CN103819315B - New crystal of a kind of trans-resveratrol three methyl ether and preparation method thereof - Google Patents
New crystal of a kind of trans-resveratrol three methyl ether and preparation method thereof Download PDFInfo
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- CN103819315B CN103819315B CN201410068782.2A CN201410068782A CN103819315B CN 103819315 B CN103819315 B CN 103819315B CN 201410068782 A CN201410068782 A CN 201410068782A CN 103819315 B CN103819315 B CN 103819315B
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- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 title claims abstract description 67
- 235000018991 trans-resveratrol Nutrition 0.000 title claims abstract description 66
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 title claims abstract description 64
- 239000013078 crystal Substances 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 35
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims abstract description 20
- 235000014493 Crataegus Nutrition 0.000 claims abstract description 16
- 241001092040 Crataegus Species 0.000 claims abstract description 16
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 15
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 11
- CCAWDIFJOBKBSE-UHFFFAOYSA-N 1-(chloromethyl)-3,5-dimethoxybenzene Chemical compound COC1=CC(CCl)=CC(OC)=C1 CCAWDIFJOBKBSE-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 230000015572 biosynthetic process Effects 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 8
- AIZMKIXPKFKGLB-UHFFFAOYSA-N COC1=CC(=CC(=C1)COP(=O)(OC)OC)OC Chemical compound COC1=CC(=CC(=C1)COP(=O)(OC)OC)OC AIZMKIXPKFKGLB-UHFFFAOYSA-N 0.000 claims description 7
- 230000006837 decompression Effects 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 4
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 238000001816 cooling Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 11
- 239000012153 distilled water Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 201000008482 osteoarthritis Diseases 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- PJANXHGTPQOBST-VAWYXSNFSA-N trans-stilbene Chemical group C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- -1 methoxy-benzyl Chemical group 0.000 description 3
- VFZRZRDOXPRTSC-UHFFFAOYSA-N 3,5-Dimethoxybenzaldehyde Chemical compound COC1=CC(OC)=CC(C=O)=C1 VFZRZRDOXPRTSC-UHFFFAOYSA-N 0.000 description 2
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- BTHIGJGJAPYFSJ-UHFFFAOYSA-N 1-(bromomethyl)-3,5-dimethoxybenzene Chemical compound COC1=CC(CBr)=CC(OC)=C1 BTHIGJGJAPYFSJ-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FKDJWPNZLPRUPO-UHFFFAOYSA-N COBrCC1=CC=CC=C1 Chemical compound COBrCC1=CC=CC=C1 FKDJWPNZLPRUPO-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 1
- 101710089543 Nitric oxide synthase, inducible Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- XCEUHXVTRJQJSR-UHFFFAOYSA-N bromo(phenyl)phosphane Chemical compound BrPC1=CC=CC=C1 XCEUHXVTRJQJSR-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012926 crystallographic analysis Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/48—Phosphonous acids [RP(OH)2] including [RHP(=O)(OH)]; Thiophosphonous acids including [RP(SH)2], [RHP(=S)(SH)]; Derivatives thereof
- C07F9/4808—Phosphonous acids [RP(OH)2] including [RHP(=O)(OH)]; Thiophosphonous acids including [RP(SH)2], [RHP(=S)(SH)]; Derivatives thereof the acid moiety containing a substituent or structure which is considered as characteristic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses new crystal of a kind of trans-resveratrol three methyl ether and preparation method thereof.In this crystal form X-ray powder diffraction
angle of diffraction has characteristic peak at 15.3 ± 0.2,16.7 ± 0.2,17.2 ± 0.2,17.6 ± 0.1,19.9 ± 0.1,20.1 ± 0.1,22.4 ± 0.2,24.4 ± 0.2,25.6 ± 0.2,27.9 ± 0.1 degree of places.The method is 3,5-dimethoxy benzyl chlorine, trimethyl phosphite reacts in a heated condition, obtains residual reaction liquid after reacting completely; Then add DMSO, aubepine, after cooling, add KOH, add DMF after question response is complete, be warmed up to 40 ~ 60 DEG C, be incubated 0.5 ~ 1.5 hour, then be cooled to 10 ~ 15 DEG C of crystallizatioies, be washed to neutrality, dry obtained.New crystal trans-resveratrol three methyl ether fusing point of the present invention is high, easily dries, has good anti-tumor activity.
