CN103319448B - A kind of Xanthone derivative and Synthesis and applications thereof - Google Patents
A kind of Xanthone derivative and Synthesis and applications thereof Download PDFInfo
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- CN103319448B CN103319448B CN201310111594.9A CN201310111594A CN103319448B CN 103319448 B CN103319448 B CN 103319448B CN 201310111594 A CN201310111594 A CN 201310111594A CN 103319448 B CN103319448 B CN 103319448B
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Abstract
The present invention relates to medicinal chemistry art, be specifically related to that a class general formula is (I), (II), (III) Xanthone derivative and preparation method thereof and at medicinal use.This Xanthone derivative is prepared by wittig reaction, and pharmacological evaluation proves, the compounds of this invention has anti-oxidant activity.
Description
Technical field
The present invention relates to medicinal chemistry art, specifically relate to Xanthone derivative of antioxidizing activity and its production and use.
Background technology
Along with going deep into of free radical medical research, people more and more pay close attention to the damage that various radical pair body causes.Modern medicine study also proves that free radical is relevant with many biological phenomenas, as the aging of cell, the generation, sport injury etc. of cancer more and more.In human body, antioxidant can effective scavenging free radicals, plays anti-aging, the effect such as cancer and cardiovascular disorder in advance, can be used as medicine.Therefore be primer with natural antioxidants, find that having novel antioxidant that is anti-oxidant, Free-radical scavenging activity has important potential using value.
Have at present the xanthone of kind more than 200 at occurring in nature, research shows that xanthone has significant resistance of oxidation, is formed with significant restraining effect to myocardial infarction or cerebral infarction; Low-density lipoprotein (LDL) oxidation that can effectively suppress free radical to cause, reduces heart disease etc.Containing more than 40 kind of xanthone in mangosteen (GarciniamangostanaL.) fruit, mangostin is the xanthone compound of isolated primary bioactivity from Garcinia Bark shell, mainly comprise α-, β-and γ-mangostin (α-, β-and γ-mangostin).Large quantity research both domestic and external show mangostin have anti-oxidant, sterilization, anti-inflammatory, AntiHIV1 RT activity, the pharmacological action such as antitumor (Lv Hong, Fang Yanxiong. Chinese medicinal materials, 2005,28 (6): 519-523).
So far the chemosynthesis of xanthone compounds and biological mechanism research deep not enough, in view of chemical structure and the good biological activity of mangostin uniqueness, chemosynthesis and the pharmacodynamic study of carrying out xanthone compounds in a deep going way have important research meaning.At present, existing scholar reports the complete synthesis of xanthone compounds mangostin, 2002, and Japanese scholars KazuhikoIikubo is the complete synthesis α-mangostin (TetrahedronLett in laboratory first, 2002,43:291-293), within 2011, king enters glad grade with brand-new synthesis strategy, complete α-, β-and γ-mangostin (Wang Jinxin, the CN102653533A such as Ye Hongchun, Gu Qinlan) complete synthesis, the rarely seen report of research of related analogs.
Summary of the invention
The present invention aims to provide new Xanthone derivative and their preparation method and application.
Technical scheme of the present invention is the effect with anti-oxidant activity and scavenging free radicals significantly based on mangostin.The invention provides Xanthone derivative, find the better compound of anti-oxidant activity.
Present invention also offers the preparation method of above-claimed cpd.
Described Xanthone derivative, this derivative is general formula (I), (II), the compound shown in (III):
In formula (I), (II), (III):
R
1, R
2simultaneously or be asynchronously hydrogen, methoxymethylene, C
1-C
4alkyl.
R
3for hydrogen; C
1-C
4alkyl; (C
nh
2n+1) OCH
2-, HO (C
nh
2n) CH
2-, (C
nh
2n+1) C=O, wherein, n=1-4; (C=O) NR
6r
7, R
6, R
7simultaneously or be asynchronously hydrogen, C
1-4alkyl, piperazine, methylpiperazine, pyrroles, morpholine.
R
4for C
2-c
6alkyl;-(CH
2) n (C=O) OR
8,-(CH
2) nCOOH ,-(CH
2) nCH
2oH, wherein, n=0-3, R
8for C
1-c
4alkyl;-(C=O) R
9,-(C=O) NHR
9,-CH
2-NHR
9,-CH
2-NH (C=O) R
9, wherein, R
9for C
1-c
4alkyl, saturated heterocyclic, aryl or heterocyclic aryl.
