes and 9.71g triethylamines (96mmol), are slowly added dropwise two dimethyl dicarbonate butyl esters of 13.97g (64mmol) under ice bath
(Boc)2O, after completion of dropping, normal-temperature reaction overnight, is spin-dried for solvent, carries out post separation with petroleum ether and ethyl acetate and obtains 6.42g
Clear viscous liquids are (S)-tert-butyl group (3- chlorine-2-hydroxyl propyl group) t-butyl carbamate 3, and which is relative to (S)-epoxy chloropropionate
The reaction yield 95.60% of alkane 1；
The clear viscous liquids Jing of above-mentioned gained1H magnetic resonance detection and high resolution mass spectrum detection, its data is respectively such as
Under：
1H-NMR(CDCl3,400MHz):δ 3.85-3.83 (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-mentioned1H magnetic resonance detection and high resolution mass spectrum detection data result show, the clear viscous of above-mentioned gained
Liquid is (S)-tert-butyl group (3- chlorine-2-hydroxyl propyl group) t-butyl carbamate 3；
(2), intermediate 5a is the preparation of three fluoro- 3- alkene -2- ketone of (E) -4- ethyoxyls -1,1,1-
In 100ml round-bottomed flasks, 1.73g (22mmol) vinyl ethyl ether 4a is added, dissolved with 35ml dichloromethane, and
1.58g (20mmol) pyridine is added, under ice salt bath, 4.20g (20mmol) trifluoroacetic anhydride, after completion of dropping, 0 DEG C is slowly added dropwise
Lower reaction 3h, removes ice bath, and normal-temperature reaction 12h after completion of the reaction, adds 35ml saturations NaHCO3Solution stirring 10 minutes, point
Go out organic layer, water layer is extracted with dichloromethane, is merged organic layer, is used anhydrous Na 2SO4It is dried, being spin-dried for solvent, to obtain 3.21g yellow saturating
Prescribed liquid-intermediate 5a i.e. (E) -4- ethyoxyl -1,1,1- tri- fluoro- 3- alkene -2- ketone, its yield relative to vinyl ethyl ether 4a
For 95.50%；
The yellow transparent liquid of above-mentioned gained-intermediate 5a Jing1H magnetic resonance detection,19F magnetic resonance detection and high score
Mass Spectrometer Method is distinguished, its data difference is as follows：
1H-NMR(CDCl3,400MHz):δ7.86(d,1H),5.83(d,1H),4.12(d,2H),1.39(t,3H).
19F NMR(CDCl3,376MHz):δ-73.8(s,3F).
HR-MS:Measured value is 168.0399；Theoretical value is 168.0398.
From above-mentioned1H magnetic resonance detection,19The data result of F magnetic resonance detection and high resolution mass spectrum detection can be seen
Go out, the yellow transparent liquid-intermediate 5a of above-mentioned gained is (E) -4- ethyoxyl -1,1,1- tri- fluoro- 3- alkene -2- ketone；
(3), the 4- (preparations of 5- (Trifluoromethyl-1 H- pyrazol-1-yls) aniline 9a
The intermediate 5a of the above-mentioned gained of 3.21g (19.1mmol) in 100ml round-bottomed flasks, is taken, is dissolved with 35ml ethanol,
And 2.92g (19mmol) 4- nitrophenyl hydrazine 6a are added, the 20h that flows back is heated to, ethanol is spin-dried for, ethyl acetate and water, extraction 3 is added
It is secondary, merge organic layer, be spin-dried for solvent, obtain intermediate 7a i.e. 1- (4- nitrobenzophenones) -5- (trifluoromethyl) -4,5- dihydro -1H-5-
Pyrazoles alcohol, is directly used in the next step；
4.70g (17.1mmol) intermediate 7a is taken, is dissolved with 35ml dichloromethane, add 3.90g (34.2mmol) trifluoro
Acetic acid, stirring at normal temperature overnight, add saturated aqueous common salt extraction, merge organic layer, be spin-dried for solvent, entered with petroleum ether and ethyl acetate
Row post separation obtains 4.10g yellow-brown solids-intermediate 8a i.e. 1- (4- nitrobenzophenones) -5- (trifluoromethyl) -1H- pyrazoles, its phase
Yield for intermediate 7a is 93.40%.
The yellow solid of above-mentioned gained-intermediate 8a Jing1H magnetic resonance detection,19F magnetic resonance detection and high-resolution matter
Spectrum detection, its data difference are as follows：
1H-NMR(CDCl3,400MHz):δ 8.14 (m, 2H), 7.61 (m, J=5Hz, 1H), 7.35 (m, 2H), 6.37 (m,
1H).
19F NMR(CDCl3,376MHz):δ-62.8(s,3F).
