CN101066919A - Process of synthesizing shikolin dimethyl ether derivative - Google Patents
Process of synthesizing shikolin dimethyl ether derivative Download PDFInfo
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- CN101066919A CN101066919A CN 200710041978 CN200710041978A CN101066919A CN 101066919 A CN101066919 A CN 101066919A CN 200710041978 CN200710041978 CN 200710041978 CN 200710041978 A CN200710041978 A CN 200710041978A CN 101066919 A CN101066919 A CN 101066919A
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Abstract
The present invention is process of synthesizing shikonin dimethyl ether derivative and belongs to the field of medicine technology. The 2-position side chain isomer of shikonin dimethyl ether and its ester derivative are synthesized with shikonin as material, and through acetylation, hydrolysis, methylation and acylation. The 6-position side chain isomer of shikonin dimethyl ether and its ester derivative are synthesized with shikonin as material, and through acetylation, hydrolysis, methylation, reduction, acetylation, demethylation, hydrolysis, methylation and acylation. The present invention performs selective methylation on shikonin material indirectly, has mild reaction condition and high yield, and is suitable for large scale production. The prepared compounds may be used in treating tumor, diminishing inflammation, treating burns and scalds, etc.
Description
Technical field
What the present invention relates to is a kind of method of medical technical field, specifically is a kind of synthetic method of alkannin dimethyl ether derivative.
Background technology
The clinical conventional Chinese medicine that Asian puccoon (Lithospermum erythrohizon) is recorded for the Pharmacopoeia of the People's Republic of China.Its main effective constituent is Shikonin and derivative thereof, has effects such as antibiotic, anti-inflammatory, anticancer, treatment burn and scald.Yet the toxic side effect of Shikonin and hydrophobicity limit its clinical application.The naphthazarin of Shikonin parent nucleus (5,8-dihydroxyl-1,4-naphthoquinones) structure may be one of reason that causes toxic side effect.We find that cytotoxicity descended water-soluble increase after the naphthazarin parent nucleus of Shikonin methylated when carrying out the synthetic of alkannin derivant and anti-tumor activity research.After methylating, the naphthazarin parent nucleus of Shikonin produces two kinds of isomer, i.e. 2 side chain isomer (2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-5,8-dimethoxy-1, the 4-naphthoquinones) and 6 side chain isomer (6-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-5,8-dimethoxy-1, the 4-naphthoquinones).The biologic activity of two kinds of isomer has than big-difference, the Korea S scholar has synthesized 5 of a series of 2 or 6 alkyl replacements, 8 dimethoxys-1,4-naphthoquinone compound (DMNQ), and carried out topoisomerase and suppressed and anti-tumor activity test, find that the activity of 6 position isomers is better than 2 position isomers.With the Shikonin is raw material, and the dimethyl ether derivative for preparing Shikonin by methylation method is a method eaily.But because the singularity of naphthazarin structure, directly methylating with usual method to obtain 2 side chain isomers of dme, and yield is low.
Find by prior art documents; people such as S.B.Katti are at " Arnebin Derivatives foranticancer activity " (β; the antitumour activity of beta-dimethyl-acryl Shikonin); IndianJournal of Chemistry (" India's chemistry "); 18B, 420-422,1979) in ether, handle β with diazomethane; it not is the compound of parent nucleus HM that beta-dimethyl-acryloyl Shikonin obtains, but also unifies a pyrrole ring on phenyl ring.Bibliographical information is not seen in synthesizing of 6 side chain isomers of alkannin dimethyl ether as yet.In order to overcome above-mentioned deficiency, the invention provides the synthetic method of 2 side chain isomers and 6 side chain isomers and the ester derivative thereof of Shikonin dimethyl ether.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, a kind of synthetic method of alkannin dimethyl ether derivative is provided.It specifically is the new synthetic method of 2 side chain isomers of Shikonin dimethyl ether and ester derivative (being structural formula I) thereof and 6 side chain isomers and ester derivative (being structural formula II) thereof.This method is raw material with the Shikonin, adopts indirect method that Shikonin is optionally methylated, the reaction conditions gentleness, and yield is higher, is suitable for mass preparation.