Description
Technical field
The invention belongs to chemosynthesis medical art, relate to new crystal of a kind of trans-resveratrol three methyl ether and preparation method thereof.
Technical background
Trans-resveratrol three methyl ether, chemistry trans-3,4', 5-trimethoxy toluylene by name, CAS No.:[22255-22-7], molecular formula: C
17h
18o
3, molecular weight: 270.32, structure is shown below:
Trans-resveratrol three methyl ether is the methylated derivative of trans-resveratrol, has obvious anti-new vascular generation, antimitotic effect, can significantly cause microtubule to decompose and tubulin depolymerization, for antineoplaston; Trans-resveratrol three methyl ether has antianaphylaxis, protection gastric mucosa injury and anti-aging effects; In addition, trans-resveratrol three methyl ether has similar anti-inflammatory effect to trans-resveratrol, both all can improve the state of an illness of osteoarthritis, trans-resveratrol three methyl ether reaches antiphlogistic effects by suppressing NF-κ B, though its mechanism of action of directly treating osteoarthritis has no report, but it can reduce the level of nitrogen protoxide (NO) in synovial fluid in rabbits with osteoarthritis and serum and iNOS, thus suppress generation and the development of osteoarthritis, therefore, trans-resveratrol three methyl ether may be a kind of potential osteoarthritis treatment medicine.
The preparation of trans-resveratrol three methyl ether, bibliographical information mainly contains 2 class methods, method 1: will react methoxybenzyl bromine and triphenylphosphine (or triethyl-phosphite) and generate methoxy-benzyl three phenyl phosphonium bromide (or to methoxy-benzyl diethyl phosphonate), again with 3,5-dimethoxy benzaldehyde is through Wittig(or Wittig-Horner) react 3 of generation cis-trans isomerism, 4', 5-trimethoxy toluylene, trans-3 are obtained finally by methods such as column chromatographies, 4', 5-trimethoxy toluylene, i.e. trans-resveratrol three methyl ether; Method 2: 3,5-dimethoxybenzyl bromide and triethyl-phosphite are reacted generation 3,5-dimethoxy-benzyl diethyl phosphonate, obtained trans-3 are reacted through Wittig-Horner again with aubepine, 4', 5-trimethoxy toluylene, i.e. trans-resveratrol three methyl ether.
Trans-resveratrol three methyl ether that two class methods of above-mentioned bibliographical information are obtained, before obtaining sterling, is viscous liquid or the mixture that there is cis-trans isomerism, and aftertreatment bothers; Obtaining sterling is Powdered substantially, and fusing point, between 47-57 DEG C, is not easily dried, less stable.
Summary of the invention
The object of the invention is for the deficiencies in the prior art, provide a kind of new crystal of trans-resveratrol three methyl ether.
The crystal formation I of trans-resveratrol three methyl ether of the present invention, in this crystal form X-ray powder diffraction, 2 θ angle of diffraction have characteristic peak at 15.3 ± 0.2,16.7 ± 0.2,17.2 ± 0.2,17.6 ± 0.1,19.9 ± 0.1,20.1 ± 0.1,22.4 ± 0.2,24.4 ± 0.2,25.6 ± 0.2,27.9 ± 0.1 degree of places.
Further, in this crystal form X-ray powder diffraction, 2 θ angle of diffraction also have characteristic peak at 12.6 ± 0.1,12.8 ± 0.1,13.5 ± 0.2,21.8 ± 0.2,23.0 ± 0.2,26.1 ± 0.2,27.3 ± 0.1,29.9 ± 0.2 degree of places.
Further, in this crystal form X-ray powder diffraction, 2 θ angle of diffraction also have characteristic peak at 5.7 ± 0.2,12.2 ± 0.2,14.0 ± 0.2,27.1 ± 0.1,28.1 ± 0.1,28.8 ± 0.2,29.2 ± 0.1,31.7 ± 0.2,32.2 ± 0.2,33.6 ± 0.2,34.4 ± 0.2,35.5 ± 0.2,35.9 ± 0.1,36.1 ± 0.1 degree of places.
