CN103102254A - Pterostilbene synthesis method - Google Patents
Pterostilbene synthesis method Download PDFInfo
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- CN103102254A CN103102254A CN201310047013XA CN201310047013A CN103102254A CN 103102254 A CN103102254 A CN 103102254A CN 201310047013X A CN201310047013X A CN 201310047013XA CN 201310047013 A CN201310047013 A CN 201310047013A CN 103102254 A CN103102254 A CN 103102254A
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/14—Styryl dyes
- C09B23/148—Stilbene dyes containing the moiety -C6H5-CH=CH-C6H5
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
Abstract
The invention discloses a pterostilbene synthesis method which comprises the following steps: by taking p-hydroxy benzaldehyde as a raw material, reacting the p-hydroxy benzaldehyde with triphenylchloromethane, and obtaining p-triphenylmethyl benzaldehyde; by taking 3,5-dimethoxybenzhydrol as a raw material, performing triphosgene chloride, esterifying the chloride through trimethyl phosphate, and obtaining 3,5-dimethoxy dimethyl benzylphosphonate, carrying out a reaction on the p-triphenylmethyl benzaldehyde and 3,5-dimethoxy dimethyl benzylphosphonate to prepare a pterostilbene intermediate through Witting-Horner, and performing detritylation on the pterostilbene intermediate to obtain pterostilbene under acid conditions. The invention provides a novel synthesis route for pterostilbene synthesis. The method is cheap and readily available in raw materials, high in yield, mild in reaction conditions, fewer in three wastes and high in yield and can be suitable for industrial production, and the used solvent can be recycled.
Description
Technical field
The invention belongs to medicine and synthesize the field, be specifically related to the synthetic method of a kind of Pterostilene.
Background technology
Pterostilene, chemical name: (E)-3, the 5-dimethoxy-4 ' '-hydroxy stibene, have another name called: Pterostilene, English name: Pterostilbene, No. CAS: 537-42-8, molecular formula: C
16H
16O
3, molecular weight: 256.30, chemical structural formula is as follows:
Pterostilene is a kind of chemical composition contained in red sandalwood, but scientist has also found the existence of Pterostilene in succession in other plant, but because it is found in red sandalwood first, Gu the called after Pterostilene.Pterostilene is white or off-white powder crystallization, and abundant pharmaceutical use is arranged, and belongs to the Active antifungal compound in blood product, for the treatment of cancer, hypertension, hyperlipidemia, certain effect is arranged.Pterostilene belongs to polyhydroxystilbene compounds, is the homologue of trans-resveratrol, its pharmacological action except to trans-resveratrol have part similar, also have stronger anti-mycotic activity, its anti-mycotic activity is five times of trans-resveratrol.
At present, the acquisition of Pterostilene has three kinds of modes, and a kind of is plant extract, and a kind of is biosynthesizing, and a kind of is chemosynthesis.
Lu Wenjie etc. (Acta Pharmaceutica Sinica 33:755-758,1998) have reported from Dracaena cochinchinensis timber and have extracted Pterostilene.
Chinese patent application CN201010582548.3(publication number CN102120996A) reported the biological synthesis process of a kind of Pterostilene, namely adopt grape resveratrol-chlB5 catalysis trans-resveratrol to prepare Pterostilene, be specially: according to the Chinese wild grape East China grape ROMT gene est sequence that obtains, utilize 5 ' and 3 ' RACE full-length gene clone technology clone grape ROMT gene, this gene open reading frame total length is 1074bp; Clone's grape STS and ROMT can change in the model plant tobacco simultaneously, utilize tobacco plant to analyze the biosynthetic pathway that grape ROMT catalysis trans-resveratrol generates Pterostilene, for orientation obtains a grape ROMT gene order, this ROMT gene can generate Pterostilene by the catalysis trans-resveratrol in transgene tobacco, provide ROMT gene order and method for utilizing the phytosynthesis Pterostilene; The method is take trans-resveratrol as raw material, and production cost is high.
