CN1193980C - Method for synthesizing stereoselectively and efficiently diphenyl butane lignan compound - Google Patents

Method for synthesizing stereoselectively and efficiently diphenyl butane lignan compound Download PDF

Info

Publication number
CN1193980C
CN1193980C CNB021337004A CN02133700A CN1193980C CN 1193980 C CN1193980 C CN 1193980C CN B021337004 A CNB021337004 A CN B021337004A CN 02133700 A CN02133700 A CN 02133700A CN 1193980 C CN1193980 C CN 1193980C
Authority
CN
China
Prior art keywords
compounds
solvent
phenylbenzene
acid
butylene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CNB021337004A
Other languages
Chinese (zh)
Other versions
CN1405142A (en
Inventor
卞修武
周向东
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
First Affiliated Hospital of TMMU
Original Assignee
First Affiliated Hospital of TMMU
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by First Affiliated Hospital of TMMU filed Critical First Affiliated Hospital of TMMU
Priority to CNB021337004A priority Critical patent/CN1193980C/en
Publication of CN1405142A publication Critical patent/CN1405142A/en
Application granted granted Critical
Publication of CN1193980C publication Critical patent/CN1193980C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Landscapes

  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a method for the high-efficiency stereo selective synthesis of a diphenyl butane lignanoid compound. The compound is represented by a formula in the specification, wherein R1, R2, R3, R4, R5, R1', R2', R3', R4' and R5' respectively and independently represent methoxyl, methyl ether group, methyl, amylene oxide group, acetoxyl, OH, H, benzoyl, ester methanesulfonate, ester p-toluenesulfonate or benzyl; R1R2, R2R3, R3R4, R4R5, R1'R2', R2'R3', R3'R4' or R4'R5' represents-OCH2O-; R6 or R6' represents alpha-methyl or beta-methyl, ethyl, propyl, -CH2OH, -CH2OCH2-or-COOCH2-, and R5R5' is zero. The method has the advantages of short synthetic route, mild reaction condition, high yield, low cost, solid main intermediate body, easy recrystallization and high stereo selectivity.

Description

The method of synthesizing stereoselectively and efficiently diphenyl butane lignan compound
Technical field
The present invention relates to the method for the synthetic diphenyl butane lignans compound of new high-efficient solid selectivity.Specifically, be a kind of method of optionally synthesizing the diphenyl butane lignans compound from phenyl aldehyde compounds high-efficient solid.
Technical background
As everyone knows, lignanoid is that a class is distributed widely in botanic compound, they have biological action widely, as anti-inflammatory, antiviral, suppress biological intravital enzymic activity, reduce emergency reaction and the effect of central nervous system etc. become protect the liver, the medicine (Liu Jiasen of transaminase lowering and treatment chronic hepatitis, Chinese science, 1978,232; Shanghai pharmaceutical chemistry institute, Acta Biochimica et Biophysica Sinica, 1976,8,333; The Academy of Traditional Chinese Medicine, Shanghai, CHINESE JOURNAL OF INTERNAL MEDICINE, 1984,170).Especially (Nordihydroguaiaretic acid NDGA) is one and has extensive bioactive compound (MacRae, W.D.et al., Phytochem., 1984,23,1207 nordihydroguaiaretic acid; Foreign medical science, pharmacy fascicle, 1985,138), it has become novel anti-inflammatory medicaments (Yue Tianli, foreign medical science to the restraining effect of lipoxidase and cyclooxygenase and the restraining effect that the cavy strip of tissue that arachidonic acid causes is shunk, the pharmacy fascicle, 1984,170).
