CN101367717B - Total synthesis method of despinner alkannin - Google Patents
Total synthesis method of despinner alkannin Download PDFInfo
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- CN101367717B CN101367717B CN2008101430957A CN200810143095A CN101367717B CN 101367717 B CN101367717 B CN 101367717B CN 2008101430957 A CN2008101430957 A CN 2008101430957A CN 200810143095 A CN200810143095 A CN 200810143095A CN 101367717 B CN101367717 B CN 101367717B
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- NEZONWMXZKDMKF-JTQLQIEISA-N Alkannin Chemical compound C1=CC(O)=C2C(=O)C([C@@H](O)CC=C(C)C)=CC(=O)C2=C1O NEZONWMXZKDMKF-JTQLQIEISA-N 0.000 title claims abstract description 15
- UNNKKUDWEASWDN-UHFFFAOYSA-N alkannin Natural products CC(=CCC(O)c1cc(O)c2C(=O)C=CC(=O)c2c1O)C UNNKKUDWEASWDN-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims abstract description 10
- 238000006257 total synthesis reaction Methods 0.000 title claims abstract description 8
- 239000004229 Alkannin Substances 0.000 title 1
- 235000019232 alkannin Nutrition 0.000 title 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- -1 isoamylene indium chloride Chemical compound 0.000 claims abstract description 17
- 241001071917 Lithospermum Species 0.000 claims abstract description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 11
- 239000008367 deionised water Substances 0.000 claims abstract description 11
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 11
- 150000004002 naphthaldehydes Chemical class 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 13
- 150000002790 naphthalenes Chemical class 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 10
- 238000007670 refining Methods 0.000 claims description 10
- 238000005868 electrolysis reaction Methods 0.000 claims description 8
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 7
- 238000001514 detection method Methods 0.000 claims description 6
- 239000012141 concentrate Substances 0.000 claims description 5
- 239000008151 electrolyte solution Substances 0.000 claims description 5
- MHCFAGZWMAWTNR-UHFFFAOYSA-M lithium perchlorate Chemical compound [Li+].[O-]Cl(=O)(=O)=O MHCFAGZWMAWTNR-UHFFFAOYSA-M 0.000 claims description 5
- 229910001486 lithium perchlorate Inorganic materials 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000012044 organic layer Substances 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- 229910052697 platinum Inorganic materials 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 4
- XAAHSJUYPNUEPT-UHFFFAOYSA-K [Cl-].[In+3].C=CC(C)C.[Cl-].[Cl-] Chemical compound [Cl-].[In+3].C=CC(C)C.[Cl-].[Cl-] XAAHSJUYPNUEPT-UHFFFAOYSA-K 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 abstract 2
- 238000007259 addition reaction Methods 0.000 abstract 1
- 230000007613 environmental effect Effects 0.000 abstract 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 235000004256 Buglossoides arvense Nutrition 0.000 description 6
- 241000118841 Lithospermum incisum Species 0.000 description 6
- 230000003595 spectral effect Effects 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 101100109871 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) aro-8 gene Proteins 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YHQXBTXEYZIYOV-UHFFFAOYSA-N 3-methylbut-1-ene Chemical compound CC(C)C=C YHQXBTXEYZIYOV-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 244000086443 Craterellus fallax Species 0.000 description 1
- 235000007926 Craterellus fallax Nutrition 0.000 description 1
- 206010012444 Dermatitis diaper Diseases 0.000 description 1
- 208000003105 Diaper Rash Diseases 0.000 description 1
- 206010019617 Henoch-Schonlein purpura Diseases 0.000 description 1
- 208000031814 IgA Vasculitis Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000015446 immunoglobulin a vasculitis Diseases 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cosmetics (AREA)
Abstract
The invention discloses a total synthesis method of racemate shikonin; the method can be discribed as follows: the raw material of naphthaldehyde protected by methylene reacts with N,N-dimethyl imidazolinone for 1h under the existing of isoamylene indium chloride, and acetone is steamed out, and then after the temperature is increased to reach 150-180 DEG C, the reaction lasts for 24-28h, and thereactant is cooled, diluted with deionized water, extracted with ethyl acetate, washed with water and sarutated salt water for many times, dried with anhydrous sodium sulfate for 1h, and filtered andcondensed to obtain 2-(1-hydroxide radical-4-methyl-3-pentenyl)-1,8:4, 5-bis(methylenedioxy) naphthalene which is electrolysed, condensed, extracted and refined to obtain the finished product. The invention overcomes the failure of regioselectivity addition reaction caused by water, greatly increases the probability of industrialized production, is fit for large scale preparation and particularlyis beneficial to healthy environmental protection with the overall yield of 82 percent to 89 percent.