HR-MS:Measured value is 257.0416；Theoretical value is 257.0412.
From above-mentioned1H magnetic resonance detection,19The data result of F magnetic resonance detection and high resolution mass spectrum detection can be seen
Go out, the yellow transparent solid body-intermediate 8a of above-mentioned gained is 1- (4- nitrobenzophenones) -5- (trifluoromethyl) -1H- pyrazoles；
In 100ml round-bottomed flasks, 4.10g (16mmol) intermediate 8a is taken, dissolved with 35ml methanol, weigh 0.45g matter
Amount percentage ratio is that 5% Pd/C adds round-bottomed flask, fills hydrogen exchange 3 times, stirring at normal temperature reaction 4h, sucking filtration, methanol washing, rotation
Dry filtrate, carries out post separation and obtains 3.55g brown colors liquid-intermediate 9a i.e. 4- (5- (fluoroforms with petroleum ether and ethyl acetate
Base) -1H- pyrazol-1-yls) aniline, which is 97.60% relative to the yield of intermediate 8a.
The brown color liquid of above-mentioned gained-intermediate 9a Jing1H magnetic resonance detection,19F magnetic resonance detection and high-resolution
Mass Spectrometer Method, its data difference are as follows：
1H-NMR(CDCl3,400MHz):δ 7.65 (m, 2H), 7.62 (m, J=5Hz, 1H), 6.95 (m, 2H), 6.25 (m,
1H),3.26(br,2H).
19F NMR(CDCl3,376MHz):δ-62.3(s,3F).
HR-MS:Measured value is 227.0668；Theoretical value is 227.0670.
From above-mentioned1H magnetic resonance detection,19The data result of F magnetic resonance detection and high resolution mass spectrum detection can be seen
Go out, the brown color liquid-intermediate 9a of above-mentioned gained is 4- (5- (Trifluoromethyl-1 H- pyrazol-1-yls) aniline.
(4), (S)-tert-butyl group (2- methyl -3- ((4- (5- (Trifluoromethyl-1 H- pyrazol-1-yls) phenyl) amino) propyl group)
The preparation of t-butyl carbamate 10a
In tube sealing, add intermediate 9a and 3.79g (18mmol) of 2.84g (11mmol) above-mentioned gained (S)-tertiary fourth
Base (3- chlorine-2-hydroxyl propyl group) t-butyl carbamate 3, control temperature at 150 DEG C, reaction overnight, terminate reaction, gained it is anti-
Answer liquid petroleum ether and ethyl acetate carry out post separation obtain 3.79g yellow solids-intermediate 10a i.e. (S)-tert-butyl group (2- methyl-
3- ((4- (5- (Trifluoromethyl-1 H- pyrazol-1-yls) phenyl) amino) propyl group) t-butyl carbamate, which is relative to intermediate
The yield of 9a is 86.30%.
The yellow solid of above-mentioned gained-intermediate 10a Jing1H magnetic resonance detection,19F magnetic resonance detection and high-resolution matter
Spectrum detection, its data difference are as follows：
1H-NMR(CDCl3,400MHz):δ 7.46 (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(CDCl3,376MHz):δ-63.8(s,3F).
HR-MS:Measured value is 400.1726；Theoretical value is 400.1722.
From above-mentioned1H magnetic resonance detection,19The data result of F magnetic resonance detection and high resolution mass spectrum detection can be seen
Go out, the yellow solid-intermediate 10a of above-mentioned gained is (S)-tert-butyl group (2- methyl -3- ((4- (5- (Trifluoromethyl-1 H- pyrroles
Azoles -1- bases) phenyl) amino) propyl group) t-butyl carbamate；
(5), (S) -5- (amino methyl) -3- (4- (5- (trifluoromethyl) -1H- pyrazol-1-yls) phenyl) oxazolidine -2- ketone
The preparation of 12a
In 100ml round-bottomed flasks, the intermediate 10a of the above-mentioned gained of 3.19g (8mmol) is taken, it is molten with 30ml tetrahydrofurans
Xie Hou, adds 1.62g (16mmol) triethylamine, and 2.59g (16mmol) carbonyl dimidazoles, normal-temperature reaction overnight, to be spin-dried for molten
Agent, ethyl acetate extraction, merges organic layer, is spin-dried for solvent, post separation is carried out with petroleum ether and ethyl acetate and obtains 2.91g yellow admittedly
Body-intermediate 11a i.e. (S)-tert-butyl group-(2- oxo -3- (4- (5- (trifluoromethyl) -1H- pyrazol-1-yls) phenyl) oxazolidine -
5- yls) carbamate, yield：85.32%.