Several in the past about ten years between, NDGA synthetic only has minority document and patent (Schroeter, G.et al.Ber.1918,51,1587; Haworth, R..D.et al.J.Chem.Soc.1934,1423; Liebermann, S.V.et al.J.Am.Chem.Soc.1947,69,1540-1541; Liebermann, S.V.et al.U.S.Patent2,644,443 (1948); Pearl.I.A.U.S.Patent 2,644, and 822 (1953); Schrecker, A.W.J.Am.Chem.Soc.1957,79,3823; Blears, J.G.et al.J.Chem.Soc.1958.1985; Clark W.Perry.J.Org.Chem.1972,37 (26), 4371; Wu Anxin etc., Acta Pharmaceutica Sinica, 1997,32 (4), 278～281).These are synthetic mainly to be to determine the structure of NDGA and to the exploration of synthetic route.Owing to its reaction scheme length, severe reaction conditions, raw material costliness, limited the suitability for industrialized production of NDGA, therefore, biology, the needed NDGA of study of pharmacy are mainly derived from the extraction of plant.
In recent years, biology and study of pharmacy find that NDGA and derivative thereof can suppress lipoxidase (Steele, V.E.et al.Expert Opin.Investig.Drugs, 2000,9,2121-2138R.), papillomavirus (Craigo, J., et al.Antivir.Res.2000,47,19-28.), hsv (Chen, H.; Et al.J.Med.Chem.1998,41,3001-3007), HIV. (Hwu, J.R.; Tseng, W.N.; Gnabre, J.; Giza, P.; Huang, R.C.J.Med.Chem.1998,41,2994-3000.), and have hypoglycemic activity (Reed, M.J.et al.Diabetologia 1999,42,102-106; Luo, J.et al.Eur.J.Pharm.1998,34,677-679), NDGA might become anti-inflammatory, antiviral and the treatment diabetes medicine.Of paramount importance be the NDGA melanoma (Lambert, J.D, Meyers, R.O., Timmermann, B.N.and Dorr, R.T.Cancer Letters.2001,171:47-56) Zuo Yong discovery, for the treatment tumour new approach is provided.
The optionally synthetic NDGA of high-efficient solid becomes the prerequisite of this kind new medicine of development.(Tetrahedron Letters 2001,42 (35), reported that 6083-6085) the new method of NDGA is synthetic for MikailH.Gezginci and Barbara N.Timmermann recently.In this synthetic route, crucial middleware body (Z)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butylene is a liquid, and needs column chromatography for separation, and one step of de-methoxy needs waterless operation, total combined coefficient is low, and its raw material, reagent costliness, is not suitable for suitability for industrialized production.
The content of invention
The synthetic precursor phenyl ketone compounds 3 that relates among the present invention is important chemical material, also is the important intermediate (U.S.Patent 2,868,818) of synthetic DOPA derivative, about in this compounds synthetic report (C.A.82,72640,1975 is arranged also; C.A.69,106243,1968; C.A.101,152292,1984; C.A.102,24290,1985), its shortcoming is to use danger that organic peroxide acid brings and can not suitability for industrialized production.
The key intermediate that relates among the present invention (Z)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butylene one class thing is colourless needle crystal, and the simple recrystallization of process can get pure product merely, is suitable for suitability for industrialized production.
The purpose of this invention is to provide a new synthetic route, be used for the synthetic diphenyl butane lignans compound of industrial high efficiency stereoselectivity.
Method of the present invention is: have different hydroxyls in the molecule of phenyl aldehyde compound 1, but all through suitable protecting group protection.
1. make solvent with benzene, toluene, tetrahydrofuran (THF) or dioxane, when phenyl aldehyde compound 1 reacts with nitro-compound, add two kinds of catalyzer, to improve condensation reaction speed.First kind of catalyzer is organic bases 4-N, N-dimethyl aminopyridine, pyridine, n-Butyl Amine 99, triethylamine, quadrol or Diisopropylamine, second kind of catalyzer is organic acid formic acid, Glacial acetic acid, propionic acid, phenylformic acid or tosic acid, after adding above catalyzer, reflux water-dividing 3～5 hours, the various phenyl nitro of acquisition vinyl compound 2 that can high yield is through the recrystallization separation and purification.