Wherein, in this crystal formation differential scanning calorimetric analysis, there is an endotherm(ic)peak at 55.14 ± 0.5 DEG C of places, and 64.85 DEG C of places are fusion and decomposition peak.
Wherein, the fusing point of this crystal formation is at 62.2 ~ 64.9 DEG C.
Closer, in this crystal form X-ray powder diffraction, the relative intensity value of 2 θ angle of diffraction characteristic peaks is:
The X-ray powder diffraction pattern characterization data of table 1 trans-resveratrol three methyl ether new crystal
Another object of the present invention there is provided the preparation method of above-mentioned trans-resveratrol three methyl ether new crystal I.
For solving the problems of the technologies described above, the inventive method comprises the following steps:
Step (1) .3,5-dimethoxy benzyl chlorine and trimethyl phosphite react in a heated condition, after TLC tracks to and reacts completely, reclaim excessive trimethyl phosphite, obtain the residual reaction liquid containing 3,5-dimethoxy-benzyl dimethyl phosphate.
In step (1), the ratio of the amount of substance of 3,5-dimethoxy benzyl chlorine and trimethyl phosphite is 1:1.5 ~ 4, is preferably 1:2;
In step (1), reacting by heating temperature is 130 ~ 150 DEG C, is preferably 140 ± 5 DEG C.
Step (2). in step (1) residual reaction liquid, add solvent dimethyl sulfoxide (DMSO) DMSO, aubepine, water-bath is cooled to 5 ~ 10 DEG C, start to add KOH after temperature-stable in batches, maintain temperature of reaction 10 ~ 15 DEG C, after TLC tracks to and reacts completely, add dimethyl formamide DMF, be warmed up to 40 ~ 60 DEG C, be incubated 0.5 ~ 1.5 hour, then be cooled to 10 ~ 15 DEG C of crystallizatioies, crystal water is washed till neutrality, dries obtained trans-resveratrol three methyl ether.
In step (2), the consumption of aubepine is 0.9 ~ 1.2 times of the amount of substance of 3,5-dimethoxy benzyl chlorine in step (1), is preferably 0.92 times;
In step (2), the consumption of dimethyl sulfoxide (DMSO) is 1 ~ 1.5 times of aubepine quality, is preferably 1 times;
In step (2), the mass ratio of dimethyl formamide and dimethyl sulfoxide (DMSO) is 1:1;
In step (2), the consumption of KOH is 1.2 ~ 1.8 times of the amount of substance of 3,5-dimethoxy benzyl chlorine in step (1), is preferably 1.5 times; Wherein, add that each amount is total amount 1/10 in batches, every minor tick 20 minutes.
In step (2), the mode of oven dry is preferably decompression drying, and temperature is preferably 45 ~ 50 DEG C.
Adopt preparation method of the present invention directly can obtain white crystalline solid, the height that fusing point is prepared than ordinary method, easily dry; The crystal compound of trans-resveratrol three methyl ether of the present invention has good anti-tumor activity.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern (X-coordinate: diffraction angle 2 θ (degree), ordinate zou: relative intensity (CPS)) of trans-resveratrol three methyl ether new crystal;
Fig. 2 is the DSC curve (X-coordinate: temperature (DEG C), ordinate zou: hot-fluid (W/g)) of trans-resveratrol three methyl ether new crystal;
Fig. 3 is the infrared spectrum (X-coordinate: wave number (cm of trans-resveratrol three methyl ether new crystal
-1), ordinate zou: transmittance (﹪));
Fig. 4 is trans-resveratrol three methyl ether new crystal
1h-NMR spectrogram (X-coordinate: chemical shift);
Fig. 5 is the ORTEP(ray crystallographic analysis of trans-resveratrol three methyl ether new crystal) figure.
Embodiment
Below in conjunction with embodiment, the invention will be further described, but protection scope of the present invention is not limited in this.
Embodiment 1: the preparation of trans-resveratrol three methyl ether
3 are added in 250ml tetra-neck flask, 5-dimethoxy benzyl chlorine 40g(0.214mol), trimethyl phosphite 54g(0.428mol), be heated to oil bath temperature 140 DEG C, TLC follows the tracks of reaction, reacts completely after about 24h, uses water pump (oil bath temperature is at about 120 DEG C), lobe pump (oil bath temperature is at about 120 DEG C) reclaim under reduced pressure to remove trimethyl phosphite respectively, the residual reaction liquid obtained containing 3,5-dimethoxy-benzyl dimethyl phosphate is about 57g.