Description
Technical field
The present invention relates to a kind of medical technical field, specifically is a kind of total synthesis method of raceme Shikonin.
Background technology
Shikonin removes has anti-inflammatory, promotes wound healing, antitumor; antibiotic, antithrombotic is outside the multiple physiologically active such as antiviral; protection liver, treatment hepatitis also there are certain curative effect, also have immunoregulation effect preferably, in AIDS preventing and controlling, demonstrated validity.The discovered in recent years Asian puccoon also can be used for treating diseases such as hepatitis virus, endocrine disturbance, anaphylactoid purpura, cervical erosion, diaper rash.In addition, Asian puccoon can also be applied in the foods and cosmetics industry as natural pigment.In the last few years, because the Asian puccoon purposes constantly widens, market potential constantly increased, and the demand of Asian puccoon is risen year by year, but its feed rate was the gesture of drop year by year.The Asian puccoon major part that present market provides is from wild, though China's Asian puccoon wild resource is than horn of plenty, along with a large amount of collections of people, at present near exhausted.Since Japanese scholar synthesizes the racemize Shikonin eighties in last century first; racemic modification to Shikonin in recent two decades has had certain progress; for the further research of Shikonin and derivative thereof is laid a good foundation; but take a broad view of these synthetic routes; the overwhelming majority is round introduce the hexa-atomic side chain unfolded of isopentene on the naphthalene nucleus of hydroxyl protection; mostly synthetic route is longer for the method for these structure side chains; the foundation of side chain is finished in have even needs seven steps reaction; all be not suitable for suitability for industrialized production; [De-Feng Xu et al such as the Xu of Shanghai Communications University; Regioselectivetransfer of the prenyl anion in the total synthesi s of (±) Shikonin; OPPI; 2008; 40 (1); 93 ~ 105] the report single stage method is introduced the side chain of six carbosilane units on the naphthaldehyde of methylene radical protection, sloughs protecting group then and gets the raceme Shikonin.The naphthaldehyde and the metallorganics that are the methylene radical protection react under certain conditions, obtain methylene radical protection Shikonin.This route is simple, yield is higher, the plain synthetic fine opportunity that provides of purple chirality natural grass is provided, but intermediary hexamethyl three phosphamides (HMAP) strong carcinogen is unfriendly to environment, and it is not very high that the metal pair zone of use is selected, yield is about 70%, and severe reaction conditions, must be anhydrous and the condition of anaerobic under react, be unfavorable for industrial production.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, provide a kind of raw material to be easy to get, synthesis step is few, and the productive rate height is environmentally friendly, and less demanding to oxygen and water, is fit to the complete synthesis preparation method of raceme Shikonin of suitability for industrialized production.