2. with benzene, toluene, tetrahydrofuran (THF), methyl alcohol, ethanol or dioxane and distillation water as solvent, by method 1 gained phenyl nitro vinyl compound 2 and iron powder, iron trichloride, concentrated hydrochloric acid reaction, refluxed 3～5 hours, can generate phenyl ketone compounds 3 by high yield, through recrystallization or underpressure distillation separation and purification.
3. phenyl ketone compounds 3 and the titanium tetrachloride by method 2 gained is dissolved in the tetrahydrofuran (THF), adds zinc powder, and back flow reaction after the aftertreatment, can obtain phenylbenzene tetramethyl ethylene ketone compounds 4 with high yield through recrystallization.Order of addition(of ingredients) also can add zinc powder earlier, drips titanium tetrachloride again, drips raw material at last.
By the phenylbenzene tetramethyl ethylene ketone compounds 4 of method 3 gained with after triethyl orthoformate and phenylformic acid mix, reacting by heating, through different solvents recrystallization can be simple step by step acquisition cis (Z)-phenylbenzene butylene compounds 5a and trans (E)-phenylbenzene butylene compounds 5b, both are needle-like crystal.
5. can be under the catalysis of iodine by trans (the E)-phenylbenzene of method 4 gained butylene compounds 5b, through UV-irradiation be transformed into cis (Z)-phenylbenzene butylene compounds 5a, through the appropriate solvent recrystallization can merely obtain cis (Z)-phenylbenzene butylene compounds 5a.
6. make solvent by method 4 or 5 gained cis (Z)-phenylbenzene butylene compounds 5a or trans (E)-phenylbenzene butylene compounds 5b with methyl alcohol, ethanol, ethyl acetate, tetrahydrofuran (THF), add an amount of acetic acid catalysis, under the normal temperature and pressure, but ground De Sushi (is meso through platinum dioxide catalysis cis hydrogenation stereospecificity, meso) and erythro form (be racemize, dl) the diphenyl butane compounds 6.
7. gained Soviet Union formula or erythro form diphenyl butane compounds 6 (protonic acid or Lewis acid) de-methoxy protection under acidic conditions diphenyl butane lignans compound that can get hydroxyl comprises NDGA etc.
The diphenyl butane lignans compound that is adopted among the present invention has following molecular formula:
Figure C0213370000101
R wherein 1, R 2, R 3, R 4, R 5, R 1', R 2', R 3', R 4' and R 5' be methoxyl group, OH, H independently of one another; R 6And R 6' be α-or Beta-methyl, ethyl, propyl group independently of one another.
In the inventive method:
1. phenyl aldehyde compound 1 is 1: 2～5: 0.01～0.50: 0～0.1 with nitro-compound, organic bases, organic acid mol ratio, reaction conditions is a reflux water-dividing, the single solvent or the separation and purification of mixed solvent recrystallization of reaction product sherwood oil, pentane, ether, isopropyl ether, acetone, ethyl acetate, methylene dichloride, trichloromethane, benzene, toluene.
2. phenyl nitro vinyl compound 2 is 1: 2～5: 0.01～0.50: 0～0.1 with iron powder, iron trichloride, concentrated hydrochloric acid mol ratio, reaction conditions is a reflux, gained phenyl ketone compounds 3 is through single solvent or the mixed solvent recrystallization or the underpressure distillation purifying of sherwood oil, pentane, methyl alcohol, ethanol, Virahol, ether, isopropyl ether, acetone, butanone ethyl acetate, methylene dichloride, trichloromethane, benzene, toluene.
3. phenyl ketone compounds 3 is 1: 1.5～3: 3～6 with the ratio of titanium tetrachloride, zinc powder; Order of addition(of ingredients) is to add raw material, titanium tetrachloride earlier, adds zinc powder again; Perhaps add zinc powder earlier, drip titanium tetrachloride again, add raw material at last; Reaction conditions is anhydrous.Reaction gained phenylbenzene tetramethyl ethylene ketone compounds 4 is through the single solvent or the mixed solvent recrystallization purifying of sherwood oil, pentane, methyl alcohol, ethanol, Virahol, ether, isopropyl ether, acetone, ethyl acetate, methylene dichloride, trichloromethane, benzene or toluene.
