CN104788396A - Preparation method of N-substituted oxazolone polymer derivatives - Google Patents

Preparation method of N-substituted oxazolone polymer derivatives Download PDF

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Publication number
CN104788396A
CN104788396A CN201510155135.XA CN201510155135A CN104788396A CN 104788396 A CN104788396 A CN 104788396A CN 201510155135 A CN201510155135 A CN 201510155135A CN 104788396 A CN104788396 A CN 104788396A
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substituted
alkyl
phenyl
reaction
formula
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邹成
周兴华
曹蓓
徐化成
P·K·阿加瓦尔
C·K·I·那迦
贺耘
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Chongqing University
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Chongqing University
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Priority to CN201610009872.3A priority patent/CN106045935A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36—One oxygen atom
    • C07D263/38—One oxygen atom attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to a preparation method of N-substituted oxazolone polymer derivatives. An available reagent boron trifluoride diethyl ether is taken as a catalyst and influences dimerization and cascading dimerization/cyclization among N-substituted oxazolone molecules under the mild reaction condition. The method is insensitive to water in a reaction system, the same reaction can be performed under the condition of water, and the same productive rate and speed are kept. The novel reaction condition and the efficient transformation mode can be more applied to synthesis of various molecules and industrial production.

Description

The preparation method of N-substituted oxazoline ketone polymeric derivative
Technical field
The invention belongs to organic synthesis and field of pharmaceutical chemistry technology, relate to N-substituted oxazoline ketone polymeric derivative and preparation method.
Background technology
At organic synthesis and medicinal chemistry art, efficient and to synthesize complicated and diversified molecular structure be the target that laboratory and industry member make great efforts to reach environmentally friendlyly all the time, this target actually operating difficulty, has very strong challenge.
According to the people such as Argade (E-Journal of Chemistry Vol.5, No.1, pp.120-129, January 2008) report, oxazolone because of its widely biological activity become one of the most attractive molecule in heterogeneous ring compound, it is also intermediate important in the complete synthesis field of natural product.But, about the organic reaction of 2,3-hydrogen-1,3-oxazoles ketone and chemically reactive research but always delayed, and its applied research in natural product synthesis is very limited.
Replace in double bond in 2, the 3-hydrogen-1,3-oxazoles ketone reactivity process in natural product is complete synthesis seeking nitrogen, invention personnel have found dimerization or the annulation of nitrogen substituted oxazoline ketone uniqueness, as shown in the formula representative boron trifluoride diethyl etherate (BF 3et 2o) the nitrogen substituted oxazoline ketone dimerization reaction of catalyzer is made:
This kind of reaction can be summarized as intermolecular Aza-Prins dimerization reaction.Find through literature search, what this kind of dimerization or annulation were reported in the literature only has two examples, the method used as the people such as G.Cum (Tetrahedron Vol.36.pp.745to 751) is using the sulfuric acid of 50%-65% as reaction reagent, but it needs the longer reaction times when cyclisation.
According to prior art, from industrial angle, be necessary to develop operability stronger and the multiple dimerization of N-substituted oxazoline ketone molecule that condition is gentleer or the technique of annulation.
Summary of the invention
The present invention develops efficiently a kind of, novel molecule dimerization, the method for cascade dimerization/cyclisation.Method in the present invention is insensitive to the water in reaction system, same reaction can occur in the presence of water and keep identical productive rate and speed.The gentle transform mode efficiently of this novel reaction conditions can more be applied in synthesis different kinds of molecules and industrial production.
The present invention, using the reagent boron trifluoride diethyl etherate that is easy to get as catalyzer, affects intermolecular conversion under the reaction conditions of gentleness, and multiple nitrogen substituted oxazoline ketone molecule reacts shown in following flow process:
R 1for substituted or non-substituted alkyl, thiazolinyl, cycloalkyl, ester group, substituted or non-substituted phenyl, the substituent R wherein on phenyl 3for alkyl, alkoxyl group, the alkoxyl group of halogen substiuted, the halogen of alkyl, halogen substiuted; R 2for hydrogen or methyl.In this flow process, multiple heterocycles molecule can be synthesized, and nitrogen substituted oxazoline ketone molecule is as alkyl, and aryl molecule can carry out this reaction, and reaction yield is high, and reaction conditions is gentle, and universality is fine.
The technical scheme adopted for technical solution problem in the present invention is: in the organic solvent solution containing reaction substrate nitrogen substituted oxazoline ketone molecule, drip catalyzer boron trifluoride diethyl etherate, reaction is carried out in tube sealing, react with alkali lye cancellation, organic solvent extraction, mixing organic phase dry filter rotary evaporation after washing, obtains thick product.Thick product, through silica gel column chromatography, obtains sterling.
Specifically, in the present invention with formula (I) compound for reaction substrate
Find to work as R 1when group is substituted or non-substituted alkyl, thiazolinyl, cycloalkyl or ester group, using boron trifluoride diethyl etherate as catalyzer, under normal temperature, there is not any reaction, under 50 DEG C of heating conditions, be obtained by reacting the dimerisation products shown in formula (II)
Work as R 1group is substituted or non-substituted phenyl, the substituent R wherein on phenyl 3for alkyl, alkoxyl group, the alkoxyl group of halogen substiuted, the halogen of alkyl, halogen substiuted, R 2when group is hydrogen, using boron trifluoride diethyl etherate as catalyzer, under normal temperature, there is not any reaction, the one-tenth ring product under 50 DEG C of heating conditions shown in production (III)
Work as R 1group is substituted or non-substituted phenyl, the substituent R wherein on phenyl 3for alkyl, alkoxyl group, the alkoxyl group of halogen substiuted, the halogen of alkyl, halogen substiuted, R 2when group is methyl, using boron trifluoride diethyl etherate as catalyzer, the dimerisation products shown in production (II) under 25 DEG C of conditions, the one-tenth ring product under 50 DEG C of heating conditions then shown in production (III).Temperature determines to react the important determinative whether ring product occurs, generates dimerisation products or become.
