CN108129438A - A kind of compound of the chroman of benzene containing 2- parent nucleus and preparation method thereof - Google Patents
A kind of compound of the chroman of benzene containing 2- parent nucleus and preparation method thereof Download PDFInfo
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- CN108129438A CN108129438A CN201711425594.0A CN201711425594A CN108129438A CN 108129438 A CN108129438 A CN 108129438A CN 201711425594 A CN201711425594 A CN 201711425594A CN 108129438 A CN108129438 A CN 108129438A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
- C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a kind of compounds for containing 2 benzene chroman parent nucleus and preparation method thereof, it is characterised in that the compound structure such as general formula（I）It is shown：
Description
Technical field
The present invention relates to a kind of compounds of the chroman of benzene containing 2- parent nucleus and preparation method thereof, belong to pharmaceutical technology field.
Background technology
The multidrug resistance (multidrug resistance, MDR) of tumour cell is so that chemotherapy of tumors faces severe challenge.
Multi-efflux pumps are one of most important mechanism of tumor multi-medicine drug-resistant.Multi-efflux pumps belong to one group of ATP-binding cassette superfamily transmembrane protein, with
ATP, which is combined and provided energy by ATP, generates antitumor drug outer row's effect, and there are three types of ABC memebrane proteins and tumor multi-medicine drug-resistants
It is closely related, i.e. mammalian transport albumen P- glycoprotein (P-gp；MDR1；ABCB1), breast drug-resistance protein BCRP (ABCG2
Or MXR) and multidrug resistance associated protein MRP1 (ABCC1).Since P-gp albumen is overexpressed in kinds of tumor cells,
It is particularly important to the research of P-gp protein inhibitors.
A variety of P-gp inhibitor are found that by the methods of structure of modification of high flux screening and reactive compound, including
The drugs such as generation Verapamil and second generation PSC-833.Third generation inhibitor include tariquidar (XR-9576),
Zosuquidar (LY335979), laniquidar (R101933) and OC144-093 etc., overcome one, two generation inhibitor activities
The shortcomings that low and toxic side effect is big, and XR-9576 etc. is carrying out anti-breast cancer phase iii clinical trial, shows good clinic
Application prospect.Nevertheless, at present still without the efficient P-gp inhibitor of low toxicity for Clinical practice.Mainly Research Challenges are
The accurate combined area of P-gp inhibitor and binding site are also unknown at present, therefore combine area of computer aided brand-new design P-gp and inhibit
Agent is difficult to obtain ideal effect.
For this present Research, new Research Thinking is to carry out structure of modification to the natural products of low toxicity to obtain low toxicity
P-gp inhibitor, such as flavonoids, catechin, curcumin and ocean piece spiral shell element class analogue all show potential P-gp
Inhibitory activity.The Chinese patent of Publication No. 102603692A discloses a kind of artitumor multi-medicine-resistant inhibitor chroman and chromene
Derivative and, structure optimization has been carried out to less toxic natural products catechin, it was found that the inhibition P-gp's of 8 high effect nontoxics is anti-
Tumor multi-medicine drug-resistant symptom of a trend compound, overriding resistance EC50 reach 140.0-280.0nM.
In the prior art, the catechin compounds containing chromene -3- alcohol esterification derivant structures of synthesis
The artitumor multi-medicine-resistant activity having is usually than relatively low, and chemistry and biological metabolism are unstable.
Invention content
In view of the above-mentioned problems, the object of the present invention is to provide one kind to have higher artitumor multi-medicine-resistant activity, low toxicity
The efficiently compound of the chroman of benzene containing 2- parent nucleus has high water solubility and bioavilability as P-gp inhibitor.
This another purpose is to provide that a kind of synthetic route is shorter, the change of the higher chroman of benzene containing the 2- parent nucleus of reaction yield
Close the preparation method of object.
In order to complete the purpose of the present invention, present invention employs following technical solutions：
The catechin compounds of compound structure of the present invention to containing the chroman parent nucleus of benzene containing 2- advanced optimize, design
With synthesized a series of new P-gp inhibitor, to improve the water solubility of P-gp inhibitor and bioavilability.The present invention is also for the first time
The compound of the chroman parent nucleus of benzene containing 2- containing the alkaline nitrogen heterocyclic ring side chain such as piperidines, morpholine with good solubility is synthesized.
The compound structure of the chroman of benzene containing 2- parent nucleus of the present invention is as shown in logical formula (I)：
Wherein 2 are configured as R types or S types, and 3 are configured as R types or S types；R1~R9Respectively hydrogen, hydroxyl, alkoxy, alkane
It is one or more in amino, alkylamidoalkyl, fluorine, benzoyl, benzamido；X is oxygen；Y is for hydrogen or such as general formula (II)
Or the structure shown in (III) or (IV)：
In the general formula (II) or (III) or (IV), R10One kind in hydrogen, fluorine, alkoxy, benzyl, benzoyl,
Preferably methoxyl group or benzoyl.
M=0 or 1 in the general formula (II)；R11、R12Respectively hydrogen, fluorine, hydroxyl, 1-10 carbon atom number alkoxy or
End is connected with one kind in the alkoxy of nitrogenous heterocyclic 1-10 carbon atom, and the end is connected with nitrogenous heterocyclic 1-10 carbon
The alkoxy of atomicity, shown in structure such as general formula (V)：
Wherein n=1~10, Z are carbon or oxygen；The nitrogen heterocyclic ring is piperidines, morpholine or methyl piperazine.
The R11Or R12Preferably piperidines ethyoxyl, morpholine ethyoxyl or 4- methyl piperazine ethyoxyls.