4. phenylbenzene tetramethyl ethylene ketone compounds 4 is 1: 1.5～5: 0.1～0.1.5 with triethyl orthoformate, benzoic mol ratio, the temperature range of reacting by heating is 85 ℃～190 ℃, gained cis (Z)-phenylbenzene butylene compounds 5a and trans (E)-phenylbenzene butylene compounds 5b are the needle-like crystal compound, can get pure product by the single solvent or the mixed solvent substep recrystallization of pentane, hexane, sherwood oil, methyl alcohol, ethanol, Virahol, ether, isopropyl ether, ethyl acetate, methylene dichloride, trichloromethane, benzene, toluene.
5. trans (E)-phenylbenzene butylene compounds 5 is 1: 0.01～0.20 with the mass ratio of iodine; Ultraviolet source is 50W～200W low-voltage mercury arc lamp; Irradiation time is 0.5～3 hour; Gained cis (Z)-phenylbenzene butylene compounds 5a gets pure product with the single solvent or the mixed solvent substep recrystallization of pentane, hexane, sherwood oil, methyl alcohol, ethanol, Virahol, ether, isopropyl ether, ethyl acetate, methylene dichloride, trichloromethane, benzene, toluene.
6. the mass ratio of cis (Z)-phenylbenzene butylene 5a or trans (E)-phenylbenzene butylene 5b and platinum dioxide is 1: 0.01～1.The acetic acid catalysis of adding 0.01～5% is with stereospecificity that improves speed of response, reaction and the consumption that reduces platinum dioxide.Products therefrom gets pure product through the single solvent or the mixed solvent substep recrystallization of pentane, hexane, sherwood oil, methyl alcohol, ethanol, Virahol, ether, isopropyl ether, ethyl acetate, methylene dichloride, trichloromethane, benzene, toluene.
7. gained Soviet Union's formula or erythro form diphenyl butane compounds 6 can get the compound of hydroxyl through the protection of acidic conditions de-methoxy.Described acid is to be selected from the protonic acid of Hydrogen bromide or acetate or to be selected from boron tribromide or the Lewis acid of aluminum chloride.When using Lewis acid, with methylene dichloride solubilizing reaction thing.Reaction conditions is room temperature or reflux.Products therefrom gets pure product through water, 10%～80% acetate, acetate, formic acid, 10%～80% formic acid, methyl alcohol, methanol-water, ethanol or alcohol-water recrystallization.
Adopt method of the present invention can obtain the phenyl ketone compounds of following structure.
Wherein, R 1, R 2, R 3, R 4, R 5Be methoxyl group, OH, H independently of one another; R 6Be methyl or ethyl or propyl group.
In other words, it can be respectively the compound of following structure, as: 1-(3, the 4-Dimethoxyphenyl) acetone, 1-(3, the 4-Dimethoxyphenyl)-2-butanone, 1-(3, the 4-Dimethoxyphenyl)-2 pentanone, 1-(3, the 4-Dimethoxyphenyl)-2 pentanone, they are key intermediates of synthetic levodopa, deoxyschizandrin, third element, fourth element, medicines such as NDGA, 4Me-NDGA.
Adopt method of the present invention can also obtain the diphenyl butane compounds of following symmetrical structure.
Figure C0213370000121
Wherein, R 1, R 2, R 3, R 4, R 5, R 1', R 2', R 3', R 4' and R 5' be methoxyl group, OH, H independently of one another; R 6And R 6' be α-or Beta-methyl, ethyl, propyl group independently of one another.
In other words, can be the compound of following structure respectively:
As 1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2, the 3-butyleneglycol, (Z)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butylene, (E)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butylene, meso-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethylbutane (4Me-NDGA), meso-1,4-two (3, the 4-dihydroxy phenyl)-2,3-dimethylbutane (NDGA), the meso-of gained or dl-diphenyl butane lignans compound can be respectively applied for synthetic anti-inflammatory as intermediate, protect the liver and antineoplastic natural compounds and medicine.Or itself can be used as anti-inflammatory, protect the liver and anti-tumor drug.