Chinese patent application CN200310111885.4(publication number CN1539805A) reported the chemical synthesis process of a kind of Pterostilene, namely adopting para-nitrotoluene and 3,5-dimethoxy benzaldehyde is raw material, through condensation, and reduction, diazotization, hydrolysis obtains product; Comprise the steps: that specifically 3,5-dimethoxy benzaldehyde, para-nitrotoluene and sodium methylate reaction make 3,5-dimethoxy-4 ' '-nitro diphenyl ethylene; Obtain 3 with hydrazine hydrate, gac and Lewis acid reaction again, 5-dimethoxy-4 '-amino-stilbene, then be dissolved in appropriate organic solvent, add sulfuric acid, stir, slowly drip mass concentration and be 10%～30% sodium nitrite solution under cryosel bath condition, make the diazonium salt of 3,5-dimethoxy-toluylene; The diazonium salt hydrolysis of 3,5-dimethoxy-toluylene obtains target compound.The yield of the method target product is lower, and cost is high, and products obtained therefrom is second-rate, is not suitable for industrialization.
Chinese patent application CN200510118277.5(publication number CN1955153A) synthetic method of a kind of Pterostilene is disclosed; the method is with 3; 5-dimethoxy-benzyl chloride and p-Hydroxybenzaldehyde or with 3; 5-dimethoxy benzaldehyde and p-Hydroxybenzylalcohol (first chloro after the protection); through adopting protection 4 '-hydroxyl and the way of making phosphonate reagent; carry out Wei Tixi-Huo Naer (WITTIG-HORNER) reaction, then get Pterostilene through hydrolysis or cracking.The yield of the method target product is very low, is not suitable for industrialization.
Summary of the invention
The synthetic method that the purpose of this invention is to provide a kind of Pterostilene is for Pterostilene synthetic provides a kind of new synthetic route.
The present invention is take p-Hydroxybenzaldehyde as raw material, by reacting with triphenylmethyl chloride, obtain the triphen methoxybenzaldehyde, again with 3, the 5-3,5-dimethoxybenzoic alcohol is raw material, by the triphosgene chlorination, the gained muriate is again with the trimethyl phosphite esterification, obtain 3,5-dimethoxy benzene dimethyl methyl phosphonate, to react by Witting-Horner triphen methoxybenzaldehyde and 3,5-dimethoxy benzene dimethyl methyl phosphonate and obtain the Pterostilene intermediate, this Pterostilene intermediate detritylation under acidic conditions will namely be got Pterostilene.Synthetic route of the present invention as shown in Figure 1.
The synthetic method of Pterostilene provided by the invention is specific as follows:
The synthetic method of a kind of Pterostilene comprises the steps:
Step (1): with the triphenylmethyl chloride shown in the p-Hydroxybenzaldehyde shown in the formula I and formula II reaction, obtain shown in the formula III to the triphen methoxybenzaldehyde;
Step (2): with 3 shown in the formula IV, 5-3,5-dimethoxybenzoic alcohol and triphosgene are carried out chlorination reaction, obtain 3 shown in the formula V, 5-dimethoxy benzyl chlorine, again with 3,5-dimethoxy benzyl chlorine and trimethyl phosphite carry out esterification, obtain 3 shown in the formula VI, 5-dimethoxy benzene dimethyl methyl phosphonate;
Step (3): will react the Pterostilene intermediate that obtains shown in the formula VII by Witting-Horner to triphen methoxybenzaldehyde and 3,5-dimethoxy benzene dimethyl methyl phosphonate;
Step (4): the Pterostilene intermediate shown in the formula VII is carried out trityl removal reaction under acidic conditions, obtain Pterostilene.
Adopt said synthesis route of the present invention, can successfully prepare Pterostilene, for Pterostilene synthetic provides a kind of new synthetic route.
Formula I formula II formula III formula IV formula V
Formula VI formula VII
In each step reaction of the present invention, the consumption between each raw material is not had strict restriction, generally get final product than being that mol ratio 1:1 or part material are excessive by the chemical reaction equation metering.Consider from economizing in raw materials, improve the industrial point of view such as yield, preferred:
In step (1), the mol ratio of p-Hydroxybenzaldehyde and triphenylmethyl chloride is 1:1～2, more preferably 1:1～1.2.
In step (2), the mol ratio of 3,5-3,5-dimethoxybenzoic alcohol and triphosgene is 1:0.34～3, and more preferably 1:0.35～0.5, most preferably be 1:0.4～0.5; The mol ratio of trimethyl phosphite and 3,5-3,5-dimethoxybenzoic alcohol is 1～3:1, and more preferably 1.05～1.5:1, most preferably be 1.3～1.5:1.