Being in the preferred version of reaction substrate with formula (I) compound, work as R 1for C 1-6the cyclosubstituted C of alkyl, benzene 1-6when alkyl, allyl group, cyclohexyl, butyl propionate base, using boron trifluoride diethyl etherate as catalyzer, under normal temperature, there is not any reaction, under 50 DEG C of heating conditions, be obtained by reacting the dimerisation products shown in formula (II); Work as R 1group is substituted or non-substituted phenyl, the substituent R on phenyl 3for C 1-3the C of alkyl, halogen substiuted 1-3alkyl, C 1-3the C of alkoxyl group, halogen substiuted 1-3alkoxyl group, halogen, R 2when group is hydrogen, using boron trifluoride diethyl etherate as catalyzer, under normal temperature, there is not any reaction, the one-tenth ring product under 50 DEG C of heating conditions shown in production (III); Work as R 1group is substituted or non-substituted phenyl, the substituent R on phenyl 3for C 1-3the C of alkyl, halogen substiuted 1-3alkyl, C 1-3the C of alkoxyl group, halogen substiuted 1-3alkoxyl group, halogen, R 2when group is methyl, using boron trifluoride diethyl etherate as catalyzer, the dimerisation products shown in production (II) under 25 DEG C of conditions, the one-tenth ring product under 50 DEG C of heating conditions shown in production (III).
In the more preferably scheme taking formula (I) compound as reaction substrate, work as R 1for C 1-3the cyclosubstituted C of alkyl, benzene 1-3when alkyl, allyl group, cyclohexyl, butyl propionate base, using boron trifluoride diethyl etherate as catalyzer, under normal temperature, there is not any reaction, under 50 DEG C of heating conditions, be obtained by reacting the dimerisation products shown in formula (II); Work as R 1group is substituted or non-substituted phenyl, the substituent R on phenyl 3for C 1-3alkyl, trifluoromethyl, methoxyl group, oxyethyl group, trifluoromethoxy, halogen, R 2when group is hydrogen, using boron trifluoride diethyl etherate as catalyzer, under normal temperature, there is not any reaction, the one-tenth ring product under 50 DEG C of heating conditions shown in production (III); Work as R 1group is substituted or non-substituted phenyl, the substituent R on phenyl 3for C 1-3alkyl, trifluoromethyl, methoxyl group, oxyethyl group, trifluoromethoxy, halogen, R 2when group is methyl, using boron trifluoride diethyl etherate as catalyzer, the dimerisation products shown in production (II) under 25 DEG C of conditions, the one-tenth ring product under 50 DEG C of heating conditions shown in production (III).
In the present invention, catalyzer boron trifluoride diethyl etherate (BF 3et 2o) with the consumption mol ratio of substrate preferably but be not limited to 1:2.
In the present invention, the organic solvent of reaction system preferably but be not limited to methylene dichloride (DCM).
In the present invention, the temperature in reaction system preferably but be not limited to 25 DEG C and 50 DEG C.
In the present invention, in reaction process preferably but be not limited to thin-layer chromatography (TLC) method to monitor reaction process.
In the present invention, extraction organic solvent preferably but be not limited to methylene dichloride.
In the present invention, the liquid of washing organic phase preferably but be not limited to water and saturated NaCl solution
In the present invention, column chromatography preferably but be not limited to silica gel as chromatography media, 300-400 order.
In the present invention, preferably but be not limited to petrol ether/ethyl acetate, its ratio preferably but be not limited to 1/1 for column chromatography moving phase.
In an embodiment of the invention, in the DCM solution of reaction substrate, drip BF 3et 2o, tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3cancellation is reacted, and stirs 5 minutes.DCM extracts 3 times, and mixing organic phase is also washed with water, saturated NaCl respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure dimerisation products.
In another embodiment of the invention, in the DCM solution of reaction substrate, drip BF 3et 2o, tube sealing.Reaction mixture stirs 12 hours under 25 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3cancellation is reacted, and stirs 5 minutes.DCM extracts 3 times, and mixing organic phase is also washed with water, saturated NaCl respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure dimerisation products.
In another embodiment of the invention, in the DCM solution of reaction substrate, drip BF 3et 2o, tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3cancellation is reacted, and stirs 5 minutes.DCM extracts 3 times, and mixing organic phase is also washed with water, saturated NaCl respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure one-tenth ring product.
Embodiment
Monitoring method in arbitrary embodiment of the present invention is: thin layer chromatography.
Structural identification technique means is the current techique means that those skilled in the art know, melting point apparatus, 400MHz nuclear magnetic resonance technique etc.
Dimerization reaction embodiment
Embodiment 1:3-allyl group-5-(3-allyl group-2-oxo oxazolidine-4-base) oxazole-2 (3H)-one
BF is dripped in the DCM solution (2ml) of reaction substrate 1a (77.6mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 2a (productive rate 98%).
Colourless oil liquid; Rf=0.21 (Hexane/EtOAc=3/2); 1h NMR (CDCl 3, 400MHz): δ 6.51 (1H, s), 5.88-5.82 (1H, m), 5.76-5.70 (1H, m), 5.34-5.15 (4H, m), 4.61 (1H, dd, J=9.2,7.2Hz), (4.60 1H, t, J=8.8Hz), 4.31 (1H, dd, J=8.4,6.8Hz), 4.16 (2H, d, J=6.4Hz), 4.10 (1H, dd, J=15.6,4.8Hz), 3.53 (1H, dd, J=15.6,7.2Hz); 13c NMR (CDCl 3, 400MHz): δ 156.9,154.5,134.2,131.4,131.1,119.7,118.9,114.5,64.6,51.3,46.4,44.9.