Adopt method of the present invention, synthetic diphenyl butane lignans compound that not only can highly-solid selectively, and reaction conditions gentleness, synthetic route is short, yield is high, with low cost, is the method that is suitable for suitability for industrialized production.
Help further to understand the present invention by following examples, but can not limit content of the present invention:
Embodiment 1
3,4-dimethoxy benzaldehyde synthetic
In 500 there-necked flasks, load onto reflux condensing tube, add the 100g vanillin food grade,1000.000000ine mesh, oil bath is heated to 90～120 ℃, when raw materials melt, drips the aqueous sodium hydroxide solution of 70～90ml methyl-sulfate and 90～120ml40% respectively rapidly from two constant pressure funnel.Reacted 10 minutes, and left standstill, add water, use ethyl acetate extraction, merge organic phase.Use the saturated common salt water washing, anhydrous sodium sulfate drying concentrates.Ethyl acetate and sherwood oil recrystallization get clear crystal 103.756g, productive rate 90%～95%.Mp:41-43 ℃; EI-MS (m/e): 166 (M), 151 (M-Me); IR (cm -1): 3020,3030,2949,2845,2766,1853,1702 (acromion), 1685,1672,1599,1588,1541,1470,1425,1275,1242,1139,1019,964,873,802,734,643; 1HNMR (600MHz, CDCl 3) δ ppm:3.948 (3H, s ,-OCH 3), 3.973 (3H, s, OCH 3), 6.986 (1H, d, J=8.4Hz), 7.419 (1H, d, J=1.8Hz, Ar-H), 7.465 (1H, d, d, J 1=0.9Hz, J 2=8.1Hz Ar-H), 9.861 (1H, s ,-CHO).
Embodiment 2
Synthesizing of 1-(3, the 4-Dimethoxyphenyl)-2-nitro-1-propylene
Figure C0213370000132
In the 250ml round-bottomed flask, load onto water trap and reflux condensing tube, add 24.559g (3, the 4-dimethoxy benzaldehyde), 15～23ml nitroethane, 0.9～1.5ml n-Butyl Amine 99,0.8～2.0mL Glacial acetic acid and 20～40ml toluene.The oil bath heating, TLC shows when raw material disappears, stopped reaction; Be chilled to room temperature, remove desolvate dark oily matter.Room temperature leaves standstill, and has a large amount of yellow needle-like crystals to separate out, suction filtration, and ethyl acetate and sherwood oil mixed solvent (volume ratio 1: 4) clean, and infrared drying gets yellow crystals 31.875g, productive rate 97%.mp：72-73℃；EI-MS(m/e)：223(M)，192，176IR(cm -1)：3016，1657，1596，1513，1315，1258， 1HNMR(600MHz，CDCl 3)δppm：2.491(3H，s，)，3.916(3H，s，)，3.937(3H，s)，6.962(2H，m，)，7.089(1H，dd，J＝1.8Hz，J 2＝8.4Hz)。
Embodiment 3
Synthesizing of 1-(3, the 4-Dimethoxyphenyl)-1-acetone
Figure C0213370000141
In the 500ml there-necked flask, (1-(3 to add the 94.117g raw material, the 4-Dimethoxyphenyl)-2-nitro-1-propylene), 120～180g iron powder, 2.0～5.0g Iron(III) chloride hexahydrate, 120～160ml toluene and 150～250ml distilled water, reflux under the mechanical stirring.Slowly drip 250～350ml concentrated hydrochloric acid, after dropwising, refluxed 1 hour.Leave standstill diatomite filtration, trichloromethane washing, water chloroform extraction.Merge organic phase, washing, saturated common salt water washing, anhydrous sodium sulfate drying removes and desolvates, and gets crude product.Underpressure distillation gets: 79.132g light yellow liquid, productive rate 90%～99%.EI-MS(m/e)：194(M)，151(M-CH 3CO)；IR(cm -1)：3003，2959，2839，1710，1517； 1H?NMR(600MHz，CDCl 3)δppm：2.137(3H，s，)，3.621(2H，s，)，3.857(6H，s，)，6.717(H，s，)，6.743(1H，d，J＝Hz)；6.743(1H，d，J＝Hz)，6.828(1H，d，J＝Hz)。
