CN106045935A - Preparation method for oxazolone heterocyclic compounds - Google Patents

Preparation method for oxazolone heterocyclic compounds Download PDF

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CN106045935A
CN106045935A CN201610009872.3A CN201610009872A CN106045935A CN 106045935 A CN106045935 A CN 106045935A CN 201610009872 A CN201610009872 A CN 201610009872A CN 106045935 A CN106045935 A CN 106045935A
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alkyl
hydrogen
reaction
phenyl
aryl
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曹蓓
邹成
周兴华
徐化成
徐标
P·K·阿加瓦尔
C·K·I·那迦
贺耘
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Chongqing University
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30Heterocyclic 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
    • C07D263/34Heterocyclic 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
    • C07D263/36One oxygen atom
    • C07D263/38One oxygen atom attached in position 2
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02Heterocyclic 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 two hetero rings
    • C07D498/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12Heterocyclic 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
    • C07D498/14Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12Heterocyclic 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
    • C07D498/18Bridged systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22Heterocyclic 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 four or more hetero rings
    • YGENERAL 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
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention relates to a preparation method for N-substituted oxazolone polymerized compounds. According to the method, the easily available reagent, boron trifluoride ether, is used as a catalyst, and dimerization, cascaded dimerization/cyclization, terminal butylene cyclization and secondary cyclization among N-substituted oxazolone molecules are influenced under mild reaction conditions. The method is not sensitive to water in a reaction system, and identical reactions and same yield and rate may be realized under aqueous conditions. The novel preparation method with the advantages of mild reaction condition and high-efficiency conversion can be more extensively applied to synthesis of a plurality of molecules and industrial production.

Description

The preparation method of oxazolone heterocyclic compounds
Technical field
The invention belongs to organic synthesis and field of pharmaceutical chemistry technology, relate to oxazolone heterocyclic compounds and preparation side Method.
Background technology
At organic synthesis and medicinal chemistry art, synthesize complicated and diversified molecular structure efficient and environmentally friendlyly and begin It is laboratory eventually and industrial quarters makes great efforts the target that reaches, this target practical operation difficulty, there is the strongest challenge.
According to Argade et al. (E-Journal of Chemistry, Vol.5, No.1, pp.120-129, January 2008) report, oxazolone is because of its one of the most attractive molecule during biological activity becomes heterocyclic compound widely, and it is also Intermediate important in the complete synthesis field of natural product.Oxazolone compounds has extensive use, can be used for medicine, pesticide, Polymer modified, organic synthesis intermediate etc., oxazolone heterocycle structure is also used as many alkaloids and the conjunction of iminosugar Become precursor.Azabicyclo alkaloid structure can be used for constituting the division center skeleton of multiple natural alkaloid.
Oxazolone structural compounds has important application in many chemical conversions reactions, such as cycloaddition reaction, freedom Base reacts, metal catalysed cross coupling reaction etc., and some natural or synthesis 2-oxazolidones have been found good Biological activity, including anti-inflammatory activity, the anti-tumor activity, (Palladium-catalyzed such as tranquillizing and allaying excitement and cardiac activity direct alkenylation of 2-oxazolones:an entry to 3,4,5-trisubstituted 2- oxazolones)。
Organic reaction and chemism research about oxazolone structural compounds are the most delayed, and it is at natural product Applied research in thing synthesis is very limited.Oxazolone compounds dimerization reported in prior art or cascade dimerization (cyclisation) Seldom, the method that G.Cum et al. (Tetrahedron Vol.36.pp.745 to 751) uses is with 50%-65% in reaction Sulphuric acid is as reaction reagent, but it needs the response time of more than 24 hours when cyclisation, and sulphuric acid is that a kind of danger is higher Reagent.
Polymerization or the annulation of the oxazolone compound of existing document report there is also a lot of problem, including reaction temperature Require harsh (subzero 78 DEG C need to be cooled to) (eactivity of chiral exocyclic N-acyliminium ions with aromatic derivatives);Response time long (reacting one day under the conditions of 180 DEG C) (2-Dienylphenacyl oxazolones and an intramolecular Diels–Alder approach to the A–B–C ring system of phenanthridone alkaloids);Reaction selectivity relatively low (two kinds of anomeric product ratios are 3.1:1) (Oxazolone cycloadducts as heterocyclic scaffolds for alkaloid construction: synthesis of(2-epi-pumiliotoxin C);Unfriendly (the One-Pot Stereoselective of environment Synthesis of 1,2-Amino Alcohol Derivatives) and reaction cost high.
According to prior art, from commercial production and the angle of realization quickly preparation, it is necessary to carry out workable And the research of the heterocycle reaction of the multiple oxazolone molecule of mild condition, exploitation operability is higher and condition is gentleer many Plant oxazolone molecule dimerization or the technique of annulation.
Summary of the invention
The inventors found that the boron trifluoride diethyl etherate (BF of uniqueness3·Et2O) catalysis carbon-carbon bond formation is anti- Should, the polymerization of the most multiple substituted oxazolone compound uniqueness or annulation.Oxazolone substrate is at BF3·Et2Under the catalysis of O The Aza-Prins reaction carried out, condition is gentleer, environmental friendliness, and reaction obtains good productivity, and in hgher efficiency, reaction Formula is as follows:
Polymerization or annulation that above-mentioned this kind of oxazolone compound is unique can be concluded and react into Aza-Prins, Overall reaction with I formula compound as substrate can be divided into again three different directions, respectively Part I dimerization/cascade dimerization (cyclisation) reaction (IIa and IIb formula compound);Part II is polysubstituted end butylene annulation (IIIa and IIIb formula Compound);Part III is secondary annulation (IVa and IVb formula compound).
The first the Direction of Reaction that the present invention provides, a kind of efficient and novel molecule with I formula compound as substrate The method of dimerization/cascade dimerization (cyclisation).This method is insensitive to the water in reaction system, it is possible to occur in the presence of water Same reaction also keeps identical productivity and speed.The gentle efficient transform mode of this novel reaction condition is many in synthesis Plant in molecule and commercial production and can more be applied.The method is with the reagent BF that is easy to get3·Et2O as catalyst, Affect intermolecular conversion under gentle reaction condition, react as shown in following flow process:
Wherein R1For substituted or non-substituted alkyl, thiazolinyl, cycloalkyl, ester group, substituted or non-substituted phenyl, wherein benzene Substituent R on base3For alkyl, the alkyl of halogen substiuted, alkoxyl, the alkoxyl of halogen substiuted, halogen;R2For hydrogen or methyl.
Specifically, this method is with compound of formula I as reaction substrate
Work as R1Group is the substituent groups such as substituted or non-substituted alkyl, thiazolinyl, cycloalkyl, ester group, R2During for hydrogen or methyl, Using boron trifluoride diethyl etherate as catalyst, under room temperature, there is not any reaction, react under 50 DEG C of heating conditions and obtain shown in Formula II a Dimerisation products
Work as R1Group be the substituent group on phenyl or substituted-phenyl, and phenyl be alkyl, the alkyl of halogen substiuted, alcoxyl Base, the alkoxyl of halogen substiuted, halogen, R2When group is hydrogen, using boron trifluoride diethyl etherate as catalyst, do not occur under room temperature to appoint What reaction, the cyclization product shown in production IIb under 50 DEG C of heating conditions
Work as R1Group be the substituent group on phenyl or substituted-phenyl, and phenyl be alkyl, the alkyl of halogen substiuted, alcoxyl Base, the alkoxyl of halogen substiuted, halogen, R2When group is methyl, using boron trifluoride diethyl etherate as catalyst, raw under the conditions of 25 DEG C Dimerisation products shown in accepted way of doing sth IIa, the then cyclization product shown in production IIb under 50 DEG C of heating conditions.
In this section, temperature is whether decision reaction occurs, is to generate dimerisation products or the important decision of cyclization product Factor.
In the preferred version with compound of formula I as reaction substrate:
(1) R is worked as1For C1-6The substituted C of alkyl, phenyl ring1-6Alkyl, pi-allyl, cyclohexyl, butyl propionate base, R2For hydrogen or first During base, using boron trifluoride diethyl etherate as catalyst, any reaction not occurring under room temperature, under 50 DEG C of heating conditions, reaction obtains formula Dimerisation products shown in IIa;
(2) R is worked as1Group is phenyl or substituted-phenyl, and the substituent group on phenyl is C1-3Alkyl, the C of halogen substiuted1-3Alkane Base, C1-3Alkoxyl, the C of halogen substiuted1-3Alkoxyl, halogen, R2When group is hydrogen, using boron trifluoride diethyl etherate as catalyst, Any reaction is there is not, the cyclization product shown in production IIb under 50 DEG C of heating conditions under room temperature;
(3) R is worked as1Group is phenyl or substituted-phenyl, and the substituent group on phenyl is C1-3Alkyl, the C of halogen substiuted1-3Alkane Base, C1-3Alkoxyl, the C of halogen substiuted1-3Alkoxyl, halogen, R2When group is methyl, using boron trifluoride diethyl etherate as catalysis Agent, the dimerisation products shown in production IIa under the conditions of 25 DEG C, the cyclization product shown in production IIb under 50 DEG C of heating conditions.
The second the Direction of Reaction that the present invention provides, a kind of efficient and eco-friendly with I formula compound for substrate system Standby oxazolone the method for 6-membered heterocyclic compound.Method in the method is insensitive to the water in reaction system, it is possible to having Same reaction occurring under conditions of water and keeps identical productivity and speed, being suitable to industrial applications, reaction equation is as follows:
Wherein R1Group isI.e. end butylene structure;R2Group is hydrogen;Replacement in end butylene structure Base R3For hydrogen, alkyl, pi-allyl, the substituted alkyl of aryl;R4For hydrogen, alkyl, pi-allyl, benzyl;R5For alkyl, pi-allyl, alkane The substituted aryl of base, the substituted aryl of alkoxyl, the aryl of halogen substiuted, heterocyclic radical etc..
Specifically, with compound of formula I as reaction substrate in this method
Wherein R1ForR2For hydrogen, R3And R4Difference can obtain different cyclization products, i.e. hexa-member heterocycle The position of middle double bond is different:
Work as R4Group is hydrogen, the R of end butylene carbochain3And R5Substituted radical is respectively: (1) R3For hydrogen, R5For alkyl, fragrance The substituted alkyl of group, pi-allyl, aryl, the aryl of halogen substiuted, the substituted aryl of alkyl;(2)R3For alkyl, R5For hydrogen; (3)R3For alkyl, R5During for alkyl, the aryl of halogen substiuted, heterocyclic radical, using boron trifluoride diethyl etherate as catalyst, temperate condition Cyclization product shown in lower production IIIa;
Work as R3Group is hydrogen, the R of end butylene carbochain4And R5Respectively: (1) R4For alkyl, R5For aryl, halogen substiuted Aryl;(2)R4For pi-allyl, R5For aryl;(3) 3,4 carbon and aforementioned R5Group cyclization, and 3, when being double bond between 4 carbon, with Boron trifluoride diethyl etherate as catalyst, the cyclization product shown in production IIIb under temperate condition.
In the preferred version with compound of formula I as reaction substrate:
(1) R is worked as4For hydrogen, the R of end butylene carbochain3And R5Substituted radical is respectively: R3For hydrogen, R5For C1-6Alkyl, aryl Substituted C1-6Alkyl, pi-allyl, aryl, the aryl of halogen substiuted, C1-6The substituted aryl of alkyl;R3For C1-6Alkyl, R5For hydrogen; R3For C1-6Alkyl, R5For C1-6When alkyl, the aryl of halogen substiuted, heterocyclic radical, using boron trifluoride diethyl etherate as catalyst, gentle Under the conditions of the product shown in production IIIa;
(2) R is worked as3Group is hydrogen, the R of end butylene carbochain4And R5Substituted radical is respectively: R4For C1-6Alkyl, R5For virtue Base, the aryl of halogen substiuted;R4For pi-allyl, R5For aryl;3,4 carbon and aforementioned R5Group becomes between phenyl ring or 3,4 carbon of one-tenth During the heterocycle of double bond, using boron trifluoride diethyl etherate as catalyst, the cyclization product shown in production IIIb under temperate condition.
In the method for this part, multiple heterocycles molecule can be synthesized, and reaction yield is high, and reaction condition is gentle, at 25-50 All can react under the conditions of DEG C, universality is good.
The third the Direction of Reaction that the present invention provides, a kind of efficient and eco-friendly with I formula compound for substrate system Standby oxazolidone the hexa-atomic and method of oxygen heterocycle cyclisation.Method in the method is insensitive to the water in reaction system, energy Enough there is same reaction in the presence of water and keep identical productivity and speed.This novel reaction condition gentleness is high The transform mode of effect can more be applied in synthesis different kinds of molecules and commercial production.
This method, using the reagent boron trifluoride diethyl etherate that is easy to get as catalyst, affects intermolecular under gentle reaction condition Converting, the reaction equation of the method is as follows:
Wherein R1ForR2For hydrogen;R9For hydrogen and other silanes or alkyls Protection group, R6And R7For hydrogen, alkyl;R8For hydrogen, halogen, alkyl;N=1-3 can be five yuan, hexa-atomic, heptatomic ring is dilute, and X is miscellaneous During atomic radical, using boron trifluoride diethyl etherate as catalyst, under temperate condition, generate two secondary rings shown in corresponding IVa or IVb Change product.