The present invention is achieved by the following technical solutions: the synthetic method that the present invention includes 2 side chain isomers and 6 side chain isomers and the ester derivative thereof of Shikonin dimethyl ether, wherein: 2 side chain isomers of Shikonin dimethyl ether and the synthetic method of ester derivative thereof, for: with the Shikonin is raw material, through acetylize, hydrolysis, methylate, acidylate makes again; The synthetic method of 6 side chain isomers of Shikonin dimethyl ether, for: with the Shikonin is raw material, through acetylize, hydrolysis, methylate, reduction, acetylize, demethylation, hydrolysis, methylate, acidylate makes again.
2 side chain isomers of Shikonin dimethyl ether and ester derivative thereof be 6 side chain isomers of structural formula I and Shikonin dimethyl ether and ester derivative thereof structural formula II as follows as follows, wherein R is H or COR ', and R ' is saturated and unsaturated alkyl, the aralkyl of 1-10 carbon atom.That these compounds can be used for is antitumor, anti-inflammatory, treatment burn and scald etc.
2 side chain isomers of the Shikonin dimethyl ether that the present invention relates to and the synthetic route of ester derivative structural formula I thereof are:
The synthetic method of 2 side chain isomer structural formula I of Shikonin dimethyl ether that the present invention relates to and ester derivative thereof specifically comprises the steps:
1. Shikonin and 15 equivalent diacetyl oxides are mixed in the anhydrous pyridine, under nitrogen protection,, obtain the triacetyl Shikonin in 0 ℃～5 ℃ stirring reactions 8 hours.
2. the triacetyl Shikonin is dissolved in methyl alcohol/tetrahydrofuran (THF) (volume ratio 4: 1), temperature of reaction is controlled below 0 ℃, slowly adds 10% K
2CO
3The aqueous solution reacted 2 hours, got 8-methoxyl group Shikonin.
3. 8-methoxyl group Shikonin is dissolved in exsiccant N; in the dinethylformamide; the potassiumiodide that adds catalytic amount simultaneously; 10 equivalent methyl iodide, 50 equivalent Anhydrous potassium carbonates are under nitrogen protection; stirring at room reaction 24 hours; obtain 5,8-dimethoxy-2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinones.
4. with 5,8-dimethoxy-2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinones and respective acids be prepared in reaction ester derivative (structural formula I) under dicyclohexylcarbodiimide (DCC) and 4-dimethylamino pyridine (DMAP) catalysis.
The synthetic route of the Shikonin dimethyl ether that the present invention relates to and 6 side chain isomer structural formula II of ester derivative thereof is:
The synthetic method of the Shikonin dimethyl ether that the present invention relates to and 6 side chain isomer structural formula II of ester derivative thereof specifically comprises the steps:
1. from Shikonin, four synthesis steps obtain 5 equally in the synthetic method of isostructure formula I, 8-dimethoxy-2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinones.
2. with 5; 8-dimethoxy-2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1, the 4-naphthoquinones is dissolved in the anhydrous methylene chloride, successively adds 4 equivalent acetate and excessive zinc powder; stirring at room reaction is 0.5 hour under nitrogen protection, and the reduzate of generation is not purified to be directly used in next step reaction.
3. under nitrogen protection, reduzate is directly dissolved in the excessive acetic anhydride via, splash into the exsiccant triethylamine after 0.5 hour, room temperature reaction 0.5 hour obtains 5,8-dimethoxy-2-(1 '-ethanoyl-4 '-methyl-3 '-amylene)-1,4-diacetoxy naphthalene.
4. with 5; 8-dimethoxy-2-(1 '-ethanoyl-4 '-methyl-3 '-amylene)-1; the 4-diacetoxy naphthalene is dissolved in the second eyeball; fully stir; slowly splash into the ceric ammonium nitrate aqueous solution, stirring at room reaction 0.5 hour obtains 5; 8-diacetoxy-6-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1, the 4-naphthoquinones.