In step (3), to the mol ratio 1:1 of triphen methoxybenzaldehyde and 3,5-dimethoxy benzene dimethyl methyl phosphonate～2, more preferably 1:1.3～1.5.
In order further to improve reaction yield, preferably:
In step (1), described reaction is carried out under triethylamine catalysis.The mol ratio of described triethylamine and p-Hydroxybenzaldehyde is preferably 1～3:1, more preferably 1.5～2:1.
In step (1), described reaction is preferably in organic solvent to be carried out, and described organic solvent is preferably toluene.Described reaction adds water washing after reacting completely, organic solvent layer is through the concentration and recovery organic solvent, and the organic solvent of recovery can be reused, and is concentrated rear refining with ethanol, can remove impurity.
In step (1), the temperature of described reaction is preferably 50 ℃～70 ℃, more preferably 55 ℃～60 ℃.The time of described reaction does not have strict restriction, by timing sampling, adopts prior art such as high performance liquid chromatography (HPLC) to carry out trace analysis, and as complete when the p-Hydroxybenzaldehyde reaction, the terminal point that is considered as reacting gets final product.Through overtesting, carry out fully in order to make reaction, generally 50 ℃～70 ℃ reactions 4～10 hours, more preferably 55 ℃～60 ℃ reactions 6～8 hours.
In step (2), described chlorination reaction is preferably carried out under DMF (DMF) and organic solvent existence, and described organic solvent is preferably toluene.Described triphosgene preferably adopts the mode of dropping to add.Preferred step specifically comprises: with 3, the 5-3,5-dimethoxybenzoic alcohol is dissolved in toluene, add N, dinethylformamide dripping the toluene solution of triphosgene below 15 ℃, continues to react completely after dripping, tell the toluene phase after reaction solution is standing, through washing and reclaim under reduced pressure toluene, obtain 3,5-dimethoxy benzyl chlorine.Described 3, the mol ratio of 5-3,5-dimethoxybenzoic alcohol and DMF is preferably 1:0.1～3, and more preferably 1:0.5～2, most preferably be 1:0.5～1.Temperature when dripping triphosgene is preferably 0 ℃～5 ℃, drips afterreaction and generally continues to react 4～5 hours.
In step (2), the reaction conditions of described esterification is back flow reaction; The time of described esterification does not have strict restriction, by timing sampling, adopts prior art such as high performance liquid chromatography (HPLC) to carry out trace analysis, and as complete when the reaction of 3,5-dimethoxy benzyl chlorine, the terminal point that is considered as reacting gets final product.
In step (3), described Witting-Horner reaction is carried out under sodium methylate catalysis.Described sodium methylate with the mol ratio of triphen methoxybenzaldehyde is preferably 1～3:1,1.5～2:1 more preferably.
In step (3), described Witting-Horner reaction is preferably in organic solvent to be carried out, and described organic solvent is preferably toluene.Described Witting-Horner reaction through simply cooling, is filtered after reacting completely, and can obtain the Pterostilene intermediate, reuses after organic solvent is recyclable.
In step (3), the temperature of described Witting-Horner reaction is preferably 50 ℃～65 ℃, more preferably 55 ℃～60 ℃.The time of described Witting-Horner reaction does not have strict restriction, pass through timing sampling, adopt prior art such as high performance liquid chromatography (HPLC) to carry out trace analysis, as complete to the triphen p-methoxybenzaldehyde in working as, the terminal point that is considered as reacting gets final product.Through overtesting, carry out fully in order to make reaction, generally 50 ℃～65 ℃ reactions 8～16 hours, more preferably 55 ℃～60 ℃ reactions 10～12 hours.
In step (4), described acidic conditions is provided by acetic acid, and further the Pterostilene intermediate shown in the preferred formula VII and the mass ratio of acetic acid are 1:1～3, most preferably are 1:1.5～2.