R
5for hydrogen, C
2-6alkyl.
(10,11) position, that dotted portion is drawn in (13,14) position is identical or not identical, independently represents double bond, epoxy bond, singly-bound, o-dihydroxy, hydroxyl, amino or substituted amido separately.
R
5for hydrogen, C
2-6alkyl.
R
1and R
2more preferably hydrogen, methyl.
R
3more preferably hydrogen, methyl, methoxymethylene, ethanoyl, propionyl, tertiary butyryl radicals.
R
1, R
2, R
3has one at least for hydrogen.
Described saturated heterocyclic is pyridine, piperidines, piperazine, morpholine, methylpiperazine, pyrroles, and the substituting group on heterocycle is positioned at each position of heterocycle, is monosubstituted or polysubstituted, and substituting group is halogen, C
1-c
4alkyl, C
1-c
4alkoxyl group, cyano group, amino, hydroxyl, carboxyl, methoxycarbonyl, ethoxycarbonyl.
Described aryl is substituted-phenyl, and substituting group is positioned at each position of phenyl ring, is monosubstituted or polysubstituted, and substituting group is halogen, C
1-c
4alkoxyl group, cyano group, amino, methoxycarbonyl, ethoxycarbonyl, carboxyl.
Described aromatic heterocycle is pyrimidine, pyrazoles, imidazoles, triazole, thiazole, indoles, indazole, benzoglyoxaline, and the substituting group on heterocycle is positioned at each position of heterocycle, is monosubstituted or polysubstituted, and substituting group is halogen, C
1-C
4alkyl, C
1-C
4alkoxyl group, cyano group, amino, hydroxyl, carboxyl, methoxycarbonyl, ethoxycarbonyl.
Described C
1-c
4alkyl is methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl.
Part of compounds of the present invention is:
The sub-methoxyl group-8-isopentene group-9H-xanthone (I-1) of 1-hydroxyl-3,6-dimethoxy-7-methoxyl group
1,7-dihydroxyl-3,6-dimethoxy-8-isopentene group-9H-xanthone (I-2)
(instead)-1-(1-hydroxyl-3,6-dimethoxy-7-methoxyl group sub-methoxyl group-9H-9-oxo xanthene)-2-butylene tert-butyl acrylate (III-1)
(instead)-1-(1,3,6,7-tetrahydroxy-9H-9-oxo xanthene)-2-butylene tert-butyl acrylate (III-2)
(instead)-1-(1,6,7-trihydroxy--3-methoxyl group-9H-9-oxo xanthene)-2-butylene tert-butyl acrylate (III-3)
(instead)-1-hydroxyl-2,8-bis-(4-methyl-pentenyl)-3,6,7-trimethoxy-9H-xanthone (I-3)
(instead)-1,3,6-trihydroxy--2,8-bis-(4-methyl-pentenyl)-7-methoxyl group-9H-xanthone (I-4)
(instead)-1,6-dihydroxyl-2,8-bis-(4-methyl-pentenyl)-3,7-dimethoxy-9H-xanthone (I-5)
(instead)-1,3,6,7 one tetrahydroxy-2,8-bis-(4-methyl-pentenyl)-9H-xanthone (I-6)
(instead)-1-[1-hydroxyl-2-(2-butylene acetoacetic ester base)-3,6,7-trimethoxy-9H-9-oxo xanthene]-2-butylene acetoacetic ester (III-4)
(instead)-4-(1-hydroxyl-3,6-dimethoxy-7-methoxyl group sub-methoxyl group-9H-9-oxo xanthene)-2-butylene acid (III-5)
The sub-methoxyl group-9H-xanthone (I-7) of (instead)-l-hydroxyl-2,8-bis-(2-hexenyl)-3,6-dimethoxy-7-methoxyl group
Sub-methoxyl group-8-[3-(4-fluorophenyl) the allyl group]-9H-xanthone (III-6) of (instead)-1-hydroxyl-3,6-dimethoxy-7-methoxyl group
Shown in formula (I), (II), (III), Xanthone derivative is obtained by following method: midbody compound (A), (B), (C) are obtained by reacting respective compound through wittig, and its building-up process is as follows:
In step (a), reaction solvent is tetrahydrofuran (THF), ethers, toluene.Wherein, R
1, R
2, R
3and R
4definition identical with claim 1.
Compd A, B, C obtain according to the document method such as (Wang Jinxin, Ye Hongchun, Gu Qinlan CN102653533A) preparation.