The yellow solid of above-mentioned gained-intermediate 11a Jing1H magnetic resonance detection,19F magnetic resonance detection and high-resolution matter
Spectrum detection, its data difference are as follows：
1H-NMR(CDCl3,400MHz):δ 7.80 (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(CDCl3,376MHz):δ-62.6(s,3F).
HR-MS:Measured value is 426.1514；Theoretical value is 426.1515.
From above-mentioned1H magnetic resonance detection,19The data result of F magnetic resonance detection and high resolution mass spectrum detection can be seen
Go out, the yellow solid-intermediate 11a of above-mentioned gained is (S)-tert-butyl group-(2- oxo -3- (4- (5- (trifluoromethyl) -1H- pyrroles
Azoles -1- bases) phenyl) oxazolidine -5- bases) carbamate；
In 100ml round-bottomed flasks, the above-mentioned intermediate 11a of 2.56g (6mmol) are taken, dissolved with 35ml dichloromethane, added
1.37g (12mmol) trifluoroacetic acid, stirring at normal temperature overnight, are spin-dried for solvent and obtain intermediate 12a, be directly used in the next step；
(6), (S)-N- ((2- oxo -3- (4- (5- (trifluoromethyl) -1H- pyrazol-1-yls) phenyl) oxazolidine -5- bases)
Methyl) acetamide 13a preparation
In 100ml round-bottomed flasks, the above-mentioned intermediate 12a of 1.96g (6mmol) are taken, dissolved with 35ml dichloromethane, added
1.82g (18mmol) triethylamine, adds 1.23g (12mmol) acetic anhydride, and stirring at normal temperature overnight, extracts 3 with dichloromethane
It is secondary, merge organic layer, be spin-dried for solvent, post separation carried out with petroleum ether and ethyl acetate and obtain 1.89g faint yellow solid 13a, yield：
85.49%.
The faint yellow solid 13a Jing of above-mentioned gained1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection
Detect with high resolution mass spectrum, its data difference is as follows：
1H-NMR(CDCl3,400MHz):δ 7.82 (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(CDCl3,376MHz):δ-62.7(s,3F).
13C NMR(CDCl3,100MHz):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-mentioned1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection and high resolution mass spectrum detection
Data result can be seen that above-mentioned gained faint yellow solid 13a be (S)-N- ((2- oxo -3- (4- (5- (fluoroforms
Base) -1H- pyrazol-1-yls) phenyl) oxazolidine -5- bases) methyl) acetamide.
Embodiment 2
A kind of fluorine-containing oxazolidinone compounds, its structural formula are as follows：
Wherein, R1、R2Independent is respectively methyl, H；
R3、R4、R5、R6Independent is respectively H, H, H, H；
RfFor trifluoromethyl.
A kind of above-mentioned Han Fu oxazolidinone compounds, i.e. (S)-N- ((3- (4- (3- methyl -5- (trifluoromethyl) -
1H- pyrazol-1-yls) phenyl) -2- oxo oxazolidine -5- bases) methyl) acetamide 13b, its structural formula is as follows：
A kind of above-mentioned Han Fu oxazolidinone compounds, i.e. (S)-N- ((3- (4- (3- methyl -5- (trifluoromethyl) -
1H- pyrazol-1-yls) phenyl) -2- oxo oxazolidine -5- bases) methyl) acetamide 13b preparation method with embodiment 1, simply will
In step (2), vinyl ethyl ether 4a replaces with 2- ethoxy propylenes, and the other the same as in Example 1 is final to obtain 1.91g faint yellow solids,
Which is 45.41% relative to the yield of raw material 2- ethoxy propylenes.
The faint yellow solid Jing of above-mentioned gained1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection and
High resolution mass spectrum detects that its data difference is as follows：
1H NMR(CDCl3,400MHz):δ 7.78 (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(CDCl3,100MHz):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(CDCl3,376MHz):δ-62.4(s,3F).
HR-MS:Measured value is 382.125；Theoretical value is 382.1253.
From above-mentioned1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection and high resolution mass spectrum detection
Data result can be seen that above-mentioned gained faint yellow solid be (S)-N- ((3- (4- (3- methyl -5- (trifluoromethyl) -
1H- pyrazol-1-yls) phenyl) -2- oxo oxazolidine -5- bases) methyl) acetamide.
Embodiment 3
A kind of fluorine-containing oxazolidinone compounds, its structural formula are as follows：
Wherein, R1、R2Independent is respectively H, H；
R3、R4、R5、R6Independent is respectively F, H, H, H；
RfFor trifluoromethyl.