In step (4), the temperature of described trityl removal reaction is preferably 30 ℃～45 ℃, more preferably 40 ℃～45 ℃.The time of described trityl removal reaction does not have strict restriction, pass through timing sampling, adopt prior art such as high performance liquid chromatography (HPLC) to carry out trace analysis, as complete when the Pterostilene intermediate reaction as shown in the formula VII, the terminal point that is considered as reacting gets final product.Through overtesting, carry out generally reacting 6～12 hours under 30 ℃～45 ℃ fully in order to make reaction, more preferably 40 ℃～45 ℃ reactions 8～10 hours.
In step (4), described trityl removal reaction is preferably in organic solvent and carries out, and described organic solvent is preferably methylene dichloride.Through simple cooling, water and sodium bicarbonate aqueous solution washing concentrate organic solvent to described trityl removal reaction, and be refining through hexanaphthene, filters after reacting completely, and drying can obtain Pterostilene, reuses after organic solvent is recyclable.
Organic solvent described in the present invention provides solvent environment for reaction.
Raw material of the present invention all can adopt the commercially available prod.
The present invention has following beneficial effect:
Synthetic method of the present invention is for Pterostilene synthetic provides a kind of new synthetic route.
Synthetic method raw material of the present invention is cheap and easy to get, and yield is high, and reaction conditions is gentle, and the three wastes are few, and the solvent that uses all can recovery, and the rate of recovery is high, is fit to very much industrialized production.
Description of drawings
Fig. 1 is synthetic route chart of the present invention.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail.
Embodiment 1
Step (1): add 200ml toluene in reaction flask, then add respectively p-Hydroxybenzaldehyde 20g (0.1638mol), triphenylmethyl chloride 50g (0.1794mol), triethylamine 25g (0.2471mol), after adding, be warming up to 57.5 ℃ ± 2.5 ℃, reacted 6 hours, be down to room temperature, with 50ml water washing twice, toluene layer is concentrated to be done, then adds 80ml ethanol refining, dry product 54g to the triphen methoxybenzaldehyde, molar yield 90.5%(is in p-Hydroxybenzaldehyde).
This product through with to the contrast of triphen methoxybenzaldehyde reference substance, HPLC goes out the peak position, the TLC speckle displacement is all consistent, shows that this product is for to the triphen methoxybenzaldehyde.
TLC condition: sherwood oil: chloroform: ethyl acetate=1:1:0.1, volume ratio;
The HPLC condition is:
Instrument: high performance liquid chromatograph; UV-detector;
Chromatographic column: C
18
Moving phase: acetonitrile: water=70:30, volume ratio;
Flow velocity: 1.0mL/min;
Column temperature: room temperature;
Sample size: 20 μ l;
Detect wavelength: 250nm.
Step (2): add 41.5g3,5-3,5-dimethoxybenzoic alcohol (0.2467mol), 100ml toluene and 18gDMF(0.2467mol toward reaction flask), be cooled to 5 ℃; 29.3g(0.0987mol) triphosgene drips after being dissolved in 80ml toluene, drips 2.5 ℃ ± 2.5 ℃ of process control temps, drips rear continuation reaction 4 hours; Standing, tell the darker oil phase of lower floor's color, upper toluene is used a small amount of frozen water and saturated sodium bicarbonate (each 20 milliliters) washing successively mutually, reconcentration reclaims toluene and obtains product 43.7g3,5-dimethoxy benzyl chlorine, molar yield 95%(is with 3,5-3,5-dimethoxybenzoic alcohol meter).
This product is through contrasting with 3,5-dimethoxy benzyl chlorine reference substance, and HPLC goes out the peak position, and the TLC speckle displacement is all consistent, shows that this product is 3,5-dimethoxy benzyl chlorine.
TLC condition: sherwood oil: chloroform: ethyl acetate=1:1:0.1, volume ratio;
The HPLC condition is:
Instrument: high performance liquid chromatograph; UV-detector;
Chromatographic column: C
18
Moving phase: acetonitrile: water=80:20, volume ratio;
Flow velocity: 1.0mL/min;
Column temperature: room temperature;
Sample size: 20 μ l;
Detect wavelength: 303nm;
With products therefrom 3,5-dimethoxy benzyl chlorine 43.7g adds 39.8g(0.3207mol) refluxed 10 hours in trimethyl phosphite, until 160 ℃ ± 5 ℃ of oil bath temperatures, 150 ℃ of interior temperature, the TLC detection reaction finishes, and obtains product 3,5-dimethoxy benzene dimethyl methyl phosphonate 57.8g, molar yield 90%(is with 3,5-3,5-dimethoxybenzoic alcohol meter).