5. with 5,8-diacetoxy-6-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1,4-naphthoquinones are dissolved in methyl alcohol/tetrahydrofuran (THF) (volume ratio 1: 1), and temperature of reaction is controlled below 0 ℃, slowly adds 5% Ce
2CO
3The aqueous solution continues reaction 1 hour, gets 5-methoxyl group-6-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-8-hydroxyl-1, the 4-naphthoquinones.
6. with 5-methoxyl group-6-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-8-hydroxyl-1; the 4-naphthoquinones is dissolved in exsiccant N; in the dinethylformamide (or second eyeball or dimethyl sulfoxide (DMSO)); the potassiumiodide that adds catalytic amount simultaneously, 10 equivalent methyl iodide or methyl-sulfates, 10 equivalent Anhydrous potassium carbonates; the stirring at room reaction is 24 hours under the nitrogen protection; obtain 5,8-dimethoxy-6-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinones.
7. with 5,8-dimethoxy-6-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinones and respective acids be prepared in reaction ester derivative (structural formula II) under DCC and DMAP catalysis.
Embodiment
Below embodiments of the invention are elaborated: present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
Synthesize 5,8-diacetoxy-2-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (2):
Take by weighing Shikonin 100mg (0.347mmol),, add 15 times of normal acetic anhydride with anhydrous pyridine 10ml dissolving.With the ice bath control reaction temperature is 0 ℃～5 ℃, and reaction is 8 hours under nitrogen protection.Add the ethyl acetate dilute reaction solution, with the saturated common salt water washing for several times, anhydrous MgSO
4Drying is filtered the pressure reducing and steaming ethyl acetate.Thick product silica gel column chromatography, ethyl acetate: sherwood oil (1: 10) wash-out obtains orange-yellow title compound (2) 134.3mg, yield 93.4%.
Its characterization parameter is: mp102-104 ℃,
1H-NMR (300MHz, CDCl
3), δ (ppm): 7.38 (d, 2H, J=1.2H
Z, H
Ar), 6.66 (s, 1H
Quin), 5.87 (dd, 1H, J=7.2,3.3Hz ,=CH), 5.07 (t, 1H, J=7.8Hz, OCH), 2.44 ~ 2.32 (m, 8H, CH
2,, 2Ar-OCOCH
3), 2.18 (s, 3H, OCOCH
3), 1.75 (s, 3H, CH
3), 1.65 (s, 3H, CH
3)
Embodiment 2
Synthetic 5-hydroxyl-8-methoxyl group-2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (3):
Compound (2) 100mg (0.242mmol) is dissolved among methyl alcohol/tetrahydrofuran (THF) (4: 1) 4ml, and-10 ℃ of temperature of reaction controls slowly add 10%K
2CO
3Aqueous solution 0.5ml continues reaction 2 hours in-10 ℃.Add saturated ammonium chloride solution in reaction solution, use ethyl acetate extraction, ethyl acetate layer is water and saturated common salt water washing respectively, anhydrous MgSO
4Drying, the pressure reducing and steaming ethyl acetate.The thick product silica gel column chromatography of gained, ethyl acetate: sherwood oil (1: 6) wash-out obtains title compound 65.9mg, yield 90.3%.
Its characterization parameter is: 1H-NMR (300MHz, CDCl
3), δ (ppm): 12.44 (s, 1H, Ar-OH), 7.30 (dd, 2H, J=9.3,9.6 Hz, H
Ar), 6.75 (d, 1H, J=1.53Hz, H
Quin), 5.94 (m, 1H ,=CH), 5.11 (d, 1H, J=4.5Hz, OCH), 3.98 (s, 3H, 0 CH
3), 2.58 ~ 2.51 (m, 1H, CH
2a), 2.41 ~ 2.37 (m, 1H, CH
2b), 1.65 (s, 3H, CH
3), 1.57 (s, 3H, CH
3).
Embodiment 3
Synthesize 5,8-dimethoxy-2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (4):
Compound (3) 100mg (0.331mmol) is dissolved in DMF, adds the KI of catalytic amount respectively, 50 times of equivalent K
2CO
3, 10 times of equivalent CH
3I.At room temperature, stirred 24 hours.Excessive K in the filtering reaction solution
2CO
3, use the ethyl acetate dilute reaction solution, water and saturated common salt water washing respectively again, the pressure reducing and steaming solvent gets crude product.Use silica gel column chromatography, ethyl acetate: sherwood oil (1: 1) wash-out obtains title compound (4) 96.8mg, yield 92.5%.