Embodiment 2:5-(2-oxo-3-propyl group oxazolidine-4-base)-3-propyl group oxazole-2 (3H)-one
BF is dripped in the DCM solution (2ml) of reaction substrate 1b (79mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 2b (productive rate 85%).
Colourless oil liquid; Rf=0.22 (Hexane/EtOAc=3/2); 1h NMR (CDCl 3, 600MHz): δ 6.54 (1H, s), 4.61 (1H, dd, J=8.4,6.6Hz), 4.45 (1H, t, J=9.3Hz), 4.30 (1H, dd, J=8.4,6.6Hz), 3.55-3.52 (2H, m), 3.39-3.34 (1H, m), 3.00-2.96 (1H, m), 1.73-1.69 (2H, m), 1.56-1.48 (2H, m), 0.96 (3H, t, J=7.2Hz), 0.90 (3H, t, J=7.2Hz); 13c NMR (CDCl 3, 400MHz): δ 157.3,154.8,134.2,114.8,64.5,51.8,45.7,43.9,22.0,20.5,10.9,10.8.
Embodiment 3:3-benzyl-5-(3-benzyl-2-oxo oxazolidine-4-base) oxazole-2 (3H)-one
BF is dripped in the DCM solution (2ml) of reaction substrate 1c (109mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 2c (productive rate 87%).
White solid (fusing point: 125-126 DEG C); Rf=0.33 (Hexane/EtOAc=3/2); 1h NMR (CDCl3,400MHz): δ 7.40-7.14 (10H, m), 6.23 (1H, s), 4.69 (1H, d, J=15.6Hz), 4.66 (2H, s), 4.38-4.29 (3H, m), 4.02 (1H, d, J=15.2Hz); 13c NMR (CDCl 3, 400MHz): δ 157.3,154.5,135.1,134.7,133.8,129.1,128.6,128.6,128.1,127.9,127.9,114.8,64.3,51.1,47.8,46.4.
Embodiment 4:3-sec.-propyl-5-(3-isopropyl-4-methyl-2-oxo oxazolidine-4-base)-4-methyl oxazole-2 (3H)-one
BF is dripped in the DCM solution (2ml) of reaction substrate 1d (87.5mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 2d (productive rate 92%).
White solid (fusing point: 130-131 DEG C); Rf=0.36 (Hexane/EtOAc=3/2); 1h NMR (CDCl 3, 400MHz): δ 4.35 (1H, d, J=8.8Hz), 4.07 (1H, d, J=8.8Hz), 4.05-4.02 (1H, m), 3.37-3.31 (1H, m), 2.12 (3H, s), 1.64 (3H, s), 1.47 (3H, d, J=2.8Hz), 1.45 (3H, d, J=3.6Hz), 1.35 (3H, d, J=6.8Hz), 1.26 (3H, d, J=7.2Hz); 13c NMR (CDCl 3, 400MHz): δ 155.0,153.2,133.5,121.4,73.4,60.0,46.1,45.0,23.4,20.6,20.1,20.0,19.8,9.2.
Embodiment 5:3-cyclohexyl-5-(3-cyclohexyl-4-methyl-2-oxo oxazolidine-4-base)-4-methyl oxazole-2 (3H)-one
BF is dripped in the DCM solution (2ml) of reaction substrate 1e (113mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally carries out drying with Na2SO4, carries out rotary evaporation after filtration, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 2e (productive rate 83%).
White solid (fusing point: 134-135 DEG C); Rf=0.36 (Hexane/EtOAc=3/2); 1h NMR (CDCl 3, 600MHz): δ 4.34 (1H, d, J=9.0Hz), 4.06 (1H, d, J=9.0Hz), 3.58-2.91 (1H, m), 2.91-2.87 (1H, m), 2.14-2.04 (7H, m), 1.88-1.66 (8H, m), 1.62 (3H, s), 1.59-1.57 (2H, m), 1.42-1.12 (7H, m); 13c NMR (CDCl 3, 400MHz): δ 155.1,153.3,133.7,121.4,73.4,59.9,54.1,53.3,30.3,29.8,29.7,29.6,26.0,26.0,25.7,24.8,24.7,23.6,9.3.
Embodiment 6:3-benzyl-5-(3-benzyl-4-methyl-2-oxo oxazolidine-4-base)-4-methyl oxazole-2 (3H)-one
BF is dripped in the DCM solution (2ml) of reaction substrate 1f (117.3mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 2f (productive rate 85%).
White solid (fusing point: 134-135 DEG C); Rf=0.36 (Hexane/EtOAc=3/2); 1h NMR (CDCl 3, 400MHz): δ 7.37-7.16 (10H, m), 4.57 (1H, d, J=15.6Hz), 4.48 (1H, d, J=16.0Hz), 4.42-4.39 (2H, m), 4.30 (1H, d, J=15.2Hz), 4.07 (1H, d, J=8.4Hz) 13c NMR (CDCl 3, 400MHz): δ 157.1,154.3,136.8,135.5,132.4,128.9,128.3,128.1,127.9,127.5,127.1,121.7,73.3,59.0,45.1,44.9,22.5,8.7.
Embodiment 7:3-(4-p-methoxy-phenyl)-5-(3-(4-p-methoxy-phenyl)-4-methyl-2-oxo oxazolidine-4-base)-4-methyl oxazole-2 (3H)-one
BF is dripped in the DCM solution (2ml) of reaction substrate 1g (127.2mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 25 DEG C of room temperature conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 2g (productive rate 85%).