This product is through contrasting with 3,5-dimethoxy benzene dimethyl methyl phosphonate reference substance, and the TLC speckle displacement is consistent, shows that this product is 3,5-dimethoxy benzene dimethyl methyl phosphonate.
TLC condition: sherwood oil: chloroform: ethyl acetate=1:1:0.1, volume ratio.
Step (3): with 54g(0.1482mol) to the triphen methoxybenzaldehyde, 3,5-dimethoxy benzene dimethyl methyl phosphonate 57.8g (0.2221mol), sodium methylate 16g (0.2962mol) joins in 200ml toluene, is warming up to 57.5 ℃ ± 2.5 ℃, reacted 12 hours, be down to room temperature, filter drying, Pterostilene intermediate 61.3g, molar yield 85%(is in to the triphen methoxybenzaldehyde).
This product is through contrasting with Pterostilene intermediate reference substance, and it is consistent that HPLC goes out the peak position, shows that this product is the Pterostilene intermediate.
The HPLC condition is:
Instrument: high performance liquid chromatograph; UV-detector;
Chromatographic column: C
18
Moving phase: acetonitrile: water=80:20, volume ratio;
Flow velocity: 1.0mL/min;
Column temperature: room temperature;
Sample size: 20 μ l;
Detect wavelength: 303nm.
Step (4): with Pterostilene intermediate 61.3g(0.126mol) join in the 200ml methylene dichloride and dissolve, then add 92g(1.532mol) acetic acid, after adding, be warming up to 42.5 ℃ ± 2.5 ℃, reacted 8 hours, and be down to room temperature, washing, the sodium bicarbonate aqueous solution washing, concentrated methylene dichloride is extremely done, then adds the 200ml hexanaphthene refining, filters, the dry the finished product Pterostilene 29g that gets, molar yield 90%(is in the Pterostilene intermediate); Mole total recovery 69.1%(is in p-Hydroxybenzaldehyde).
Pterostilene structural identification data are as follows:
These the finished product are through contrasting with the Pterostilene reference substance, and it is consistent that HPLC goes out the peak position, can judge tentatively that this material is Pterostilene.
The HPLC condition is:
Instrument: high performance liquid chromatograph; UV-detector;
Chromatographic column: C
18
Moving phase: acetonitrile: water=80:20, volume ratio;
Flow velocity: 1.0mL/min;
Column temperature: room temperature;
Sample size: 20 μ l;
Detect wavelength: 303nm;
LC-MS:m/e255 (M
+-1) molecular weight that shows this finished product material is 256.3, and is consistent with the molecular weight of Pterostilene.
Ultimate analysis: C75.06%, H6.35%, consistent with the hydrocarbon content of Pterostilene.
Nuclear magnetic data (hydrogen spectrum): solvent deuterated acetone, 300MHz: δ 3.80 (s, 6H), 6.39 (t, J=2.1Hz, 1H), 6.74 (d, J=2.4Hz, 2H), 6.86-6.89 (m, 2H), (6.99 d, J=16.5Hz, 1H), (7.19 d, J=16.5Hz, 1H), (7.44-7.47 m, 2H) 8.60 (brs, 1H-OH).The structural formula that nuclear magnetic data reacts is consistent with Pterostilene.
In sum, the gained the finished product are Pterostilene.
Embodiment 2
Step (1): add 200ml toluene in reaction flask, then add respectively p-Hydroxybenzaldehyde 20g (0.1638mol), triphenylmethyl chloride 54.8g (0.1966mol), triethylamine 33.2g (0.3276mol), after adding, be warming up to 57.5 ℃ ± 2.5 ℃, reacted 8 hours, be down to room temperature, with 50ml water washing twice, toluene layer is concentrated to be done, then adds 80ml ethanol refining, dry product 54.5g to the triphen methoxybenzaldehyde, molar yield 91.3%(is in p-Hydroxybenzaldehyde).
This product through with to the contrast of triphen methoxybenzaldehyde reference substance, HPLC goes out the peak position, the TLC speckle displacement is all consistent, shows that this product is for to the triphen methoxybenzaldehyde.