Specifically, with compound of formula I as reaction substrate in this method
Wherein R1ForR2For hydrogen;
Work as R1ForTime, R9For hydrogen and other silanes or alkyls protection group, R6And R7For hydrogen, alkyl, R8During for hydrogen, halogen, alkyl, using boron trifluoride diethyl etherate as catalyst, the secondary cyclization shown in production IVa under temperate condition Product
Work as R1ForTime, n=1-3, X are heteroatom group, R9For hydrogen and other silanes or alkyl Class protection group, R6And R7During for hydrogen, alkyl, using boron trifluoride diethyl etherate as catalyst, under temperate condition shown in production IVb Secondary cyclization product
In the preferred version with compound of formula I as reaction substrate:
(1) R is worked as1ForTime, R2For hydrogen, R9For hydrogen and other silanes or alkyls protection group, R6And R7 For hydrogen, C1-6Alkyl, R8For hydrogen, halogen, C1-6During alkyl, using boron trifluoride diethyl etherate as catalyst, production under temperate condition Secondary cyclization product shown in IVa;
(2) R is worked as1ForTime, n=1-3, R2For hydrogen, R6And R7For hydrogen, C1-6Alkyl;R9For hydrogen and His silanes or alkyls protection group, X is O, NH, N, SH, SO of being protected by protection group2Time, using boron trifluoride diethyl etherate as urging Agent, the secondary cyclization product shown in production IVb under temperate condition.
In the method for this part, multiple heterocycles molecule can be synthesized, and reaction yield is high, and reaction condition is gentle, at 25-50 All can react under the conditions of DEG C, universality is good.
Three directions (three parts) of the present invention, all by using special catalyst, control reaction temperature condition, choosing Select the R of I formula substrate1And R2Different substituents, reaction obtains a series of oxazolone heterocyclic compounds.
Present invention also offers the preparation method of a kind of oxazolone heterocyclic compounds, including:
A) in the organic solvent solution containing reaction substrate oxazolone molecule, catalyst BF is dripped3·Et2O;
B) alkali liquor cancellation reaction;
C) organic solvent extraction;
D) mixing organic facies, scrubbed rear dry filter rotary evaporation obtains thick product;
E) thick product is through silica gel column chromatography, obtains finished product.
In the present invention, catalyst boron trifluoride diethyl etherate (BF3·Et2O) 1 it is preferably but not limited to the consumption mol ratio of substrate: 2。
In the present invention, the organic solvent of reaction system is preferably but not limited to dichloromethane (DCM).
In the present invention, the temperature of the product of Formulas I substrate reactions production IIa and IIb is preferably but not limited to 25 DEG C and 50 DEG C; Production IIIa, preferred 25-50 DEG C of the temperature range of product of IIIb, IVa and IVb, most preferably 25 DEG C.
In the present invention, thin layer chromatography (TLC) method that is preferably but not limited in course of reaction is to monitor reaction process.
In the present invention, extraction organic solvent is preferably but not limited to dichloromethane.
In the present invention, the liquid of washing organic facies is preferably but not limited to water and saturated aqueous common salt (NaCl) solution.
In the present invention, column chromatography is preferably but not limited to silica gel as chromatography media, 300-400 mesh.
In the present invention, column chromatography flowing is preferably but not limited to petrol ether/ethyl acetate mutually, and its ratio is preferably but not limited to 1/ 1。
In some embodiments of the present invention, the DCM solution of reaction substrate drips BF3·Et2O, tube sealing.Reaction is mixed Compound stirs 12 hours under the conditions of 50 DEG C, after terminating with TLC board monitoring reaction, with saturated sodium bicarbonate (NaHCO3) cancellation Reaction, and stir 5 minutes.DCM extracts 3 times, and mixing organic facies is also washed with water, saturated NaCl respectively, finally uses anhydrous slufuric acid Sodium (Na2SO4) be dried, carry out rotary evaporation after filtration, obtain thick product.Thick product, through silica gel column chromatography, obtains dimerization Product IIa.
In other embodiments of the present invention, the DCM solution of reaction substrate drips BF3·Et2O, tube sealing.Reaction Mixture stirs 12 hours under the conditions of 25 DEG C, after terminating with TLC board monitoring reaction, uses saturated NaHCO3Cancellation is reacted, and Stir 5 minutes.DCM extracts 3 times, and mixing organic facies is also washed with water, saturated NaCl respectively, finally uses Na2SO4It is dried, mistake Carry out rotary evaporation after filter, obtain thick product.Thick product, through silica gel column chromatography, obtains dimerisation products IIa.
In other embodiments of the present invention, the DCM solution of reaction substrate drips BF3·Et2O, tube sealing.Reaction Mixture stirs 12 hours under the conditions of 50 DEG C, after terminating with TLC board monitoring reaction, uses saturated NaHCO3Cancellation is reacted, and Stir 5 minutes.DCM extracts 3 times, and mixing organic facies is also washed with water, saturated NaCl respectively, finally uses Na2SO4It is dried, mistake Carry out rotary evaporation after filter, obtain thick product.Thick product, through silica gel column chromatography, obtains cyclization product IIb.
In other embodiments of the present invention, the DCM solution of reaction substrate drips BF3·Et2O, tube sealing.Reaction Mixture stirs 12 hours under the conditions of 25-50 DEG C, after terminating with TLC board monitoring reaction, uses saturated NaHCO3Cancellation is reacted, And stir 5 minutes.DCM extracts 3 times, and mixing organic facies is also washed with water, saturated NaCl respectively, finally uses Na2SO4It is dried, Carry out rotary evaporation after filtration, obtain thick product.Thick product, through silica gel column chromatography, obtains terminal olefin cyclisation product IIIa.
In another embodiment of the invention, the DCM solution of reaction substrate drips BF3·Et2O, tube sealing.Reaction Mixture stirs 12 hours under the conditions of 25-50 DEG C, after terminating with TLC board monitoring reaction, uses saturated NaHCO3Cancellation is reacted, And stir 5 minutes.DCM extracts 3 times, and mixing organic facies is also washed with water, saturated NaCl respectively, finally uses Na2SO4It is dried, Carry out rotary evaporation after filtration, obtain thick product.Thick product, through silica gel column chromatography, obtains terminal olefin cyclisation product IIIb.
In another embodiment of the invention, the DCM solution of reaction substrate drips BF3·Et2O, tube sealing.Reaction Mixture stirs 12 hours under the conditions of 25-50 DEG C, after terminating with TLC board monitoring reaction, uses saturated NaHCO3Cancellation is reacted, And stir 5 minutes.DCM extracts 3 times, and mixing organic facies is also washed with water, saturated NaCl respectively, finally uses Na2SO4It is dried, Carry out rotary evaporation after filtration, obtain thick product.Thick product, through silica gel column chromatography, obtains secondary cyclization product IV a.
In another embodiment of the invention, the DCM solution of reaction substrate drips BF3·Et2O, tube sealing.Reaction Mixture stirs 12 hours under the conditions of 25-50 DEG C, after terminating with TLC board monitoring reaction, uses saturated NaHCO3Cancellation is reacted, And stir 5 minutes.DCM extracts 3 times, and mixing organic facies is also washed with water, saturated NaCl respectively, finally uses Na2SO4It is dried, Carry out rotary evaporation after filtration, obtain thick product.Thick product, through silica gel column chromatography, obtains secondary cyclization product IV b.
Reaction substrate used by the present invention all can be prepared according to prior art literature, e.g., and 2- Dienylphenacyloxazolones and an intramolecular Diels-Alder approach to the A- B-C ring system of phenanthridone alkaloids、A Dichlorination-Reductive- Dechlorination Route to N-Acetyl-2-Oxazolone、Stereoselective Synthesis of the Epicoccin Core、A Single-Step Synthesis of 4-Oxazolin-2-ones and Their Use in the Construction of Polycyclic Structures Bearing Quaternary Stereocenters、 Oxazolone cycloadducts as heterocyclic scaffolds for alkaloid construction: synthesis of 2-epi-pumiliotoxin C。
Present invention also offers according to a series of compounds prepared by preparation method involved in the present invention, i.e. oxazolone Heterocyclic compounds, and these compounds are in preparation purposes be applicable to antitumor drug.These compounds also can be with medicine On, acceptable auxiliary material combination, makes preparation compositions;Also can combine with other anti-tumor active ingredients, make compound preparation Compositions.
The invention provides the dimerization of oxazolone compounds, cascade dimerization, cyclization, the novel preparation side of secondary cyclization Method, for those skilled in the art, the reaction dissolvent system in this route, conventional reagent reagent, technique Parameter, operating procedure etc., all can be according to the practical situation in laboratory or industrialized production workshop in conjunction with existing technical know-how It is optimized screening with practical experience and adjusts, it is not limited to limited embodiment cited in the present invention.
Detailed description of the invention
In order to further illustrate the present invention, the preparation method provided the present invention below in conjunction with embodiment is retouched in detail State.
Structural identification technological means is the current techique means that those skilled in the art know, 400MHz and 600MHz core Mr techniques, high resolution mass spectrum, infrared spectrometer.
Dimerization reaction embodiment
Embodiment 1:3-pi-allyl-5-(3-pi-allyl-2-oxo oxazolidine-4-base) oxazole-2 (3H)-one
In the dichloromethane solution (2ml) of reaction substrate I-1 (77.6mg, 0.62mmol), dropping boron trifluoride diethyl etherate is molten Liquid (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is tying with lamellae monitoring reaction Shu Hou, reacts with saturated sodium bicarbonate (5ml) cancellation, and stirs 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mix organic Wash mutually and respectively with water (10mL), saturated aqueous common salt (10mL), be finally dried with anhydrous sodium sulfate, revolve after filtration Turn evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I Ia-1 (productivity 98%).
Colourless oil liquid;Rf=0.21 (petrol ether/ethyl acetate=3/2);IR(KBr)νmax 3198,3163, 1746,1398,756cm-11H NMR(400MHz,CDCl3) δ=6.51 (s, 1H), 5.88-5.80 (m, 1H), 5.76-5.68 (m, 1H), 5.34-5.15 (m, 4H), 4.60 (dd, J=9.2,7.2Hz, 1H), 4.46 (t, J=8.8Hz, 1H), 4.32 (dd, J =8.4,6.8Hz, 1H), 4.17 (d, J=6.4Hz, 2H), 4.13 (dd, J=15.6,4.8Hz, 1H), 3.53 (dd, J= 15.6,7.2Hz,1H);13C NMR(400MHz,CDCl3) 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;HRMS Calcd for C12H14N2O4Na+[M+Na+]:273.08513, found 273.08505.
Embodiment 2:5-(2-oxo-3-propyl group oxazolidine-4-base)-3-propyl group oxazole-2 (3H)-one
Dropping boron trifluoride ether solution in the dichloromethane solution (2ml) of reaction substrate I-2 (79mg, 0.62mmol) (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is terminating with lamellae monitoring reaction After, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mix organic facies And respectively with water (10mL), saturated aqueous common salt (10mL) washing, be finally dried with anhydrous sodium sulfate, rotate after filtration Evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I Ia-2 (productivity 85%).
Colourless oil liquid;Rf=0.22 (petrol ether/ethyl acetate=3/2);IR(KBr)νmax 3135,2966, 1751,1400,1131,754cm-11H NMR(600MHz,CDCl3) δ=6.54 (s, 1H), 4.61 (dd, J=8.4,6.6Hz, 1H), 4.45 (t, J=9.3Hz, 1H), 4.30 (dd, J=8.4,6.6Hz, 1H), 3.55-3.52 (m, 2H), 3.39-3.34 (m, 1H), 3.00-2.96 (m, 1H), 1.73-1.69 (m, 2H), 1.56-1.48 (m, 2H), 0.96 (t, J=7.2Hz, 3H), 0.90 (t, J=7.2Hz, 3H);13C NMR(400MHz,CDCl3) 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;HRMS Calcd for C12H18N2O4Na+[M+Na+]:277.11643, found 277.11617.
Embodiment 3:3-benzyl-5-(3-benzyl-2-oxo oxazolidine-4-base) oxazole-2 (3H)-one
In the dichloromethane solution (2ml) of reaction substrate I-3 (109mg, 0.62mmol), dropping boron trifluoride diethyl etherate is molten Liquid (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is tying with lamellae monitoring reaction Shu Hou, reacts with saturated sodium bicarbonate (5ml) cancellation, and stirs 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mix organic Wash mutually and respectively with water (10mL), saturated aqueous common salt (10mL), be finally dried with anhydrous sodium sulfate, revolve after filtration Turn evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I Ia-3 (productivity 87%).
White solid (fusing point: 125-126 DEG C);Rf=0.33 (petrol ether/ethyl acetate=3/2);IR(KBr)νmax 3239,3093,1748,1400,1068,752cm-11H NMR(400MHz,CDCl3) δ=7.40-7.14 (m, 10H), 6.23 (s, 1H), 4.69 (d, J=15.6Hz, 1H), 4.66 (s, 2H), 4.38-4.29 (m, 3H), 4.02 (d, J=15.2Hz, 1H);13C NMR(400MHz,CDCl3) 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;HRMS Calcd for C20H18N2O4Na+[M+Na+]: 373.11643,found 373.11630.
Embodiment 4:3-isopropyl-5-(3-isopropyl-4-methyl-2-oxo oxazolidine-4-base)-4-methyl oxazole-2 (3H)-one
In the dichloromethane solution (2ml) of reaction substrate I-4 (87.5mg, 0.62mmol), dropping boron trifluoride diethyl etherate is molten Liquid (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is tying with lamellae monitoring reaction Shu Hou, reacts with saturated sodium bicarbonate (5ml) cancellation, and stirs 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mix organic Wash mutually and respectively with water (10mL), saturated aqueous common salt (10mL), be finally dried with anhydrous sodium sulfate, revolve after filtration Turn evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I Ia-4 (productivity 92%).
White solid (fusing point: 130-131 DEG C);Rf=0.36 (petrol ether/ethyl acetate=3/2);IR(KBr)νmax 3229,3129,2979,1743,1355,763cm-11H NMR(400MHz,CDCl3) δ=4.35 (d, J=8.8Hz, 1H), 4.07 (d, J=8.8Hz, 1H), 4.05-4.02 (m, 1H), 3.37-3.31 (m, 1H), 2.12 (s, 3H), 1.64 (s, 3H), 1.47 (d, J=2.8Hz, 3H), 1.45 (d, J=3.6Hz, 3H), 1.35 (d, J=6.8Hz, 3H), 1.26 (d, J=7.2Hz, 3H);13C NMR(400MHz,CDCl3) 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;HRMS Calcd for C14H22N2O4Na+[M+Na+]:305.14773,found 305.14749.