DMSO27g, aubepine 26.9g(0.198mol is added in 57g residual reaction liquid), water-bath is cooled to 10 DEG C, starts to add KOH after temperature-stable, adds about 2g at every turn, within about 20 minutes, adds once, adds common 19g(0.339mol).Maintain temperature of reaction 10 DEG C, have solid to separate out in reaction process gradually, TLC follows the tracks of reaction, after reacting completely, add 27g DMF, be warmed up to 50 DEG C, be incubated 1 hour, be cooled to 10 DEG C, crystallize out, slowly add 10 ~ 25 DEG C of distilled water of 100ml, stir 1 hour at 10 ~ 25 DEG C, suction filtration, filter cake wash with water to pH value be 7, gained white crystalline solid and product, decompression drying at 50 DEG C, obtained trans-resveratrol three methyl ether 52g, yield 90.0 ﹪, fusing point: 62.2 ~ 64.9 DEG C.
Trans-resveratrol front three ether structure characterizes:
(1) X-ray powder diffraction (XRD) characterizes, and sees Fig. 1:
Instrument: Rigaku D/Max-2550PC;
Test condition: power 40Kv*250mA, 2 θ angle of diffraction sweep limits 3 ~ 40., walk wide (stepwidth) 0.02.；
Scan mode: continuous sweep.
In this crystal form X-ray powder diffraction, the relative intensity value of 2 θ angle of diffraction characteristic peaks is as shown in table 1.
(2) means of differential scanning calorimetry (DSC) characterizes, and sees Fig. 2:
Instrument: TA company DSC Q100;
Test condition: 50mL/min N
2protection, 10 DEG C/min, heating rate, 30 ~ 200 DEG C of temperature ranges;
As seen from Figure 2, there is an endotherm(ic)peak at 55.14 DEG C of places, and 64.85 DEG C of places are fusion and decomposition peak.
(3) nuclear-magnetism (
1h-NMR) characterize, see Fig. 4:
Instrument: 400,000,000 nuclear magnetic resonance analyser (BRUKER company of Switzerland)
Model: ADVANCE2B/400MHZ
1H-NMR(CDCl
3)δ：3.80(9H,s),6.37(1H,s),6.64(2H,s),6.87-7.05(4H,m),7.42-7.44(2H,d)。
(4) infrared spectra, see Fig. 3:
Instrument: BRUKER VECTOR22 infrared spectrometer;
Absorption peak is (cm
-1):
1587,1512,1470,1426,1322,1309,1275,1255,1237,1199,1175,1151,1062,1032,988,963,826,793,771,672,638；
(5) ORTEP of trans-resveratrol three methyl ether new crystal I as shown in Figure 5.
Embodiment 2: the preparation of trans-resveratrol three methyl ether
Change the consumption of trimethyl phosphite into 40.5g(0.321mol), remaining reaction condition, with embodiment 1, obtains trans-resveratrol three methyl ether 48g, yield 83.1 ﹪.
Embodiment 3: the preparation of trans-resveratrol three methyl ether
Change the consumption of trimethyl phosphite into 108g(0.857mol), remaining reaction condition, with embodiment 1, obtains trans-resveratrol three methyl ether 52.2g, yield 90.3 ﹪.
Embodiment 4: the preparation of trans-resveratrol three methyl ether
Change the consumption of aubepine into 29.2g(0.215mol), remaining reaction condition, with embodiment 1, obtains trans-resveratrol three methyl ether 52.1g, yield 90.2 ﹪.
Embodiment 5: the preparation of trans-resveratrol three methyl ether
Change the consumption of solvent DMSO into 40.5g, DMF consumption is 40.5g, and remaining reaction condition, with embodiment 1, obtains trans-resveratrol three methyl ether 52g, yield 90.0 ﹪.
Embodiment 6: the preparation of trans-resveratrol three methyl ether
Change the consumption of KOH into 14.5g(0.259mol), remaining reaction condition, with embodiment 1, obtains trans-resveratrol three methyl ether 46.7g, yield 80.8 ﹪.