TLC condition: with embodiment 1;
HPLC condition: with embodiment 1.
Step (2): add 35.8g3,5-3,5-dimethoxybenzoic alcohol (0.2127mol), 100ml toluene and 7.8gDMF(0.1064mol toward reaction flask), be cooled to 5 ℃; 31.6g(0.1064mol) triphosgene drips after being dissolved in 80ml toluene, drips 2.5 ℃ ± 2.5 ℃ of process control temps, drips rear continuation reaction 5 hours; Standing, tell the darker oil phase of lower floor's color, upper toluene is used a small amount of frozen water and saturated sodium bicarbonate (each 20 milliliters) washing successively mutually, reconcentration reclaims toluene and obtains product 38.5g3,5-dimethoxy benzyl chlorine, molar yield 96.9%(is with 3,5-3,5-dimethoxybenzoic alcohol meter).
This product is through contrasting with 3,5-dimethoxy benzyl chlorine reference substance, and HPLC goes out the peak position, and the TLC speckle displacement is all consistent, shows that this product is 3,5-dimethoxy benzyl chlorine.This TLC condition: with embodiment 1; HPLC condition: with embodiment 1.
With products therefrom 3,5-dimethoxy benzyl chlorine 38.5g adds 39.6g(0.319mol) refluxed 10.5 hours in trimethyl phosphite, until 160 ℃ ± 5 ℃ of oil bath temperatures, 150 ℃ of interior temperature, the TLC detection reaction finishes, and obtains product 3,5-dimethoxy benzene dimethyl methyl phosphonate 50.6g, molar yield 91.4%(is with 3,5-3,5-dimethoxybenzoic alcohol meter).
This product is through contrasting with 3,5-dimethoxy benzene dimethyl methyl phosphonate reference substance, and the TLC speckle displacement is consistent, shows that this product is 3,5-dimethoxy benzene dimethyl methyl phosphonate.TLC condition: with embodiment 1.
Step (3): with 54.5g(0.1495mol) to the triphen methoxybenzaldehyde, 3,5-dimethoxy benzene dimethyl methyl phosphonate 50.6g (0.1944mol), sodium methylate 16.2g (0.299mol) joins in 200ml toluene, is warming up to 57.5 ℃ ± 2.5 ℃, reacted 10 hours, be down to room temperature, filter drying, Pterostilene intermediate 62.7g, molar yield 86.2%(is in to the triphen methoxybenzaldehyde).
This product is through contrasting with Pterostilene intermediate reference substance, and it is consistent that HPLC goes out the peak position, shows that this product is the Pterostilene intermediate.The HPLC condition is: with embodiment 1.
Step (4): with Pterostilene intermediate 62.7g(0.1288mol) join in the 200ml methylene dichloride and dissolve, then add 125.4g(2.088mol) acetic acid, after adding, be warming up to 42.5 ℃ ± 2.5 ℃, reacted 10 hours, and be down to room temperature, washing, the sodium bicarbonate aqueous solution washing, concentrated methylene dichloride is extremely done, then adds the 200ml hexanaphthene refining, filters, the dry the finished product Pterostilene 30g that gets, molar yield 90.9%(is in the Pterostilene intermediate); Mole total recovery 71.5%(is in p-Hydroxybenzaldehyde).
Pterostilene structural identification data are as follows:
These the finished product are through contrasting with the Pterostilene reference substance, and it is consistent that HPLC goes out the peak position, can judge tentatively that this material is Pterostilene.HPLC condition: with embodiment 1.
LC-MS:m/e255 (M
+-1) molecular weight that shows this finished product material is 256.3, and is consistent with the molecular weight of Pterostilene.
Ultimate analysis: C75.06%, H6.35%, consistent with the hydrocarbon content of Pterostilene.
Nuclear magnetic data (hydrogen spectrum): solvent deuterated acetone, 300MHz: δ 3.80 (s, 6H), 6.39 (t, J=2.1Hz, 1H), 6.74 (d, J=2.4Hz, 2H), 6.86-6.89 (m, 2H), (6.99 d, J=16.5Hz, 1H), (7.19 d, J=16.5Hz, 1H), (7.44-7.47 m, 2H) 8.60 (brs, 1H-OH).The structural formula that nuclear magnetic data reacts is consistent with Pterostilene.