White solid (fusing point: 166-167 DEG C); Rf=0.22 (Hexane/EtOAc=3/2); 1h NMR (CDCl 3, 400MHz): δ 7.14 (2H, d, J=8.4Hz), δ 7.11 (2H, d, J=8.8Hz), δ 6.98 (2H, d, J=8.8Hz), δ 6.92 (2H, d, J=8.8Hz), 4.72 (1H, d, J=8.4Hz), 4.27 (1H, d, J=8.4Hz), 3.83 (3H, s), 3.82 (3H, s), 1.77 (3H, s), 1.69 (3H, s); 13c NMR (CDCl 3, 400MHz): δ 159.9,159.1,156.1,153.6,133.1,128.9,128.8,126.9,125.1,123.0,114.9,114.6,73.3,61.3,55.5,55.4,22.8,9.4.
Embodiment 8:4-methyl-5-(4-methyl-2-oxo-3-(4-(trifluoromethoxy) phenyl) oxazolidine-4-base)-3-(4-(trifluoromethoxy) phenyl) oxazole-2 (3H)-one
BF is dripped in the DCM solution (2ml) of reaction substrate 1h (160.7mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 25 DEG C of room temperature conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 2h (productive rate 92%).
White solid (fusing point: 125-126 DEG C); Rf=0.47 (Hexane/EtOAc=3/2); 1h NMR (CDCl 3, 400MHz): δ 7.35-7.26 (8H, m), 4.70 (1H, d, J=8.4Hz), 4.30 (1H, d, J=8.4Hz), 1.85 (3H, s), 1.75 (3H, s); 13cNMR (CDCl 3, 400MHz): δ 155.6,152.9,149.3,147.9,133.6,133.3,130.9,129.1,127.6,122.2,122.1,121.8,73.7,61.2,22.3,9.4.
Embodiment 9:4-methyl-5-(4-methyl-2-oxo-3-(4-(trifluoromethyl) phenyl) oxazolidine-4-base)-3-(4-(trifluoromethyl) phenyl) oxazole-2 (3H)-one
BF is dripped in the DCM solution (2ml) of reaction substrate 1i (151mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 14 hours under 25 DEG C of room temperature conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 2i (productive rate 86%).
White solid (fusing point: 171-172 DEG C); Rf=0.50 (Hexane/EtOAc=3/2); 1h NMR (CDCl 3, 400MHz): δ 7.78 (2H, d, J=8.4Hz), δ 7.68 (2H, d, J=8.0Hz), δ 7.44 (2H, d, J=9.6Hz), δ 7.42 (2H, d, J=8.4Hz), 4.68 (1H, d, J=8.4Hz), 4.30 (1H, d, J=8.4Hz), 1.88 (3H, s), 1.79 (3H, s); 13c NMR (CDCl 3, 400MHz): δ 155.2,152.7,138.3,135.7,133.9,127.8,126.9,126.9,126.6,126.5,124.8,121.7,74.1,61.1,21.9,9.4.
Embodiment 10:3-(4-chloro-phenyl-)-5-(3-(4-chloro-phenyl-)-4-methyl-2-oxo oxazolidine-4-base)-4-methyl oxazole-2 (3H)-one
BF is dripped in the DCM solution (2ml) of reaction substrate 1j (130mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 25 DEG C of room temperature conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 2j (productive rate 89%).
White solid (fusing point: 195-197 DEG C); Rf=0.50 (Hexane/EtOAc=3/2); 1h NMR (CDCl 3, 400MHz): δ 7.47 (2H, d, J=9.2Hz), δ 7.38 (2H, d, J=9.2Hz), δ 7.19 (2H, d, J=8.4Hz), δ 7.18 (2H, d, J=8.8Hz), 4.68 (1H, d, J=8.8Hz), 4.27 (1H, d, J=8.4Hz), 1.81 (3H, s), 1.72 (3H, s); 13c NMR (CDCl 3, 400MHz): δ 155.5,152.9,135.3,133.5,133.3,131.0,130.0,129.6,128.8,127.4,122.3,73.7,61.2,22.4,9.4.
Embodiment 11:3-(3,5-3,5-dimethylphenyl)-5-(3-(3,5-3,5-dimethylphenyl)-4-methyl-2-oxo oxazolidine-4-base)-4-methyl oxazole-2 (3H)-one
BF is dripped in the DCM solution (2ml) of reaction substrate 1k (126mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 13 hours under 25 DEG C of room temperature conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 2k (productive rate 88%).
White solid (fusing point: 164-165 DEG C); Rf=0.54 (Hexane/EtOAc=3/2); 1h NMR (CDCl 3, 400MHz): δ 7.07 (1H, s), 6.96 (1H, s), 6.81 (4H, d, J=8.8Hz), 4.70 (1H, d, J=8.8Hz), 4.25 (1H, d, J=8.8Hz), 2.35 (6H, s), 2.32 (6H, s), 1.78 (3H, s), 1.69 (3H, s); 13c NMR (CDCl 3, 400MHz): δ 155.9,153.4,139.6,138.9,134.3,133.3,132.4,130.9,129.5,125.1,124.5,122.8,73.4,61.2,22.6,21.2,21.1,9.4.
Embodiment 12:5-(2-oxo-3-((S)-1-styroyl) oxazolidine-4-base)-3-((S)-1-styroyl) oxazole-2 (3H)-one
BF is dripped in the DCM solution (2ml) of reaction substrate 1l (117.5mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 2l (productive rate 84%, dr=1:1).