The present invention by mangostin derivative to the Scavenging activity of 1,1-phenylbenzene picryl phenylhydrazine (DPPH) free radical to detect the power of its oxidation-resistance.DPPH is a kind of organic free radical of early stage synthesis, be commonly used to the hydrogen supply capacity assessing polyphenoils, it is highly stable in organic solvent, in purple, and have a charateristic avsorption band at place, when running into free-radical scavengers, the lone-pair electron of DPPH are paired and make it fade, and namely diminish at the light absorption value of maximum absorption wave strong point.Therefore, the change by measuring light absorption value carrys out the elimination effect of assess sample to DPPH free radical.The pharmacology test of part of compounds is as follows:
The preparation of reagent
(1) preparation of DPPH methanol solution: accurately DPPH reagent 3.94mg, be settled in 50mL volumetric flask with anhydrous methanol, obtaining DPPH Stock concentrations is 2 × 10
-4mol/L.Keep in Dark Place at 0 ~ 4 DEG C.
(2) the preparation sample anhydrous methanol of tested material solution dissolves, and preparation volumetric molar concentration is followed successively by 0.1746 × 10
- 4mol/L, 0.3493 × 10
-4mol/L, 0.5238 × 10
-4mol/L, 0.6985 × 10
-4mol/L, 0.7303 × 10
-4mol/L, is then converted into the mass concentration of corresponding each sample.Contrast is tocopherol, is made into same concentrations with sample.
The mensuration of clearance rate:
By table 1 application of sample in microwell plate, shake up with micro oscillator, dark place left standstill after 30 minutes, by microplate reader at 517nm place, surveyed absorbance A
1.Each light absorption value replicate(determination) 3 times, finally gets its mean value.
Table 1, determining free radicals system application of sample table
| Light absorption value | Add sample value |
| A 0 | 0.1mL2×10 -4The solvent (methyl alcohol) of mol/LDPPH free-atom aqueous solution+0.1mL sample |
| A 1 | 0.1mL2×10 -4Mol/LDPPH free-atom aqueous solution+0.1mL sample |
The clearance rate of each sample to DPPH free radical is calculated as follows
IP: inhibiting rate (%)=(A
0-A
1)/A
0
The anti-oxidant activity of table 2, part of compounds of the present invention
| Numbering | IC 50(μg·mL -1) | Numbering | IC 50(μg·mL -1) |
| I-1 | ＞200 | I-2 | 184 |
| III-1 | ＞200 | III-2 | 15.3 |
| III-3 | 10.7 | I-3 | ＞200 |
| I-4 | 90.7 | I-5 | 159.6 |
| I-6 | 12.5 | III-5 | ＞200 |
| α-mangostin | 89.2 | Tocopherol | 10.3 |
Embodiment
By the following examples the present invention is further elaborated, but does not limit the present invention in any way.
In following embodiment, agents useful for same is commercially available, the 100-200 column chromatography silica gel that involved column chromatography silica gel all adopts Haiyang Chemical Plant, Qingdao to produce.
The sub-methoxyl group-8-isopentene group-9H-xanthone (I-1) of embodiment 1:1-hydroxyl-3,6-dimethoxy-7-methoxyl group
112mg (0.30mmol, 1eq) compound 1-hydroxyl-3,6-dimethoxy-7-methoxyl group sub-methoxyl group-8-allyl group-9H-xanthone is dissolved in 12mL tetrahydrofuran (THF), add 10mL water, the 2mL trimethyl carbinol, 5.52mg (0.015mmol, 0.05eq) two hydration potassium osmates, 64.2mg (0.30mmol, 1eq) sodium periodate, stir after 8 hours, steam solvent to the greatest extent, organic solvent diluting, saturated sodium sulfite solution washing, washing, anhydrous sodium sulfate drying.
693mg (1.80mmol) bromo isopropyl triphenyl phosphine is added in 50mL three-necked bottle, add tetrahydrofuran (THF) 15mL, cryosel bath cooling, be injected into the hexane solution of 0.6mL (2.4eq) n-Butyl Lithium, then the tetrahydrofuran solution that previous step obtains product is injected into, room temperature reaction 24h.After terminating reaction, add the n-Butyl Lithium that the cancellation of 0.5mL methyl alcohol is unnecessary, evaporated under reduced pressure solvent, ethyl acetate is extracted, washing, anhydrous sodium sulfate drying.Column chromatographic isolation and purification, obtains yellow needles solid 47mg, mp:73-74 DEG C, yield 39%.