Embodiment 4
1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2,3-butyleneglycol synthetic
The 250ml there-necked flask is loaded onto reflux condensing tube, mechanical stirring, vacuum flame drying, N 2Protection adds 18.00 gram raw materials (1-(3, the 4-Dimethoxyphenyl)-2-nitro-1-acetone), 15～20 gram zinc powders, 50～120mlTHF down, drips 10～20ml TiCl under the mechanical stirring 4Oil bath reflux 5 hours.Reduce to room temperature, Dropwise 5 0～1000ml 10%K 2CO 3Hydrolysis, diatomite filtration.3 * 150ml CHCl 3Clean anhydrous Na 2SO 4Dry.Remove and desolvate to such an extent that oily matter 33.904 restrains.Ethyl acetate-sherwood oil recrystallization gets 16.286 gram clear crystals, productive rate 72～95%.Mp:144-146 ℃; MS-EI (m/e): 390 (M), 372 (M-H 2O); IR (cm -1): 3550,3515,1608,1589,1515; 1H NMR (600MHz, CDCl 3) δ ppm:1.142 (3H, s ,-CH 3), 1.177 (3H, s ,-CH 3), 1.571 (1H, br ,-OH), 2.015 (2H, d, J=6Hz), 2.673 (2H, dd, J 1=5.1Hz, J 2=13.5Hz); 3.100 (2H, dd, J 1=20.4Hz, J 2=13.8Hz), 3.876,3.882,3.890,3.896 (12H, q), 6.832 (6H, m, Ar-H); 13C NMR (600MHz, CDCl 3): 21.458,21.835,41.366,41.732,55.902,111.068,114.292,114.343,122.929,122.970,130.121,147.841,148.675. ultimate analysis (C 27H 42O 5): calculated value C:67.67%, H:7.74%; Measured value: C:67.53%, H:7.58%.
Embodiment 5
(Z)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butylene and
(E)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butylene synthetic
In the 50ml egg type bottle, add 13.925 gram raw materials (1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2,3-butyleneglycol), 5～10 gram phenylformic acid, 15～25 gram triethyl orthoformates (about 24.00ml) are heated to 100～105 °, are incubated 1 hour; Be warming up to 180 ℃, be incubated 3 hours, reduce to room temperature, remove desolvate 21.852 gram oily matter, add the re-crystallizing in ethyl acetate recrystallization, (E)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butylene 5.857 grams, productive rate 46%.Mp.121.4-122.6 ℃, mp:121-122 ℃; EI-MS (m/e): 356 (M), 386 (M-HOAc); IR (cm -1): 3000,2994,2843,1837,1605,1590,1516,1464; 1H NMR (600MHz, CDCl 3) δ ppm:1.733 (6H, s ,-CH 3), 3.386 (4H, s ,-OCH 3), 3.796 (6H, s ,-OCH 3), 3.833 (6H, s ,-OCH 3), 6.678 (2H, d, J=1.8Hz, H); 6.700 and 6.713. (2H, dd, J 1=1.8Hz, J 2=7.8Hz), 6.762 (2H, d, J=8.4Hz); 13CNMR (600MHz, CDCl 3): 18.598,39.779,55.765,55.923,111.250,111.843,120.216,128.916,133.419,147.263,148.921; Ultimate analysis (C 22H 28O 4), calculated value C, 74.13%, H, 7.92%; Measured value, C:73.80%, H:7.88%.Mother liquor gets (Z)-1 through dehydrated alcohol from crystallization, 4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butylene crystal 5.594 grams, productive rate 44%.Mp:82-83 ℃; EI-MS (m/e): 356 (M); IR (cm -1): 3001,2955,1852,1604,1589,1514; 1HNMR (600MHz, CDCl 3) δ ppm:1.689 (6H, s ,-OCH 3), 3.482 (4H, s ,-H 3), 3.817 (6H, s ,-OCH 3), 3.852 (6H, s ,-OCH 3), 6.672 (2H, d, J=1.8Hz, H); 6.715. (2H, dd, J 1=1.8Hz, J 2=8.4Hz), 6.785 (1H, d, J=8.4Hz); 13C NMR (600MHz, CDCl 3): 18.593,39.652,55.917,55.786,111.208,112.054,120.373,128.641,133.304,147.263,148.884. ultimate analysis: (C 22H 28O 4), calculated value: C, 74.13%, H, 7.92%; Measured value C, 74.16%, H, 7.79%.