White solid (fusing point: 164-165 DEG C); Rf=0.54 (Hexane/EtOAc=3/2); 1h NMR (CDCl 3, 400MHz): δ 7.07 (1H, s), 6.96 (1H, s), 6.81 (4H, d, J=8.8Hz), 4.70 (1H, d, J=8.8Hz), 4.25 (1H, d, J=8.8Hz), 2.35 (6H, s), 2.32 (6H, s), 1.78 (3H, s), 1.69 (3H, s); 13c NMR (CDCl 3, 400MHz): δ 155.9,153.4,139.6,138.9,134.3,133.3,132.4,130.9,129.5,125.1,124.5,122.8,73.4,61.2,22.6,21.2,21.1,9.4.
Embodiment 13:n butyl (2S)-2-(4-(3-((S)-Ding-1-1-oxo third-2-base)-2-oxo-2,3-dihydro-oxazole-5-base)-2-oxo oxazolidine-pyridin-3-yl) ethyl propionate
BF is dripped in the DCM solution (2ml) of reaction substrate 1m (97mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture exists, and stirs 13 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 2m (productive rate 87%, dr=3:2).
Colourless oil liquid; Rf=0.40 (Hexane/EtOAc=3/2); 1h NMR (CDCl 3, 400MHz): δ 7.07 (1H, s), 6.96 (1H, s), 6.81 (4H, d, J=8.8Hz), 4.70 (1H, d, J=8.8Hz), 4.25 (1H, d, J=8.8Hz), 2.35 (6H, s), 2.32 (6H, s), 1.78 (3H, s), 1.69 (3H, s); 13c NMR (CDCl 3, 400MHz): δ 155.9,153.4,139.6,138.9,134.3,133.3,132.4,130.9,129.5,125.1,124.5,122.8,93.4,61.2,22.6,21.2,21.1,9.4.
Cascade dimerization/annulation embodiment
Embodiment 1:(3aS, 3bS, 11bS)-10-methoxyl group-1-(4-p-methoxy-phenyl)-3b, 11b-dimethyl-3a, 3b, 4,11b-tetrahydrochysene-6H-dioxazole also [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone
BF is dripped in the DCM solution (2ml) of reaction substrate 1g (127.2mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 11a (productive rate 86%).
White solid (fusing point: 210-211 DEG C); Rf=0.17 (Hexane/EtOAc=1/1); 1h NMR (CDCl 3, 400MHz): δ 7.92 (1H, d, J=8.8Hz), 6.92 (1H, dd, J=8.4,2.0Hz), 6.89 (1H, d, J=8.4Hz), 6.77 (1H, d, J=8.4Hz), 6.03 (1H, d, J=2.4Hz), 4.80 (1H, d, J=8.8Hz), 4.58 (1H, s), 4.17 (1H, d, J=8.8Hz), 3.80 (3H, s), 3.53 (3H, s), 1.82 (3H, s), 1.41 (3H, s); 13c NMR (CDCl 3, 400MHz): δ 159.9,155.6,154.9,154.1,131.8,127.1,125.8,124.6,122.9,115.4,114.4,112.8,83.6,70.0,61.4,59.0,55.5,55.2,27.5,21.1.
Embodiment 2:(3aS, 3bS, 11bS)-1-(3,5-3,5-dimethylphenyl)-3b, 9,11,11b-tetramethyl--3a, 3b, 4,11b-tetrahydrochysene-6H-dioxazole also [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone
BF is dripped in the DCM solution (2ml) of reaction substrate 1k (126mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 11b (productive rate 89%).
White solid (fusing point: >250 DEG C); Rf=0.44 (Hexane/EtOAc=1/1); 1h NMR (CDCl 3, 400MHz): δ 7.70 (1H, s), 7.01 (1H, s), 6.61 (1H, s), 6.39 (2H, s), 4.80 (1H, d, J=8.8Hz), 4.54 (1H, s), 4.15 (1H, d, J=8.8Hz), 2.32 (3H, s), 2.22 (6H, s), 2.03 (3H, s), 1.54 (3H, s), 1.39 (3H, s); 13c NMR (CDCl 3, 400MHz): δ 154.8,154.2,139.3,139.0,138.2,134.1,132.8,130.8,130.6,128.0,122.9,121.6,88.2,69.8,63.3,58.1,29.9,23.7,21.0,20.8,20.7.
Embodiment 3:(3aS, 3bS, 11bS)-10-oxyethyl group-1-(4-ethoxyl phenenyl)-3b, 11b-dimethyl-3a, 3b, 4,11b-tetrahydrochysene-6H-dioxazole also [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone
BF is dripped in the DCM solution (2ml) of reaction substrate 1n (136mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 11c (productive rate 81%).
White solid (fusing point: 149-150 DEG C); Rf=0.28 (Hexane/EtOAc=1/1); 1h NMR (CDCl 3, 400MHz): δ 7.89 (1H, d, J=8.4Hz), 6.90 (1H, d, J=8.8Hz), 6.85 (2H, d, J=8.4Hz), 6.75 (2H, d, J=8.4Hz), 6.04 (1H, s), 4.80 (1H, d, J=8.4Hz), 4.57 (1H, s), 4.17 (1H, d, J=8.4Hz), 4.04-3.99 (2H, m), 3.82-3.76 (1H, m), 3.66-3.62 (1H, m), 1.80 (3H, s), 1.42-1.40 (6H, m), (1.27 3H, t, J=6.8Hz); 13cNMR (CDCl 3, 400MHz): δ 159.3,155.0,154.9,154.1,131.8,127.1,125.6,124.6,122.8,115.9,114.9,113.7,83.7,70.0,63.7,63.7,61.4,59.1,27.5,21.2,14.6,14.6.