Its characterization parameter is:
1HNMR (300MHz, CDCl
3), δ (ppm): 7.32 (s, 2H, H
Ar), 6.79 (d, 1H, J=1.2H
ZH
Quin), 5.17 (t, 1H, J=7.80Hz ,=CH), 4.75 (m, 1H, OCH), 3.98 (s, 6H, 20CH
3), 2.45 (m, 2H, CH
2), 1.72 (s, 3H, CH
3), 1.62 (s, 3H, CH
3).
Embodiment 4
2 side chain isomers (5) of the Shikonin dimethyl ether of synthetic compound (4):
Synthetic logical method: compound (4) is dissolved in the exsiccant methylene dichloride, the DMAP and the corresponding carboxylic acid that add DCC and catalytic amount, stirring at room 24 hours, in reaction solution, add sherwood oil, filter, filtrate is through concentrating under reduced pressure, the residue silica gel column chromatography, sherwood oil: vinyl acetic monomer (4: 1) wash-out gets ester derivative (5).
Below represent with 5a～5c difference.
5,8-dimethoxy-2-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (5a), its characterization parameter is:
1H-NMR (300MHz, CDCl
3), δ ppm:7.32 (s, 2H, H
Ar), 6.66 (d, 1H, J=1.5H
ZH
Quin), 5.91 (t, 1H, J=8.1H
Z,=CH), 5.11 (t, 1H, J=7.5Hz, OCH), 3.96 (s, 6H, 20Me), 2.60 ~ 2.42 (m, 2H, CH
2), 2.11 (s, 3H, OCOCH
3), 1.67 (s, 3H, CH
3), 1.57 (s, 3H, CH
3).
5,8-dimethoxy-2-(1 '-β, beta-dimethyl-acryloxy-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (5b), its characterization parameter is:
1HNMR (300MHz, CDCl
3), δ ppm:7.30 (s, 2H, H
Ar), 6.65 (s, 1H, H
Quin), 5.91 (m, 1H ,=CH), 5.88 (s, 1H, COCH=), 5.11 (t, 1H, J=4.8Hz, OCH), 3.94 (s, 3H, OMe), 3.92 (s, 3H, OMe), 2.70 ~ 2.55 (m, 1H, CH
2a), 2.54 ~ 2.42 (m, 1H, CH
2b), 2.13 (s, 3H, CH
3), 1.90 (s, 3H, CH
3), 1.65 (s, 3H, CH
3), 1.54 (s, 3H, CH
3).
5,8-dimethoxy-2-(1 '-cinnamoyloxy group-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (5c), its characterization parameter is:
1HNMR (300MHz, CDCl
3), δ ppm:7.72 (d, IH, J=15.9Hz ,=CH-COO), 7.56 ~ 7.31 (m, 7H, 7H
Ar), 6.72 (d, 1H, J=1.2Hz, H
Quin), 6.51 (d, 1H, J=15.9Hz ,=CH-Ar), 5.91 (m, 1H ,=CH), 5.11 (m, 1H, J=7.5Hz, OCH), 3.97 (s, 3H, OMe) 3.96 (s, 3H, OMe), 2.75 ~ 2.60 (m, 1H, CH
2a), 2.58 ~ 2.49 (m, 1H, CH
2b), 1.67 (s, 3H, CH
3), 1.58 (s, 3H, CH
3).
Embodiment 5
Synthesize 5,8-dimethoxy-2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-dihydroxy naphthlene (6):
Take by weighing 100mg (0.316mmol) compound (4),, add 4 times of normal acetic acid and excessive zinc powder, room temperature reaction half an hour under nitrogen protection with anhydrous methylene chloride 10ml dissolving.Solution is become colorless by orange red, filters fast, and the filtrate water washing is used the saturated common salt water washing, anhydrous MgSO for several times again
4Drying, the pressure reducing and steaming methylene dichloride.Not purified directly next step reaction of thick product.