1HNMR(CDCl
3)1.68(3H，s，-CH
3)，1.84(3H，s，-CH
3)，3.63-3.98(9H，s，3×OCH
3)，4.17-4.20(2H，d，J＝5.79Hz，-CH
2-)，5.05(1H，s，-OCH
2O-)，5.23-5.25(1H，d，J＝6.33Hz，-CH＝)，6.31-6.76(3H，s，Ar-H)，13.43(1H，s，Ar-OH)；
ESI-HRMScalcdforC
22H
25O
7：401.1595，found：m/z：401.159[M+H]
+.
Embodiment 2:1,7-dihydroxyl-3,6-dimethoxy-8-isopentene group-9H-xanthone (I-2)
By (47.0mg, 0.1mmol) compound 1-hydroxyl-3,6-dimethoxy-7-methoxyl group sub-methoxyl group-8-isopentene group-9H-xanthone is dissolved in 5ml tetrahydrofuran (THF), add 6mol/L hydrochloric acid soln 5ml, be heated to about 40 DEG C reactions 4 hours, about slowly adding 10% sodium bicarbonate cold soln adjust pH to 3 after being cooled to room temperature, rear extraction into ethyl acetate (2 × 30ml), merge organic layer, column chromatography purification after anhydrous sodium sulfate drying, obtain faint yellow needle-like solid 38mg, yield 89.6%.
1HNMR(CDCl
3)1.68(3H，s，-CH
3)，1.84(3H，s，-CH
3)，3.63-3.98(9H，s，2×OCH
3)，4.17-4.20(2H，d，J＝5.79Hz，-CH
2-)，5.23-5.25(1H，d，J＝6.33Hz，-CH＝)，6.31-6.92(3H，s，Ar-H)，13.43(1H，s，Ar-OH)；
ESI-HRMScalcdforC
22H
25O
7：356.1595，found：m/z：356.159[M+H]
+.
Embodiment 3:(is anti-)-1-(1-hydroxyl-3,6-dimethoxy-7-methoxyl group sub-methoxyl group-9H-9-oxo xanthene)-2-butylene tert-butyl acrylate (III-1)
112mg (0.30mmol, 1eq) compound 1-hydroxyl-3,6-dimethoxy-7-methoxyl group sub-methoxyl group-8-allyl group-9H-xanthone is dissolved in 12mL tetrahydrofuran (THF), add 10mL water, the 2mL trimethyl carbinol, 5.52mg (0.015mmol, 0.05eq) two hydration potassium osmates, 64.2mg (0.30mmol, 1eq) sodium periodate, stir after 8 hours, steaming desolventizes, organic solvent diluting, saturated sodium sulfite solution washing, washing, anhydrous sodium sulfate drying.
In the mono-neck bottle of 25mL, add the toluene solution that previous step obtains product, add triphenyl tertbutyloxycarbonyl methyne phosphine alkane 316mg (0.9mmol) and be warming up to 90 DEG C of reactions 12 hours, stopped reaction, boils off toluene.Column chromatographic isolation and purification, obtains beige solid 114mg, mp:135-137 DEG C, yield 80.5%.
1HNMR(CDCl
3)1.43(9H，s，3×CH
3)，3.61-3.96(9H，s，3×OCH
3)，4.35-4.37(2H，d，J＝4.71Hz，-CH
2-)，5.04(2H，s，-OCH
2O-)，5.62-5.67(1H，m，CH
2C
H＝)，6.29-6.78(3H，s，Ar-H)，7.10-7.15(1H，d，J＝15.63Hz，-COC
H＝)，13.28(1H，s，Ar-OH)；
ESI-HRMScalcdforC
25H
28NaO
9：495.1626，found：m/z：495.1621[M+Na]
+.
Embodiment 4:(is anti-)-1-(1,3,6,7-tetrahydroxy-9H-9-oxo xanthene)-2-butylene tert-butyl acrylate (III-2) and (instead)-1-(1,6,7-trihydroxy--3-methoxyl group-9H-9-oxo xanthene)-2-butylene tert-butyl acrylate (III-3)
By 283mg (0.60mmol, 1eq) compound (instead)-1-(1-hydroxyl-3,6-dimethoxy-7-methoxyl group sub-methoxyl group-9H-9-oxo xanthene)-2-butylene tert-butyl acrylate is dissolved in 20mlDMSO, add 2eqKOH, be warming up to 200 DEG C of reaction 8h, ethyl acetate is extracted, washing, anhydrous sodium sulfate drying.Column chromatographic isolation and purification, obtains the faint yellow needle-like solid compound III-2 of 131mg, the faint yellow needle-like solid compound III-3 of yield 54.6%, 61mg, yield 24.6%.