The compound of the chroman of benzene containing 2- parent nucleus of the present invention, is preferably but not limited to following compound：(2R,3R)-5,7-
Dimethoxy -2- (3,4- Dimethoxyphenyl) -3,4- dihydros-chromene -3- alcohol (1), (2R, 3R) -5,7- dimethoxys -
2- (3,4- Dimethoxyphenyl) -3,4- dihydros-chromene -3- alcohol, 3,4,5- trimethoxybenzoates (2), (2R,
3R) -5,7- dimethoxys -2- (3,4- Dimethoxyphenyl) -3,4- dihydros-chromene -3- alcohol, 3,4,5- trimethoxy meat
Cinnamic acid ester (3), (2R, 3R) -5,7- dimethoxys -2- (3,4- Dimethoxyphenyl) -3,4- dihydros-chromene -3- alcohol, 3-
(3,4,5- trimethoxy-benzamide base) -4- fluorobenzoates (4), (2R, 3R) -5,7- dimethoxys -2- (3,4,5- front threes
Phenyl) -3,4- dihydros-chromene -3- alcohol, 1- (3,4,5- trimethoxy benzyl) piperidines -4- formic acid esters (5), (2R,
3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -3,4- dihydros-chromene -3- alcohol, 1- (4- methoxybenzyls
Base) piperidines -4- formic acid esters (6), (2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -3,4- dihydros-benzo
Pyrans -3- alcohol, 1- (4- methoxy-benzyls) piperidines -3- formic acid esters (7), (2R, 3R) -5,7- dimethoxys -2- (3,4- dimethoxies
Base phenyl) -3,4- dihydros-chromene -3- alcohol, 1- (3,4,5- trimethoxy benzyl) piperidines -4- formic acid esters (8), (2R,
3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -3,4- dihydros-chromene -3- alcohol, 1- (3,4,5- front threes
Oxy-benzyl) piperidines -3- formic acid esters (9), (2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -3,4- bis-
Hydrogen-chromene -3- alcohol, 1- (3,4- dimethoxy-benzyl) piperidines -3- formic acid esters (10), (2R, 3S) -5,7- dimethoxys -
2- (3,4- Dimethoxyphenyl) -3,4- dihydros-chromene -3- alcohol, 1- (3,4,5- trimethoxy benzyl) piperidines -4- formic acid
Ester (11), (2R, 3S) -5,7- dimethoxys -2- (3,4- Dimethoxyphenyl) -3,4- dihydros-chromene -3- alcohol, 1- (3,
4,5- trimethoxy benzyls) piperidines -3- formic acid esters (12), (2R, 3R) -5,7- dimethoxys -2- (3,4- Dimethoxyphenyl) -
3,4- dihydros-chromene -3- alcohol, 1- (3,4,5- trimethoxy benzyl) piperidines -4- formic acid esters (13), (2R, 3R) -5,7- bis-
Methoxyl group -2- (3,4- Dimethoxyphenyl) -3,4- dihydros-chromene -3- alcohol, 1- (3,4,5- trimethoxy benzyl) -3-
Piperidinecarboxylic acid ester (14), (2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -3,4- dihydro-chromenes -
3- alcohol, 1- (3,4,5- trimethoxy-benzamide base) piperidines -4- formic acid esters (15), (2R, 3R) -5,7- dimethoxys -2- (3,
4,5- trimethoxyphenyls) -3,4- dihydros-chromene -3- alcohol, 1- (3,4,5- trimethoxy-benzamide base) piperidines -3-
Formic acid esters (16), (2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -3,4- dihydros-chromene -3-
Alcohol, 3- (4- methoxyl groups -3- (2- (4- methyl piperazines) ethyoxyl)) benzamido -4- fluorobenzoates (17), (2R, 3R) -
5,7- dimethoxy -2- (3,4,5- trimethoxyphenyl) -3,4- dihydros-chromene -3- alcohol, 3- (4- methoxyl group -3- (2-
Morpholine ethyoxyl)) benzamido -4- fluorobenzoates (18), (2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxies
Base phenyl) -3,4- dihydros-chromene -3- alcohol, 3- (4- methoxyl groups -3- (2- piperidines ethyoxyl)) benzamido -4- fluorobenzene
Formic acid esters (19).
The preparation method of the compound of the chroman of benzene containing 2- parent nucleus of the present invention is as follows：
Be raw material with epicatechin 22 of the purity more than 98%, under the conditions of existing for Anhydrous potassium carbonate with dimethyl sulfate
Ester reacts, and compound 1 is obtained through silica gel column chromatography.Synthetic method is as follows：
Reagent and condition：K2CO3, Me2SO4, rt, 12h.
Using cis- nutgall catechin gallic acid ester of the purity more than 98% as raw material, reacted with dimethyl suflfate
23, midbody compound 20 is hydrolyzed to obtain under conditions of Anhydrous potassium carbonate.
Reagent and condition：(a)K2CO3/ MeOH, rt.
Using trans- nutgall catechin gallic acid ester of the purity more than 98% as raw material, reacted with dimethyl suflfate
24, midbody compound 21 is then hydrolyzed to obtain under conditions of Anhydrous potassium carbonate.
Reagent and condition：(a)K2CO3/ MeOH, rt.
(1) synthesis of the compound of the unsubstituted chroman of benzene containing 2- parent nucleus：
Compound 1 is respectively with 3,4,5- trimethoxybenzoic acids, 3,4,5- trimethoxy cinnamic acids, 3- (3,4,5- front threes
Oxygroup benzamido) -4- fluobenzoic acids, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCI) with
Target product 2,3,4 is obtained by the reaction under the conditions of 4-dimethylaminopyridine (DMAP) is existing.Reaction route is as follows：
Reagent and condition：a)EDCI/DMAP/DCM
(2) synthesis of the compound of the chroman parent nucleus of benzene containing 2- containing piperidines group：
Contain the synthesis of the EGCG analogs of piperidines group for side chain, experiment uses permethylated epi-nutgall catechu
Plain (EGC) is raw material 20 under conditions of 4-dimethylaminopyridine (DMAP) and EDCI, respectively with 1- (4- methoxybenzyls) piperidines-
4- formic acid, 1- (3,4- veratryl) piperidines -4- formic acid, 1- (3,4,5- trimethoxy benzyl) piperidines -4- formic acid react to change
Conjunction object 6,8,5, with 1- (4- methoxybenzyls) piperidines -3- formic acid, 1- (3,4- veratryl) piperidines -3- formic acid, 1- (3,4,5-
Trimethoxy benzyl) piperidines -3- formic acid reacts to obtain compound 7, and 10,9, with 1- (3,4,5- trimethoxybenzoy) piperidines -4-
Formic acid, 1- (3,4,5- trimethoxybenzoy) piperidines -3- formic acid react to obtain compound 15,16, and all intermediates all need
To pass through stringent vacuum freeze drying to handle.Synthesis for compound 13 and 14, by compound 1 respectively with intermediate 1-
(3,4,5- trimethoxy benzyl) piperidines -4- formic acid and the reaction of 1- (3,4,5- trimethoxy benzyl) piperidines -3- formic acid, in DMAP and
Compound 13,14 is made under conditions of EDCI.The design of the catechin compounds 11,12 of the group containing piperidines is synthesized, I
With permethylated catechin 21 (CG) be raw material, then respectively with intermediate 1- (3,4,5- trimethoxy benzyl) piperidines -4-
Formic acid and the reaction of 1- (3,4,5- trimethoxy benzyl) piperidines -3- formic acid, synthetic method still use the condition of DMAP and EDCI, and then
Compound 11 and 12 is made.More than compound synthesis method is as follows.