Embodiment 4:(3aS, 3bS, 11bS)-3b, 10,11b-trimethylammonium-1-(p-methylphenyl)-3a, 3b, 4,11b-tetrahydrochysene-6H-dioxazole is [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone also
BF is dripped in the DCM solution (2ml) of reaction substrate 1o (117.3mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 11d (productive rate 92%).
White solid (fusing point: 196-197 DEG C); Rf=0.38 (Hexane/EtOAc=1/1); 1h NMR (CDCl 3, 400MHz): δ 7.93 (1H, d, J=8.4Hz), 7.18-7.14 (3H, m), 6.68 (2H, d, J=8.0,1.6Hz), 6.62 (1H, s), 4.81 (1H, d, J=8.4Hz), 4.59 (1H, s), 4.17 (1H, d, J=8.0Hz), 2.37 (3H, s), 2.08 (3H, s), 1.82 (3H, s), 1.42 (3H, s); 13c NMR (CDCl 3, 400MHz): δ 154.8,153.9,139.1,133.5,130.6,130.5,130.2,129.6,128.9,128.2,125.5,121.1,83.6,70.0,61.3,58.9,27.4,21.2,21.1,20.8.
Embodiment 5:(3aS, 3bS, 11bS)-1-phenyl-3a, 3b, 4,11b-tetrahydrochysene-6H-dioxazole also [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone
BF is dripped in the DCM solution (2ml) of reaction substrate 10a (100mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 11e (productive rate 71%).
White solid (fusing point: >250 DEG C); Rf=0.28 (Hexane/EtOAc=1/1); 1h NMR (DMSO-d6,400MHz): δ 7.78 (1H, d, J=7.6Hz), 7.42-7.25 (7H, m), 6.88 (1H, t, J=7.4Hz), 6.73 (1H, d, J=8.0Hz), 5.88 (1H, d, J=8.4Hz), 5.41 (1H, d, J=8.0Hz), 4.65 (1H, t, J=8.4Hz), 4.54-4.44 (2H, m); 13c NMR (DMSO-d6,400MHz): δ 154.4,154.2,136.4,135.0,129.4,129.3,126.9,125.7,124.6,124.4,120.2,73.8,63.2,56.2,54.8.
Embodiment 6:(3aS, 3bS, 11bS) the fluoro-1-of-10-(4-fluorophenyl)-3a, 3b, 4,11b-tetrahydrochysene-6H-dioxazole is [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone also
BF is dripped in the DCM solution (2ml) of reaction substrate 10b (111mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 11f (productive rate 80%).
White solid (fusing point: 213-214 DEG C); Rf=0.21 (Hexane/EtOAc=1/1); 1h NMR (CDCl 3, 400MHz): δ 8.10 (1H, dd, J=9.2,4.8Hz), 7.11-7.04 (5H, m), 6.30 (1H, dd, J=8.4,2.8Hz), 5.36 (1H, d, J=8.4Hz), 5.22 (1H, dd, J=8.8,2.0Hz), 4.69 (1H, t, J=8.2Hz), 4.62 (1H, t, J=9.0Hz), 4.30-4.25 (1H, m); 13c NMR (DMSO-d6,400MHz): δ 161.9,169.5,159.3,156.9,154.9,154.2,132.4,131.5,128.5,128.4,126.5,126.4,122.2,122.1,116.7,116.6,116.5,116.4,116.3,115.9,115.7,73.7,63.2,56.5,54.9.
Embodiment 7:(3aS, 3bS, 11bS)-10-methyl isophthalic acid-(p-methylphenyl)-3a, 3b, 4,11b-tetrahydrochysene-6H-dioxazole also [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone
BF is dripped in the DCM solution (2ml) of reaction substrate 10c (109mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 11g (productive rate 92%).
White solid (fusing point: >250 DEG C); Rf=0.32 (Hexane/EtOAc=1/1); 1h NMR (CDCl 3, 400MHz): δ 7.94, (1H, d, J=8.0Hz), 7.16 (2H, d, J=7.6Hz), 7.12 (1H, d, J=8.4Hz), 6.96 (2H, d, J=6.8Hz), 6.37 (1H, s), 5.33 (1H, d, J=8.4Hz), 5.18 (1H, d, J=8.8Hz), 4.67 (1H, t, J=8.0Hz), 4.59 (1H, t, J=9.0Hz), 4.25 (1H, dd, J=8.8,4.8Hz), 2.31 (3H, s), 2.03 (3H, s); 13c NMR (DMSO-d6,400MHz): δ 153.9,153.8,135.9,133.4,132.8,131.9,129.5,129.4,129.4,125.5,123.8,119.5,73.2,62.8,56.0,54.3,20.5,20.3.
Embodiment 8:(3aS, 3bS, 11bS)-10-(trifluoromethoxy)-1-(4-(trifluoromethoxy) phenyl)-3a, 3b, 4,11b-tetrahydrochysene-6H-dioxazole also [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone
BF is dripped in the DCM solution (2ml) of reaction substrate 10d (152mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 13.5 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 11h (productive rate 86%).
White solid (fusing point: 212-213 DEG C); Rf=0.25 (Hexane/EtOAc=1/1); 1h NMR ((DMSO-d6,400MHz): δ 7.92 (1H, d, J=9.0Hz), 7.45 (2H, d, J=8.4Hz), 7.40 (2H, d, J=8.4Hz), 7.34 (1H, dd, J=9.0,1.8Hz), 6.70 (1H, s), 5.92 (1H, d, J=7.8Hz), 5.48 (1H, d, J=8.4Hz), 4.67 (1H, t, J=9.0Hz), 4.56 (1H, t, J=7.5Hz), 4.48 (1H, dd, J=8.4,6.6); 13c NMR ((DMSO-d6,400MHz): δ 153.9,153.5,146.3,134.6,133.9,127.6,125.6,122.3,121.9,121.4,121.3,120.8,120.5,119.1,118.8,73.2,62.9,55.8,54.4.