Embodiment 6
Synthesize 5,8-dimethoxy-2-(1 '-ethanoyl-4 '-methyl-3 '-amylene)-1,4-diacetoxy naphthalene (7):
Under nitrogen protection, the thick product of compound (6) to be dissolved among the diacetyl oxide 3ml, stirring at room drips exsiccant triethylamine 1.5ml after half an hour, continues reaction half an hour.Add ethyl acetate 10ml dilution, use 4% hydrochloric acid, water, saturated common salt water washing respectively, anhydrous magnesium sulfate drying filters the pressure reducing and steaming ethyl acetate.Thick product silica gel column chromatography, ethyl acetate: sherwood oil (1: 2) wash-out obtains faint yellow oily compound
(7) 109.2mg, two step total yields 78.2%.
Its characterization parameter is:
1H NMR (300MHz, CDCl
3), δ ppm:7.11 ~ 7.04 (m, 1H, ArH), 6.76 (s, 2H, H
Ar), 6.03 (m, 1H ,=CH), 5.05 (dd, 1H, J=7.5,1.5H
Z, CHOH), 3.83 (s, 3H, OCH
3), 3.81 (s, 3H, OCH
3), 2.58 ~ 2.43 (m, 2H, CH
2), 2.36 (s, 3H, OCOCH
3), 2.34 (s, 3H, OCOCH
3), 2.05 (s, 3H, OCOCH
3), 1.68 (s, 3H, CH
3), 1.58 (s, 3H, CH
3).
Embodiment 7
Synthesize 5,8-diacetoxy-6-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (8):
With compound (7) 100mg (0.226mmol) (be dissolved among the second eyeball 5ml, stir, splash into the ceric ammonium nitrate solution (the 615mg cerous nitrate dissolves in the 5ml water) for preparing), 25 ℃ were reacted 30 minutes.Pressure reducing and steaming second eyeball divides the reextraction residue with ethyl acetate, and combined ethyl acetate is used anhydrous MgSO
4Drying, the pressure reducing and steaming ethyl acetate.Thick product silica gel column chromatography, ethyl acetate: sherwood oil (4: 6) wash-out obtains light yellow oily compound (8) 87.9mg, yield 94.02%.
Its characterization parameter is:
1H-NMR (300MHz, CDCl
3), δ ppm:7.39 (s, 1H, ArH), 6.74 (s, 2H, H
Quin), 6.02 ~ 5.89 (m, 1H, CHOAc), 5.00 (t, J=7.2Hz, 1H ,=CH), 2.54 ~ 2.37 (m, 8H, CH
2, 2OCOCH
3), 2.03 (s, 3H, OCOCH
3), 1.64 (s, 3H, CH
3), 1.49 (s, 3H, CH
3).
Embodiment 8
Synthetic 5-methoxyl group-6-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-8-hydroxyl-1,4-naphthoquinones (9):
Compound (8) 100mg (0.242mmol) is dissolved among methyl alcohol/tetrahydrofuran (THF) (1: 1) 4ml, and-16 ℃ of temperature of reaction controls slowly add 5%Ce
2CO
3Aqueous solution 0.5ml ,-16 ℃ are continued reaction 1 hour.Add saturated ammonium chloride solution 5ml, use ethyl acetate extraction, water and saturated aqueous common salt wash ethyl acetate layer respectively, anhydrous MgSO
4Drying, the pressure reducing and steaming ethyl acetate.Thick product silica gel column chromatography, ethyl acetate: sherwood oil (1: 8) wash-out obtains light yellow oil compound (9) 37.61mg, yield 50.8%.
Its characterization parameter is:
1H-NMR (300MHz, CDCl
3), δ (ppm): 12.54 (s, 1H, Ar-OH), 7.24 (d, 2H, J=3.3H
Z, Ar-H), 6.92 (s, 1H, H
Quin), 5.91 (t, 1H, J=7.5 ,=CH), 5.41 (m, 1H, CHOH), 3.94 (s, 3H, OCH
3), 3.93 (s, 3H, OCH
3), 2.55 ~ 2.42 (m, 2H, CH
2), 1.68 (s, 3H, CH
3), 1.59 (s, 3H, CH
3).