A kind of above-mentioned 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- bases) methyl) acetamide 13c, its structural formula is as follows：
A kind of above-mentioned 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- bases) methyl) acetamide 13c preparation method with embodiment 1, simply will step
Suddenly in (3), 4- nitrophenyl hydrazine 6a replace with the fluoro- 4- nitrophenyl hydrazines of 2-, and the other the same as in Example 1 obtains 1.87g faint yellow solids, its phase
For the yield of feed ethylene base ether is 42.60%.
The faint yellow solid Jing of above-mentioned gained1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection and
High resolution mass spectrum detects that its data difference is as follows：
1H-NMR(CDCl3,400MHz):δ 7.82 (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(CDCl3,100MHz):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(CDCl3,376MHz):δ-62.7(s,3F),-121.2(s,1F).
HR-MS:Measured value is 386.1006；Theoretical value is 386.1002.
From above-mentioned1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection and high resolution mass spectrum detection
Data result can be seen that above-mentioned gained faint yellow solid be (S)-N- ((3- (the fluoro- 4- of 3- (5- (trifluoromethyl) -1H-
Pyrazol-1-yl) phenyl) -2- oxo oxazolidine -5- bases) methyl) acetamide.
Embodiment 4
A kind of fluorine-containing oxazolidinone compounds, its structural formula are as follows：
Wherein, R1、R2Independent is respectively methyl, H；
R3、R4、R5、R6Independent is respectively F, H, H, H；
RfFor trifluoromethyl.
A kind of above-mentioned Han Fu oxazolidinone compounds, i.e. (S)-N- ((3- (the fluoro- 4- of 3- (3- methyl -5- (fluoroforms
Base) -1H- pyrazol-1-yls) phenyl) -2- oxo oxazolidine -5- bases) methyl) acetamide 13d, its structural formula is as follows：
A kind of above-mentioned Han Fu oxazolidinone compounds, i.e. (S)-N- ((3- (the fluoro- 4- of 3- (3- methyl -5- (fluoroforms
Base) -1H- pyrazol-1-yls) phenyl) -2- oxo oxazolidine -5- bases) methyl) and acetamide 13d preparation method with embodiment 2, only
It is that 4- nitrophenyl hydrazine 6a in step (3) are replaced with into the fluoro- 4- nitrophenyl hydrazines of 2-, the other the same as in Example 2 obtains 1.92g off-white colors solid
Body, which is 45.02% relative to the yield of raw material 2- ethoxy propylenes.
The faint yellow solid Jing of above-mentioned gained1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection and
High resolution mass spectrum detects that its data difference is as follows：
1H-NMR(CDCl3,400MHz):δ 7.75 (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(CDCl3,100MHz):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(CDCl3,376MHz):δ-63.9(s,3F),-121.2(s,1F).
HR-MS:Measured value is 400.1156；Theoretical value is 400.1159.
From above-mentioned1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection and high resolution mass spectrum detection
Data result can be seen that above-mentioned gained faint yellow solid be (S)-N- ((3- (the fluoro- 4- of 3- (3- methyl -5- (fluoroforms
Base) -1H- pyrazol-1-yls) phenyl) -2- oxo oxazolidine -5- bases) methyl) acetamide.
Embodiment 5
A kind of fluorine-containing oxazolidinone compounds, its structural formula are as follows：
Wherein, R1、R2Independent is respectively H, H；
R3、R4、R5、R6Independent is respectively H, H, H, H；
RfFor difluoromethyl.
A kind of above-mentioned Han Fu oxazolidinone compounds, i.e. (S)-N- ((3- (4- (5- (difluoromethyl) -1H- pyrazoles -
1- yls) phenyl) -2- oxo oxazolidine -5- bases) methyl) acetamide 13e, its structural formula is as follows：
A kind of above-mentioned Han Fu oxazolidinone compounds, i.e. (S)-N- ((3- (4- (5- (difluoromethyl) -1H- pyrazoles -
1- yls) phenyl) -2- oxo oxazolidine -5- bases) methyl) acetamide 13e preparation method with embodiment 1, simply by step (2)
Middle trifluoroacetic anhydride replaces with difluoroacetic acid acid anhydride, and the other the same as in Example 1 obtains 1.72g faint yellow solids, and which is relative to feed ethylene
The yield of base ether is 41.09%.
The faint yellow solid Jing of above-mentioned gained1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection and
High resolution mass spectrum detects that its data difference is as follows：
1H-NMR(CDCl3,400MHz):δ 7.84 (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(CDCl3,100MHz):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(CDCl3,376MHz):δ-112.7(s,2F).
HR-MS:Measured value is 350.1194；Theoretical value is 350.1190.
From above-mentioned1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection and high resolution mass spectrum detection
Data result can be seen that above-mentioned gained faint yellow solid be (S)-N- ((3- (4- (5- (difluoromethyl) -1H- pyrazoles -
1- yls) phenyl) -2- oxo oxazolidine -5- bases) methyl) acetamide.