Embodiment 9:(3aS, 3bS, 11bS)-10-(trifluoromethyl)-1-(4-(trifluoromethyl) phenyl)-3a, 3b, 4,11b-tetrahydrochysene-6H-dioxazole also [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone
BF is dripped in the DCM solution (2ml) of reaction substrate 10e (142.1mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 11i (productive rate 74%).
White solid (fusing point: >250 DEG C); Rf=0.28 (Hexane/EtOAc=1/1); 1h NMR ((DMSO-d6,400MHz): δ 8.06 (1H, d, J=8.4Hz), 7.94 (1H, dd, J=40,8.0Hz), 7.96 (2H, d, J=8.0Hz), 7.69 (1H, d, J=8.4Hz), 7.61 (2H, d, J=8.4Hz), 7.06 (1H, s), 6.07 (1H, d, J=8.0Hz), 5.53 (1H, dd, J=8.0,1.2Hz), 4.69 (1H, t, J=8.8Hz), 4.62-4.58 (1H, m), 4.49 (1H, dd, J=8.0,6.4Hz); 13c NMR (DMSO-d6,400MHz): δ 153.7,153.3,139.4,138.4,127.9,126.9,126.6,126.2,126.1,125.9,125.3,124.9,123.8,123.5,122.6,122.2,119.7,73.1,63.0,55.4,54.3.
Embodiment 10:(3aS, 3bS, 11bS)-10-(trifluoromethyl)-1-(4-(trifluoromethyl) phenyl)-3a, 3b, 4,11b-tetrahydrochysene-6H-dioxazole also [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone
BF is dripped in the DCM solution (2ml) of reaction substrate 10f (117.3mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 15 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 11j (productive rate 85%).
White solid (fusing point: >250 DEG C); Rf=0.25 (Hexane/EtOAc=1/1); 1h NMR (DMSO-d6): δ 7.47 (1H, s), 6.95 (1H, s), 6.75 (1H, s), 6.41 (2H, s), 4.68 (1H, d, J=8.4Hz), 5.38 (1H, dd, J=9.0,2.4Hz), 4.58 (1H, t, J=9.3Hz), 4.45 (1H, dd, J=9.0,6.0Hz), 4.28-4.19 (1H, m), 2.26 (3H, s), 2.55 (6H, s), 1.57 (3H, s); 13c NMR (DMSO-d6,400MHz): δ 154.9,153.9,138.4,138.1,138.0,136.5,135.7,129.5,127.0,126.2,121.3,118.1,75.0,62.4,55.9,54.5,20.8,20.6,18.2.
Embodiment 11:(3aS, 3bS, 11bS) the chloro-1-of-10-(4-chloro-phenyl-)-3a, 3b, 4,11b-tetrahydrochysene-6H-dioxazole is [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone also
BF is dripped in the DCM solution (2ml) of reaction substrate 10g (121.3mg, 0.62mmol) 3et 2o (41 μ L, 0.5equiv.), tube sealing.Reaction mixture stirs 12 hours under 50 DEG C of conditions, after terminating with TLC board monitoring reaction, uses saturated NaHCO 3(5ml) cancellation reaction, and stir 5 minutes.DCM extracts 3 times (5mL x 3), and mixing organic phase also uses water (10mL), saturated NaCl (10mL) to wash respectively, finally uses Na 2sO 4carry out drying, after filtration, carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product 11k (productive rate 77%).
White solid (fusing point: 231-233 DEG C); Rf=0.22 (Hexane/EtOAc=1/1); 1h NMR (CDCl 3, 400MHz): δ 7.83 (1H, d, J=9.2Hz), 7.50 (2H, d, J=8.4Hz), 7.43 (1H, d, J=2.4Hz), 7.39 (2H, d, J=9.2Hz), 6.80 (1H, d, J=2.4Hz), 5.85 (1H, d, J=8.4Hz), 5.43 (1H, d, J=8.8Hz), 4.65 (1H, t, J=8.6Hz), 4.54-4.50 (1H, m), 4.47-4.38 (1H, m); 13c NMR (DMSO-d6,400MHz): δ 153.8,153.6,134.6,133.7,130.9,129.1,129.0,128.6,127.6,127.2,125.8,121.3,73.2,62.9,55.4,54.3.
The invention provides the preparation method of the dimerization of nitrogen substituted oxazoline ketone or the novelty of Cheng Huan, for those skilled in the art, reaction solvent system in this route, conventional reagent reagent, processing parameter, operation steps etc., all the practical situation in experimentally room or suitability for industrialized production workshop can be optimized screening and adjustment in conjunction with existing technical know-how and practical experience again, be not limited in the present invention cited limited embodiment.

Claims (20)

1. a preparation method for N-substituted oxazoline ketone polymeric derivative, is characterized in that, the reaction formula of this preparation method is:
Wherein with formula (I) compound for reaction substrate
R 1for substituted or non-substituted alkyl, thiazolinyl, cycloalkyl, ester group, substituted or non-substituted phenyl, the substituent R on phenyl 3for alkyl, alkoxyl group, the alkoxyl group of halogen substiuted, the halogen of alkyl, halogen substiuted; R 2for hydrogen or methyl; Catalyzer is boron trifluoride diethyl etherate; Reaction completes in organic solvent system.
2. preparation method as claimed in claim 1, is characterized in that, R 1for substituted or non-substituted C 1-6alkyl, allyl group, cyclohexyl, butyl propionate base, substituted or non-substituted phenyl, the substituent R on phenyl 3for C 1-3the C of alkyl, halogen substiuted 1-3alkyl, C 1-3the C of alkoxyl group, halogen substiuted 1-3alkoxyl group, halogen; R 2for hydrogen or methyl.