Reagent and condition：(a) EDCI/DMAP/DCM, 1- (4- methoxy-benzyls) piperidines -4- formic acid,；
1- (3,4- dimethoxy-benzyl) piperidines -4- formic acid；1- (3,4,5- trimethoxy benzyl) piperidines -4- formic acid, rt；
(b) EDCI/DMAP/DCM, 1- (4- methoxy-benzyls) piperidines -3- formic acid；
1- (3,4- dimethoxy-benzyl) piperidines -3- formic acid 1- (3,4,5- trimethoxy benzyl) piperidines -3- formic acid, rt.
Reagent and condition：(a) EDCI/DMAP/DCM, 1- (3,4,5- trimethoxybenzoy) piperidines -4- formic acid, rt；
(b) EDCI/DMAP/DCM, 1- (trimethoxybenzoy) piperidines -4- formic acid, rt.
Reagent and condition：(a) EDCI/DMAP/DCM, 1- (3,4,5- tri- Jia Yang Ji Benzyl yls) piperidines -4- formic acid, rt；
(b) EDCI/DMAP/DCM, 1- (3,4,5- trimethoxy benzyl) piperidines -3- formic acid, rt.
(3) synthesis of the compound of the chroman parent nucleus of benzene containing 2- containing the basic group connected there are two carbochain：
Compound 1 is first with 3- (3- (2- bromine oxethyls) -4- Methoxybenzamidos) -4- fluobenzoic acids in EDC/DMAP
Intermediate product 25 is obtained by the reaction under the conditions of existing, then reacts at room temperature to obtain compound with methyl piperazine, morpholine, piperidines respectively
17、18、19.Shown under reaction route.
Reagent and condition:(a) EDCI/DMAP/DCM, 3- (3- (2- bromine oxethyls) -4- methoxy benzamides base) -4-
Fluobenzoic acid, rt.
In 19 compounds according to the present invention, the piperidines with good druggability, morpholine, first are increased in structure
The basic groups such as base piperazine to improve the water solubility of P-gp inhibitor and bioavilability, can and then develop and be used for by these compounds
Treat the drug of breast cancer, colon cancer, prostate cancer, leukaemia, myeloma, cancer of pancreas etc..In synthetic method, condensation is utilized
The one-step synthesis such as agent EDC, DMAP, for the compound 17 of more difficult synthesis, 18,19, it is starting material using 1,2- Bromofumes,
Synthetic route is shortened, improves the yield of reaction.
Specific embodiment
Invention is described further, but following embodiments are not intended to limit the protection of the present invention below in conjunction with specific embodiment
Range.
Embodiment 1：(2R, 3R) -5,7- dimethoxys -2- (3,4- Dimethoxyphenyls) -3,4- dihydro-chromenes -
The synthesis of 3- alcohol (1)：
Epicatechin (2.00g, 6.9mmol) is dissolved in 30mL acetone, addition Anhydrous potassium carbonate (5.70g,
41.2mmol), 0.5h is stirred under conditions of room temperature, 1.5mL dimethyl suflfates are then added dropwise dropwise, are heated to reflux, reaction is stirred
After mixing 8h, the reaction was complete for TLC detections, and solvent rotation is steamed, 30mL ethyl acetate and 30mL water are added in into reaction bulb, fully
Pour into separatory funnel after shaking up, stand liquid separation, take organic phase, saturated sodium bicarbonate solution washes twice, with anhydrous magnesium sulfate into
Row drying, last silica gel column chromatography obtain white solid, yield 86.4%.
1H NMR(CDCl3, 500MHz) and δ 7.08 (d, J=1.7Hz, 1H), 7.05 (dd, J=8.3,1.6Hz, 1H), 6.91
(d, J=8.3Hz, 1H), 6.20 (d, J=2.3Hz, 1H), 6.12 (d, J=2.3Hz, 1H), 4.96 (s, 1H), 4.28 (s,
1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 2.95 (dd, J=17.2,1.6Hz, 1H),
2.88 (dd, J=17.2,4.3Hz, 1H)13C NMR(CDCl3,126MHz)δ159.7,159.3,155.2,149.1,148.8,
130.8,118.6,111.2,109.68,100.3,93.3,92.2,78.4,66.4,56.0,55.4,28.1.HRMS calcd
for(C19H22O6+H)+347.1488,found 347.1489。
Embodiment 2：(2R, 3R) -5,7- dimethoxys -2- (3,4- Dimethoxyphenyls) -3,4- dihydro-chromenes -
3- alcohol, 3,4,5- trimethoxybenzoates (2)
By midbody compound 1 (0.10g, 0.3mmol), 3,4,5- trimethoxybenzoic acids (0.12g, 0.6mmol),
EDCHCl (0.11g, 0.6mmol) and DMAP (0.07g, 0.6mmol) are placed in the two-mouth bottle of 50mL, under the protection of nitrogen
The dried dichloromethane of 20mL is added in, is stirred to react 10h under room temperature, the reaction was complete for TLC detections.Reaction solution is transferred to
Separatory funnel is washed with distilled water twice, takes organic phase, anhydrous magnesium sulfate drying, and silica gel column chromatography obtains white solid, and yield is
70%.