III-2：
1HNMR(CDCl
3)1.45(9H，s，3×CH
3)，4.37(2H，d，J＝4.71Hz，-CH
2-)，5.62-5.67(1H，m，CH
2C
H＝)，6.29-6.88(3H，s，Ar-H)，7.10-7.15(1H，d，J＝15.63Hz，-COC
H＝)，13.28(1H，s，Ar-OH)；
III-3：
1HNMR(CDCl
3)1.43(9H，s，3×CH
3)，3.61-3.96(3H，s，OCH
3)，4.35(2H，d，J＝4.71Hz，-CH
2-)，5.62-5.67(1H，m，CH
2C
H＝)，6.29-6.70(3H，s，Ar-H)，7.10-7.15(1H，d，J＝15.63Hz，-COC
H＝)，13.28(1H，s，Ar-OH).
Embodiment 5:(is anti-)-1-hydroxyl-2,8-bis-(4-methyl-pentenyl)-3,6,7-trimethoxy-9H-xanthone (I-3)
By 112mg (0.30mmol, 1eq) compound 1-hydroxyl-3,6,7-trimethoxy-8-allyl group-9H-xanthone is dissolved in 12mL tetrahydrofuran (THF), adds 10mL water, the 2mL trimethyl carbinol, 5.52mg (0.015mmol, 0.05eq) two hydration potassium osmate, 64.2mg (0.30mmol, 1eq) sodium periodate, stirred after 8 hours, steamed solvent to the greatest extent, organic solvent diluting, saturated sodium sulfite solution washing, washing, anhydrous sodium sulfate drying.
960mg (2.4mmol) bromo isobutyl-triphenylphosphine is added in 50mL three-necked bottle, add tetrahydrofuran (THF) 15mL, cryosel bath cooling, be injected into the hexane solution of 0.6mL (2.4eq) n-Butyl Lithium, then the tetrahydrofuran solution that previous step obtains product is injected into, room temperature reaction 24h.After terminating reaction, add the n-Butyl Lithium that the cancellation of 0.5mL methyl alcohol is unnecessary, evaporated under reduced pressure solvent, ethyl acetate is extracted, washing, anhydrous sodium sulfate drying.Column chromatographic isolation and purification, obtains yellow oily solid 38mg, mp:168-174 DEG C, yield 26%.
1HNMR(CDCl
3)0.79-0.81(6H，d，J＝7.10Hz，2×CH
3)，0.95-0.98(6H，d，J＝6.90Hz，2×CH
3)，2.83-2.97(2H，m，2×CH)，3.56-3.86(9H，s，3×OCH
3)，3.85-3.93(2H，m，2×-CH＝)，4.18-4.20(2H，d，J＝6.90Hz，-CH
2-)，5.10-5.14(2H，d，J＝7.1Hz，-CH
2-)，5.20-5.35(2H，m，2×-CH＝)，6.24-6.70(3H，s，Ar-H)，13.34(1H，s，Ar-OH)；
ESI-HRMScalcdforC
28H
35O
6：467.2428found：m/z：467.2419[M+H]
+.
Embodiment 6:(is anti-)-1,3,6-trihydroxy--2,8-bis-(4-methyl-pentenyl)-7-methoxyl group-9H-xanthone (I-4) and (instead)-1,6-dihydroxyl-2,8-bis-(4-methyl-pentenyl)-3,7-dimethoxy-9H-xanthone (I-5)
By 280mg (0.60mmol, 1eq) compound (instead)-1-hydroxyl-2,8-bis-(4-methyl-pentenyl)-3,6,7-trimethoxy-9H-xanthone-but-2-ene tert-butyl acrylate is dissolved in 20mlDMSO, adds 2eqKOH, be warming up to 200 DEG C of reaction 8h, ethyl acetate is extracted, washing, anhydrous sodium sulfate drying.Column chromatographic isolation and purification, obtains the faint yellow needle-like solid Compound I-7 of 169mg, the faint yellow needle-like solid Compound I-8 of yield 64.6%, 77mg, yield 28.6%.