Embodiment 9
Synthesize 5,8-dimethoxy-6-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (10):
Compound (9) 100mg (0.331mmol) is dissolved among the dry DMF 10ml, adds the KI of catalytic amount respectively, 10 times of equivalent K
2CO
3, 10 times of equivalent CH
3I, stirring reaction is 24 hours under the room temperature.Excessive K in the filtering reacting liquid
2CO
3, use the ethyl acetate dilute reaction solution, water and saturated common salt water washing respectively, anhydrous MgSO
4Drying, the pressure reducing and steaming ethyl acetate gets crude product.The crude product silica gel column chromatography, use ethyl acetate: sherwood oil (1: 3) wash-out obtains orange-yellow oily thing 96.9mg, yield 92.7%.
Its characterization parameter is:
1H-NMR (300MHz, CDCl
3), δ ppm:7.55 (s, 1H, ArH), 6.79 (d, 2H, J=3Hz, H
Quin), 5.24 (dd, 1H, J=7.5,1.2H
Z,=CH), 5.10 (t, 1H, J=5.7Hz, CHOH), 3.97 (s, 3H, OCH
3), 3.89 (s, 3H, OCH
3), 2.35 ~ 2.19 (m, 2H, CH
2), 1.76 (s, 3H, CH
3), 1.65 (s, 3H, CH
3).
Embodiment 10
The carboxylates derivatives of synthetic compound (10) i.e. is 6 side chain isomers (being structural formula II):
Synthetic logical method: compound (10) is dissolved in the exsiccant methylene dichloride, the DMAP and the corresponding carboxylic acid that add DCC and catalytic amount, stirring at room 24 hours, in reaction solution, add sherwood oil, filter, filtrate is through concentrating under reduced pressure, the residue silica gel column chromatography, sherwood oil: vinyl acetic monomer (4: 1) wash-out gets ester derivative and represents with 11a～11c difference respectively.
5,8-dimethoxy-6-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (11a), its characterization parameter is:
1H-NMR (300MHz, CDCl
3), δ ppm:7.26 (s, 1H, ArH), 6.79 (s, 2H, H
Quin), 6.16 (dd, 1H, J=7.5,5.1H
Z,=CH), 5.12 (t, 1H, J=7.8Hz, OCH), 3.97 (s, 3H, OCH
3), 3.82 (s, 3H, OCH
3), 2.63 ~ 2.41 (m, 2H, CH
2), 2.10 (s, 3H, OCOCH
3), 1.68 (s, 3H, CH
3), 1.52 (s, 3H, CH
3).
5,8-dimethoxy-6-(1 '-β, beta-dimethyl-acryloxy-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (11b), its characterization parameter is:
1H-NMR (300MHz, CDCl
3), δ ppm:7.24 (s, 1H, H
Ar), 6.78 (d, 2H, J=0.9Hz H
Quin), 5.90 (m, 1H ,=CH), 5.43 (s, 1H, COCH=), 5.13 (m, 1H, OCH), 3.94 (s, 3H, OCH
3), 3.92 (s, 3H, OCH
3), 2.53-2.43 (m, 2H, CH
2), 2.15 (s, 3H, CH
3), 1.93 (s, 3H, CH
3), 1.65 (s, 3H, CH
3), 1.54 (s, 3H, CH
3).
5,8-dimethoxy-6-(1 '-cinnamoyloxy group-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (11c), its characterization parameter is:
1H-NMR (300MHz, CDCl
3), δ ppm:7.75 (d, 1H, J=16.2Hz ,=CH-COOH), 7.58 ~ 7.20 (6H, ArH), 6.79 (s, 2H, H
Quin), 6.55 (d, 1H, J=16.2Hz ,=CH-Ar), 6.25 (dd, 1H, J=7.6,4.8H
Z, CH=), 5.19 (t, 1H, J=6.0Hz, CHOR), 3.96 (s, 3H, OCH
3), 3.94 (s, 3H, OCH
3), 2.57 (m, 2H, CH
2), 1.69 (s, 3H, CH
3), 1.56 (s, 3H, CH
3).