1H NMR(CDCl3, 500MHz) and δ 7.16 (s, 2H), 7.02 (d, J=8.2Hz, 2H), 6.82 (d, J=8.2Hz,
1H), 6.24 (d, J=2.0Hz, 1H), 6.11 (d, J=2.0Hz, 1H), 5.63 (s, 1H), 5.12 (s, 1H), 3.85 (s, 3H),
3.84 (s, 3H), 3.82 (s, 6H), 3.79 (s, 3H), 3.77 (s, 3H), 3.69 (s, 3H), 3.04 (d, J=2.5Hz, 2H)13C
NMR(CDCl3,126MHz)δ165.2,159.7,158.9,155.6,152.8,148.8,142.3,130.4,125.1,
119.0,110.8,109.8,107.0,100.1,93.2,91.8,77.5,68.9,60.9,56.2,25.8.HRMS calcd
for(C29H32O10+H)+541.2063,found541.2068。
Embodiment 3：(2R, 3R) -5,7- dimethoxys -2- (3,4- Dimethoxyphenyls) -3,4- dihydro-chromenes -
3- alcohol, 3,4,5- elemicin acid esters (3)
With midbody compound 1 (0.20g) and (E) -3,4,5- trimethoxy cinnamic acids (0.21g) are raw material, preparation side
Compound 3, yield 86.0% is made with compound 2 in method.
1H NMR(CDCl3, 500MHz) and δ 7.48 (d, J=15.9Hz, 1H), 7.05 (s, 1H), 7.01 (d, J=8.3Hz,
1H), 6.85 (d, J=8.3Hz, 1H), 6.67 (s, 2H), 6.28 (d, J=15.9Hz, 1H), 6.24 (s, 1H), 6.13 (s,
1H), 5.64 (s, 1H), 5.08 (s, 1H), 3.85 (d, J=4.8Hz, 15H), 3.79 (s, 6H), 3.00 (d, J=5.3Hz,
2H).13C NMR(CDCl3,126MHz)δ166.1,159.75,159.0,155.5,153.0,148.8,145.2,140.1,
130.2,129.7,119.0,117.0,110.8,109.8,105.1,100.1,93.3,92.0,77.5,67.6,61.0,
56.1,55.8,55.4,26.1.HRMS calcd for(C31H34O10+H)+567.2225,found 567.2225.
Embodiment 4：(2R, 3R) -5,7- dimethoxys -2- (3,4- Dimethoxyphenyls) -3,4- dihydro-chromenes -
3- alcohol, 3- (3,4,5- trimethoxybenzoyl amino) -4- fluorobenzoates (4)
With midbody compound 1 (0.20g) and 3- (3,4,5- trimethoxybenzoyl amino) -4- fluobenzoic acids
(0.30g) is raw material, and compound 4, yield 75% is made with compound 2 in preparation method.
1H NMR(CDCl3, 500MHz) and δ 8.88 (dd, J=7.5,1.9Hz, 1H), 7.92 (d, J=2.0Hz, 1H), 7.71
(ddd, J=8.4,4.9,2.0Hz, 1H), 7.10 (dd, J=10.2,8.9Hz, 1H), 7.07 (s, 3H), 7.03 (dd, J=
8.3,1.6Hz, 1H), 6.83 (d, J=8.3Hz, 1H), 6.26 (d, J=2.2Hz, 1H), 6.10 (d, J=2.2Hz, 1H),
5.64 (d, J=2.7Hz, 1H), 5.12 (s, 1H), 3.91 (s, 6H), 3.90 (s, 3H), 3.83 (s, 3H), 3.78 (s, 3H),
3.77(s,3H),3.73(s,3H),3.05(s,2H)；13C NMR(CDCl3,126MHz)δ165.1,164.5,159.6,
158.8,155.6,154.8,153.4,148.7,141.5,130.3,129.5,126.8,124.2,119.1,115.0,
114.9,110.9,109.7,104.6,100.1,93.5,91.9,77.5,69.2,61.0,56.4,55.8,55.4,
25.9.HRMS calcd for(C36H36FNO11+H)+678.2351,found 678.2345。
Embodiment 5：(2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -3,4- dihydros-benzo pyrrole
It mutters -3- alcohol, 1- (3,4,5- trimethoxy benzyl) -4- piperidinecarboxylic acids ester (5)
With permethylated EGCG hydrolysates and the 1- after vacuum freeze drying (3,4,5- trimethoxy benzyl) -4- piperazines
Pyridine formic acid is raw material, and EDCHCl (306mg, 1.6mmol) and DMAP (195mg, 1.6mmol) are placed in the two-mouth bottle of 50mL,
The dried dichloromethane of 20mL is added under the protection of nitrogen, the dried DMF of 5mL is added, stirs at ambient temperature
12h is reacted, the reaction was complete for TLC detections.Reaction solution is transferred in 100mL eggplant-shape bottles, solvent is steamed with oil pump rotation, then with two
Chloromethanes and distilled water liquid separation extraction take organic phase, and distilled water washes twice rear anhydrous magnesium sulfate drying, and silica gel column chromatography obtains white
Color solid, yield 70.5%.
1H NMR(CDCl3, 500MHz) and δ 6.68 (s, 2H), 6.48 (s, 2H), 6.20 (d, J=1.9Hz, 1H), 6.09 (d,
J=1.9Hz, 1H), 5.48 (s, 1H), 5.00 (s, 1H), 4.01-3.60 (s, 24H), 3.34-3.25 (s, 2H), 2.92 (m,
2H), 2.72-2.56 (m, 2H), 2.17 (m, 1H), 1.89 (t, J=9.6Hz, 2H), 1.59 (m, 4H)13C NMR(CDCl3,
126MHz)δ174.4,159.6,158.8,155.2,153.0,137.6,133.4,105.6,103.5,100.0,93.4,
92.0,77.2,67.6,63.3,60.8,56.1,55.4,52.7,52.5,40.9,28.2,27.8,25.8。
Embodiment 6：(2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -3,4- dihydros-benzo pyrrole
It mutters -3- alcohol, 1- (4- methoxy-benzyls) -4- piperidinecarboxylic acids ester (6)
EGCG hydrolysates, -4 piperidines first of 1- (4- methoxy-benzyls) after vacuum freeze drying after will be permethylated
Compound 6, yield 73.0% is made with compound 5 in acid, preparation method.