Embodiment 6
A kind of fluorine-containing oxazolidinone compounds, its structural formula are as follows：
Wherein, R1、R2Independent is respectively methyl, H；
R3、R4、R5、R6Independent is respectively H, H, H, H；
RfFor difluoromethyl.
A kind of above-mentioned Han Fu oxazolidinone compounds, i.e. (S)-N- ((3- (4- (5- (difluoromethyl) -3- methyl -
1H- pyrazol-1-yls) phenyl) -2- oxo oxazolidine -5- bases) methyl) acetamide 13f, its structural formula is as follows：
A kind of above-mentioned Han Fu oxazolidinone compounds, i.e. (S)-N- ((3- (4- (5- (difluoromethyl) -3- methyl -
1H- pyrazol-1-yls) phenyl) -2- oxo oxazolidine -5- bases) methyl) acetamide 13f preparation method with embodiment 5, simply will
Step (2) medium vinyl ether 4a replaces with 2- ethoxy propylenes, and the other the same as in Example 5 is final to obtain 1.69g off-white powders,
Which is 40.05% relative to the yield of raw material 2- ethoxy propylenes.
Off-white powder Jing of above-mentioned gained1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection and
High resolution mass spectrum detects that its data difference is as follows：
1H-NMR(CDCl3,400MHz):δ 7.81 (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, 1H), 3.94 (dd, J=5Hz, 1H), 3.62 (d, J
=2.6Hz, 2H), 2.35 (s, 3H), 1.97 (s, 3H).
13C NMR(CDCl3,100MHz):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(CDCl3,376MHz):δ-113.9(s,2F).
HR-MS:Measured value is 364.1346；Theoretical value is 364.1347.
From above-mentioned1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection and high resolution mass spectrum detection
Data result can be seen that above-mentioned gained off-white powder be (S)-N- ((3- (4- (5- (difluoromethyl) -3- methyl -
1H- pyrazol-1-yls) phenyl) -2- oxo oxazolidine -5- bases) methyl) acetamide.
Embodiment 7
A kind of fluorine-containing oxazolidinone compounds, its structural formula are as follows：
Wherein, R1、R2Independent is respectively H, H；
R3、R4、R5、R6Independent is respectively F, H, H, H；
RfFor difluoromethyl.
A kind of above-mentioned Han Fu oxazolidinone compounds, i.e. (S)-N- ((3- (4- (5- (difluoromethyl) -1H- pyrazoles -
1- yls) -3- fluorophenyls) -2- oxo oxazolidine -5- bases) methyl) acetamide 13g, its structural formula is as follows：
A kind of above-mentioned Han Fu oxazolidinone compounds, i.e. (S)-N- ((3- (4- (5- (difluoromethyl) -1H- pyrazoles -
1- yls) -3- fluorophenyls) -2- oxo oxazolidine -5- bases) methyl) acetamide 13g preparation method with embodiment 5, simply will step
Suddenly in (3), 4- nitrophenyl hydrazine 6a replace with the fluoro- 4- nitrophenyl hydrazines of 2-, and the other the same as in Example 5 is final to obtain 1,76g faint yellow solids,
Which is 43.64% relative to the yield of feed ethylene base ether.
The faint yellow solid Jing of above-mentioned gained1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection and
High resolution mass spectrum detects that its data difference is as follows：
1H-NMR(CDCl3,400MHz):δ 7.84 (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(CDCl3,100MHz):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(CDCl3,376MHz):δ-115.4(s,2F),-117.2(s,1F).
HR-MS:Measured value is 368.1097；Theoretical value is 368.1096.
From above-mentioned1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection and high resolution mass spectrum detection
Data result can be seen that above-mentioned gained faint yellow solid be (S)-N- ((3- (4- (5- (difluoromethyl) -1H- pyrazoles -
1- yls) -3- fluorophenyls) -2- oxo oxazolidine -5- bases) methyl) acetamide.
Embodiment 8
A kind of fluorine-containing oxazolidinone compounds, its structural formula are as follows：
Wherein, R1、R2Independent is respectively methyl, H；
R3、R4、R5、R6Independent is respectively F, H, H, H；
RfFor difluoromethyl.