In sum, the gained the finished product are Pterostilene.
Embodiment 3
Step (1): add 200ml toluene in reaction flask, then add respectively p-Hydroxybenzaldehyde 20g (0.1638mol), triphenylmethyl chloride 91.3g (0.3276mol), triethylamine 49.7g (0.4914mol), after adding, be warming up to 50 ℃, reacted 10 hours, be down to room temperature, with 50ml water washing twice, toluene layer is concentrated to be done, then adds 80ml ethanol refining, dry product 52.3g to the triphen methoxybenzaldehyde, molar yield 87.6%(is in p-Hydroxybenzaldehyde).
This product through with to the contrast of triphen methoxybenzaldehyde reference substance, HPLC goes out the peak position, the TLC speckle displacement is all consistent, shows that this product is for to the triphen methoxybenzaldehyde.
TLC condition: with embodiment 1;
HPLC condition: with embodiment 1.
Step (2): add 27.7g3,5-3,5-dimethoxybenzoic alcohol (0.1648mol), 100ml toluene and 0.78gDMF(0.01648mol toward reaction flask), be cooled to 10 ℃; 146.7g(0.4944mol) triphosgene drips after being dissolved in 80ml toluene, drips 5 ℃ ± 5 ℃ of process control temps, drips rear continuation reaction 6 hours; Standing, tell the darker oil phase of lower floor's color, upper toluene is used a small amount of frozen water and saturated sodium bicarbonate (each 20 milliliters) washing successively mutually, reconcentration reclaims toluene and obtains product 27.7g3,5-dimethoxy benzyl chlorine, molar yield 90%(is with 3,5-3,5-dimethoxybenzoic alcohol meter).
This product is through contrasting with 3,5-dimethoxy benzyl chlorine reference substance, and HPLC goes out the peak position, and the TLC speckle displacement is all consistent, shows that this product is 3,5-dimethoxy benzyl chlorine.This TLC condition: with embodiment 1; HPLC condition: with embodiment 1.
With products therefrom 3,5-dimethoxy benzyl chlorine 27.7g adds 20.4g(0.1648mol) refluxed 11 hours in trimethyl phosphite, until 160 ℃ ± 5 ℃ of oil bath temperatures, 150 ℃ of interior temperature, the TLC detection reaction finishes, and obtains product 3,5-dimethoxy benzene dimethyl methyl phosphonate 37.3g, molar yield 87%(is with 3,5-3,5-dimethoxybenzoic alcohol meter).
This product is through contrasting with 3,5-dimethoxy benzene dimethyl methyl phosphonate reference substance, and the TLC speckle displacement is consistent, shows that this product is 3,5-dimethoxy benzene dimethyl methyl phosphonate.TLC condition: with embodiment 1.
Step (3): with 52.3g(0.1435mol) to the triphen methoxybenzaldehyde, 3,5-dimethoxy benzene dimethyl methyl phosphonate 37.3g(0.1435mol), sodium methylate 7.8g(0.1435mol) join in 200ml toluene, be warming up to 50 ℃, reacted 16 hours, be down to room temperature, filter drying, Pterostilene intermediate 58g, molar yield 83.1%(is in to the triphen methoxybenzaldehyde).
This product is through contrasting with Pterostilene intermediate reference substance, and it is consistent that HPLC goes out the peak position, shows that this product is the Pterostilene intermediate.The HPLC condition is: with embodiment 1.
Step (4): with Pterostilene intermediate 58g(0.1192mol) join in the 200ml methylene dichloride and dissolve, then add 174g(2.8976mol) acetic acid, after adding, be warming up to 30 ℃, reacted 12 hours, and be down to room temperature, washing, the sodium bicarbonate aqueous solution washing, concentrated methylene dichloride is extremely done, then adds the 200ml hexanaphthene refining, filters, the dry the finished product Pterostilene 26.9g that gets, molar yield 88%(is in the Pterostilene intermediate); Mole total recovery 64.1%(is in p-Hydroxybenzaldehyde).