I-4：
1HNMR(CDCl
3)0.79-0.81(6H，d，J＝7.10Hz，2×CH
3)，0.95-0.98(6H，d，J＝6.90Hz，2×CH
3)，2.83-2.97(2H，m，2×CH)，3.56-3.86(3H，s，OCH
3)，3.85-3.93(2H，m，2×-CH＝)，4.18(2H，d，J＝6.90Hz，-CH
2-)，5.10(2H，d，J＝7.1Hz，-CH2-)，5.20-5.35(2H，m，2×-CH＝)，6.21-6.50(3H，s，Ar-H)，13.34(1H，s，Ar-OH)；
I-5：
1HNMR(CDCl
3)0.79-0.81(6H，d，J＝7.10Hz，2×CH
3)，0.95-0.98(6H，d，J＝6.90Hz，2×CH
3)，2.83-2.97(2H，m，2×CH)，3.56-3.86(6H，s，2×OCH
3)，3.85-3.93(2H，m，2×-CH＝)，4.20(2H，d，J＝6.90Hz，-CH
2-)，5.14(2H，d，J＝7.1Hz，-CH2-)，5.20-5.35(2H，m，2×-CH＝)，6.24-6.54(3H，s，Ar-H)，13.34(1H，s，Ar-OH).
Embodiment 7:(is anti-)-1,3,6,7-tetrahydroxy-2,8-bis-(4-methyl-pentenyl)-9H-xanthone (I-6)
By compound (instead)-1,3,6-trihydroxy--2,8-bis-(4-methyl-pentenyl)-7-methoxyl group-9H-xanthone 100mg is dissolved in 2mL ethylene dichloride, add 1.0mL pyridine, under stirring, slowly add aluminum chloride, add the sodium iodide of catalytic amount, mixed-liquor return is after 3 hours, be cooled to room temperature, reaction solution poured in the mixture of dilute hydrochloric acid and frozen water, be extracted with ethyl acetate, merge organic layer, adjust PH with triethylamine.Organic layer is washed with water and saturated common salt successively, anhydrous sodium sulfate drying.Column chromatographic isolation and purification, obtains yellow solid (instead)-1,3,6,7-tetrahydroxy-2,8-bis-(4-methyl-pentenyl)-9H-xanthone 60mg, yield 55%.
1HNMR(CDCl
3)0.79-0.81(6H，d，J＝7.10Hz，2×CH
3)，0.95-0.98(6H，d，J＝6.90Hz，2×CH
3)，2.83-2.97(2H，m，2×CH)，3.85-3.93(2H，m，2×-CH＝)，4.18-4.20(2H，d，J＝6.90Hz，-CH
2-)，5.10-5.14(2H，d，J＝7.1Hz，-CH
2-)，5.20-5.35(2H，m，2×-CH＝)，6.14-6.50(3H，s，Ar-H)，13.34(1H，s，Ar-OH).
Embodiment 8:(is anti-)-1-[1-hydroxyl-2-(2-butylene acetoacetic ester base)-3,6,7-trimethoxy-9H-9-oxo xanthene]-2-butylene acetoacetic ester (III-4)
By 764mg (2mmol, 1eq) compound 1-hydroxyl-3,6,7-dimethoxy-8-allyl group-9H-xanthone is dissolved in 12mL tetrahydrofuran (THF), adds 10mL water, the 2mL trimethyl carbinol, 5.52mg (0.015mmol, 0.05eq) two hydration potassium osmate, 64.2mg (0.30mmol, 1eq) sodium periodate, stirred after 8 hours, and solvent is to the greatest extent steamed in decompression, organic solvent diluting, saturated sodium sulfite solution washing, washing, anhydrous sodium sulfate drying.
In the mono-neck bottle of 100mL, add the toluene solution that previous step obtains product, add triphenyl ethoxycarbonyl methyne phosphine alkane 2.09g (6mmol) and be warming up to 90 DEG C of reactions 24 hours, stopped reaction, boils off toluene.Column chromatographic isolation and purification, obtains beige solid 452mg, mp:110-115 DEG C, yield 52%.
1HNMR(CDCl
3)1.32(6H，t，J＝7.17Hz，2×CH
3)，3.53(2H，d，J＝6.3Hz，-CH
2-)，3.81-3.99(9H，s，3×OCH
3)，4.14-4.16(2H，d，J＝4.5Hz，-CH
2-)，4.33-4.35(2H，d，J＝4.77Hz，C
H＝CHCH
2)，5.68-5.80(2H，m，CH＝C
HCH
2)，6.35(1H，s，Ar-H)，6.82(1H，s，Ar-H)，13.39(1H，s，Ar-OH)；
ESI-HRMScalcdforC
28H
31O
10：527.1912found：m/z：527.1904[M+H]
+.