Claims (6)
1, a kind of synthetic method of alkannin dimethyl ether derivative, it is characterized in that, the synthetic method that comprises 2 side chain isomers and 6 side chain isomers and the ester derivative thereof of Shikonin dimethyl ether, wherein: 2 side chain isomers of Shikonin dimethyl ether and the synthetic method of ester derivative thereof, for: with the Shikonin is raw material, through acetylize, hydrolysis, methylate, acidylate makes again; 6 side chain isomers of Shikonin dimethyl ether and the synthetic method of ester derivative thereof, for: with the Shikonin is raw material, through acetylize, hydrolysis, methylate, reduction, acetylize, demethylation, hydrolysis, methylate, acidylate makes again.
2, the synthetic method of alkannin dimethyl ether derivative according to claim 1, it is characterized in that, 2 side chain isomers of Shikonin dimethyl ether and ester derivative thereof be 6 side chain isomers of structural formula I and Shikonin dimethyl ether and ester derivative thereof structural formula II as follows as follows, wherein R is H or COR ', R ' is saturated and unsaturated alkyl, the aralkyl of 1-10 carbon atom
According to the synthetic method of claim 1 or 2 described alkannin dimethyl ether derivatives, it is characterized in that 3,2 side chain isomers of described Shikonin dimethyl ether and the synthetic route of ester derivative structural formula I thereof are:
According to the synthetic method of claim 1 or 2 described alkannin dimethyl ether derivatives, it is characterized in that 4,2 side chain isomers of described Shikonin dimethyl ether and the synthetic method of ester derivative structural formula I thereof specifically comprise the steps:
1. Shikonin (1) and 15 equivalent diacetyl oxides are mixed in the anhydrous pyridine, under nitrogen protection,, obtain triacetyl Shikonin (2) in 0 ℃～5 ℃ stirring reactions 8 hours;
2. triacetyl Shikonin (2) is dissolved in methyl alcohol/tetrahydrofuran (THF) (volume ratio 4: 1), temperature of reaction is controlled below 0 ℃, slowly adds 10% K
2CO
3The aqueous solution reacted 2 hours, got 8-methoxyl group Shikonin (3);
3. 8-methoxyl group Shikonin (3) is dissolved in exsiccant N, in the dinethylformamide, the potassiumiodide that adds catalytic amount simultaneously, 10 equivalent methyl iodide, 50 equivalent Anhydrous potassium carbonates are under nitrogen protection, stirring at room reaction 24 hours, obtain 5,8-dimethoxy-2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinones;
4. with 5,8-dimethoxy-2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1, the ester derivative (structural formula I) (5) of 4-naphthoquinones (4) and respective acids 2 side chain isomers of prepared in reaction Shikonin dimethyl ether under dicyclohexylcarbodiimide (DCC) and 4-dimethylamino pyridine (DMAP) catalysis.
5, the synthetic method of alkannin dimethyl ether derivative according to claim 1 is characterized in that, 6 side chain isomers of described Shikonin dimethyl ether and the synthetic route of ester derivative structural formula II thereof are:
According to the synthetic method of claim 1 or 5 described alkannin dimethyl ether derivatives, it is characterized in that 6,6 side chain isomers of Shikonin dimethyl ether and the synthetic method of ester derivative structural formula II thereof specifically comprise the steps:
1. from Shikonin,, obtain 5 equally, 8-dimethoxy-2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (4) with four synthesis steps in claim 4 synthetic method;
2. with 5,8-dimethoxy-2-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (4) is dissolved in the anhydrous methylene chloride, successively add 4 equivalent acetate and excessive zinc powder, stirring at room reaction is 0.5 hour under nitrogen protection, and the reduzate of generation (6) is not purified to be directly used in next step reaction;