Pterostilene structural identification data are as follows:
These the finished product are through contrasting with the Pterostilene reference substance, and it is consistent that HPLC goes out the peak position, can judge tentatively that this material is Pterostilene.HPLC condition: with embodiment 1.
LC-MS:m/e255 (M
+-1) molecular weight that shows this finished product material is 256.3, and is consistent with the molecular weight of Pterostilene.
Ultimate analysis: C75.06%, H6.35%, consistent with the hydrocarbon content of Pterostilene.
Nuclear magnetic data (hydrogen spectrum): solvent deuterated acetone, 300MHz: δ 3.80 (s, 6H), 6.39 (t, J=2.1Hz, 1H), 6.74 (d, J=2.4Hz, 2H), 6.86-6.89 (m, 2H), (6.99 d, J=16.5Hz, 1H), (7.19 d, J=16.5Hz, 1H), (7.44-7.47 m, 2H) 8.60 (brs, 1H-OH).The structural formula that nuclear magnetic data reacts is consistent with Pterostilene.
In sum, the gained the finished product are Pterostilene.
In synthetic method of the present invention, the variation of parameter does not affect the synthetic of Pterostilene, so in synthetic method of the present invention, the combination of arbitrary parameter all can realize the preparation of Pterostilene.Do not repeat them here.
Claims (9)
1. the synthetic method of a Pterostilene, is characterized in that, comprises step:
Step (1): with p-Hydroxybenzaldehyde and triphenylmethyl chloride reaction, obtain the triphen methoxybenzaldehyde;
Step (2): 3,5-3,5-dimethoxybenzoic alcohol and triphosgene are carried out chlorination reaction, obtain 3,5-dimethoxy benzyl chlorine, then 3,5-dimethoxy benzyl chlorine and trimethyl phosphite are carried out esterification, obtain 3,5-dimethoxy benzene dimethyl methyl phosphonate;
Step (3): will react the Pterostilene intermediate that obtains shown in the formula VII by Witting-Horner to triphen methoxybenzaldehyde and 3,5-dimethoxy benzene dimethyl methyl phosphonate;
Step (4): the Pterostilene intermediate shown in the formula VII is carried out trityl removal reaction under acidic conditions, obtain Pterostilene;
The formula VII.
2. the synthetic method of Pterostilene according to claim 1, is characterized in that, in step (1), the mol ratio of p-Hydroxybenzaldehyde and triphenylmethyl chloride is 1:1～2;
In step (2), the mol ratio of 3,5-3,5-dimethoxybenzoic alcohol and triphosgene is 1:0.34～3; The mol ratio of trimethyl phosphite and 3,5-3,5-dimethoxybenzoic alcohol is 1～3:1;
In step (3), to the mol ratio 1:1 of triphen methoxybenzaldehyde and 3,5-dimethoxy benzene dimethyl methyl phosphonate～2.
3. the synthetic method of Pterostilene according to claim 1, is characterized in that, in step (1), described reaction is carried out in toluene solvant under triethylamine catalysis.
4. the synthetic method of Pterostilene according to claim 1, is characterized in that, in step (2), described chlorination reaction is carried out under DMF and toluene solvant existence; Described triphosgene adopts the mode that drips to add.
5. the synthetic method of Pterostilene according to claim 4, is characterized in that, the temperature when dripping triphosgene is 0 ℃～5 ℃.
6. the synthetic method of Pterostilene according to claim 1, is characterized in that, in step (3), described Witting-Horner reaction is carried out in toluene solvant under sodium methylate catalysis.
7. the synthetic method of Pterostilene according to claim 1, is characterized in that, in step (4), described acidic conditions is provided by acetic acid, and the mass ratio of the Pterostilene intermediate shown in the formula VII and acetic acid is 1:1～3.
8. the synthetic method of Pterostilene according to claim 1, is characterized in that, in step (4), described trityl removal reaction carries out in dichloromethane solvent.
9. the synthetic method of Pterostilene according to claim 1, is characterized in that, in step (1), the temperature of described reaction is 50 ℃～70 ℃;
In step (2), the temperature of described chlorination reaction is below 15 ℃; The reaction conditions of described esterification is back flow reaction;
In step (3), the temperature of described Witting-Horner reaction is 50 ℃～65 ℃;
In step (4), the temperature of described trityl removal reaction is 30 ℃～45 ℃.
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