Embodiment 7: the preparation of trans-resveratrol three methyl ether
Change the consumption of KOH into 21.5g(0.384mol), remaining reaction condition, with embodiment 1, obtains trans-resveratrol three methyl ether 51.8g, yield 89.7 ﹪.
Embodiment 8: the preparation of trans-resveratrol three methyl ether
3 are added in four neck flasks, 5-dimethoxy benzyl chlorine 100g(0.536mol), trimethyl phosphite 135g(1.072mol), be heated to oil bath temperature 135 DEG C, TLC follows the tracks of reaction, reacts completely after about 24h, uses water pump (oil bath temperature is at about 120 DEG C), lobe pump (oil bath temperature is at about 120 DEG C) reclaim under reduced pressure to remove trimethyl phosphite respectively, obtain the residual reaction liquid containing 3,5-dimethoxy-benzyl dimethyl phosphate.
DMSO66.8g, aubepine 66.8g(0.491mol is added in residual reaction liquid), water-bath is cooled to 5 DEG C, starts to add KOH after temperature-stable, adds about 4.5g at every turn, within about 20 minutes, adds once, adds common 45g(0.803mol).Maintain temperature of reaction 15 DEG C, have solid to separate out in reaction process gradually, TLC follows the tracks of reaction, after reacting completely, add 66.8g DMF, be warmed up to 40 DEG C, be incubated 1.5 hours, be cooled to 10 DEG C, crystallize out, slowly add 10 ~ 25 DEG C of distilled water of 100ml, stir 1 hour at 10 ~ 25 DEG C, suction filtration, filter cake wash with water to pH value be 7, gained white crystalline solid and product, decompression drying at 45 DEG C, obtained trans-resveratrol three methyl ether 131g, yield 90.5 ﹪.
Embodiment 9: the preparation of trans-resveratrol three methyl ether
3 are added in four neck flasks, 5-dimethoxy benzyl chlorine 100g(0.536mol), trimethyl phosphite 101.3g(0.804mol), be heated to oil bath temperature 145 DEG C, TLC follows the tracks of reaction, reacts completely after about 24h, uses water pump (oil bath temperature is at about 120 DEG C), lobe pump (oil bath temperature is at about 120 DEG C) reclaim under reduced pressure to remove trimethyl phosphite respectively, obtain the residual reaction liquid containing 3,5-dimethoxy-benzyl dimethyl phosphate.
DMSO98.3g, aubepine 65.5g(0.482mol is added in residual reaction liquid), water-bath is cooled to 8 DEG C, starts to add KOH after temperature-stable, adds about 4g at every turn, within about 20 minutes, adds once, adds common 40g(0.714mol).Maintain temperature of reaction 12 DEG C, have solid to separate out in reaction process gradually, TLC follows the tracks of reaction, after reacting completely, add 98.3g DMF, be warmed up to 60 DEG C, be incubated 0.5 hour, be cooled to 15 DEG C, crystallize out, slowly add 10 ~ 25 DEG C of distilled water of 100ml, stir 1 hour at 10 ~ 25 DEG C, suction filtration, filter cake wash with water to pH value be 7, gained white crystalline solid and product, decompression drying at 46 DEG C, obtained trans-resveratrol three methyl ether 128.8g, yield 89 ﹪.
Embodiment 10: the preparation of trans-resveratrol three methyl ether
3 are added in four neck flasks, 5-dimethoxy benzyl chlorine 50g(0.268mol), trimethyl phosphite 135g(1.072mol), be heated to oil bath temperature 130 DEG C, TLC follows the tracks of reaction, reacts completely after about 24h, uses water pump (oil bath temperature is at about 120 DEG C), lobe pump (oil bath temperature is at about 120 DEG C) reclaim under reduced pressure to remove trimethyl phosphite respectively, obtain the residual reaction liquid containing 3,5-dimethoxy-benzyl dimethyl phosphate.