Embodiment 5:3-cyclohexyl-5-(3-cyclohexyl-4-methyl-2-oxo oxazolidine-4-base)-4-methyl oxazole-2 (3H)-one
In the dichloromethane solution (2ml) of reaction substrate I-5 (113mg, 0.62mmol), dropping boron trifluoride diethyl etherate is molten Liquid (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is tying with lamellae monitoring reaction Shu Hou, reacts with saturated sodium bicarbonate (5ml) cancellation, and stirs 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mix organic Wash mutually and respectively with water (10mL), saturated aqueous common salt (10mL), be finally dried with anhydrous sodium sulfate, revolve after filtration Turn evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I Ia-5 (productivity 83%).
White solid (fusing point: 134-135 DEG C);Rf=0.36 (petrol ether/ethyl acetate=3/2);IR(KBr)νmax 2934,2857,1745,1346,1020,736cm-11H NMR(600MHz,CDCl3) δ=4.33 (d, J=9.0Hz, 1H), 4.07 (d, J=9.0Hz, 1H), 3.55-3.52 (m, 1H), 2.89-2.86 (m, 1H), 2.14-2.04 (m, 7H), 1.88-1.66 (m,8H),1.62(s,3H),1.59-1.57(m,2H),1.42-1.12(m,6H);13C NMR(400MHz,CDCl3) 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;HRMS Calcd for C20H30N2O4Na+[M+Na+]:385.21033,found 385.21051.
Embodiment 6:3-benzyl-5-(3-benzyl-4-methyl-2-oxo oxazolidine-4-base)-4-methyl oxazole-2 (3H)- Ketone
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-6 (117.3mg, 0.62mmol) Solution (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is reacting with lamellae monitoring After end, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, are mixed with Machine washs mutually and respectively with water (10mL), saturated aqueous common salt (10mL), is finally dried with anhydrous sodium sulfate, carries out after filtration Rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I Ia-6 (productivity 85%).
White solid (fusing point: 134-135 DEG C);Rf=0.36 (petrol ether/ethyl acetate=3/2);IR(KBr)νmax 3166,3108,1750,1403,1022,722cm-11H NMR(400MHz,CDCl3) δ=7.37-7.16 (m, 10H), 4.57 (d, J=15.6Hz, 1H), 4.49 (d, J=16.0Hz, 1H), 4.42-4.39 (m, 2H), 4.30 (d, J=15.2Hz, 1H), 4.07 (d, J=8.4Hz, 1H), 1.72 (s, 3H), 1.53 (s, 3H);13C NMR(400MHz,CDCl3) 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;HRMS Calcd for C22H22N2O4Na+[M+Na+]:401.14773,found 401.14767.
Embodiment 7:3-(4-methoxyphenyl)-5-(3-(4-methoxyphenyl)-4-methyl-2-oxo oxazolidine-4- Base)-4-methyl oxazole-2 (3H)-one
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-7 (127.2mg, 0.62mmol) Solution (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under 25 DEG C of room temperature conditions, is monitoring with lamellae After reaction terminates, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixed Close organic facies and respectively with water (10mL), saturated aqueous common salt (10mL) washing, be finally dried with anhydrous sodium sulfate, after filtration Carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I Ia-7 (productivity 85%).
White solid (fusing point: 166-167 DEG C);Rf=0.22 (petrol ether/ethyl acetate=3/2);IR(KBr)νmax 3173,1766,1496,1398,1152,755cm-11H NMR(400MHz,CDCl3) δ=7.14 (d, J=8.4Hz, 2H), 7.11 (d, J=8.8Hz, 2H), 6.98 (d, J=8.8Hz, 2H), 6.92 (d, J=8.8Hz, 2H), 4.72 (d, J=8.4Hz, 1H), 4.27 (d, J=8.4Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 1.77 (s, 3H), 1.69 (s, 3H);13C NMR (400MHz,CDCl3) δ=159.9,159.1,156.1,153.6,133.1,128.9,128.8,126.9,125.1,12 3.0, 114.9,114.6,73.3,61.3,55.5,55.4,22.8,9.4;HRMS Calcd for C22H22N2O6Na+[M+Na+]: 433.13756,found 433.13757.
Embodiment 8:4-methyl-5-(4-methyl-2-oxo-3-(4-(trifluoromethoxy) phenyl) oxazolidine-4-base)-3- (4-(trifluoromethoxy) phenyl) oxazole-2 (3H)-one
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-8 (160.7mg, 0.62mmol) Solution (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under 25 DEG C of room temperature conditions, is monitoring with lamellae After reaction terminates, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixed Close organic facies and respectively with water (10mL), saturated aqueous common salt (10mL) washing, be finally dried with anhydrous sodium sulfate, after filtration Carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I Ia-8 (productivity 92%).
White solid (fusing point: 125-126 DEG C);Rf=0.47 (petrol ether/ethyl acetate=3/2);IR(KBr)νmax 3483,3414,2962,1768,1513,1266,1222,756cm-11H NMR(400MHz,CDCl3) δ=7.36-7.28 (m, 8H), 4.70 (d, J=8.4Hz, 1H), 4.30 (d, J=8.4Hz, 1H), 1.85 (s, 3H), 1.75 (s, 3H);13C NMR (400MHz,CDCl3) δ=155.6,152.9,149.3,147.9,133.6,133.3,130.9,129.1,127.6,12 2.2, 122.1,121.8,73.7,61.2,22.3,9.4;HRMS Calcd for C22H16F6N2O6Na+[M+Na+]:541.08103, found 541.08101.
Embodiment 9:4-methyl-5-(4-methyl-2-oxo-3-(4-(trifluoromethyl) phenyl) oxazolidine-4-base)-3- (4-(trifluoromethyl) phenyl) oxazole-2 (3H)-one
In the dichloromethane solution (2ml) of reaction substrate I-9 (151mg, 0.62mmol), dropping boron trifluoride diethyl etherate is molten Liquid (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 14 hours under 25 DEG C of room temperature conditions, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I Ia-9 (productivity 86%).
White solid (fusing point: 171-172 DEG C);Rf=0.50 (petrol ether/ethyl acetate=3/2);IR(KBr)νmax 3243,3093,1760,1401,1325,1068,755cm-11H NMR(400MHz,CDCl3) δ=7.78 (d, J=8.4Hz, 2H), 7.68 (d, J=8.0Hz, 2H), 7.44 (d, J=9.6Hz, 2H), 7.42 (d, J=8.4Hz, 2H), 4.68 (d, J= 8.4Hz, 1H), 4.30 (d, J=8.4Hz, 1H), 1.88 (s, 3H), 1.79 (s, 3H);13C NMR(400MHz,CDCl3) 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;HRMS Calcd for C22H16F6N2O4Na+[M+Na+]:509.09120,found 509.09182.
Embodiment 10:3-(4-chlorphenyl)-5-(3-(4-chlorphenyl)-4-methyl-2-oxo oxazolidine-4-base)-4-first Base oxazole-2 (3H)-one
In the dichloromethane solution (2ml) of reaction substrate I-10 (130mg, 0.62mmol), dropping boron trifluoride diethyl etherate is molten Liquid (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under 25 DEG C of room temperature conditions, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I Ia-10 (productivity 89%).
White solid (fusing point: 195-197 DEG C);Rf=0.50 (petrol ether/ethyl acetate=3/2);IR(KBr)νmax 3481,2960,1765,1270,749cm-11H NMR(400MHz,CDCl3) δ=7.47 (d, J=9.2Hz, 2H), 7.38 (d, J=9.2Hz, 2H), 7.20 (d, J=2.4Hz, 2H), 7.18 (d, J=2.8Hz, 2H), 4.68 (d, J=8.8Hz, 1H), 4.27 (d, J=8.4Hz, 1H), 1.81 (s, 3H), 1.72 (s, 3H);13C NMR(400MHz,CDCl3) 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;HRMS Calcd for C20H16Cl2N2O4Na+[M+Na+]:441.03848,found 441.03879.
Embodiment 11:3-(3,5-3,5-dimethylphenyl)-5-(3-(3,5-3,5-dimethylphenyl)-4-methyl-2-oxo oxazole Alkane-4-base)-4-methyl oxazole-2 (3H)-one
In the dichloromethane solution (2ml) of reaction substrate I-11 (126mg, 0.62mmol), dropping boron trifluoride diethyl etherate is molten Liquid (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 13 hours under 25 DEG C of room temperature conditions, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I Ia-11 (productivity 88%).
White solid (fusing point: 164-165 DEG C);Rf=0.54 (petrol ether/ethyl acetate=3/2);IR(KBr)νmax 3122,2920,1768,1398,1269,708cm-11H NMR(400MHz,CDCl3) δ=7.07 (s, 1H), 6.96 (s, 1H), 6.81 (d, J=8.8Hz, 4H), 4.70 (d, J=8.8Hz, 1H), 4.25 (d, J=8.8Hz, 1H), 2.35 (s, 6H), 2.32 (s,6H),1.78(s,3H),1.69(s,3H);13C NMR(400MHz,CDCl3) 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; HRMS Calcd for C24H26N2O4Na+[M+Na+]:429.17903,found 429.17902.
Embodiment 12:5-(2-oxo-3-((S)-1-phenethyl) oxazolidine-4-base)-3-((S)-1-phenethyl) oxazole- 2 (3H)-one
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-12 (117.5mg, 0.62mmol) Solution (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is reacting with lamellae monitoring After end, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, are mixed with Machine washs mutually and respectively with water (10mL), saturated aqueous common salt (10mL), is finally dried with anhydrous sodium sulfate, carries out after filtration Rotary evaporation, obtains thick product.Thick product through silica gel column chromatography, obtain pure product I Ia-12 (productivity 84%, dr=1: 1)。
White solid (fusing point: 164-165 DEG C);Rf=0.54 (petrol ether/ethyl acetate=3/2);IR(KBr)νmax 3419,3249,3063,1742,1045,753cm-11H NMR(400MHz,CDCl3) δ=7.49-7.01 (m, 10H), 5.93 (s, 1H), 5.18 (q, J=7.2Hz, 1H), 5.06 (q, J=7.2Hz, 1H), 4.35 (t, J=8.9Hz, 1H), 4.26-4.20 (m, 1H), 4.09 (t, J=7.6Hz, 1H), 1.68 (d, J=7.2Hz, 3H), 1.50 (d, J=6.8Hz, 3H);13C NMR (400MHz,CDCl3) δ=157.4,153.6,139.5,138.9,134.0,128.9,128.5,128.0,127.7,12 7.1, 126.6,111.7,64.6,52.5,51.7,49.6,18.9,15.9;HRMS Calcd for C22H22N2O4Na+[M+Na+]: 401.14773,found 401.14794.
Embodiment 13: normal-butyl (2S)-2-(4-(3-((S)-butyl-1-1-oxo acrylate-2-yl)-2-oxo-2,3-dihydro Oxazole-5-base)-2-oxo oxazolidine-pyridin-3-yl) ethyl propionate
In the dichloromethane solution (2ml) of reaction substrate I-13 (97mg, 0.62mmol), dropping boron trifluoride diethyl etherate is molten Liquid (41 μ L, 0.5equiv.), tube sealing.Reactant mixture exists, and stirs 13 hours under the conditions of 50 DEG C, is reacting with lamellae monitoring After end, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, are mixed with Machine washs mutually and respectively with water (10mL), saturated aqueous common salt (10mL), is finally dried with anhydrous sodium sulfate, carries out after filtration Rotary evaporation, obtains thick product.Thick product through silica gel column chromatography, obtain pure product I Ia-13 (productivity 87%, dr=3: 2)。
Colourless oil liquid;Rf=0.40 (petrol ether/ethyl acetate=3/2) IR (KBr) νmax 3416,3187,2962, 1747,1422,1218cm-11H NMR(400MHz,CDCl3) δ=6.81 (s, 1H), 5.13 (t, J=8.0Hz, 1H), 4.79 (q, J=7.6Hz, 2H), 4.50 (t, J=8.8Hz, 2H), 4.17-4.10 (m, 4H), 1.66-1.55 (m, 8H), 1.39-1.34 (m, 6H), 0.93 (t, J=7.4Hz, 6H);13C NMR(400MHz,CDCl3) δ=171.5,170.2,157.5,154.1, 135.5,113.7,65.9,65.6,65.2,64.7,52.2,51.4,51.3,30.4,30.3,18.9,17.1,15.7,14.4, 13.6;HRMS Calcd for C20H30N2O8Na+[M+Na+]:449.18999,found 449.19958.
Cascade dimerization/cyclization embodiment
Embodiment 1:(3aS, 3bS, 11bS)-10-methoxyl group-1-(4-methoxyphenyl)-3b, 11b-dimethyl-3a, 3b, 4,11b-tetrahydrochysene-6H-dioxazole also [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-7 (127.2mg, 0.62mmol) Solution (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is reacting with lamellae monitoring After end, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, are mixed with Machine washs mutually and respectively with water (10mL), saturated aqueous common salt (10mL), is finally dried with anhydrous sodium sulfate, carries out after filtration Rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I Ib-1 (productivity 86%).
White solid (fusing point: 210-211 DEG C);Rf=0.17 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3125,2938,1761,1513,1385,1224,756cm-11H NMR(400MHz,CDCl3) δ=7.92 (d, J=8.8Hz, 1H), 6.92 (dd, J=8.4,2.0Hz, 1H), 6.87 (d, J=8.4Hz, 2H), 6.77 (d, J=8.4Hz, 2H), 6.03 (d, J =2.4Hz, 1H), 4.80 (d, J=8.4Hz, 1H), 4.58 (s, 1H), 4.17 (d, J=8.4Hz, 1H), 3.80 (s, 3H), 3.53(s,3H),1.82(s,3H),1.41(s,3H);13C NMR(400MHz,CDCl3) 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;HRMS Calcd for C22H22N2O6Na+[M+Na+]:433.13756,found 433.13730.