3. preparation method as claimed in claim 2, is characterized in that, R 1for substituted or non-substituted C 1-3alkyl, allyl group, cyclohexyl, butyl propionate base, substituted or non-substituted phenyl, the substituent R on phenyl 3for C 1-3alkyl, trifluoromethyl, methoxyl group, oxyethyl group, trifluoromethoxy, halogen; R 2for hydrogen or methyl.
4. the preparation method as described in any one of claim 1-3, is characterized in that, organic solvent system is methylene dichloride.
5. preparation method as claimed in claim 4, it is characterized in that, the consumption mol ratio of boron trifluoride diethyl etherate and substrate is 1:2.
6. preparation method as claimed in claim 5, is characterized in that, work as R 1during for substituted or non-substituted alkyl, thiazolinyl, cycloalkyl, ester group, under 50 DEG C of conditions, be obtained by reacting the dimerisation products shown in formula (II)
7. preparation method as claimed in claim 6, is characterized in that, work as R 1for substituted or non-substituted C 1-6when alkyl, allyl group, cyclohexyl, butyl propionate base, under 50 DEG C of conditions, be obtained by reacting the dimerisation products shown in formula (II).
8. preparation method as claimed in claim 7, is characterized in that, work as R 1for substituted or non-substituted C 1-3when alkyl, allyl group, cyclohexyl, butyl propionate base, under 50 DEG C of conditions, be obtained by reacting the dimerisation products shown in formula (II).
9. preparation method as claimed in claim 5, is characterized in that, work as R 1for substituted or non-substituted phenyl, the substituent R on phenyl 3for alkyl, alkoxyl group, the alkoxyl group of halogen substiuted, the halogen of alkyl, halogen substiuted, R 2during for hydrogen, under 50 DEG C of conditions, be obtained by reacting the one-tenth ring product shown in formula (III)
10. preparation method as claimed in claim 9, is characterized in that, work as R 1for substituted or non-substituted phenyl, the substituent R on phenyl 3for C 1-3the C of alkyl, halogen substiuted 1-3alkyl, C 1-3the C of alkoxyl group, halogen substiuted 1-3alkoxyl group, halogen, R 2during for hydrogen, under 50 DEG C of conditions, be obtained by reacting the one-tenth ring product shown in formula (III).
11. preparation methods as claimed in claim 10, is characterized in that, work as R 1for substituted or non-substituted phenyl, the substituent R on phenyl 3for C 1-3alkyl, trifluoromethyl, methoxyl group, oxyethyl group, trifluoromethoxy, halogen, R 2during for hydrogen, under 50 DEG C of conditions, be obtained by reacting the one-tenth ring product shown in formula (III).
12. preparation methods as claimed in claim 5, is characterized in that, work as R 1for substituted or non-substituted phenyl, the substituent R on phenyl 3for alkyl, alkoxyl group, the alkoxyl group of halogen substiuted, the halogen of alkyl, halogen substiuted, R 2during for methyl, under 25 DEG C of conditions, be obtained by reacting the dimerisation products shown in formula (II), under 50 DEG C of conditions, be obtained by reacting the one-tenth ring product shown in formula (III).
13. preparation methods as claimed in claim 12, is characterized in that, work as R 1for substituted or non-substituted phenyl, the substituent R on phenyl 3for C 1-3the C of alkyl, halogen substiuted 1-3alkyl, C 1-3the C of alkoxyl group, halogen substiuted 1-3alkoxyl group, halogen, R 2during for methyl, under 25 DEG C of conditions, be obtained by reacting the dimerisation products shown in formula (II), under 50 DEG C of conditions, be obtained by reacting the one-tenth ring product shown in formula (III).
14. preparation methods as claimed in claim 13, is characterized in that, work as R 1for substituted or non-substituted phenyl, the substituent R on phenyl 3for 3for C 1-3alkyl, trifluoromethyl, methoxyl group, oxyethyl group, trifluoromethoxy, halogen, R 2during for methyl, under 25 DEG C of conditions, be obtained by reacting the dimerisation products shown in formula (II), under 50 DEG C of conditions, be obtained by reacting the one-tenth ring product shown in formula (III).
15. preparation methods as claimed in claim 4, is characterized in that, comprise the steps: to drip boron trifluoride diethyl etherate in the dichloromethane solution of the reaction substrate shown in formula (I), react and carry out in tube sealing.Reaction mixture stirs under 25 DEG C or 50 DEG C of conditions, after reaction terminates, uses saturated NaHCO 3cancellation is reacted.Dichloromethane extraction 3 times, mixing organic phase is also washed with water, saturated NaCl respectively, finally uses Na 2sO 4carry out drying, carry out rotary evaporation after filtration, obtain crude product, crude product crosses column chromatography, obtains the sterling of compound shown in formula (II) or formula (III).
16. preparation methods as claimed in claim 15, it is characterized in that, column chromatography medium is silica gel.
17. preparation methods as claimed in claim 16, it is characterized in that, silica gel specification is 300-400 order.
18. preparation methods as claimed in claim 17, is characterized in that, the moving phase of silica gel column chromatography is sherwood oil and ethyl acetate mixture.
19. preparation methods as claimed in claim 18, is characterized in that, sherwood oil: ethyl acetate=3:1.
20. preparation methods as described in any one of claim 19, is characterized in that, adopt thin layer chromatography monitoring reaction process.
CN201510155135.XA 2015-04-02 2015-04-02 Preparation method of N-substituted oxazolone polymer derivatives Pending CN104788396A (en)

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