The present invention includes following steps:
(1) synthetic: under nitrogen protection and normal temperature condition, the naphthaldehyde and the N of the protection of raw material methylene radical, the N-dimethyl-imidazolinone, in the presence of isopentene indium chloride organism, reacted 1 hour, steam acetone, be warmed up to 150 ~ 180 ℃ again, reacted 24 ~ 48 hours, cooling is diluted with deionized water, use ethyl acetate extraction, water and saturated common salt are washed for several times respectively then, and anhydrous sodium sulfate drying 1 hour filters, concentrate, get 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes of 5-;
(2) electrolysis: at normal temperatures, with 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, the volume ratio that two (methylene-dioxy) naphthalenes of 5-are dissolved in acetonitrile/water is in the system of 9:1, add and have in the electrolyzer of two platinum electrodes, add 0.1M lithium perchlorate electrolytic solution simultaneously, control voltage is 2.5 ~ 3V, electrolysis 12 ~ 24 hours;
(3) concentrate extraction: concentration of reaction solution, add deionized water and ethyl acetate extraction again, merge organic layer, difference water and saturated common salt water washing several, anhydrous sodium sulfate drying obtains crude product;
(4) refining: the gained crude product is through recrystallizing methanol or to carry out post with ethyl acetate/petroleum ether refining.
Described making with extra care through recrystallizing methanol is with the dissolving of methyl alcohol reflux, adds 5% gac, refluxes 30 minutes, and filtered while hot is cooled to carry out below 0 ℃ crystallization.
It is described that to cross post refining be with the direct upper prop of crude product, with the ethyl acetate/petroleum ether volume ratio be 1:10 as moving phase, the TLC qualitative detection merges elutriant, concentrated pure product.
The invention has the beneficial effects as follows: (1) replaces metal halide organism such as zinc, copper, magnesium with isopentene indium chloride organism, overcome the failure that causes the regioselectivity addition because of water, must under the anhydrous and oxygen-free condition, carry out with respect to traditional metal organic reaction, the present invention has suitable superiority undoubtedly, has increased the possibility of suitability for industrialized production greatly.(2), with 1,3-methylimidazole ketone and acetone replace the tetrahydrofuran (THF) of deleterious hexamethyl three phosphamides and foul smelling smell as aprotic solvent respectively, and total yield brings up to 81% ~ 89%, is suitable for mass preparation, and is more conducive to health environment-friendly.
Embodiment
Embodiment 1:
(1) under nitrogen protection; in 50ml three strength bottles, drop into the naphthaldehyde (0.01mol) and the N of methylene radical protection in normal temperature; N-dimethyl-imidazolinone 5ml drips standby isopentene indium bromide organism 0.1mol with constant pressure funnel then in reaction flask, add entry 0.5ml.Reacted 1 hour, and steamed acetone.At 150 ℃, reacted 24 hours, the reaction postcooling is with deionized water 50ml dilution, extract with ethyl acetate 60x3ml, water and saturated common salt are washed for several times respectively, anhydrous sodium sulfate drying, filtering and concentrating, get the 2.80 faint yellow oily thing 2-of gram (1-hydroxy-4-methyl-3-pentenyl)-1 through column chromatography, 8:4, two (methylene-dioxy) naphthalenes of 5-, yield is 89.1%.
Spectral data is as follows:
1H NMR (300MHz, CDCl
3, δ ppm): δ 7.04 (s, 1H, H
Ar), 6.82 (s, 1H, J=3.0Hz, H
Ar), 5.59-5.53 (t, 2H, J=4.8Hz ,-OCH
2O-), 5.49-5.47 (t, 2H, J=3.6Hz ,-OCH
2O-), 5.21-5.11 (m, 2H, CHO ,-CH=), 2.53-2.35 (m, 2H ,-CH
2-), 1.73 (s, 3H ,-CH
3), 1.63 (s, 3H ,-CH
3) .MS (EI, m/e): 314[M+].
13C NMR (75MHz, CDCl
3, δ ppm): δ 144.7,144.6,144.6,140.6,136.1,125.3,119.6,115.1,114.6,109.1,108.4,107.0,92.0,91.78,68.07,37.13,26.15,18.23.
(2) electrolysis: at normal temperatures, with 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes (0.01mol) of 5-be dissolved in acetonitrile/water (V/V, 9:1,10ml).Adding has in the electrolyzer of two platinum electrodes, adds 0.1M lithium perchlorate electrolytic solution (1ml) simultaneously, and voltage control is 3V, electrolysis 24 hours.TLC detection reaction progress.