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
In the dichloromethane solution (2ml) of reaction substrate I-11 (126mg, 0.62mmol), dropping boron trifluoride diethyl etherate is molten Liquid (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is tying with lamellae monitoring reaction Shu Hou, reacts with saturated sodium bicarbonate (5ml) cancellation, and stirs 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mix organic Wash mutually and respectively with water (10mL), saturated aqueous common salt (10mL), be finally dried with anhydrous sodium sulfate, revolve after filtration Turn evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I Ib-2 (productivity 89%).
White solid (fusing point: > 250 DEG C);Rf=0.44 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3416, 3155,1764,1401,1137,728cm-11H NMR(400MHz,CDCl3) δ=7.70 (s, 1H), 7.01 (s, 1H), 6.61 (s, 1H), 6.39 (s, 2H), 4.80 (d, J=8.8Hz, 1H), 4.54 (s, 1H), 4.15 (d, J=8.8Hz, 1H), 2.32 (s, 3H),2.22(s,6H),2.03(s,3H),1.54(s,3H),1.39(s,3H);13C NMR(400MHz,CDCl3) 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;HRMS Calcd for C24H26N2O4Na+[M+Na+]: 429.17903,found 429.17874.
Embodiment 3:(3aS, 3bS, 11bS)-10-ethyoxyl-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
In the dichloromethane solution (2ml) of reaction substrate I-14 (136mg, 0.62mmol), dropping boron trifluoride diethyl etherate is molten Liquid (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is tying with lamellae monitoring reaction Shu Hou, reacts with saturated sodium bicarbonate (5ml) cancellation, and stirs 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mix organic Wash mutually and respectively with water (10mL), saturated aqueous common salt (10mL), be finally dried with anhydrous sodium sulfate, revolve after filtration Turn evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I Ib-3 (productivity 81%).
White solid (fusing point: 149-150 DEG C);Rf=0.28 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3415,2982,1762,1511,1402,1142,736cm-1;1H NMR (400MHz, CDCl3) δ=7.89 (d, J=8.4Hz, 1H), 6.90 (d, J=8.8Hz, 1H), 6.85 (d, J=8.4Hz, 2H), 6.75 (d, J=8.4Hz, 2H), 6.04 (s, 1H), 4.80 (d, J=8.4Hz, 1H), 4.57 (s, 1H), 4.17 (d, J=8.4Hz, 1H), 4.04-3.99 (m, 2H), 3.82-3.76 (m, 1H), 3.67-3.62 (m, 1H), 1.80 (s, 3H), 1.42-1.40 (m, 6H), 1.27 (t, J=6.8Hz, 3H);13C NMR (600MHz, CDCl3) δ=159.3,155.0,154.9,154.1,131.8,127.1,125.6,124.6,122.8,11 5.9, 114.9,113.7,83.7,70.0,63.7,63.7,61.4,59.1,27.5,21.2,14.6,14.6;HRMS Calcd for C24H26N2O6Na+[M+Na+]:461.16886,found 461.16866.
Embodiment 4:(3aS, 3bS, 11bS)-3b, 10,11b-trimethyl-1-(p-methylphenyl)-3a, 3b, 4,11b-tetra- Hydrogen-6H-dioxazole also [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-15 (117.3mg, 0.62mmol) Solution (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is reacting with lamellae monitoring After end, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, are mixed with Machine washs mutually and respectively with water (10mL), saturated aqueous common salt (10mL), is finally dried with anhydrous sodium sulfate, carries out after filtration Rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I Ib-4 (productivity 92%).
White solid (fusing point: 196-197 DEG C);Rf=0.38 (petrol ether/ethyl acetate=1/1) IR (KBr) ν max 3412,2923,1763,1513,1404,1076,755cm-1;1H NMR (400MHz, CDCl3) δ=7.93 (d, J=8.4Hz, 1H), 7.18-7.14 (m, 3H), 6.69 (d, J=8.0Hz, 2H), 6.26 (s, 1H), 4.81 (d, J=8.4Hz, 1H), 4.59 (s, 1H), 4.18 (d, J=8.0Hz, 1H), 2.37 (s, 3H), 2.08 (s, 3H), 1.82 (s, 3H), 1.42 (s, 3H);13C NMR (400MHz, CDCl3) 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;HRMS Calcd for C22H22N2O4Na+[M+Na+]:401.14773,found 401.14741.
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
In the dichloromethane solution (2ml) of reaction substrate I-16 (100mg, 0.62mmol), dropping boron trifluoride diethyl etherate is molten Liquid (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is tying with lamellae monitoring reaction Shu Hou, reacts with saturated sodium bicarbonate (5ml) cancellation, and stirs 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mix organic Wash mutually and respectively with water (10mL), saturated aqueous common salt (10mL), be finally dried with anhydrous sodium sulfate, revolve after filtration Turn evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I Ib-5 (productivity 71%).
White solid (fusing point: > 250 DEG C);Rf=0.28 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3204,3091,1740,1706,737cm-1;1H NMR (400MHz, DMSO-d6) δ=7.79 (d, J=7.6Hz, 1H), 7.42-7.25 (m, 6H), 6.88 (t, J=7.4Hz, 1H), 6.73 (d, J=8.0Hz, 1H), 5.88 (d, J=8.4Hz, 1H), 5.41 (d, J=8.0Hz, 1H), 4.65 (t, J=8.4Hz, 1H), 4.54-4.44 (m, 2H);13C NMR(400MHz,DMSO- D6) δ=154.4,154.2,136.4,135.0,129.5,129.3,126.9,125.7,124.6,12 4.4,120.2,73.8, 63.2,56.2,54.8;HRMS Calcd for C18H14N2O4Na+[M+Na+]:345.08513,found 345.08466.
Embodiment 6:(3aS, 3bS, 11bS) the fluoro-1-of-10-(4-fluorophenyl)-3a, 3b, 4,11b-tetrahydrochysene-6H-dioxazole And [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone
In the dichloromethane solution (2ml) of reaction substrate I-17 (111mg, 0.62mmol), dropping boron trifluoride diethyl etherate is molten Liquid (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is tying with lamellae monitoring reaction Shu Hou, reacts with saturated sodium bicarbonate (5ml) cancellation, and stirs 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mix organic Wash mutually and respectively with water (10mL), saturated aqueous common salt (10mL), be finally dried with anhydrous sodium sulfate, revolve after filtration Turn evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I Ib-6 (productivity 80%).
White solid (fusing point: 213-214 DEG C);Rf=0.21 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3482,2925,1754,1509,1417,1147,752cm-1;1H NMR (400MHz, CDCl3) δ=8.09 (dd, J=9.2, 4.8Hz, 1H), 7.11-7.04 (m, 5H), 6.31 (dd, J=8.4,2.8Hz, 1H), 5.36 (d, J=8.4Hz, 1H), 5.22 (dd, J=8.8,2.0Hz, 1H), 4.69 (t, J=8.2Hz, 1H), 4.62 (t, J=9.0Hz, 1H), 4.30-4.26 (m, 1H); 13C NMR (400MHz, DMSO-d6) δ=161.9,159.5,159.3,156.9,154.5,154.2,132.4,131.6, 128.5,128.4,126.5,126.4,122.2,122.1,116.7,116.6,116.5,116.3,115.9,115.7,73.7, 63.2,56.5,54.9;HRMS Calcd for C18H12F2N2O4Na+[M+Na+]:381.06628,found 381.06594.
Embodiment 7:(3aS, 3bS, 11bS)-10-methyl isophthalic acid-(p-methylphenyl)-3a, 3b, 4,11b-tetrahydrochysene-6H-two dislikes Azoles also [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone
In the dichloromethane solution (2ml) of reaction substrate I-18 (109mg, 0.62mmol), dropping boron trifluoride diethyl etherate is molten Liquid (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is tying with lamellae monitoring reaction Shu Hou, reacts with saturated sodium bicarbonate (5ml) cancellation, and stirs 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mix organic Wash mutually and respectively with water (10mL), saturated aqueous common salt (10mL), be finally dried with anhydrous sodium sulfate, revolve after filtration Turn evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I Ib-7 (productivity 92%).
White solid (fusing point: > 250 DEG C);Rf=0.32 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3196,3103,1752,1511,1404,1130,753cm-1;1H NMR (400MHz, CDCl3) δ=7.94 (d, J=8.0Hz, 1H), 7.16 (d, J=7.6Hz, 2H), 7.12 (d, J=8.4Hz, 1H), 6.96 (d, J=6.8Hz, 2H), 6.37 (s, 1H), 5.33 (d, J=8.4Hz, 1H), 5.18 (d, J=8.8Hz, 1H), 4.67 (t, J=8.0Hz, 1H), 4.59 (t, J=9.0Hz, 1H), 4.25 (dd, J=8.8,7.2Hz, 1H), 2.35 (s, 3H), 2.03 (s, 3H);13C NMR (400MHz, DMSO-d6) 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, 62.7,56.0,54.3,20.5,20.3;HRMS Calcd for C20H18N2O4Na+[M+Na+]:373.11643,found 373.11604.
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
In the dichloromethane solution (2ml) of reaction substrate I-19 (152mg, 0.62mmol), dropping boron trifluoride diethyl etherate is molten Liquid (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 13.5 hours under the conditions of 50 DEG C, is reacting with lamellae monitoring After end, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, are mixed with Machine washs mutually and respectively with water (10mL), saturated aqueous common salt (10mL), is finally dried with anhydrous sodium sulfate, carries out after filtration Rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I Ib-8 (productivity 86%).
White solid (fusing point: 212-213 DEG C);Rf=0.25 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3183,3159,2928,1767,1733,1513,1255,1202,751cm-1;1H NMR (600MHz, DMSO-d6) δ=7.92 (d, J=9.0Hz, 1H), 7.46 (d, J=8.4Hz, 2H), 7.40 (d, J=8.4Hz, 2H), 7.35 (dd, J=9.0,1.8Hz, 1H), 6.70 (s, 1H), 5.92 (d, J=7.8Hz, 1H), 5.48 (d, J=8.4Hz, 1H), 4.67 (t, J=9.0Hz, 1H), 4.56 (t, J=7.5Hz, 1H), 4.48 (dd, J=8.4,6.6Hz, 1H);13C NMR (600MHz, DMSO-d6) δ=153.9, 153.5,146.3,143.5,134.6,133.9,127.6,125.6,122.3,121.9,121.4,121.3,120.8, 120.5,119.1,118.8,73.2,62.9,55.8,54.4;HRMS Calcd for C20H12F6N2O6Na+[M+Na+]: 513.04972,found 513.05006.
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
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-20 (142.1mg, 0.62mmol) Solution (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is reacting with lamellae monitoring After end, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, are mixed with Machine washs mutually and respectively with water (10mL), saturated aqueous common salt (10mL), is finally dried with anhydrous sodium sulfate, carries out after filtration Rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I Ib-9 (productivity 74%).
White solid (fusing point: > 250 DEG C);Rf=0.28 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 2932,1774,1751,1385,1232,1142,742cm-1;1H NMR (400MHz, DMSO-d6) δ=8.06 (d, J= 8.4Hz, 1H), 7.78 (d, J=8.0Hz, 2H), 7.69 (d, J=8.4Hz, 1H), 7.61 (d, J=8.4Hz, 2H), 7.06 (s, 1H), 6.07 (d, J=8.0Hz, 1H), 5.53 (dd, J=8.0,1.2Hz, 1H), 4.69 (t, J=8.8Hz, 1H), 4.62- 4.58 (m, 1H), 4.49 (dd, J=8.0,6.4Hz, 1H);13C NMR (400MHz, DMSO-d6) δ=153.7,153.3, 139.4,138.4,127.9,126.9,126.6,126.2,126.1,125.9,125.3,124.9,124.3,123.8, 123.5,122.6,122.2,119.7,73.1,63.0,55.4,54.3;HRMS Calcd for C20H12F6N2O4Na+[M+ Na+]:481.05990,found 481.05995.
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
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-21 (117.3mg, 0.62mmol) Solution (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 15 hours under the conditions of 50 DEG C, is reacting with lamellae monitoring After end, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, are mixed with Machine washs mutually and respectively with water (10mL), saturated aqueous common salt (10mL), is finally dried with anhydrous sodium sulfate, carries out after filtration Rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I Ib-10 (productivity 85%).
White solid (fusing point: > 250 DEG C);Rf=0.25 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3163,3149,1751,1611,1401,1242,752cm-1;1H NMR (600MHz, DMSO-d6) δ=7.47 (s, 1H), 6.95 (s, 1H), 6.65 (s, 1H), 6.41 (s, 2H), 5.68 (d, J=8.4Hz, 1H), 5.38 (dd, J=9.0,2.4Hz, 1H), 4.58 (t, J=9.3Hz, 1H), 4.45 (dd, J=9.0,6.0Hz, 1H), 4.23-4.19 (m, 1H), 2.26 (s, 3H), 2.15(s,6H),1.57(s,3H);13C NMR (600MHz, DMSO-d6) 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;HRMS Calcd for C22H22N2O4Na+[M+Na+]:401.14773,found 401.14745.
Embodiment 11:(3aS, 3bS, 11bS) the chloro-1-of-10-(4-chlorphenyl)-3a, 3b, 4,11b-tetrahydrochysene-6H-dioxazole And [3,4-a:5', 4'-c] quinoline-2,6-(1H)-diketone
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-22 (121.3mg, 0.62mmol) Solution (41 μ L, 0.5equiv.), tube sealing.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is reacting with lamellae monitoring After end, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, are mixed with Machine washs mutually and respectively with water (10mL), saturated aqueous common salt (10mL), is finally dried with anhydrous sodium sulfate, carries out after filtration Rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I Ib-11 (productivity 77%).
White solid (fusing point: 231-233 DEG C);Rf=0.22 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3217,3143,2921,1746,1493,1408,1093,741cm-1;1H NMR (400MHz, DMSO-d6) δ=7.83 (d, J =9.2Hz, 1H), 7.50 (d, J=8.4Hz, 2H), 7.43 (d, J=2.4Hz, 1H), 7.39 (d, J=9.2Hz, 2H), 6.80 (d, J=2.4Hz, 1H), 5.86 (d, J=8.4Hz, 1H), 5.44 (d, J=8.8Hz, 1H), 4.65 (t, J=8.6Hz, 1H), 4.54-4.50(m,1H),4.47-4.38(m,1H);13C NMR (600MHz, DMSO-d6) 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; HRMS Calcd for C18H12Cl2N2O4Na+[M+Na+]:413.00718,found 413.00698.