1H NMR(CDCl3, 500MHz) and δ 7.15 (d, J=8.6Hz, 2H), 6.82 (d, J=8.6Hz, 2H), 6.69 (s,
2H), 6.21 (d, J=2.3Hz, 1H), 6.11 (d, J=2.3Hz, 1H), 5.48-5.45 (m, 1H), 5.01 (s, 1H), 3.86
(d, J=4.2Hz, 6H), 3.83 (s, 3H), 3.79 (s, 9H), 3.32 (s, 2H), 2.95 (dd, J=17.9,4.6Hz, 1H),
2.88 (dd, J=17.9,1.5Hz, 1H), 2.71-2.58 (m, 2H), 2.19-2.12 (m, 1H), 1.87 (t, J=10.9Hz,
2H),1.66(s,1H),1.63–1.56(m,2H),1.56–1.49(m,1H).13C NMR(CDCl3,126MHz)δ174.4,
159.6,158.8,158.6,155.2,153.1,133.3,130.2,113.5,103.5,100.1,93.4,92.0,77.3,
67.6 62.5,60.9,56.2,55.5,55.3,55.2 52.6,52.40,41.1,28.2,27.9,25.8.
Embodiment 7：(2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -3,4- dihydros-benzo pyrrole
It mutters -3- alcohol, 1- (4- methoxy-benzyls)-nipecotic acid ester (7)
With permethylated EGCG hydrolysates and the 1- after vacuum freeze drying (4- methoxy-benzyls)-nipecotic acid
For raw material, compound 6, yield 75.5% is made with compound 5 in preparation method.
1H NMR(CDCl3, 500MHz) and δ 7.12 (d, J=6.9Hz, 2H), 6.81 (dd, J=8.5,4.0Hz, 2H), 6.68
(s, 2H), 6.22 (d, J=2.2Hz, 1H), 6.11 (dd, J=5.4,2.2Hz, 1H), 5.45 (s, 1H), 5.01 (s, 1H),
3.86 (s, 6H), 3.82 (s, 3H), 3.81-3.75 (s, 9H), 3.42 (d, J=13.1Hz, 1H), 3.33 (s, 1H), 3.25 (d,
J=13.0Hz, 1H), 2.93 (ddd, J=37.4,21.1,11.3Hz, 2H), 2.77 (t, J=12.9Hz, 1H), 2.65-2.57
(m,1H),2.50–2.38(m,1H),2.05–1.73(m,3H),1.69–1.63(m,1H),1.58–1.49(m,1H),1.46–
1.35(m,1H).13C NMR(CDCl3,126MHz)δ173.5,159.6,158.8,158.6,155.2,153.1,133.4,
130.2,113.5,103.5,100.1,93.3,92.0,77.3,67.6,62.5,60.8,56.1,55.4,55.2,55.0,
53.1,52.7,42.2,41.8,27.0,25.8,24.4.
Embodiment 8：(2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -3,4- dihydros-benzo pyrrole
It mutters -3- alcohol, 1- (3,4- dimethoxy-benzyl) -4- piperidinecarboxylic acids ester (8)
With permethylated EGCG hydrolysates and the 1- after vacuum freeze drying (3,4- dimethoxy-benzyl) -4- piperidines
Formic acid is raw material, and compound 8, yield 78.0% is made with compound 5 in preparation method.
1H NMR(CDCl3, 500MHz) and δ 6.82 (s, 1H), 6.76 (d, J=3.6Hz, 2H), 6.69 (s, 2H), 6.21 (d,
J=2.2Hz, 1H), 6.11 (d, J=2.2Hz, 1H), 5.48 (s, 1H), 5.02 (s, 1H), 3.89-3.84 (s, 12H), 3.82
(s, 3H), 3.79 (s, J=3.3Hz, 6H), 3.32 (d, J=3.4Hz, 2H), 2.97-2.87 (m, 2H), 2.68 (d, J=
10.9Hz, 2H), 2.21-2.12 (m, 1H), 1.87 (s, 2H), 1.67 (d, J=10.3Hz, 1H), 1.53 (dd, J=17.7,
7.1Hz,1H).13C NMR(CDCl3,151MHz)δ174.6,159.7,159.0,155.3,153.2,148.9,148.1,
137.7,133.5,131.1,121.2,112.1,110.8,103.6,100.2,93.4,92.1,77.4,67.7,63.0,
61.0,56.2,56.0,55.5,52.8,52.6,41.2,28.4,28.0,25.9。
Embodiment 9：(2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -3,4- dihydros-benzo pyrrole
It mutters -3- alcohol, 1- (3,4,5- trimethoxy benzyl)-nipecotic acid ester (9)
With permethylated EGCG hydrolysates and the 1- after vacuum freeze drying (3,4,5- trimethoxy benzyl) -3- piperazines
Pyridine formic acid is raw material, and compound 9 is made with compound 5 in preparation method.Yield 69.0%.
1H NMR(CDCl3, 500MHz) and δ 6.69 (d, J=3.7Hz, 2H), 6.48 (s, 2H), 6.21 (d, J=1.8Hz,
1H), 6.12 (d, J=1.8Hz, 1H), 5.47 (s, 1H), 5.01 (s, 1H), 3.86 (s, 6H), 3.82 (s, 12H), 3.77 (s,
6H), 3.45 (d, J=13.3Hz, 1H), 3.20 (d, J=13.3Hz, 1H), 2.99-2.93 (m, 1H), 2.88 (d, J=
17.4Hz, 1H), 2.76 (d, J=11.0Hz, 1H), 2.64 (d, J=11Hz, 1H), 2.49 (td, J=10.8,5.5Hz, 1H),
1.96 (t, J=10.8Hz, 1H), 1.77 (dd, J=20.0,11.2Hz, 3H), 1.58-1.52 (m, 1H), 1.46-1.37 (m,
1H).13C NMR(CDCl3,126MHz)δ173.4,159.6,158.9,155.2,153.1,134.2,133.4,105.5,
103.5,100.1,93.3,92.0,77.3,67.7,63.2,60.8,56.1,55.8,55.4,52.9,42.2,26.8,25.8,
24.4。
Embodiment 10：(2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -3,4- dihydros-benzo pyrrole
It mutters -3- alcohol, 1- (3,4- dimethoxy-benzyl)-nipecotic acid ester (10)
With permethylated EGCG hydrolysates and the 1- after vacuum freeze drying (3,4- methoxy-benzyl) -3- piperidines first
Acid is raw material, and compound 10 is made with compound 5 in preparation method.Yield 68.5%.