Embodiment 9:(is anti-)-4-(1-hydroxyl-3,6-dimethoxy-7-methoxyl group sub-methoxyl group-9H-9-oxo xanthene)-2-butylene acid (III-5)
Compound (instead)-1-(1-hydroxyl-3,6-dimethoxy-7-methoxyl group sub-methoxyl group-9H-9-oxo xanthene)-2-butylene acetoacetic ester 157mg (0.354mmol), add 2mL dissolve with ethanol, the sodium hydroxide solution 1.77mL (1.77mmol) of 1M, stirring at room temperature is after 3 hours, stopped reaction, revolve except after ethanol, adjust PH to 3-4 with the dilute hydrochloric acid of 1M, obtain beige solid 101mg, yield 69%.
1HNMR(CDCl
3)3.63-4.01(9H，s，3×OCH
3)，4.41-4.43(2H，d，J＝5.94Hz，-CH
2-)，5.07(1H，s，-CH
2-)，5.27(1H，m，-CH＝)，5.71-5.765.69-5.74(1H，d，J＝15.78Hz，-CH＝)，6.31-6.83(3H，s，Ar-H)，13.25(1H，s，Ar-OH)；
ESI-HRMScalcdforC
21H
21O
9：417.118found：m/z：417.1174[M+H]
+
Embodiment 10:(is anti-) the sub-methoxyl group-9H-xanthone (I-7) of-1-hydroxyl-2,8-bis-(2-hexenyl)-3,6-dimethoxy-7-methoxyl group
By 114.6mg (0.30mmol, 1eq) compound 1-hydroxyl-3,5,6-trimethoxy-2,8-allyl group-9H-xanthone is dissolved in 12mL tetrahydrofuran (THF), adds 10mL water, the 2mL trimethyl carbinol, 5.52mg (0.015mmol, 0.05eq) two hydration potassium osmate, 64.2mg (0.30mmol, 1eq) sodium periodate, stirred after 8 hours, steam solvent to the greatest extent, organic solvent diluting, saturated sodium sulfite solution washing, washing, anhydrous sodium sulfate drying.
960mg (2.4mmol) bromo normal-butyl triphenylphosphine is added in 50mL three-necked bottle, add tetrahydrofuran (THF) 15mL, cryosel bath cooling, be injected into the hexane solution of 0.6mL (2.4eq) n-Butyl Lithium, then the tetrahydrofuran solution that previous step obtains product is injected into, room temperature reaction 24h.After terminating reaction, add the n-Butyl Lithium that the cancellation of 0.5mL methyl alcohol is unnecessary, evaporated under reduced pressure solvent, ethyl acetate is extracted, washing, anhydrous sodium sulfate drying.Column chromatographic isolation and purification, obtains yellow oily solid 39mg, mp:148-151 DEG C, yield 28%.
1HNMR(CDCl
3)1.06-1.11(6H，t，J＝5.94Hz，CH
3)，1.41-1.51(4H，m，2×-CH
2-)，1.93-1.95(2H，m，-CH
2-)，2.23-2.30(2H，m，-CH
2-)，3.40-3.42(2H，d，J＝6.90Hz，-CH2-)，3.81-3.97(9H，s，3×OCH
3)，4.19-4.20(2H，d，J＝6.90Hz，-CH
2-)，5.44-5.51(4H，m，4×-CH＝)，6.33(1H，s，Ar-H)，6.76(3H，s，Ar-H)，13.45(1H，s，Ar-OH)；
ESI-HRMScalcdforC
28H
35O
6：467.2428found：m/z：467.2421[M+H]
+.
Embodiment 11:(is anti-) sub-methoxyl group-8-[3-(4-fluorophenyl) the allyl group]-9H-xanthone (III-6) of-1-hydroxyl-3,6-dimethoxy-7-methoxyl group
112mg (0.30mmol, 1eq) compound 1-hydroxyl-3,6-dimethoxy-7-methoxyl group sub-methoxyl group-8-allyl group-9H-xanthone is dissolved in 12mL tetrahydrofuran (THF), add 10mL water, the 2mL trimethyl carbinol, 5.52mg (0.015mmol, 0.05eq) two hydration potassium osmates, 64.2mg (0.30mmol, 1eq) sodium periodate, stir after 8 hours, solvent is to the greatest extent steamed in decompression, organic solvent diluting, saturated sodium sulfite solution washing, washing, anhydrous sodium sulfate drying.