A kind of above-mentioned Han Fu oxazolidinone compounds, i.e. (S)-N- ((3- (4- (5- (difluoromethyl) -3- methyl -
1H- pyrazol-1-yls) -3- fluorophenyls) -2- oxo oxazolidine -5- bases) methyl) acetamide 13h, its structural formula is as follows：
A kind of above-mentioned Han Fu oxazolidinone compounds, i.e. (S)-N- ((3- (4- (5- (difluoromethyl) -3- methyl -
1H- pyrazol-1-yls) -3- fluorophenyls) -2- oxo oxazolidine -5- bases) methyl) acetamide 13h preparation method with embodiment 6,
Step (2) wherein vinyl ethyl ether 4a is replaced with into 2- ethoxy propylenes simply, other are with embodiment 6, final that 1.77g is yellowish
Color solid, which is 42.29% relative to the yield of raw material 2- ethoxy propylenes.
The faint yellow solid Jing of above-mentioned gained1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection and
High resolution mass spectrum detects that its data difference is as follows：
1H-NMR(CDCl3,400MHz):δ 7.74 (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(CDCl3,100MHz):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(CDCl3,376MHz):δ-117.6(s,2F),-121.4(s,1F).
HR-MS:Measured value is 382.1257；Theoretical value is 382.1253.
From above-mentioned1H magnetic resonance detection,13C magnetic resonance detection,19F magnetic resonance detection and high resolution mass spectrum detection
Data result can be seen that above-mentioned gained faint yellow solid be (S)-N- ((3- (4- (5- (difluoromethyl) -3- methyl -
1H- pyrazol-1-yls) -3- fluorophenyls) -2- oxo oxazolidine -5- bases) methyl) acetamide.
Application Example 1
By 8 kinds of Han Fu oxazolidinone compounds obtained by embodiment 1-8 to cotton standing dead, Phytophthora capsici, Phytophthora infestans, Herba Marsileae Quadrifoliae
Fruit wheel stricture of vagina, the indoor inhibitory activity of six kinds of phytopathogen mycelial growth rates of Citrullus vulgariss anthrax and Fructus Cucumidis sativi grey mold are tested, with
Fluoxastrobin active compound is comprised the following steps that as control：
(1), test material
Tested target：
A. cotton seedling blight cause of disease Rhizoctonia solani K ü hn. belong to Deuteromycotina funguses, without born of the same parents' mesh, silk core
Category, Rhizoctonia solani Kuhn.The Ministry of Agriculture of Plant Protection institute, Chinese Academy of Agricultral Sciences chemistry of pesticide opens real with application technology emphasis
Test room and separate preservation strain.
B. Phytophthora capsici disease cause of disease Phytophthora capsici Leon, Mastigomycotina, Peronosporales, Phytophthora,
Phytophthora capsici.The Ministry of Agriculture of Plant Protection institute, Chinese Academy of Agricultral Sciences chemistry of pesticide and application technology emphasis open laboratory point
From preservation strain.
C. tomato late blight cause of disease Phytophthora infestans (Mont.) de Bary category funguses mastigomycetes are sub-
Door, Peronosporales, Phytophthora, phytophthora infestans.The Ministry of Agriculture of Plant Protection institute, Chinese Academy of Agricultral Sciences chemistry of pesticide with apply skill
Art emphasis open laboratory separates and preserves strain.
D. ring rot of apple cause of disease Botryosphaeria dothidea (Moug.Ex Fr) Ces.et de Not. belong to
Funguses Ascomycotina, lattice spore chamber Zoopagales, Botryosphaeria.Plant Protection institute, Chinese Academy of Agricultral Sciences's pesticides application work
Skill innovation group is separated and preserves strain.
E. watermelon anthrax cause of disease Colletotrichum orbiculare (Berk.et Mont.) Arx, belongs to Fungi Imperfecti
Subphylum, Melanconiales, colletotrichum, melon anthrax.The Ministry of Agriculture of Plant Protection institute, Chinese Academy of Agricultral Sciences chemistry of pesticide
Preservation strain is separated with application technology emphasis open laboratory.
F. gray mold of cucumber cause of disease Botrytis cinerea Pers., belong to Deuteromycotina, hyphomycetales, Botrytis,
Botrytis cinerea.Academy of Agricultural Sciences of state Plant Protection Institute Ministry of Agriculture chemistry of pesticide is separated with application technology emphasis open laboratory
Preserve strain.
Tested noval chemical compound：By compound 13a-13l prepared by examples detailed above method, 93% Fluoxastrobin active compound (elder generation of Britain
Company limited is being reached just)
(2), test method
This test is according to People's Republic of China's agricultural industry criteria (NY/T 1156.2-2006), fast using mycelial growth
Rate method is measured.
By cultured various pathogen, under aseptic technique with the sterilization punchers of diameter 7mm, from colony edge
Bacteria cake is cut, with inoculator by pure culture biscuits involvng inoculation in pastille flat board central authorities, mycelia faces down, covers ware lid, be placed in 25 DEG C of incubators
Middle culture.