1H NMR(CDCl3,500MHz)δ6.81(s,1H),6.75(m,2H),6.69(s,2H),6.22(s,1H),6.11
(dd, J=7.1,2.2Hz, 1H), 5.46 (s, 1H), 5.01 (s, 1H), 3.90-3.84 (m, 12H), 3.83 (d, J=4.9Hz,
3H), 3.78 (dd, J=12.4,9.1Hz, 6H), 3.45 (d, J=13.1Hz, 1H), 3.33 (d, J=2.4Hz, 1H), 3.22
(d, J=13.1Hz, 1H), 2.96 (m, 1H), 2.88 (d, J=18.2Hz, 1H), 2.78 (t, J=12.6Hz, 1H), 2.62 (s,
1H), 2.46 (m, 1H), 2.05-1.90 (m, 2H), 1.86 (m, 1H), 1.76 (t, J=10.1Hz, 1H), 1.66 (d, J=
12.3Hz,1H),1.46–1.36(m,1H).13C NMR(CDCl3,151MHz)δ173.7,159.7,159.0,155.3,
153.2,148.9,148.1,137.7,133.5,121.2,112.2,110.8,103.6,100.2,93.4,92.1,77.4,
67.7,62.9,61.0,56.2,55.9,55.5,55.4,53.2,,52.8,27.3,27.0,25.9。
Embodiment 11：(2R, 3S) -5,7- dimethoxys -2- (3,4- Dimethoxyphenyls) -3,4- dihydros-benzo pyrrole
It mutters -3- alcohol, 1- (3,4,5- trimethoxy benzyl) -4- piperidinecarboxylic acids ester (11)
With (+)-catechin hydrate and 1- (3,4,5- trimethoxy benzyl) -4- piperidinecarboxylic acids for raw material, preparation method
Compound 11 is made with compound 5.Yield 65.8%.
1H NMR(CDCl3, 500MHz) and δ 6.91 (dd, J=8.2,1.8Hz, 1H), 6.89 (d, J=1.8Hz, 1H), 6.82
(d, J=8.2Hz, 1H), 6.52 (s, 2H), 6.14 (d, J=2.2Hz, 1H), 6.09 (d, J=2.2Hz, 1H), 5.37 (m,
1H),4.94(m,1H),3.87–3.83(s,12H),3.82(s,3H),3.77(s,3H),3.75(s,3H),3.34(s,2H),
2.97 (dd, J=16.5,5.6Hz, 1H), 2.73 (d, J=10.9Hz, 1H), 2.63 (dd, J=16.5,7.6Hz, 2H),
2.22-2.14 (m, 1H), 1.93 (d, J=10.2Hz, 2H), 1.71 (d, J=10.0Hz, 1H), 1.67-1.59 (m, 2H),
1.54(m,1H).13C NMR(CDCl3,126MHz)δ174.2,159.8,158.6,155.0,153.0,149.0,136.8,
134.3,130.1,119.7,111.0,109.9,105.6,100.8,93.0,91.9,78.7,68.8,63.3,60.8,56.1,
55.9,55.4,52.8,52.6,41.0,28.1,27.9,24.7。
Embodiment 12：(2R, 3S) -5,7- dimethoxys -2- (3,4- Dimethoxyphenyls) -3,4- dihydros-benzo pyrrole
It mutters -3- alcohol, 1- (3,4,5- trimethoxy benzyl)-nipecotic acid ester (12)
With (+)-catechin hydrate and 1- (3,4,5- trimethoxy benzyl)-nipecotic acid for raw material, preparation method
Compound 12 is made with compound 5.Yield 60.7%.
1H NMR(CDCl3, 500MHz) and δ 6.89 (s, 2H), 6.80 (dd, J=18.7,8.4Hz, 1H), 6.52 (d, J=
2.7Hz, 2H), 6.14 (d, J=2.3Hz, 1H), 6.09 (d, J=2.3Hz, 1H), 5.32 (m, 1H), 4.94 (m, 1H), 3.88-
3.81 (s, 15H), 3.78-3.74 (s, 6H), 3.39-3.33 (m, 2H), 3.01-2.96 (m, 1H), 2.81 (d, J=9.7Hz,
1H), 2.75-2.55 (m, 3H), 2.50-2.42 (m, 1H), 2.01 (ddd, J=51.8,20.4,10.5Hz, 3H), 1.58 (dd,
J=8.4,4.7Hz, 1H), 1.51-1.44 (m, 1H)13C NMR(CDCl3,126MHz)δ173.2,159.8,158.6,
155.0,153.0,149.0,134.3,130.1,119.8,110.9,109.8,105.5,100.9,93.0,91.9,78.8,
68.9,63.4,60.8,55.9,55.8,55.6,55.3,53.4,53.1,41.8,26.9,24.9,24.4。
Embodiment 13：(2R, 3R) -5,7- dimethoxys -2- (3,4- Dimethoxyphenyls) -3,4- dihydros-benzo pyrrole
It mutters -3- alcohol, 1- (3,4,5- trimethoxy benzyl) -4- piperidinecarboxylic acids ester (13)
With epicatechin and 1- (3,4,5- trimethoxy benzyl) -4 piperidine-1-carboxylic acids for raw material, preparation method is the same as compound 5
Compound 13 is made.Yield 66.5%.
1H NMR(CDCl3, 500MHz) and δ 7.02 (d, J=1.7Hz, 1H), 6.97 (dd, J=8.3,1.7Hz, 1H), 6.85
(d, J=8.3Hz, 1H), 6.50 (s, 2H), 6.20 (d, J=2.2Hz, 1H), 6.11 (d, J=2.2Hz, 1H), 5.49-5.45
(m,1H),5.04(s,1H),3.90(s,3H),3.87(s,3H),3.84(s,6H),3.82(s,3H),3.78(s,6H),3.32
(d, J=2.2Hz, 2H), 2.96 (dd, J=17.8,4.7Hz, 1H), 2.87 (d, J=16.5Hz, 1H), 2.69 (dd, J=
21.4,11.0Hz,2H),2.17(m,1H),1.89(m,2H),1.65(m,3H),1.55–1.49(m,1H).13C NMR
(CDCl3,126MHz)δ173.5,158.6 157.9,154.4,152.0,147.7,133.3,129.3,117.7,109.8,
108.7,104.6,99.1,92.3,90.9,76.1,66.7,64.5,63.0,54.4,51.8,51.6,40.0,27.3,
26.924.8。
Embodiment 14：(2R, 3R) -5,7- dimethoxys -2- (3,4- Dimethoxyphenyls) -3,4- dihydros-benzo pyrrole
It mutters -3- alcohol, 1- (3,4,5- trimethoxy benzyl)-nipecotic acid ester (14)
With epicatechin and 1- (3,4,5- trimethoxy benzyl)-nipecotic acid for raw material, preparation method is the same as compound 5
Compound 14 is made.Yield 69.0%.