DMSO52.5g, aubepine 43.8g(0.322mol is added in residual reaction liquid), water-bath is cooled to 10 DEG C, starts to add KOH after temperature-stable, adds about 2.7g at every turn, within about 20 minutes, adds once, adds common 27g(0.482mol).Maintain temperature of reaction 10 DEG C, have solid to separate out in reaction process gradually, TLC follows the tracks of reaction, after reacting completely, add 52.5g DMF, be warmed up to 50 DEG C, be incubated 1 hour, be cooled to 12 DEG C, crystallize out, slowly add 10 ~ 25 DEG C of distilled water of 100ml, stir 1 hour at 10 ~ 25 DEG C, suction filtration, filter cake wash with water to pH value be 7, gained white crystalline solid and product, decompression drying at 48 DEG C, obtained trans-resveratrol three methyl ether 63g, yield 87.1 ﹪.
Embodiment 11: the preparation of trans-resveratrol three methyl ether
3 are added in four neck flasks, 5-dimethoxy benzyl chlorine 50g(0.268mol), trimethyl phosphite 135g(1.072mol), be heated to oil bath temperature 150 DEG C, TLC follows the tracks of reaction, reacts completely after about 24h, uses water pump (oil bath temperature is at about 120 DEG C), lobe pump (oil bath temperature is at about 120 DEG C) reclaim under reduced pressure to remove trimethyl phosphite respectively, obtain the residual reaction liquid containing 3,5-dimethoxy-benzyl dimethyl phosphate.
DMSO52.5g, aubepine 43.8g(0.322mol is added in residual reaction liquid), water-bath is cooled to 10 DEG C, starts to add KOH after temperature-stable, adds about 2.4g at every turn, within about 20 minutes, adds once, adds common 24g(0.429mol).Maintain temperature of reaction 10 DEG C, have solid to separate out in reaction process gradually, TLC follows the tracks of reaction, after reacting completely, add 52.5g DMF, be warmed up to 50 DEG C, be incubated 0.5 hour, be cooled to 12 DEG C, crystallize out, slowly add 10 ~ 25 DEG C of distilled water of 100ml, stir 1 hour at 10 ~ 25 DEG C, suction filtration, filter cake wash with water to pH value be 7, gained white crystalline solid and product, decompression drying at 50 DEG C, obtained trans-resveratrol three methyl ether 63.2g, yield 87.3 ﹪.
Embodiment 12: trans-resveratrol three methyl ether is tested the restraining effect of tumour cell
Non-small cell lung carcinoma cell line A549 with containing 10 ﹪ foetal calf serums DMEM nutrient solution in, at 37 DEG C, 5 ﹪ CO
2cultivate under condition.Get and be in logarithmic phase cell, conventional trysinization, be inoculated in 96 orifice plates, every hole 8 × 10
3individual cell, often multiple 4, the hole of group.Add trans-resveratrol three methyl ether that concentration is 10^-7mol/L, 10^-6mol/L, 10^-5mol/L, 10^-4mol/L after 24h respectively, and establish blank.Continue to cultivate 24h, MTT dyeing, under microplate reader 490nm wavelength, measure OD value, calculate the inhibiting rate of cell proliferation: inhibiting rate (﹪)=(OD value control wells-OD is worth dosing holes)/OD value control wells × 100 ﹪; According to each control of the concentration rate, adopt LOGIT method calculation of half inhibitory concentration IC
50.Result is as shown in table 2, shows that trans-resveratrol three methyl ether suppresses better.
Table 2 trans-resveratrol three methyl ether is to Non-small cell lung carcinoma cell inhibitory rate, IC
50
Above-described embodiment is not that the present invention is not limited only to above-described embodiment for restriction of the present invention, as long as meet application claims, all belongs to protection scope of the present invention.
Claims (10)
1. a crystal formation for trans-resveratrol three methyl ether, in this crystal form X-ray powder diffraction, 2 θ angle of diffraction have characteristic peak at 15.3 ± 0.2,16.7 ± 0.2,17.2 ± 0.2,17.6 ± 0.1,19.9 ± 0.1,20.1 ± 0.1,22.4 ± 0.2,24.4 ± 0.2,25.6 ± 0.2,27.9 ± 0.1 degree of places.
2. the crystal formation of a kind of trans-resveratrol three methyl ether as claimed in claim 1, it is characterized in that, in this crystal form X-ray powder diffraction, 2 θ angle of diffraction also have characteristic peak at 12.6 ± 0.1,12.8 ± 0.1,13.5 ± 0.2,21.8 ± 0.2,23.0 ± 0.2,26.1 ± 0.2,27.3 ± 0.1,29.9 ± 0.2 degree of places.