End butylene annulation embodiment
Embodiment 1:(5R, 8aS)-5-ethyl-7-methyl 1,5,8,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyridine-3-ketone
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-23 (144.9mg, 0.80mmol) Solution (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 25 DEG C, is monitoring with lamellae After reaction terminates, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixed Close organic facies and respectively with water (10mL), saturated aqueous common salt (10mL) washing, be finally dried with anhydrous sodium sulfate, after filtration Carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I IIa-1,127mg (productivity 88%).
White solid (fusing point: 246-247 DEG C);Rf=0.29 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3415,2967,1752,1415,1236,1068,765cm-1;1H NMR (400MHz, CDCl3) δ=5.45 (s, 1H), 4.46 (t, J=8.3Hz, 1H), 4.07-4.01 (m, 2H), 3.83-3.78 (m, 1H), 2.13-1.98 (m, 2H), 1.73 (s, 3H), 1.63-1.47 (m, 2H), 0.96 (t, J=7.4Hz, 3H);13C NMR (400MHz, CDCl3) δ=157.7,130.9, 122.4,68.5,52.3,48.8,34.4,28.0,23.7,10.4;HRMS Calcd for C10H15NO2Na+[M+Na+]: 181.11028,found 181.11028.
Embodiment 2:(5R, 8aS)-5-butyl-7-phenyl-1,5,8,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyridine-3- Ketone
In the dichloromethane solution (2ml) of reaction substrate I-24 (217mg, 0.80mmol), dropping boron trifluoride diethyl etherate is molten Liquid (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 30 DEG C, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I IIa-2,167mg (productivity 77%).
Yellow liquid;Rf=0.50 (petrol ether/ethyl acetate=3/1);IR(KBr)νmax 2931,1752,1416, 1225,1074,160cm-11H NMR(400MHz,CDCl3) δ=7.36-7.27 (m, 5H), 6.05 (s, 1H), 4.53 (td, J =8.6,1.6Hz, 1H), 4.35 (s, 1H), 4.14-4.12 (m, 1H), 3.94 (dd, J=4.0,1.9Hz, 1H), 2.67-2.43 (m, 2H), 1.73-1.55 (m, 2H), 1.44-1.30 (m, 4H), 0.92 (t, J=6.9Hz, 3H);13C NMR(600MHz, CDCl3) δ=157.1,140.1,133.6,128.3,127.4,125.0,124.9,68.2,51.1,48.5,34.4,31.6, 27.9,22.4,13.8;HRMS Calcd for C17H21NO2Na+[M+Na+]:294.14700,found 294.14778.
Embodiment 3:(5R, 8aS)-5-amyl group-7-phenyl-1,5,8,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyridine-3- Ketone
In the dichloromethane solution (2ml) of reaction substrate I-25 (228mg, 0.80mmol), dropping boron trifluoride diethyl etherate is molten Liquid (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 35 DEG C, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I IIa-3,180mg (productivity 79%).
Colorless gum body;Rf=0.37 (petrol ether/ethyl acetate=7/3);IR(KBr)νmax 3155(br),2930, 1753,1403,1226,1074,760cm-11H NMR(600MHz,CDCl3) δ=7.37-7.27 (m, 5H), 6.06 (t, J= 2.8Hz, 1H), 4.55 (t, J=8.3Hz, 1H), 4.37 (s, 1H), 4.15 (dd, J=8.6,3.4Hz, 1H), 3.96-3.93 (m, 1H), 2.60 (dd, J=16.1,4.4Hz, 1H), 2.53-2.48 (m, 1H), 1.73-1.67 (m, 1H), 1.63-1.57 (m, 1H), 1.48-1.43 (m, 2H), 1.37-1.25 (m, 4H), 0.90 (t, J=6.9Hz, 3H);13C NMR(600MHz,CDCl3)δ =157.4,140.5,133.9,128.6,127.8,125.4,68.5,51.5,48.9,35.0,32.1,31.8,25.7, 22.7,14.1;HRMS Calcd for C18H23NO2Na+[M+Na+]:308.16265,found 308.16311.
Embodiment 4:(5R, 8aS)-5-phenethyl-7-phenyl-1,5,8,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyridine- 3-ketone
In the dichloromethane solution (2ml) of reaction substrate I-26 (256mg, 0.80mmol), dropping boron trifluoride diethyl etherate is molten Liquid (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I IIa-4,181mg (productivity 71%).
Colorless oil;Rf=0.50 (petrol ether/ethyl acetate=7/3);IR(KBr)νmax 3326,2924,1755, 1420,1066,762cm-1;1H NMR(CDCl3, 400MHz): δ 7.39 7.20 (10H, m), 6.06 (1H, d, J=2.3Hz), 4.49-4.43 (2H, m), 4.14 (1H, dd, J=4.0,2.9Hz), 3.95 3.89 (1H, m), 2.81 (2H, t, J=7.9Hz), 2.62–2.47(2H,m),2.09–1.92(2H,m).;13C NMR(CDCl3,400MHz):δ170.59,155.27,145.49, 140.35,128.45,127.76,126.14,115.86,66.79,53.64,37.21,31.10,28.43,22.15,13.83; (trans:cis=5:1);HRMS Calcd for C20H19NO2Na+[M+Na+]:328.13135,found 328.13124.
Embodiment 5:(5R, 8aS)-5-methyl-7-phenyl-1,5,8,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyridine-3- Ketone
In the dichloromethane solution (2ml) of reaction substrate I-27 (183mg, 0.80mmol), dropping boron trifluoride diethyl etherate is molten Liquid (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 25 DEG C, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I IIa-5,155mg (productivity 84%).
Yellow colloidal body;Rf=0.50 (petrol ether/ethyl acetate=7/3);IR(KBr)νmax 3147(br),1749, 1402,1268,1041,760cm-11H NMR(400MHz,CDCl3) δ=7.27-7.19 (m, 5H), 5.94 (s, 1H), 4.49 (t, J=8.3Hz, 1H), 4.42-4.40 (m, 1H), 4.05 (dd, J=8.4,5.0Hz, 1H), 3.92-3.87 (m, 1H), 2.56 (dd, J=16.0,4.1Hz, 1H), 2.44-2.40 (m, 1H), 1.27 (d, J=6.8Hz, 3H);13C NMR(400MHz, CDCl3) δ=156.7,140.2,133.4,128.5,127.7,126.2,125.3,68.6,48.1,46.9,32.2,19.7; HRMS Calcd for C14H15NO2Na+[M+Na+]:252.10005,found 252.10383.
Embodiment 6:(5R, 8aS)-7-phenyl-5-vinyl-1,5,8,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyridine- 3-ketone
In the dichloromethane solution (2ml) of reaction substrate I-28 (193mg, 0.80mmol), dropping boron trifluoride diethyl etherate is molten Liquid (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I IIa-6,124mg (productivity 64%).
Yellow jelly;Rf=0.50 (petrol ether/ethyl acetate=7/3);IR(KBr)νmax 3189,2920,1750, 1415,1257,1074,761cm-11H NMR(CDCl3, 400MHz) and δ=7.50-7.24 (m, 5H), 6.05 (s, 1H), 5.93- 5.85 (m, 1H), 5.27 (d, J=17.2Hz, 1H), 5.22 (d, J=10.2Hz, 1H), 4.90 (s, 1H), 4.56 (t, J= 8.3Hz, 1H), 4.14 (dd, J=8.6,4.5Hz, 1H), 3.96-3.90 (m, 1H), 2.62 (dd, J=16.2,4.5Hz, 1H), 2.55-2.48(m,1H);13C NMR(400MHz,CDCl3) δ=156.9,140.3,135.0,134.8,129.2,128.7, 128.0,126.3,125.4,122.9,116.5,68.8,52.7,48.4,32.2;HRMS Calcd for C15H15NO2Na+[M +Na+]:264.10005,found 264.10390.
Embodiment 7:(5R, 8aS)-5-ethyl-1,5,8,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyridine-3-ketone
In the dichloromethane solution (2ml) of reaction substrate I-29 (133mg, 0.80mmol), dropping boron trifluoride diethyl etherate is molten Liquid (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 25 DEG C, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I IIa-7,100mg (productivity 75%).
Yellow liquid;Rf=0.46 (petrol ether/ethyl acetate=3/1);IR(KBr)νmax 3416,2967,1748, 1419,1234,1068,764cm-11H NMR(400MHz,CDCl3) δ=5.82-5.72 (m, 2H), 4.48 (t, J=8.3Hz, 1H), 4.14-4.08 (m, 1H), 4.03 (dd, J=8.6,4.0Hz, 1H), 3.84-3.77 (m, 1H), 2.25-2.09 (m, 2H), 1.72-1.62 (m, 1H), 1.59-1.52 (m, 1H), 0.98 (t, J=7.4Hz, 3H);13C NMR(400MHz,CDCl3) δ= 157.5,128.6,123.1,68.6,52.4,48.4,29.6,27.7,10.3;HRMS Calcd for C9H13NO2Na+[M+H+]:168.10245,found 168.10188.
Embodiment 8:(5R, 8aS)-5-ethyl-7-(4-fluorophenyl)-1,5,8,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyrrole Pyridine-3-ketone
In the dichloromethane solution (2ml) of reaction substrate I-30 (209mg, 0.80mmol), dropping boron trifluoride diethyl etherate is molten Liquid (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I IIa-8,182mg (productivity 87%).
Yellow oil;Rf=0.55 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3307,2966,1751, 1151,1421,1228,831cm-11H NMR(400MHz,CDCl3) δ=7.31-7.28 (m, 2H), 7.03 (t, J=8.6Hz, 2H), 6.01 (s, 1H), 4.55 (t, J=8.3Hz, 1H), 4.30 (s, 1H), 4.15 (dd, J=8.7,3.5Hz, 1H), 3.96- 3.93 (m, 1H), 2.58-2.44 (m, 2H), 1.79-1.71 (m, 1H), 1.69-1.58 (m, 1H), 1.04 (t, J=7.4Hz, 3H);13C NMR(400MHz,CDCl3) δ=163.5,161.1,157.4,136.5,133.1,126.9,126.9,126.8, 124.8,115.5,115.3,68.4,52.6,48.9,32.1,27.9,10.5;HRMS Calcd for C15H16FNO2Na+[M+ Na+]:284.10628,found 284.10569.
Embodiment 9:(5R, 8aS)-5-ethyl-7-phenyl-1,5,8,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyridine-3- Ketone
In the dichloromethane solution (2ml) of reaction substrate I-31 (195mg, 0.80mmol), dropping boron trifluoride diethyl etherate is molten Liquid (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 25 DEG C, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I IIa-9,142mg (productivity 73%).
Yellow liquid;Rf=0.35 (petrol ether/ethyl acetate=3/1);IR(KBr)νmax 3177,2967,1752, 1402,1067,760,698cm-11H NMR(400MHz,CDCl3) δ=7.35-7.25 (m, 5H), 6.05 (t, J=2.7Hz, 1H), 4.54 (t, J=8.3Hz, 1H), 4.33-4.27 (m, 1H), 4.16 (dd, J=8.6,3.5Hz, 1H), 3.96-3.91 (m, 1H), 2.63-2.46 (m, 2H), 1.75-1.73 (m, 1H), 1.70-1.59 (m, 1H), 1.04 (t, J=7.4Hz, 3H);13C NMR(400MHz,CDCl3) δ=157.4,140.4,134.1,128.5,127.7,125.3,125.1,124.9,68.4, 52.6,48.9,32.0,27.9,10.4;HRMS Calcd for C15H17NO2Na+[M+Na+]:243.12593,found 243.12593.
Embodiment 10:(5R, 8aS)-7-(9-hydrogen carbazole)-5-methyl isophthalic acid, 5,8,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] Pyridine-3-ketone
In the dichloromethane solution (2ml) of reaction substrate I-32 (255mg, 0.80mmol), dropping boron trifluoride diethyl etherate is molten Liquid (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I IIa-10,214mg (productivity 84%).
White solid (fusing point: 303-306 DEG C);Rf=0.35 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3416,2927,1754,1453,1232,754cm-11H NMR(400MHz,CDCl3) δ=8.09 (d, J=7.7Hz, 2H), 7.44 (t, J=7.6Hz, 2H), 7.32 (d, J=8.1Hz, 2H), 7.28 (d, J=7.5Hz, 2H), 6.16 (s, 1H), 4.78- 4.76 (m, 1H), 4.60 (t, J=8.4Hz, 1H), 4.29-4.22 (m, 1H), 4.10 (dd, J=8.7,4.8Hz, 1H), 2.66- 2.51 (m, 2H), 1.50 (d, J=6.8Hz, 3H);13C NMR(600MHz,CDCl3) δ=156.7,139.9,130.9, 129.8,126.2,126.1,123.5,120.6,120.2,120.1,109.6,109.5,68.3,48.6,46.7,32.3, 20.2;HRMS Calcd for C20H18N2O2Na+[M+Na+]:341.12660,found 341.12623.
Embodiment 11:(5R, 8aS)-7-(4-fluorophenyl)-1,5,8,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyridine-3- Ketone
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-33 (186.6mg, 0.80mmol) Solution (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 25 DEG C, is monitoring with lamellae After reaction terminates, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixed Close organic facies and respectively with water (10mL), saturated aqueous common salt (10mL) washing, be finally dried with anhydrous sodium sulfate, after filtration Carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I IIa-11,162.3mg (productivity 87%).