1H NMR(CDCl3, 500MHz) and δ 7.02-6.90 (m, 2H), 6.73 (d, J=8.3Hz, 1H), 6.49 (s, 2H),
6.19 (d, J=2.2Hz, 1H), 6.09 (d, J=2.2Hz, 1H), 5.44-5.39 (m, 1H), 5.00 (s, 1H), 3.91-3.79
(m, 15H), 3.79-3.69 (m, 6H), 3.44-3.24 (m, 2H), 2.99-2.80 (m, 3H), 2.77 (d, J=10.3Hz, 1H),
2.64 (s, 1H), 2.48 (d, J=7.3Hz, 1H), 1.98-1.71 (m, 3H), 1.62-1.52 (m, 1H), 1.43 (d, J=
11.0Hz,1H).13C NMR(CDCl3,126MHz)δ173.4,159.6,158.8,155.4,153.0,148.7,130.3,
118.8,110.8,109.8,105.4,100.1,77.1,67.8,63.0,60.8,56.1,55.9,55.8,55.4,53.0,
41.9,26.6,25.8,24.3。
Embodiment 15：(2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -3,4- dihydros-benzo pyrrole
It mutters -3- alcohol, 1- (3,4,5- trimethoxybenzoy) -4- piperidinecarboxylic acids ester (15)
With permethylated EGCG hydrolysates and 1- (3,4,5- trimethoxybenzoy) -4- piperidinecarboxylic acids for raw material, system
Compound 15 is made with compound 5 in Preparation Method.Yield 78.3%.
1H NMR(CDCl3, 500MHz) and δ 6.68 (s, 2H), 6.53 (s, 2H), 6.20 (d, J=2.2Hz, 1H), 6.10 (d,
J=2.2Hz, 1H), 5.52 (dd, J=2.8,1.3Hz, 1H), 5.02 (s, 1H), 3.85 (s, 6H), 3.83 (s, 9H), 3.80
(s, 3H), 3.78 (d, J=2.4Hz, 6H), 2.95 (d, J=4.5Hz, 3H), 2.90 (s, 1H), 2.44 (ddd, J=14.2,
10.1,3.9Hz,1H),1.90–1.34(m,6H).13C NMR(CDCl3,126MHz)δ173.3,170.0,159.7,158.8,
155.1,153.2,139.1,137.7,133.2,131.2,104.0,103.3,99.8,93.4,92.0,77.0,68.0,
60.8,56.18(s),55.4,40.7,25.8。
Embodiment 16：(2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -3,4- dihydros-benzo pyrrole
It mutters -3- alcohol, 1- (3,4,5- trimethoxybenzoy) nipecotic acid ester (16)
With permethylated EGCG hydrolysates and 1- (3,4,5- trimethoxybenzoy)-nipecotic acid for raw material, system
Compound 16 is made with compound 5 in Preparation Method.Yield 75.5%.
1H NMR(CDCl3, 500MHz) and δ 6.67 (s, 2H), 6.53 (s, 2H), 6.19 (s, 1H), 6.09 (d, J=1.8Hz,
1H),5.50(s,1H),4.99(s,1H),3.86(s,5H),3.81(s,7H),3.78(s,6H),3.76(s,6H),2.89
(ddd, J=32.7,21.6,8.7Hz, 4H), 2.40 (s, 1H), 1.97-1.75 (m, 2H), 1.65-1.24 (m, 4H)13C NMR
(CDCl3,126MHz)δ170.1,159.7,158.8,155.1,153.2,139.1,137.6,133.2,104.1,103.3,
99.7,93.4,92.1,68.1,60.8,56.2,55.4,27.30(s),25.9。
Embodiment 17：(2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -3,4- dihydros-benzo pyrrole
It mutters -3- alcohol, 3- (4- methoxyl groups -3- (2- (4- methyl piperazines) ethyoxyl)) benzamido -4- fluorobenzoates (17)
With permethylated EGCG hydrolysates and 3- (3- (2- bromine oxethyls) -4- Methoxybenzamidos) -4- fluorobenzene
Intermediate product 35 is obtained by the reaction in formic acid under the conditions of existing for EDC/DMAP, preparation method with compound 5, then with methyl piperazine room
Temperature reaction 4h, the reaction was complete for the detection of TLC plates, is extracted through dichloromethane and water, merges organic phase, is steamed after anhydrous magnesium sulfate drying
It is dry, through the isolated compound 17 of silicagel column, two step yields 60.5%.
1H NMR(500MHz,cd3Od) δ 8.23 (d, J=7.2Hz, 1H), 7.78-7.74 (m, 1H), 7.59 (d, J=
8.4Hz, 1H), 7.55 (s, 1H), 7.22 (t, J=9.3Hz, 1H), 7.04 (d, J=8.5Hz, 1H), 6.82 (s, 2H), 6.22
(s, 1H), 6.14 (s, 1H), 5.65 (s, 1H), 5.15 (s, 1H), 4.19 (t, J=5.2Hz, 2H), 3.89 (s, 3H), 3.75
(d, J=10.1Hz, 3H), 3.72 (d, J=11.6Hz, 3H), 3.71-3.61 (m, 8H), 3.07 (dd, J=17.7,4.6Hz,
1H), 2.95 (d, J=17.8Hz, 1H), 2.84 (t, J=5.2Hz, 2H), 2.79-2.45 (m, 8H), 2.30 (s, 3H)13C
NMR(126MHz,cd3od)δ166.72(s),164.18(s),159.85(s),158.87(s),157.91(s),155.36
(s),153.10(s),152.86(s),147.93(s),137.16(s),134.23(s),128.24(s),128.17(s),
127.71(s),126.30(s),126.07(s),125.97(s),125.71(s),121.74(s),115.88(s),115.71
(s),112.80(s),110.92(s),103.62(s),99.73(s),93.31(s),91.37(s),77.31(s),69.32
(s),66.69(s),59.73(s),56.56(s),55.17(s),55.13(s),54.59(s),54.41(s),54.13(s),
52.56 (s), 44.44 (s), 29.11 (d, J=53.2Hz), 25.39 (s), 6.32 (s).