(3) after reaction finished, concentration of reaction solution added deionized water 10ml again, and ethyl acetate (10X3ml) extraction merges organic layer, respectively water and saturated common salt water washing for several times, anhydrous sodium sulfate drying obtains crude product 3.8 grams;
(4) refining: the gained crude product dissolves through 30 milliliters methyl alcohol reflux, adds 5% gac simultaneously, refluxes 30 minutes, and filtered while hot is cooled to carry out crystallization below 0 ℃, obtains the pure product of 2.6 grams.Product is the puce crystal.
The following M.p.146 of its spectral data ~ 147 ℃,
1H NMR (300MHz, CDCl
3. δ ppm): δ 12.59 (s, 1H, H
ArOH), 12.58 (s, 1H, H
ArOH), 7.19 (s, 2H, H
Ar), 7.16 (s, 1H, H
Quin), 5.20 (1H, t, J=8.1Hz ,-CH=), 4.91 (d, 1H, J=7.2Hz ,-CHO), 2.31-2.38 (m, 1H ,-CH
a), 2.62-2.66 (m, 1H ,-CH
b), 1.65 (s, 3H ,-CH
3), 1.75 (s, 3H ,-CH
3).
13C NMR (75MHz, CDCl
3. δ ppm): δ 180.6,180.1,165.7,165.1,151.5,137.7,132.5,132.3,132.0,118.6,112.3,111.7,68.6,35.1,25.2,18.3.EI-MS:m/z:288.2[M
+], 287.4[M
+-1].
Embodiment 2:
(1) under nitrogen protection; in 50ml three strength bottles, drop into the naphthaldehyde (0.01mol) and the N of methylene radical protection in normal temperature; N-dimethyl-imidazolinone (2ml) drips standby isopentene indium bromide organism (0.1mol) with constant pressure funnel then in reaction flask, add entry (0.5ml).Reacted about 1 hour, and steamed acetone.At 180 ℃, reacted 36 hours, the reaction postcooling is with deionized water (50ml) dilution, extract with ethyl acetate 60x3ml, water and saturated common salt are washed for several times respectively, anhydrous sodium sulfate drying, filtering and concentrating, get the 2.55 faint yellow oily thing 2-of gram (1-hydroxy-4-methyl-3-pentenyl)-1 through column chromatography, 8:4, two (methylene-dioxy) naphthalenes of 5-, yield is 81.2%.Spectral data is the same.
(2) electrolysis: at normal temperatures, with 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes (0.01mol) of 5-be dissolved in acetonitrile/water (V/V, 9:1,10ml).Adding has in the electrolyzer of two platinum electrodes, adds 0.1M lithium perchlorate electrolytic solution (1ml) simultaneously, and voltage control is 2.5V, reacts 24 hours.TLC detection reaction progress.
(3) the concentrated extraction: after reacting end, concentration of reaction solution adds deionized water 10ml again, ethyl acetate (10X3ml) extraction, and the merging organic layer, difference water and saturated common salt water washing several, anhydrous sodium sulfate drying obtains crude product 3.5 and restrains.
(4) refining: the gained crude product be moving phase through 200 ~ 300 order silica gel column chromatographies with ethyl acetate/petroleum ether (1:10), the direct upper prop of crude product, and the TLC qualitative detection merges elutriant, concentrated 2.8 pure product.Product is the puce crystal.Spectral data is the same.