White solid (fusing point: 57-58 DEG C);Rf=0.27 (petrol ether/ethyl acetate=2/1);IR(KBr)νmax 3414,1754,1511,1423,1228,1077,811cm-11H NMR(600MHz,CDCl3) δ=7.30 (dd, J=8.5, 5.4Hz, 2H), 7.04 (t, J=8.6Hz, 2H), 6.02 (d, J=2.5Hz, 1H), 4.58 (t, J=8.2Hz, 1H), 4.35 (d, J=18.7Hz, 1H), 4.14 (dd, J=8.6,4.9Hz, 1H), 3.97-3.92 (m, 1H), 3.86 (d, J=18.6Hz, 1H), 2.64-2.51(m,2H);13C NMR(600MHz,CDCl3) δ=163.3,161.6,157.4,136.6,133.3,126.9, 126.9,120.4,115.6,115.5,68.8,50.8,41.4,32.4;HRMS Calcd for C13H12FNO2Na+[M+Na+]:256.07498,found 256.07468.
Embodiment 12:(5R, 8aS)-7-phenyl-1,5,8,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyridine-3-ketone
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-34 (172.2mg, 0.80mmol) Solution (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is monitoring with lamellae After reaction terminates, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixed Close organic facies and respectively with water (10mL), saturated aqueous common salt (10mL) washing, be finally dried with anhydrous sodium sulfate, after filtration Carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I IIa-12,140mg (productivity 81%).
White solid (fusing point: 87-88 DEG C);Rf=0.35 (petrol ether/ethyl acetate=2/1);IR(KBr)νmax 3182,3055,1753,1400,1075,753cm-11H NMR(400MHz,CDCl3) δ=7.36-7.24 (m, 5H), 6.05 (d, J=2.8Hz, 1H), 4.56 (t, J=8.2Hz, 1H), 4.33 (d, J=18.7Hz, 1H), 4.13 (dd, J=8.6, 5.0Hz, 1H), 3.96-3.90 (m, 1H), 3.85 (dd, J=18.7,2.0Hz, 1H), 2.67-2.50 (m, 2H);13C NMR (400MHz,CDCl3) δ=157.3,140.3,134.1,128.5,127.7,125.1,120.2,68.7,50.7,41.3, 32.1;HRMS Calcd for C13H13NO2Na+[M+Na+]:238.08440,found 238.08383.
Embodiment 13:(5R, 8aS)-7-methyl isophthalic acid, 5,8,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyridine-3-ketone
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-35 (122.5mg, 0.80mmol) Solution (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 25 DEG C, is monitoring with lamellae After reaction terminates, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixed Close organic facies and respectively with water (10mL), saturated aqueous common salt (10mL) washing, be finally dried with anhydrous sodium sulfate, after filtration Carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I IIa-13,98mg (productivity 80%).
White solid (fusing point: 42-43 DEG C);Rf=0.36 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3184 (br),1750,1402,1320,1069,699cm-11H NMR(400MHz,CDCl3) δ=5.43 (s, 1H), 4.49 (t, J= 8.2Hz, 1H), 4.09 (d, J=17.7Hz, 1H), 4.01 (dd, J=8.4,5.3Hz, 1H), 3.83-3.78 (m, 1H), 3.62 (d, J=17.7Hz, 1H), 2.17-2.06 (m, 2H), 1.74 (s, 3H);13C NMR(400MHz,CDCl3) δ=157.3, 131.0,117.3,68.7,50.5,40.7,34.3,23.4;HRMS Calcd for C8H11NO2Na+[M+Na+]: 176.06875,found 176.06873.
Embodiment 14:(5R, 8aS)-7-(4-isopropyl phenyl)-1,5,8,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyrrole Pyridine-3-ketone
In the dichloromethane solution (2ml) of reaction substrate I-36 (206mg, 0.80mmol), dropping boron trifluoride diethyl etherate is molten Liquid (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I IIa-14,148mg (productivity 72%).
White solid (fusing point: 84-85 DEG C);Rf=0.12 (petrol ether/ethyl acetate=3/1);IR(KBr)νmax 3224,3195,1755,1403,1075,808cm-11H NMR(600MHz,CDCl3) δ=7.28 (d, J=8.1Hz, 2H), 7.21 (d, J=8.1Hz, 2H), 6.04 (d, J=2.8Hz, 1H), 4.57 (t, J=8.2Hz, 1H), 4.33 (d, J=18.6Hz, 1H), 4.14 (dd, J=8.6,5.0Hz, 1H), 3.95-3.91 (m, 1H), 3.85 (dd, J=18.6,1.7Hz, 1H), 2.94- 2.87 (m, 1H), 2.66 (dd, J=15.8,2.0Hz, 1H), 2.55-2.50 (m, 1H), 1.25 (d, J=6.9Hz, 6H);13C NMR(600MHz,CDCl3) δ=157.4,148.7,137.9,134.0,126.7,125.2,119.6,68.8,50.9,41.5, 33.9,32.3,24.0;HRMS Calcd for C16H19NO2+[M+H+]:258.14940,found 258.14909.
Embodiment 15:(6R, 8aS)-6-methyl-7-phenyl-1,5,6,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyridine-3- Ketone
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-37 (183.4mg, 0.80mmol) Solution (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 25 DEG C, is monitoring with lamellae After reaction terminates, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixed Close organic facies and respectively with water (10mL), saturated aqueous common salt (10mL) washing, be finally dried with anhydrous sodium sulfate, after filtration Carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I IIb-1,148.6mg (productivity 81%).
White solid (fusing point: 97-98 DEG C);Rf=0.25 (petrol ether/ethyl acetate=7/3);IR(KBr)νmax 3220,1754,1416,1045,761cm-11H NMR(600MHz,CDCl3) δ=7.37-7.26 (m, 5H), 5.79 (s, 1H), 4.63-4.57 (m, 2H), 4.01 (t, J=7.3Hz, 1H), 3.90 (d, J=13.3Hz, 1H), 3.34 (dd, J=13.3, 4.2Hz, 1H), 2.92-2.88 (m, 1H), 1.09 (d, J=7.0Hz, 3H);13C NMR(600MHz,CDCl3) δ=157.9, 144.2,139.6,128.7,128.1,126.1,120.7,68.3,52.9,44.5,32.2,19.4;HRMS Calcd for C14H15NO2Na+[M+Na+]:252.10005,found 252.09934.
Embodiment 16:(6R, 8aS)-6-methyl-7-(4-fluorophenyl)-1,5,6,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] Pyridine-3-ketone
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-38 (197.8mg, 0.80mmol) Solution (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 40 DEG C, is monitoring with lamellae After reaction terminates, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixed Close organic facies and respectively with water (10mL), saturated aqueous common salt (10mL) washing, be finally dried with anhydrous sodium sulfate, after filtration Carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I IIb-2,170mg (productivity 86%).
White solid (fusing point: 83-85 DEG C);Rf=0.48 (petrol ether/ethyl acetate=13/7);IR(KBr)νmax 3322(br),2927,1752,1510,1227,839cm-11H NMR(400MHz,CDCl3) δ=7.30 (dd, J=7.2, 5.6Hz, 2H), 7.05 (t, J=8.2Hz, 2H), 5.75 (s, 1H), 4.63-4.55 (m, 2H), 4.00 (t, J=6.6Hz, 1H), 3.90 (d, J=13.4Hz, 1H), 3.33 (dd, J=13.4,3.8Hz, 1H), 2.89-2.81 (m, 1H), 1.08 (d, J= 6.9Hz,3H);13C NMR(400MHz,CDCl3) δ=163.4,161.7,157.9,143.2,135.7,135.7,127.8, 127.7,120.8,120.8,115.6,115.5,68.3,52.9,44.4,32.3,19.3;HRMS Calcd for C14H14NO2Na+[M+Na+]:270.09063,found 270.09028.
Embodiment 17:(6R, 8aS)-6-pi-allyl-7-phenyl-1,5,6,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyridine- 3-ketone
In the dichloromethane solution (2ml) of reaction substrate I-39 (204mg, 0.80mmol), dropping boron trifluoride diethyl etherate is molten Liquid (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 30 DEG C, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I IIb-3,180mg (productivity 88%).
Colorless gum;Rf=0.25 (petrol ether/ethyl acetate=7/3);IR(KBr)νmax 3328(br),2924, 1755,1416,1068,764cm-11H NMR(400MHz,CDCl3) δ=7.36-7.34 (m, 5H), 5.85 (s, 1H), 5.79- 5.69 (m, 1H), 5.16-5.07 (m, 2H), 4.64-4.55 (m, 2H), 4.10 (d, J=13.5Hz, 1H), 4.02-3.95 (m, 1H), 3.20 (dd, J=13.5,3.4Hz, 1H), 2.79 (d, J=9.3Hz, 1H), 2.14-1.93 (m, 2H);13C NMR (400MHz,CDCl3) δ=157.5,142.5,139.6,135.2,128.7,128.1,126.2,121.7,118.2,68 .3, 52.8,40.4,37.3,36.5;HRMS Calcd for C16H17NO2Na+[M+Na+]:278.11570,found 278.11524.
Embodiment 18:(6R, 8aS)-6-benzyl-7-phenyl-1,5,6,8a tetrahydrochysene-3 hydrogen-oxazole also [3,4-a] pyridine-3- Ketone
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-40 (244.3mg, 0.80mmol) Solution (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 25 DEG C, is monitoring with lamellae After reaction terminates, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixed Close organic facies and respectively with water (10mL), saturated aqueous common salt (10mL) washing, be finally dried with anhydrous sodium sulfate, after filtration Carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I IIb-4,213mg (productivity 87%).
White solid (fusing point: 153 DEG C);Rf=0.33 (petrol ether/ethyl acetate=3/1);IR(KBr)νmax 3326, 2924,1755,1420,1066,762cm-11H NMR(400MHz,CDCl3) δ=7.44-7.19 (m, 10H), 5.89 (s, 1H), 4.65-4.59 (m, 2H), 4.03-3.98 (m, 2H), 3.10 (dd, J=13.6,3.6Hz, 1H), 2.95 (d, J= 10.8Hz, 1H), 2.66 (d, J=13.6Hz, 1H), 2.42 (dd, J=13.6,11.2Hz, 1H);13C NMR(400MHz, CDCl3) δ=157.6,142.8,139.7,139.6,129.5,128.9,128.5,128.3,126.4,12 6.3,122.0, 68.4,53.0,40.2,39.8,38.0;HRMS Calcd for C20H19NO2Na+[M+Na+]:328.13135,found 328.13124.
Embodiment 19:(6R, 8aS)-6-benzyl-7-(4-isopropyl phenyl)-1,5,6,8a tetrahydrochysene-3 hydrogen-oxazole also [3, 4-a] pyridine-3-ketone
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-41 (277.9mg, 0.80mmol) Solution (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, is monitoring with lamellae After reaction terminates, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixed Close organic facies and respectively with water (10mL), saturated aqueous common salt (10mL) washing, be finally dried with anhydrous sodium sulfate, after filtration Carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I IIb-5,222.3mg (productivity 80%).
White solid (fusing point: 112 DEG C);Rf=0.54 (petrol ether/ethyl acetate=3/1);IR(KBr)νmax 3481, 3415,2961,1757,1417,1066,702cm-11H NMR(400MHz,CDCl3) δ=7.41-7.22 (m, 9H), 5.89 (s, 1H), 4.66-4.57 (m, 2H), 4.04-3.98 (m, 2H), 3.10 (dd, J=13.6,3.6Hz, 1H), 3.01-2.96 (m, 2H), 2.72 (d, J=13.6Hz, 1H), 2.44 (dd, J=13.4,11.6Hz, 1H), 1.31 (d, J=7.2Hz, 6H);13C NMR(400MHz,CDCl3) δ=157.7,149.2,142.6,139.8,137.0,129.5,128.5,127.0,126.4, 126.2,121.2,68.5,53.1,40.1,39.9,38.1,33.9,24.0;HRMS Calcd for C23H25NO2Na+[M+Na+]:370.17830,found 370.17821.
Embodiment 20:8,9-dimethoxy-1,5,6,10b-tetrahydrochysene-3 hydrogen-oxazole also [4,3-a] isoquinolin-3-ketone
Dropping boron trifluoride diethyl etherate in the dichloromethane solution (2ml) of reaction substrate I-42 (199.4mg, 0.80mmol) Solution (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 25 DEG C, is monitoring with lamellae After reaction terminates, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixed Close organic facies and respectively with water (10mL), saturated aqueous common salt (10mL) washing, be finally dried with anhydrous sodium sulfate, after filtration Carry out rotary evaporation, obtain thick product.Thick product, through silica gel column chromatography, obtains pure product I IIb-6,187.5mg (productivity 94%).
White solid (fusing point: 218-219 DEG C);Rf=0.30 (petrol ether/ethyl acetate=1/4);IR(KBr)νmax 3154,2932,1754,1517,1402,1258,772cm-11H NMR(600MHz,CDCl3) δ=6.62 (s, 1H), 6.44 (s, 1H), 4.96 (t, J=7.5Hz, 1H), 4.77 (t, J=8.4Hz, 1H), 4.16 (dd, J=8.0,6.7Hz, 1H), 4.09 (dd, J=13.3,6.2Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.21-3.16 (m, 1H), 3.02-2.97 (m, 1H), 2.62 (dd, J=16.1,3.8Hz, 1H);13C NMR(600MHz,CDCl3) δ=157.6,148.6,148.5,126.3, 125.9,112.1,107.5,69.5,56.2,56.0,54.2,38.9,27.1;HRMS Calcd for C13H15NO4Na+[M+ Na+]:272.08988,found 272.09337.
Embodiment 21:5-pi-allyl-8,9-dimethoxy-1,5,6,10b-tetrahydrochysene-3 hydrogen-oxazole also [4,3-a] isoquinoline Quinoline-3-ketone
In the dichloromethane solution (2ml) of reaction substrate I-43 (232mg, 0.80mmol), dropping boron trifluoride diethyl etherate is molten Liquid (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I IIb-7,211mg (productivity 91%).