Embodiment 18：(2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -3,4- dihydros-benzo pyrrole
It mutters -3- alcohol, 3- (4- methoxyl groups -3- (2- morpholines ethyoxyl)) benzamido -4- fluorobenzoates (18)
It is raw material with intermediate 35, solvent room temperature reaction is made with morpholine, compound is made with compound 17 in preparation method
18.Yield 66.5%.
1H NMR(500MHz,cd3Od) δ 8.24 (dd, J=7.3,2.1Hz, 1H), 7.77 (ddd, J=8.6,4.7,
2.2Hz, 1H), 7.58 (dd, J=8.4,2.1Hz, 1H), 7.54 (d, J=2.1Hz, 1H), 7.24-7.19 (m, 1H), 7.03
(d, J=8.5Hz, 1H), 6.81 (s, 2H), 6.22 (d, J=2.3Hz, 1H), 6.14 (dd, J=5.1,2.4Hz, 1H), 5.65
(dd, J=2.7,1.2Hz, 1H), 5.14 (s, 1H), 4.19 (t, J=5.5Hz, 2H), 3.89 (d, J=3.2Hz, 3H), 3.76
(d, J=5.1Hz, 3H), 3.74 (s, 3H), 3.72-3.66 (m, 13H), 3.10-3.04 (m, 1H), 2.96 (d, J=16.8Hz,
1H), 2.82 (t, J=5.5Hz, 2H), 2.66-2.59 (m, 4H)13C NMR(126MHz,cd3od)δ166.71(s),164.15
(s),159.86(s),158.87(s),157.85(s),155.37(s),153.17(s),152.90(s),147.99(s),
137.21(s),134.20(s),128.20(s),128.14–128.06(m),127.62(s),127.62–127.55(m),
126.33(s),126.31–126.25(m),126.07(s),125.97(s),125.72(s),121.70(s),115.76(d,J
=21.3Hz), 115.66-115.39 (m), 112.89 (s), 110.90 (s), 103.62 (s), 99.73 (s), 93.29 (s),
91.37(s),77.32(s),69.28(s),66.64(s),66.24(s),59.69(s),57.18(s),55.14(s),55.07
(s),54.55(s),54.37(s),53.76(s),25.38(s)。
Embodiment 19：(2R, 3R) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyl) -3,4- dihydros-benzo pyrrole
It mutters -3- alcohol, 3- (4- methoxyl groups -3- (2- piperidines ethyoxyl)) benzamido -4- fluorobenzoates (19)
It is raw material with intermediate 35, solvent room temperature reaction is made with piperidines, compound is made with compound 17 in preparation method
19.Yield 68.5%.
1H NMR(500MHz,cd3Od) δ 8.24 (dd, J=7.3,2.1Hz, 1H), 7.79-7.74 (m, 1H), 7.25-
7.19 (m, 1H), 7.05 (d, J=8.5Hz, 1H), 6.82 (d, J=5.4Hz, 2H), 6.22 (d, J=2.3Hz, 1H), 6.18-
6.13 (m, 1H), 5.67-5.63 (m, 1H), 5.14 (s, 1H), 4.24 (t, J=5.6Hz, 2H), 3.90 (d, J=5.8Hz,
3H), 3.79-3.72 (m, 6H), 3.72-3.64 (m, 9H), 3.10-3.04 (m, 1H), 2.97 (dd, J=17.4,11.8Hz,
3H), 2.77 (s, 4H), 1.68 (dt, J=11.3,5.7Hz, 4H), 1.60-1.46 (m, 3H)13C NMR(126MHz,cd3od)
δ166.63(s),164.14(s),159.87(s),158.87(s),157.85(s),155.37(s),153.15(s),152.91
(s),147.72(s),137.21(s),134.20(s),128.22(s),128.17–128.10(m),127.62(s),
127.61–127.55(m),126.34(s),126.33–126.29(m),126.07(s),125.99–125.93(m),125.79
(s),121.94(s),115.86(s),115.69(s),113.11(s),110.96(s),103.62(s),99.73(s),
93.29(s),91.36(s),77.33(s),69.29(s),65.83(s),59.68(s),56.99(s),55.14(s),55.11
(s),54.54(s),54.37(s),54.31(s),25.38(s),24.55(s),23.02(s)。
The above description is merely a specific embodiment, but protection scope of the present invention is not limited thereto, any
The change or replacement expected without creative work, should be covered by the protection scope of the present invention.Therefore, it is of the invention
Protection domain should be determined by the scope of protection defined in the claims.
Claims (4)
1. a kind of compound of the chroman of benzene containing 2- parent nucleus, it is characterised in that the compound structure is as shown in logical formula (I)：
Wherein 2 are configured as R types or S types, and 3 are configured as R types or S types；R1~R9Respectively hydrogen, hydroxyl, alkoxy, alkylamino,
It is one or more in alkylamidoalkyl, fluorine, benzoyl, benzamido；X is oxygen；Y is for hydrogen or such as general formula (II) or (III)
Or the structure shown in (IV)：
In the general formula (II) or (III) or (IV), R10One kind in hydrogen, fluorine, alkoxy, benzyl, benzoyl；
M=0 or 1 in the general formula (II)；R11、R12Respectively hydrogen, alkoxy, fluorine, hydroxyl, 1-10 carbon atom alkoxy or
End is connected with one kind in the alkoxy of nitrogenous heterocyclic 1-10 carbon atom number, and the end is connected with nitrogenous heterocyclic 1-10
The alkoxy of carbon atom number, shown in structure such as general formula (V)：
Wherein n=1~10, Z are carbon or oxygen；The nitrogen heterocyclic ring is piperidines, morpholine or methyl piperazine.
2. compound according to claim 1, it is characterised in that the R10For methoxyl group or benzoyl.
3. compound according to claim 1, it is characterised in that the R11For piperidines ethyoxyl, morpholine ethyoxyl or 4- first
Base piperazine ethyoxyl.
4. compound according to claim 1, it is characterised in that the R12For piperidines ethyoxyl, morpholine ethyoxyl or 4- first
Base piperazine ethyoxyl.
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