(3), operational approach
The preparation of mother solution：With a ten thousandth electronic balance weigh respectively 8 noval chemical compounds 50 obtained by embodiment 1-8 ±
2mg, is prepared into the mother solution of 10000 μ g/mL respectively with 5mL DMF dissolvings.Weigh 53.8mg Fluoxastrobin active compounds 5mL DMF dissolvings
It is prepared into the mother solution of 10000 μ g/mL.
The setting of concentration, under aseptic technique, is diluted to 50 μ the 10000 μ g/mL mother solution culture medium for preparing
The toxic culture medium flat plate of g/mL, test set the blank without chemicals treatment, and each process is repeated 3 times.
(4), experimental result
8 13a-13h of oxazolidinone compounds containing fluorine of the present invention are under 50 μ g/mL concentration to six kinds of phytopathogens
Mycelial growth rate suppresses the measurement result of situation to be shown in Table 1.
The inhibitory action of table 1,8 kind of medicament to different phytopathogen mycelial growth rates
From table 1 it follows that this toxicity measurement result shows, the Han Fu oxazolidinone chemical combination in the present invention
Thing 13a-13h is general to the inhibitory activity of cotton standing dead, Phytophthora capsici, Phytophthora infestans and Fructus Mali pumilae wheel stricture of vagina bacterium, and to Citrullus vulgariss anthrax,
Botrytis cinerea pers are particularly the inhibitory activity of botrytis cinerea pers preferably, therefore the Han Fu oxazolidinone chemical combination in the present invention
Thing can be used as the disinfectant use in agriculture of Citrullus vulgariss anthrax, botrytis cinerea pers.
The above is only the basic explanation under present inventive concept, and according to technical scheme made it is any etc.
Effect conversion, all should belong to protection scope of the present invention.
Claims (5)
1. a kind of fluorine-containing oxazolidinone compounds, it is characterised in that its structural formula is as follows：
Wherein, RfFor trifluoromethyl or difluoromethyl；
R1、R2It is independently H, C1～C6Straight or branched alkyl, C1～C6Straight or branched perfluoroalkyl, C1～C6Straight chain is propped up
Chain alkoxy, halogen F, Cl, Br or I, nitro, cyano group or phenyl；
R3、R4、R5、R6It is independently H, F, Cl, Br, I or C1～C3Alkyl.
2. such as claim 1 Suo Shu oxazolidinone compounds, it is characterised in that：
Described R1、R2It is independently H, methyl, ethyl, methoxyl group, F, Cl, Br, cyano group or phenyl；
RfFor trifluoromethyl, difluoromethyl.
3. such as claim 1 Suo Shu oxazolidinone compounds, it is characterised in that：
Described R1For H or methyl；
Described R2For H；
Described R3For H or F；
Described R4、R5、R6It is H；
Described RfFor trifluoromethyl or difluoromethyl.
4. a kind of preparation method of Han Fu oxazolidinone compounds as claimed in claim 1, it is characterised in which was prepared
Journey specifically includes following 11 step reaction：
The first step, 1 mole of (S)-epoxychloropropane (1) and 1 mole of benzaldehyde in 16 milliliters of mass percent concentration are
After 35-40 DEG C of stirring reaction 6h, at 18-25 DEG C, stirring reaction 14h is obtained containing the anti-of imine intermediate 25% ammonia again
Answer liquid；
Second step, it is toward the hydrochloric acid containing 1.5 moles of addition in imine intermediate reactant liquor of above-mentioned gained, anti-at 35-45 DEG C
The chloro- 2- propanol hydrochlorides (2) of (S) -1- amino -3- should be generated；
3rd step：1 mole of the chloro- 2- propanol hydrochlorides (2) of (S) -1- amino -3- are existed with 2 moles of two dimethyl dicarbonate butyl esters
Reaction under room temperature generates (S)-tert-butyl group-(3- chlorine-2-hydroxyl propyl group) t-butyl carbamate (3)；
4th step：The acetic anhydride that 1.1 moles of alkenyl ether compound (4) fluoro-containing group different from 1 mole replaces is in 1 mole of pyrrole
Under pyridine effect, after 3h being reacted in 0 DEG C successively in dichloromethane solvent, react 12h at 25 DEG C of room temperature of control and generate intermediate
(5)；The acetic anhydride that described different fluoro-containing groups replace is trifluoroacetic anhydride or difluoroacetic acid acid anhydride；
The structural formula of described alkenyl ether compound (4) is as follows：
Wherein R1、R2For the R described in independent claims 11、R2, it is independently H, C1～C6Straight or branched