White solid (fusing point: 180-186 DEG C);Rf=0.50 (petrol ether/ethyl acetate=7/3);IR(KBr)νmax 3216,3078,1751,1518,1401,1119,728cm-11H NMR(400MHz,CDCl3) δ=6.60 (s, 1H), 6.44 (s, 1H), 5.88-5.78 (m, 1H), 5.11-5.06 (m, 2H), 4.87 (t, J=7.4Hz, 1H), 4.77 (t, J=8.3Hz, 1H), 4.29 (dd, J=14.1,6.9Hz, 1H), 4.19 (t, J=7.1Hz, 1H), 3.86 (s, 6H), 3.10 (dd, J=16.2, 6.4Hz, 1H), 2.57 (d, J=16.2Hz, 1H), 2.39-2.24 (m, 2H);13C NMR(400MHz,CDCl3) δ=157.5, 148.7,148.3,134.3,125.3,124.4,117.9,112.4,107.2,69.4,56.1,55.9,51.2,48.1, 35.8,30.9;HRMS Calcd for C16H19NO4Na+[M+Na+]:312.12118,found 312.12753.
Embodiment 22:5,6,11,11b-tetrahydrochysene-1H, 3H-oxazole also [3', 4':1,2] pyrido [3,4-b] indole-3- Ketone
In the dichloromethane solution (2ml) of reaction substrate I-44 (263mg, 0.80mmol), dropping boron trifluoride diethyl etherate is molten Liquid (52 μ L, 0.5equiv.), round-bottomed flask.Reactant mixture stirs 12 hours under the conditions of 50 DEG C, anti-with lamellae monitoring After should terminating, react with saturated sodium bicarbonate (5ml) cancellation, and stir 5 minutes.3 times (5mL × 3) of dichloromethane extraction, mixing Organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively, is finally dried with anhydrous sodium sulfate, filters laggard Row rotary evaporation, obtains thick product.Thick product, through silica gel column chromatography, obtains pure product I IIb-8,210.1mg (productivity 80%).
White solid (fusing point: 190-192 DEG C);Rf=0.20 (petrol ether/ethyl acetate=3/2);IR(KBr)νmax 3477,3415,1729,1406,1218,761cm-11H NMR(400MHz,DMSO-d6) δ=11.00 (s, 1H), 7.43 (d, J =7.8Hz, 1H), 7.36 (d, J=8.1Hz, 1H), 7.10 (t, J=7.5Hz, 1H), 7.00 (t, J=7.4Hz, 1H), 5.23- 5.21 (m, 1H), 4.67 (t, J=8.5Hz, 1H), 4.32 (dd, J=8.6,4.1Hz, 1H), 3.97 (dd, J=13.5, 5.8Hz,1H),3.30-3.22(m,1H),2.83-2.67(m,2H);13C NMR(400MHz,DMSO-d6) δ=157.8, 136.1,131.7,126.3,121.5,118.8,117.9,111.3,107.3,66.9,52.0,19.4;HRMS Calcd for C13H12N2O2Na+[M+Na+]:251.07965,found 251.07934.
Secondary annulation embodiment
Embodiment 1: tetrahydrochysene-1H-5,8-methylene oxazole [3,4-d] [1,4] oxygen azatropylidene-3 (8H)-one
In the dichloromethane solution (2ml) of reaction substrate I-45 (207.4mg, 0.80mmol), at 25 DEG C, drip trifluoro Changing borate ether solution (52 μ L, 0.5equiv.), 25 DEG C are stirred 12 hours, after reaction terminates, quench with saturated sodium bicarbonate (5ml) Go out reaction, dichloromethane extraction (5mL × 3), mixing organic facies also washs with water (10mL), saturated aqueous common salt (10mL) the most respectively, Anhydrous sodium sulfate is dried, and carries out rotary evaporation after filtration, and pillar layer separation obtains product IV-1,124.5mg (productivity 92%).
In the dichloromethane solution (2ml) of reaction substrate I-46 (326.0mg, 0.80mmol), at 25 DEG C, drip trifluoro Changing borate ether solution (52 μ L, 0.5equiv.), 25 DEG C are stirred 12 hours, after reaction terminates, quench with saturated sodium bicarbonate (5ml) Go out reaction, dichloromethane extraction (5mL × 3), mixing organic facies also washs with water (10mL), saturated aqueous common salt (10mL) the most respectively, Anhydrous sodium sulfate is dried, and carries out rotary evaporation after filtration, and pillar layer separation obtains product IV-1,116.4mg (productivity 86%).
In the dichloromethane solution (2ml) of reaction substrate I-47 (135.3mg, 0.80mmol), at 30 DEG C, drip trifluoro Changing borate ether solution (52 μ L, 0.5equiv.), 30 DEG C are stirred 12 hours, after reaction terminates, quench with saturated sodium bicarbonate (5ml) Go out reaction, dichloromethane extraction (5mL × 3), mixing organic facies also washs with water (10mL), saturated aqueous common salt (10mL) the most respectively, Anhydrous sodium sulfate is dried, and carries out rotary evaporation after filtration, and pillar layer separation obtains product IV-1,127.2mg (productivity 94%).White Solid (fusing point: 49-50 DEG C);Rf=0.34 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax3479(br),2957, 1746,1421,1244,1043,762cm-11H NMR(400MHz,DMSO-d6) δ=4.50 (t, J=5.5Hz, 1H), 4.35 (t, J=8.3Hz, 1H), 4.27 (s, 1H), 4.13-4.06 (m, 1H), 3.96-3.91 (m, 2H), 3.79 (dd, J=8.9, 3.6Hz, 1H), 1.87-1.78 (m, 2H), 1.72 (d, J=11.4Hz, 1H), 1.43 (dd, J=12.8,10.4Hz, 1H);13C NMR(400MHz,DMSO-d6) δ=155.9,73.4,70.5,67.4,52.6,50.1,37.0,35.8;HRMS Calcd for C8H11NO3Na+[M+Na+]:192.06366,found 192.06643.
Embodiment 2:6-methyl tetrahydrochysene-1H-5,8-methylene oxazole [3,4-d] [1,4] oxygen azatropylidene-3 (8H)-one
In the dichloromethane solution (2ml) of reaction substrate I-48 (218.6mg, 0.80mmol), at 35 DEG C, drip trifluoro Changing borate ether solution (52 μ L, 0.5equiv.), 35 DEG C are stirred 12 hours, after reaction terminates, quench with saturated sodium bicarbonate (5ml) Go out reaction, dichloromethane extraction (5mL × 3), mixing organic facies also washs with water (10mL), saturated aqueous common salt (10mL) the most respectively, Anhydrous sodium sulfate is dried, and carries out rotary evaporation after filtration, and pillar layer separation obtains product IV-2,108.4mg (productivity 74%).White Solid (fusing point: 84-85 DEG C);Rf=0.30 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax3485(br),3123, 2957,1753,1417,1094,801cm-11H NMR(400MHz,DMSO-d6) δ=4.47 (d, J=5.7Hz, 1H), 4.42 (t, J=8.3Hz, 1H), 4.19-4.11 (m, 1H), 4.08-4.02 (m, 2H), 3.95 (t, J=7.6Hz, 1H), 2.04-2.00 (m, 1H), 1.91-1.85 (m, 1H), 1.70 (d, J=11.5Hz, 1H), 1.38 (dd, J=12.6,10.2Hz, 1H), 1.19 (d, J=6.3Hz, 3H);13C NMR(400MHz,DMSO-d6) δ=156.9,76.2,73.2,68.1,54.9,50.3,37.9, 35.2,14.3;HRMS Calcd for C9H13NO3Na+[M+Na+]:206.07931,found 206.07912.
Embodiment 3:10-methyl tetrahydrochysene-1H-5,8-methylene oxazole [3,4-d] [1,4] oxygen azatropylidene-3 (8H)-one
In the dichloromethane solution (2ml) of reaction substrate I-49 (218.6mg, 0.80mmol), at 40 DEG C, drip trifluoro Changing borate ether solution (52 μ L, 0.5equiv.), 40 DEG C are stirred 12 hours, after reaction terminates, quench with saturated sodium bicarbonate (5ml) Go out reaction, dichloromethane extraction (5mL × 3), mixing organic facies also washs with water (10mL), saturated aqueous common salt (10mL) the most respectively, Anhydrous sodium sulfate is dried, and carries out rotary evaporation after filtration, and pillar layer separation obtains product IV-3,104.0mg (productivity 71%).White Solid (fusing point: 86-88 DEG C);Rf=0.23 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax3219,3151,3136, 3115,1748,1400,865cm-11H NMR(600MHz,CDCl3) δ=4.49 (t, J=8.5Hz, 1H), 4.30 (t, J= 5.2Hz,1H),4.20(s,1H),4.18-4.13(m,1H),4.00-3.96(m,3H),2.27-2.22(m,1H),1.89- 1.85 (m, 1H), 1.56 (dd, J=13.3,10.1Hz, 1H), 1.10 (d, J=6.9Hz, 3H);13C NMR(600MHz, CDCl3) δ=156.7,76.8,71.6,68.7,55.3,49.7,39.2,30.8,9.9;HRMS Calcd for C9H13NO3Na+[M+Na+]:206.07931,found 206.07886.
Embodiment 4:8-bromine tetrahydrochysene-1H-5,8-methylene oxazole [3,4-d] [1,4] oxygen azatropylidene-3 (8H)-one
In the dichloromethane solution (2ml) of reaction substrate I-50 (270.6mg, 0.80mmol), at 50 DEG C, drip trifluoro Changing borate ether solution (52 μ L, 0.5equiv.), 50 DEG C are stirred 12 hours, after reaction terminates, quench with saturated sodium bicarbonate (5ml) Go out reaction, dichloromethane extraction (5mL × 3), mixing organic facies also washs with water (10mL), saturated aqueous common salt (10mL) the most respectively, Anhydrous sodium sulfate is dried, and carries out rotary evaporation after filtration, and pillar layer separation obtains product IV-4,160.7mg (productivity 81%).White Solid (fusing point: 113-115 DEG C);Rf=0.62 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3482(br),3128, 2972,1756,1400,1239,999,756cm-11H NMR(600MHz,CDCl3) δ=4.44-4.41 (m, 2H), 4.33 (dd, J=9.1,3.3Hz, 1H), 4.25-4.20 (m, 1H), 4.04 (d, J=9.1Hz, 1H), 4.00 (dd, J=8.8, 4.8Hz, 1H), 2.67-2.64 (m, 1H), 2.60-2.57 (m, 1H), 2.37 (d, J=12.1Hz, 1H), 2.14 (dd, J= 12.8,10.1Hz,1H);13C NMR(600MHz,CDCl3) δ=156.6,92.6,74.3,66.9,53.9,52.3,48.5, 48.3;HRMS Calcd for C8H10BrNO3Na+[M+Na+]:269.97418,found 269.97592.
Embodiment 5:8-normal-butyl tetrahydrochysene-1H-5,8-methylene oxazole [3,4-d] [1,4] oxygen azatropylidene-3 (8H)-one
In the dichloromethane solution (2ml) of reaction substrate I-51 (252.3mg, 0.80mmol), at 50 DEG C, drip trifluoro Changing borate ether solution (52 μ L, 0.5equiv.), 50 DEG C are stirred 12 hours, after reaction terminates, quench with saturated sodium bicarbonate (5ml) Go out reaction, dichloromethane extraction (5mL × 3), mixing organic facies also washs with water (10mL), saturated aqueous common salt (10mL) the most respectively, Anhydrous sodium sulfate is dried, and carries out rotary evaporation after filtration, and pillar layer separation obtains product IV-5,140.5mg (productivity 78%).White Solid;Rf=0.67 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax3466(br),3134,2933,1755,1416, 1246,1050,806cm-11H NMR(400MHz,CDCl3) δ=4.47 (s, 1H), 4.37 (t, J=8.3Hz, 1H), 4.20- 4.13 (m, 1H), 3.99-3.95 (m, 3H), 1.85 (dd, J=12.7,5.0Hz, 1H), 1.79-1.72 (m, 2H), 1.66- 1.62 (m, 2H), 1.50-1.43 (m, 1H), 1.33-1.21 (m, 4H), 0.91 (t, J=6.7Hz, 3H);13C NMR(400MHz, CDCl3) δ=156.8,82.9,71.6,67.9,54.4,51.3,41.1,40.9,38.9,26.6,23.2,14.1;HRMS Calcd for C12H19NO3Na+[M+Na+]:248.12626,found 248.12989.
Embodiment 6:8-isobutyl group tetrahydrochysene-1H-5,8-methylene oxazole [3,4-d] [1,4] oxygen azatropylidene-3 (8H)-one
In the dichloromethane solution (2ml) of reaction substrate I-52 (252.3mg, 0.80mmol), at 25 DEG C, drip trifluoro Changing borate ether solution (52 μ L, 0.5equiv.), 25 DEG C are stirred 12 hours, after reaction terminates, quench with saturated sodium bicarbonate (5ml) Go out reaction, dichloromethane extraction (5mL × 3), mixing organic facies also washs with water (10mL), saturated aqueous common salt (10mL) the most respectively, Anhydrous sodium sulfate is dried, and carries out rotary evaporation after filtration, and pillar layer separation obtains product IV-6,142.4mg (productivity 79%).White Solid (fusing point: 83-86 DEG C);Rf=0.67 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3354(br),3143, 2914,1737,1399,1060,753cm-11H NMR(400MHz,CDCl3) δ=4.47 (s, 1H), 4.33 (t, J=8.4Hz, 1H),4.19-4.12(m,1H),3.99-3.95(m,3H),1.89-1.71(m,4H),1.60-1.57(m,2H),1.45(dd,J =12.5,10.4Hz, 1H), 0.96 (d, J=3.9Hz, 3H), 0.94 (d, J=3.9Hz, 3H);13C NMR(400MHz, CDCl3) δ=156.9,83.1,71.5,67.9,54.4,51.4,47.6,41.7,41.5,24.6,24.3,23.9;HRMS Calcd for C12H19NO3Na+[M+Na+]:248.12626,found 248.12582.