3. the crystal formation of a kind of trans-resveratrol three methyl ether as claimed in claim 2, it is characterized in that, in this crystal form X-ray powder diffraction, 2 θ angle of diffraction also have characteristic peak at 5.7 ± 0.2,12.2 ± 0.2,14.0 ± 0.2,27.1 ± 0.1,28.1 ± 0.1,28.8 ± 0.2,29.2 ± 0.1,31.7 ± 0.2,32.2 ± 0.2,33.6 ± 0.2,34.4 ± 0.2,35.5 ± 0.2,35.9 ± 0.1,36.1 ± 0.1 degree of places.
4. the crystal formation of a kind of trans-resveratrol three methyl ether as claimed in claim 3, is characterized in that:
This crystal form X-ray powder diffraction pattern characterizes as follows:
5. the crystal formation of a kind of trans-resveratrol three methyl ether as claimed in claim 1, is characterized in that the fusing point of this crystal formation is at 62.2 ~ 64.9 DEG C.
6. prepare the method for a kind of trans-resveratrol three methyl ether crystal formation as claimed in claim 1, it is characterized in that the method comprises the following steps:
Step (1) .3,5-dimethoxy benzyl chlorine and trimethyl phosphite react in a heated condition, after TLC tracks to and reacts completely, reclaim excessive trimethyl phosphite, obtain the residual reaction liquid containing 3,5-dimethoxy-benzyl dimethyl phosphate;
In step (1), the ratio of the amount of substance of 3,5-dimethoxy benzyl chlorine and trimethyl phosphite is 1:1.5 ~ 4;
In step (1), reacting by heating temperature is 130 ~ 150 DEG C;
Step (2). in step (1) residual reaction liquid, add dimethyl sulfoxide (DMSO), aubepine, water-bath is cooled to 5 ~ 10 DEG C, start to add KOH after temperature-stable in batches, maintain temperature of reaction 10 ~ 15 DEG C, after TLC tracks to and reacts completely, add dimethyl formamide, be warmed up to 40 ~ 60 DEG C, be incubated 0.5 ~ 1.5 hour, then be cooled to 10 ~ 15 DEG C of crystallizatioies, crystal water is washed till neutrality, dries obtained trans-resveratrol three methyl ether;
In step (2), the consumption of aubepine is 0.9 ~ 1.2 times of the amount of substance of 3,5-dimethoxy benzyl chlorine in step (1);
In step (2), the consumption of dimethyl sulfoxide (DMSO) is 1 ~ 1.5 times of aubepine quality;
In step (2), the mass ratio of dimethyl formamide and dimethyl sulfoxide (DMSO) is 1:1;
In step (2), total consumption of KOH is 1.2 ~ 1.8 times of the amount of substance of 3,5-dimethoxy benzyl chlorine in step (1); Wherein, add that each amount is total amount 1/10 in batches, every minor tick 20 minutes.
7. the preparation method of a kind of trans-resveratrol three methyl ether crystal formation as claimed in claim 6, it is characterized in that the ratio of the amount of substance of 3,5-dimethoxy benzyl chlorine and trimethyl phosphite in step (1) is 1:2, reacting by heating temperature is 140 ± 5 DEG C.
8. the preparation method of a kind of trans-resveratrol three methyl ether crystal formation as claimed in claim 6, is characterized in that the consumption of step (2) aubepine is 0.92 times of the amount of substance of 3,5-dimethoxy benzyl chlorine in step (1); The consumption of dimethyl sulfoxide (DMSO) is 1 times of aubepine quality.
9. the preparation method of a kind of trans-resveratrol three methyl ether crystal formation as claimed in claim 6, is characterized in that total consumption of KOH in step (2) is 1.5 times of the amount of substance of 3,5-dimethoxy benzyl chlorine in step (1); Wherein, add that each amount is total amount 1/10 in batches, every minor tick 20 minutes.
10. the preparation method of a kind of trans-resveratrol three methyl ether crystal formation as claimed in claim 6, it is characterized in that the mode of drying in step (2) is decompression drying, temperature is 45 ~ 50 DEG C.
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