Alkyl, C1～C6Straight or branched perfluoroalkyl, C1～C6Straight or branched alkoxyl, halogen F, Cl, Br or I, nitro, cyano group
Or phenyl；
The structural formula of the intermediate (5) is as follows：
Wherein R1、R2With the R in alkenyl ether compound described above (4)1、R2It is identical；
RfFor the R described in independent claims 1f, it is trifluoromethyl or difluoromethyl；
5th step：1 mole of intermediate (5) is reacted from paranitrophenylhydrazine (6) the Jing alcohol refluxs of 1 mole of different substituent groups
Obtain intermediate (7)；
The structural formula of the paranitrophenylhydrazine (6) of the different substituent groups is as follows：
Wherein R3、R4、R5、R6For the R described in independent claims 13、R4、R5、R6, it is independently
H, F, Cl, Br, I or C1～C3Alkyl；
The structural formula of the intermediate (7) is as follows：R therein1、R2Close with alkene etherificate in the 4th step
R in thing (4)1、R2It is identical, R3、R4、R5、R6From the R in the paranitrophenylhydrazine (6) of above-mentioned different substituent groups3、R4、R5、R6Phase
Together, RfFor the R described in independent claims 1f, it is trifluoromethyl or difluoromethyl；
6th step：1 mole of intermediate (7) reacts dehydroxylation at room temperature with 2 moles of trifluoroacetic acid and generates intermediate (8)；
The structural formula of the intermediate (8) is as follows：
R therein1、R2With the R in alkenyl ether compound (4) in the 4th step1、R2It is identical, R3、R4、R5、
R6From the R in the paranitrophenylhydrazine (6) of above-mentioned different substituent groups3、R4、R5、R6It is identical, RfDescribed in independent claims 1
Rf, it is trifluoromethyl or difluoromethyl；
7th step：Intermediate (8) Jing Pd/C catalytic hydrogenations obtain intermediate (9)；
The structural formula of the intermediate (9) is as follows：
R therein1、R2With the R in alkenyl ether compound (4) in the 4th step1、R2It is identical, R3、R4、R5、
R6From the R in the paranitrophenylhydrazine (6) of above-mentioned different substituent groups3、R4、R5、R6It is identical, RfDescribed in independent claims 1
Rf, it is trifluoromethyl or difluoromethyl；；
8th step：1 mole of intermediate (9) and 1.6 moles of (S)-tert-butyl group-(3- chlorine-2-hydroxyl propyl group) carbamic acid uncle
Butyl ester (3) reacts generation intermediate (10) under microwave condition；
The structure of the intermediate (10) is as follows：
R therein1、R2With the R in alkenyl ether compound (4) in the 4th step1、R2Phase
Together, R3、R4、R5、R6From the R in the paranitrophenylhydrazine (6) of above-mentioned different substituent groups3、R4、R5、R6It is identical, RfFor independent right
Require the R described in 1f, it is trifluoromethyl or difluoromethyl；；
9th step intermediate (10) at room temperature 2 moles of middle Jing carbonyl dimidazoles cyclisation obtain intermediate (11)；
The structure of the intermediate (11) is as follows：
R therein1、R2With the R in alkenyl ether compound (4) in the 4th step1、R2Phase
Together, R3、R4、R5、R6From the R in the paranitrophenylhydrazine (6) of above-mentioned different substituent groups3、R4、R5、R6It is identical, RfFor independent right
Require the R described in 1f, it is trifluoromethyl or difluoromethyl；
Tenth step；1 mole of intermediate (11) obtains intermediate Jing after the de- tertbutyloxycarbonyl protection of 2 moles of trifluoroacetic acid
(12)；
The structure of the intermediate (12) is as follows：
R therein1、R2With the R in alkenyl ether compound (4) in the 4th step1、R2It is identical,
R3、R4、R5、R6From the R in the paranitrophenylhydrazine (6) of above-mentioned different substituent groups3、R4、R5、R6It is identical, RfFor independent claims
R described in 1f, it is trifluoromethyl or difluoromethyl；
11st step：1 mole of intermediate (12) is finally given again with 2 moles of acetic anhydride under 3 moles of triethylamine effect
Han Fu oxazolidinone compounds (13)；
The structural formula of the Han Fu oxazolidinone compounds (13) is as follows：
R therein1、R2With the R in alkenyl ether compound (4) in the 4th step1、R2It is identical,
R3、R4、R5、R6From the R in the paranitrophenylhydrazine (6) of above-mentioned different substituent groups3、R4、R5、R6It is identical, RfFor independent claims
R described in 1f, it is trifluoromethyl or difluoromethyl.
5. a kind of fluorine-containing oxazolidinone compounds as described in claim 1,2 or 3 are used as to watermelon anthrax bacteria or Huang
The disinfectant use in agriculture of melon ash arrhizus bacteria is used.
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