480mg (1.2mmol) is added to fluorine bromobenzyl triphenylphosphine in 50mL three-necked bottle, add tetrahydrofuran (THF) 15mL, cryosel bath cooling, be injected into the hexane solution of 0.6mL (2.4eq) n-Butyl Lithium, then the tetrahydrofuran solution that previous step obtains product is injected into, room temperature reaction 24h.After terminating reaction, add the n-Butyl Lithium that the cancellation of 0.5mL methyl alcohol is unnecessary, evaporated under reduced pressure solvent, ethyl acetate is extracted, and washing, anhydrous sodium sulfate drying column chromatographic isolation and purification, obtains yellow oil 31mg, mp:113-117 DEG C, yield 25%.
1HNMR(CDCl
3)3.28-3.92(9H，s，3×OCH
3)，4.45-4.47(2H，d，J＝5.88Hz，CH＝CHC
H 2)，4.85(2H，s，-OCH
2O-)，5.66-5.70(1H，m，C
H＝CHCH
2)，6.29(2H，s，Ar-H)，6.40-6.44(2H，d，J＝11.46Hz，CH＝C
HCH
2)，6.74(1H，s，Ar-H)，7.04-7.26(4H，m，Ar-H)，13.34(1H，s，Ar-OH)；
ESI-HRMScalcdforC
26H
24FO
7：467.1501found：m/z：467.1509[M+H]
+.
Claims (4)
1. an Xanthone derivative, is characterized in that this derivative general formula is (I), the compound shown in (III):
In formula (I), (III):
R
1, R
2simultaneously or be asynchronously hydrogen, C
1-C
4alkyl;
R
3for hydrogen;
R
5for hydrogen;
(10,11) position, (13,14) position are drawn dotted portion and are represented double bond;
In formula (I), R
4for C
2-c
6alkyl;
In formula (III), R
4for-(CH
2) n (C=O) OR
8, wherein, n=0, R
8for C
1-C
4alkyl.
2. a kind of Xanthone derivative according to claim 1, is characterized in that R
1and R
2for hydrogen, methyl.
3. the preparation method of Xanthone derivative according to claim 1, is characterized in that:
Xanthone derivative shown in formula (I), (III) is prepared through wittig reaction by midbody compound (A), (C), and its building-up process is as follows:
In step (a), reaction solvent is tetrahydrofuran (THF), ethers, toluene.
4. arbitrary Xanthone derivative according to claim 1 is used for the application in anti-oxidation field.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009093259A2 (en) * | 2008-01-21 | 2009-07-30 | Ganga Raju Gokaraju | A PROCESS FOR PRODUCING γ-MANGOSTIN |
| EP2108645A1 (en) * | 2008-04-07 | 2009-10-14 | INSERM (Institut National de la Santé et de la Recherche Medicale) | Use of xanthone derivatives as a medicament for cancer |
| CN102653533A (en) * | 2011-10-09 | 2012-09-05 | 中国药科大学 | Total synthesis method of mangostin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009093259A2 (en) * | 2008-01-21 | 2009-07-30 | Ganga Raju Gokaraju | A PROCESS FOR PRODUCING γ-MANGOSTIN |
| EP2108645A1 (en) * | 2008-04-07 | 2009-10-14 | INSERM (Institut National de la Santé et de la Recherche Medicale) | Use of xanthone derivatives as a medicament for cancer |
| CN102653533A (en) * | 2011-10-09 | 2012-09-05 | 中国药科大学 | Total synthesis method of mangostin |
Non-Patent Citations (3)
| Title |
|---|
| Cytotoxic Geranylated Xanthones and O-Alkylated Derivatives of ａ-Mangostin;Ly Dieu HA et al.;《Chem. Pharm. Bull》;20090512;第57卷(第8期);第830-834页 * |
| Xanthones as antioxidants: A theoretical study on the thermodynamics and kinetics of the single electron transfer mechanism;Ana Martínez et al.;《Food & function》;20120213;第3卷(第4期);摘要，表格1，表格3，第449页，第1栏 * |
| 呫吨酮类衍生物的合成与体外抗氧化活性研究;路浩;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20090915;E079-18 * |
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