3. under nitrogen protection, reduzate (6) is directly dissolved in the excessive acetic anhydride via, splash into the exsiccant triethylamine after 0.5 hour, room temperature reaction 0.5 hour, obtain 5,8-dimethoxy-2-(1 '-ethanoyl-4 '-methyl-3 '-amylene)-1,4-diacetoxy naphthalene (7);
4. with 5,8-dimethoxy-2-(1 '-ethanoyl-4 '-methyl-3 '-amylene)-1,4-diacetoxy naphthalene (7) is dissolved in the second eyeball, fully stir, slowly splash into the ceric ammonium nitrate aqueous solution, stirring at room reaction 0.5 hour obtains 5,8-diacetoxy-6-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (8);
5. with 5,8-diacetoxy-6-(1 '-acetoxyl group-4 '-methyl-3 '-amylene)-1,4-naphthoquinones (8) are dissolved in methyl alcohol/tetrahydrofuran (THF) (volume ratio 1: 1), and temperature of reaction is controlled below 0 ℃, slowly adds 5% Ce
2CO
3The aqueous solution continues reaction 1 hour, gets 5-methoxyl group-6-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-8-hydroxyl-1,4-naphthoquinones (9);
6. with 5-methoxyl group-6-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-8-hydroxyl-1, the 4-naphthoquinones is dissolved in exsiccant N, in the dinethylformamide (or second eyeball or dimethyl sulfoxide (DMSO)), the potassiumiodide that adds catalytic amount simultaneously, 10 equivalent methyl iodide or methyl-sulfates, 10 equivalent Anhydrous potassium carbonates, the stirring at room reaction is 24 hours under the nitrogen protection, obtain 5,8-dimethoxy-6-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1,4-naphthoquinones;
7. with 5,8-dimethoxy-6-(1 '-hydroxyl-4 '-methyl-3 '-amylene)-1, the ester derivative (11) of 4-naphthoquinones (10) and respective acids 6 side chain isomers of prepared in reaction Shikonin dimethyl ether under DCC and DMAP catalysis.
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| CN101781308A (en) * | 2010-03-19 | 2010-07-21 | 上海交通大学 | Oxygen alkylated derivative of parent nucleus of alkannin naphthazarin and preparation method and application thereof |
| CN101182290B (en) * | 2007-12-13 | 2010-08-11 | 上海交通大学 | Shikonin dimethyl ether 6-site side chain isomer as well as derivatives and synthesis method thereof |
| CN101863786A (en) * | 2010-06-26 | 2010-10-20 | 上海交通大学 | Water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative and preparation and application methods thereof |
| CN102211997A (en) * | 2011-03-28 | 2011-10-12 | 上海交通大学 | Alkannin naphthazarine mother nucleus acetoxylation derivative as well as preparation method and application thereof |
| CN101683331B (en) * | 2008-09-27 | 2013-01-30 | 厦门大学 | Application of alkannin derivant |
| CN104045566A (en) * | 2013-03-14 | 2014-09-17 | 南京理工大学 | Fatty acid ester compounds of 2, 3-dihydroxymethyl-2, 3-dinitro-1, 4-butanediol and synthesis method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101182290B (en) * | 2007-12-13 | 2010-08-11 | 上海交通大学 | Shikonin dimethyl ether 6-site side chain isomer as well as derivatives and synthesis method thereof |
| CN101683331B (en) * | 2008-09-27 | 2013-01-30 | 厦门大学 | Application of alkannin derivant |
| CN101781308A (en) * | 2010-03-19 | 2010-07-21 | 上海交通大学 | Oxygen alkylated derivative of parent nucleus of alkannin naphthazarin and preparation method and application thereof |
| WO2011113284A1 (en) * | 2010-03-19 | 2011-09-22 | 上海交通大学 | Shikonin naphthazarin derivatives, preparation method and antitumor use thereof |
| CN101863786A (en) * | 2010-06-26 | 2010-10-20 | 上海交通大学 | Water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative and preparation and application methods thereof |
| CN101863786B (en) * | 2010-06-26 | 2013-05-01 | 上海交通大学 | Water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative and preparation and application methods thereof |
| CN102211997A (en) * | 2011-03-28 | 2011-10-12 | 上海交通大学 | Alkannin naphthazarine mother nucleus acetoxylation derivative as well as preparation method and application thereof |
| CN104045566A (en) * | 2013-03-14 | 2014-09-17 | 南京理工大学 | Fatty acid ester compounds of 2, 3-dihydroxymethyl-2, 3-dinitro-1, 4-butanediol and synthesis method thereof |
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