Embodiment 3:
(1) under nitrogen protection; in 50ml three strength bottles, drop into the naphthaldehyde (0.01mol) and the N of methylene radical protection in normal temperature; N-dimethyl-imidazolinone (2ml) drips standby isopentene indium bromide organism (0.1mol) with constant pressure funnel then in reaction flask, add entry (0.5ml).Reacted about 1 hour, and steamed tetrahydrofuran (THF).At 160 ℃, reacted 26 hours, the reaction postcooling is with deionized water (50ml) dilution, extract with ethyl acetate 60x3ml, water and saturated common salt are washed for several times respectively, anhydrous sodium sulfate drying, filtering and concentrating, get the 2.74 faint yellow oily thing 2-of gram (1-hydroxy-4-methyl-3-pentenyl)-1 through column chromatography, 8:4, two (methylene-dioxy) naphthalenes of 5-, yield is 87.3%.Spectral data is the same.
(2) electrolysis: at normal temperatures, with 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes (0.01mol) of 5-be dissolved in acetonitrile/water (V/V, 9:1,10ml).Adding has in the electrolyzer of two platinum electrodes, adds 0.1M lithium perchlorate electrolytic solution (1ml) simultaneously, and voltage control is 3.0V, reacts 18 hours.TLC detection reaction progress.
(3) the concentrated extraction: after reacting end, concentration of reaction solution adds deionized water 10ml again, ethyl acetate (10X3ml) extraction, and the merging organic layer, difference water and saturated common salt water washing several, anhydrous sodium sulfate drying obtains crude product 3.2 and restrains.
(4) refining: the gained crude product dissolves through 30 milliliters methyl alcohol reflux, adds 5% gac simultaneously, refluxes 30 minutes, and filtered while hot is cooled to carry out crystallization below 0 ℃, obtains the pure product of 2.7 grams.Product is the puce crystal.Spectral data is the same.
Claims (3)
1. the total synthesis method of a raceme Shikonin is characterized in that, may further comprise the steps:
(1) synthetic: under nitrogen protection and normal temperature condition, the naphthaldehyde and the N of the protection of raw material methylene radical, the N-dimethyl-imidazolinone, in the presence of the isopentene indium chloride, reacted 1 hour, steam acetone, be warmed up to 150～180 ℃ again, reacted 24～48 hours, cooling is diluted with deionized water, use ethyl acetate extraction, water and saturated common salt are washed for several times respectively then, and anhydrous sodium sulfate drying 1 hour filters, concentrate, get 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalenes of 5-;
(2) electrolysis: at normal temperatures, with 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, the volume ratio that two (methylene-dioxy) naphthalenes of 5-are dissolved in acetonitrile/water is in the system of 9:1, add and have in the electrolyzer of two platinum electrodes, add 0.1M lithium perchlorate electrolytic solution simultaneously, control voltage is 2.5～3V, electrolysis 12～24 hours;
(3) concentrate extraction: concentration of reaction solution, add deionized water and ethyl acetate extraction again, merge organic layer, difference water and saturated common salt water washing several, anhydrous sodium sulfate drying obtains crude product;
(4) refining: the gained crude product is through recrystallization or to carry out post with ethyl acetate/petroleum ether refining.
2. the total synthesis method of a kind of raceme Shikonin according to claim 1 is characterized in that, described recrystallizing and refining is with the dissolving of methyl alcohol reflux, adds 5% gac, refluxes 30 minutes, and filtered while hot is cooled to carry out below 0 ℃ crystallization.
3. the total synthesis method of a kind of raceme Shikonin according to claim 1 is characterized in that, described post excessively is refining to be with the direct upper prop of crude product, with the ethyl acetate/petroleum ether volume ratio is that 1:10 is as moving phase, the TLC qualitative detection merges elutriant, concentrate pure product.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1686994A (en) * | 2005-04-21 | 2005-10-26 | 上海交通大学 | Total synthesis method for preparing receme alkannin |
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| CN1686994A (en) * | 2005-04-21 | 2005-10-26 | 上海交通大学 | Total synthesis method for preparing receme alkannin |
Non-Patent Citations (1)
| Title |
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| 赵立明等.异戊烯金属有机化合物与羰基化合物加成的区域选择性研究进展.《化学研究与应用》.2008,第20卷(第1期),第5-6页. * |
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