Embodiment 7:8-isopropyl base tetrahydrochysene-1H-5,8-methylene oxazole [3,4-d] [1,4] oxygen azatropylidene-3 (8H)-one
In the dichloromethane solution (2ml) of reaction substrate I-53 (241.1mg, 0.80mmol), at 50 DEG C, drip trifluoro Changing borate ether solution (52 μ L, 0.5equiv.), 50 DEG C are stirred 12 hours, after reaction terminates, quench with saturated sodium bicarbonate (5ml) Go out reaction, dichloromethane extraction (5mL × 3), mixing organic facies also washs with water (10mL), saturated aqueous common salt (10mL) the most respectively, Anhydrous sodium sulfate is dried, and carries out rotary evaporation after filtration, and pillar layer separation obtains product IV-7,135.2mg (productivity 80%).White Solid (fusing point: 95-97 DEG C);Rf=0.46 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax3170,3155,3124, 1749,1405,1394,1220,1045cm-11H NMR(400MHz,CDCl3) δ=4.81-4.73 (m, 1H), 4.41 (t, J= 8.2Hz, 1H), 4.95 (d, J=11.8Hz, 1H), 3.88-3.79 (m, 3H), 2.19-2.15 (m, 2H), 1.71-1.67 (m, 2H),1.57-1.49(m,1H),1.34(s,3H),1.28(s,3H);13C NMR(400MHz,CDCl3) δ=156.4,73.1, 68.5,65.2,50.7,44.7,34.1,31.6,27.8,27.2,22.5;HRMS Calcd for C11H17NO3Na+[M+Na+]:234.11061,found 234.11030.
Embodiment 8:8-methyltetrahydro-1H-5,8-methylene oxazole [3,4-d] [1,4] oxygen azatropylidene-3 (8H)-one
In the dichloromethane solution (2ml) of reaction substrate I-54 (218.6mg, 0.80mmol), at 25 DEG C, drip trifluoro Changing borate ether solution (52 μ L, 0.5equiv.), 25 DEG C are stirred 12 hours, after reaction terminates, quench with saturated sodium bicarbonate (5ml) Going out reaction, 3 times (5mL × 3) of dichloromethane extraction, mixing organic facies is also washed with water (10mL), saturated aqueous common salt (10mL) respectively Washing, anhydrous sodium sulfate is dried, and carries out rotary evaporation after filtration, and pillar layer separation obtains product IV-8,120.2mg (productivity 82%).
White solid (fusing point: 75-76 DEG C);Rf=0.35 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax 3462 (br),2928,1754,1411,1248,1030,761cm-11H NMR(400MHz,CDCl3) δ=4.48 (s, 1H), 4.43 (t, J=8.3Hz, 1H), 4.19-4.12 (m, 1H), 4.03 (dd, J=9.1,3.5Hz, 1H), 3.99-3.94 (m, 2H), 1.89-1.84 (m, 1H), 1.81-1.74 (m, 2H), 1.46 (dd, J=12.7,10.4Hz, 1H), 1.39 (s, 3H);13C NMR (400MHz,CDCl3) δ=156.8,80.4,72.0,67.8,54.7,51.3,43.2,42.4,25.4;HRMS Calcd for C9H13NO3Na+[M+Na+]:206.07931,found 206.08205.
Embodiment 9: hexahydro-5,7a-methylene oxazole [3,4-d] thiophene [3,4-f] [1,4] oxygen azatropylidene-3 (8H)- Ketone 9,9-dioxide
In the dichloromethane solution (2ml) of reaction substrate I-55 (279.5mg, 0.80mmol), at 50 DEG C, drip trifluoro Changing borate ether solution (52 μ L, 0.5equiv.), 50 DEG C are stirred 12 hours, after reaction terminates, quench with saturated sodium bicarbonate (5ml) Go out reaction, dichloromethane extraction (5mL × 3), mixing organic facies also washs with water (10mL), saturated aqueous common salt (10mL) the most respectively, Anhydrous sodium sulfate is dried, and carries out rotary evaporation after filtration, and pillar layer separation obtains product IV-9,168.0mg (productivity 81%).White Powder;Rf=0.24 (petrol ether/ethyl acetate=1/1);IR(KBr)νmax3134(br),1738,1409,1297,1126, 1019,768cm-11H NMR(600MHz,DMSO-d6) δ=4.38 (s, 1H), 4.31 (t, J=8.4Hz, 1H), 4.20 (d, J =4.8Hz, 1H), 3.99-3.95 (m, 3H), 3.55 (d, J=13.8Hz, 1H), 3.44-3.40 (m, 1H), 3.35 (s, 1H), 2.92 (t, J=12.6Hz, 1H), 2.55-2.52 (m, 1H), 2.00 (s, 2H);13C NMR(600MHz,DMSO-d6) δ= 156.4,85.1,71.9,66.3,59.9,55.4,53.5,53.3,45.9,39.3;HRMS Calcd for C10H13NO5SNa+ [M+Na+]:282.04121,found 282.04123.
Determination of activity
Employing MTT (tetrazolium blue) colorimetric method for determining proliferative activity o f tumor:
1. tumor cell line is cultivated: A549, SMMC-7721, SK-OV-3, U266, MM1S cell strain is with containing 10%FBS's RPMI-1640 culture medium culturing;
2. sample configuration:
(1) sample is dissolved in DMSO to ultimate density 100mmol/L;It is 10 concentration with DMSO serial dilution sample, dilution Coefficient is 3 times;
(2) taking 1 μ l sample during dosing to add in 1ml culture medium, in 96 orifice plates, every hole culture medium is 100 μ l;
(3) ultimate density of sample is 100 μm ol/L, 33 μm ol/L, 11 μm ol/L, 3.7 μm ol/L, 1.2 μm ol/L, 0.4 μm ol/L, 0.13 μm ol/L, 0.04 μm ol/L, 0.013 μm ol/L, 0 μm ol/L;
(4) ultimate density of DMSO is 1:1000;MTT sample after weighing is dissolved in PBS solution so that it is final concentration of 5mg/ml, subpackage after 2.2 μm membrane filtrations ,-20 DEG C keep in Dark Place;
3.MTT tests detection:
(1) collecting exponential phase cell, adjust concentration of cell suspension, every hole adds 100 μ L bed boards makes cell to be measured adjust Density 5000-9000 cells/well;
(2) 5%CO2, 37 DEG C of overnight incubation, remove culture fluid, add the medicine of Concentraton gradient.Each medicine set 10 dense Degree gradient (100 μm ol/L, 33.3 μm ol/L, 11.1 μm ol/L, 3.7 μm ol/L, 1.23 μm ol/L, 0.41 μm ol/L, 0.13 μ Mol/L, 0.04 μm ol/L, 0.013 μm ol/L, 0 μm ol/L), every hole 100 μ l, each concentration sets 2 multiple holes;
(3) 5%CO2, hatch 72 hours for 37 DEG C;
(4) outwelling pastille culture medium, the final concentration 1mg/ml MTT that every hole adds 100 μ l serum-free medium preparations is molten Liquid, continues to cultivate 4h;
(5) every hole adds lysate 25%SDS+50%DMF 100 μ l, 37 DEG C of overnight incubation;
(6) read the light absorption value in each hole in OD570nm with the multi-functional plate reading machine of synergy 4;
4. statistical analysis:
(1) enumeration data represents with means standard deviation, and result uses one factor analysis of variance (ANOVA).
(2) IC50 curve GraphPad Prism 5 software of various samples is analyzed generating.
The suppression percentage ratio of growth of tumour cell is by sample:
(sample well OD average-blank well OD average)/(negative control hole OD average-blank well OD average)
(3) sample carries out nonlinear regression analysis to the suppression percentage ratio of growth of tumour cell, intends by below equation Close, obtain the concentration-effect dependency curve of sample, Y=1/ (1+10 (log IC50-X) × HillSlope), wherein IC50 For suppressing the sample concentration of tumor growth 50%.
5. inhibitory action (IC50) measurement result that 5 tumor cell lines are bred by test sample is as follows:
When IC50 value approximates 20 μMs, can be considered that the propagation to tumor cell line is inhibited.
Described herein, above example is only in order to illustrate technical scheme and unrestricted, although by ginseng According to the preferred embodiments of the present invention, invention has been described, it should be appreciated by those of ordinary skill in the art that can In the form and details it is made various change, without departing from the spirit and scope of the present invention.

Claims (10)

1. a preparation method for oxazolone heterocyclic compounds, the reaction equation of this preparation method is:
It is characterized in that, with boron trifluoride diethyl etherate as catalyst, formula (I) compound is reaction substrate
Work as R1For substituted or non-substituted alkyl, thiazolinyl, cycloalkyl, ester group, R2During for hydrogen or methyl, under the conditions of 50 DEG C, reaction is raw Dimerisation products shown in an accepted way of doing sth (IIa)
Work as R1It is alkyl, the alkyl of halogen substiuted, alkoxyl, halogen substiuted for the substituent group on phenyl or substituted-phenyl, and phenyl Alkoxyl, halogen, R2During for hydrogen, under the conditions of 50 DEG C, react the cyclization product shown in production (IIb)
Work as R1It is alkyl, the alkyl of halogen substiuted, alkoxyl, halogen substiuted for the substituent group on phenyl or substituted-phenyl, and phenyl Alkoxyl, halogen, R2During for methyl, under the conditions of 25 DEG C, react the dimerisation products shown in production (IIa);Under the conditions of 50 DEG C instead Answer the cyclization product shown in production (IIb).
Preparation method the most according to claim 1, it is characterised in that
Work as R1For C1-6The substituted C of alkyl, phenyl ring1-6Alkyl, pi-allyl, cyclohexyl, butyl propionate base, R2During for hydrogen or methyl, 50 The dimerisation products shown in production (IIa) is reacted under DEG C heating condition;
Work as R1It is C for the substituent group on phenyl or substituted-phenyl, and phenyl1-3Alkyl, the C of halogen substiuted1-3Alkyl, C1-3Alcoxyl Base, the C of halogen substiuted1-3Alkoxyl, halogen, R2During for hydrogen, under 50 DEG C of heating conditions, react the cyclization shown in production (IIb) Product;
Work as R1It is C for the substituent group on phenyl or substituted-phenyl, and phenyl1-3Alkyl, the C of halogen substiuted1-3Alkyl, C1-3Alcoxyl Base, the C of halogen substiuted1-3Alkoxyl, halogen, R2When group is methyl, under the conditions of 25 DEG C, react two shown in production (IIa) Poly-product, the cyclization product shown in production (IIb) under 50 DEG C of heating conditions.
3. a preparation method for oxazolone heterocyclic compounds, the reaction equation of this preparation method is:
It is characterized in that, with boron trifluoride diethyl etherate as catalyst, formula (I) compound is reaction substrate, wherein, R1Group isR2Group is hydrogen;
Work as R4For hydrogen, R3And R5Respectively: (1) R3For hydrogen, R5Take for alkyl, the substituted alkyl of aryl, pi-allyl, aryl, halogen The substituted aryl of the aryl in generation, alkyl;(2)R3For alkyl, R5For hydrogen;(3)R3For alkyl, R5For alkyl, the virtue of halogen substiuted When base, heterocyclic radical, the cyclization product shown in reaction production (IIIa);
Work as R3Group is hydrogen, R4And R5Respectively: (1) R4For alkyl, R5For aryl, the aryl of halogen substiuted;(2)R4For allyl Base, R5For aryl;(3) 3,4 carbon and aforementioned R5During group cyclization, the cyclization product shown in reaction production (IIIb).
Preparation method the most according to claim 3, it is characterised in that
Work as R4For hydrogen, R3And R5It is respectively as follows: (1) R3For hydrogen, R5For C1-6The substituted C of alkyl, aryl1-6Alkyl, pi-allyl, aryl, The aryl of halogen substiuted, C1-6The substituted aryl of alkyl;(2)R3For C1-6Alkyl, R5For hydrogen;(3)R3For C1-6Alkyl, R5For C1-6 When alkyl, the aryl of halogen substiuted, heterocyclic radical, the product shown in reaction production (IIIa);
Work as R3For hydrogen, R4And R5It is respectively as follows: (1) R4For C1-6Alkyl, R5For aryl, the aryl of halogen substiuted;(2)R4For pi-allyl, R5For aryl;(3) 3,4 carbon and aforementioned R5Group becomes phenyl ring or becomes between 3,4 carbon when be the heterocycle of double bond, reaction production (IIIb) the cyclization product shown in.
5. a preparation method for oxazolone heterocyclic compounds, the reaction equation of this preparation method is:
It is characterized in that, with boron trifluoride diethyl etherate as catalyst, wherein with formula (I) compound as reaction substrate;
Work as R1ForR2For hydrogen, R9For hydrogen and other silanes or alkyls protection group, R6And R7For hydrogen, alkyl, R8During for hydrogen, halogen, alkyl, the secondary cyclization product shown in reaction production (IVa);
Work as R1ForN=1-3, R2For hydrogen, X is heteroatom group, R9For hydrogen and other silanes or alkyls Protection group, R6And R7During for hydrogen, alkyl, the secondary cyclization product shown in reaction production (IVb).
Preparation method the most according to claim 5, it is characterised in that
Work as R1ForR2For hydrogen, R9For hydrogen and other silanes or alkyls protection group, R6And R7For hydrogen, C1-6Alkane Base, R8For hydrogen, halogen, C1-6During alkyl, the secondary cyclization product shown in reaction production (IVa);
Work as R1ForN=1-3, R2For hydrogen, R6And R7For hydrogen, C1-6Alkyl, R9For hydrogen and other silanes or Alkyls protection group, X is O, NH, N, SH, SO of being protected by protection group2Time, the secondary cyclization shown in reaction production (IVb) produces Thing.
7. according to the preparation method described in any one of claim 3-6, it is characterised in that reaction temperature is 25-50 DEG C.
Preparation method the most according to claim 7, it is characterised in that reaction temperature is 25 DEG C or 50 DEG C.
9. according to the compound prepared by the preparation method described in any one of claim 1-6.
Compound the most according to claim 9 is for preparing the medicinal usage for the treatment of tumor.
CN201610009872.3A 2015-04-02 2016-01-08 Preparation method for oxazolone heterocyclic compounds Pending CN106045935A (en)

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