Embodiment 6
(Z)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butylene synthetic
In the 250ml egg type bottle, and adding 10 gram raw materials ((E)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butylene), with 50～250ml ethyl acetate-petroleum ether solution dissolving, add 50～200mg iodine, with 100W low pressure mercury arc light irradiation 1 hour, remove desolvate 10.095 gram oily matter, add re-crystallizing in ethyl acetate, 5b (trans) 6.128 gram crystal, mp:123-124 ℃, do not fall with the standard substance mixed melting point.Mother liquor gets 5a (cis) productive rate 3.805g, yield 35～60% with the dehydrated alcohol recrystallization.Mp:82-83 ℃, do not fall with the standard substance mixed melting point.
Embodiment 7
(meso)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butane synthetic
Figure C0213370000172
In the 100ml egg type bottle, add raw material (Z)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butylene) 3.022 grams, 0.03～2.0g PtO 23H 2O, 0～50ml ethyl acetate, 0～10ml Glacial acetic acid.Under the induction stirring, normal pressure hydrogenation 1.5 hours, diatomite filtration, 3 * 15mL ethyl acetate is cleaned, remove desolvate 3.661 gram oily matter, add the sherwood oil recrystallization and get 3.02 gram needle-like crystals, productive rate 88%～99%.Mp:95～96 ℃; EI-MS (m/e): 358 (M); IR (cm -1): 3005,2960,2816,2837,1606,1589,1516,1258,1237,1154,1137,1025,807,767 1H NMR (600MHz, CDCl 3) δ ppm:0.825 (6H, d, J=6.6Hz), 1.774 (2H, m), 2.293 and 2.316 (2H, dd, J 1=9.6Hz, J 2=13.8Hz), 2.743 and 2.765 (2H, dd, J 1=4.8Hz, J 2=13.2Hz-COCH 3), 3.849 (6H, s) 3.855 (6H, s); 6.652 (2H, d, J=18Hz), 6.703 and 6.690 (2H, dd, J 1=2.1Hz, J 2=8.1Hz); 6.791 and 6.778 (2H, d, J=7.8Hz); 13C NMR (600MHz, CDCl 3): 16.219,38.861,39.193,55.818,55.932,111.140,112.373,120.970,134.498,147.135,148.792; Ultimate analysis (C 22H 30O 4) calculated value, C, 73.71%, H, 8.43%; Measured value, C, 73.76%, H, 8.35%.
Embodiment 8
NDGA (meso)-1,4-two (3,4-dihydroxyl base phenyl)-2,3-dimethyl-2-butane synthetic
In the 50ml egg type bottle, add 918mg raw material (meso)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butane), N 2Protection adds 10～50ml 40%HBr acid, 0～50ml Glacial acetic acid, oil bath reflux 10 hours down; TLC shows that raw material disappears, and stirred overnight at room temperature adds big water gaging dilution, has light gray solid to separate out; suction filtration, dry light grey crude product 766mg, productive rate 90%～99%.Mp.179.7～183.3 ℃, 10%～80% acetate recrystallization gets colourless acicular crystal, mp.184～185 ℃; Measuring purity through HPLC is 99.7%, (HPLC, LC4000, WATERS, C18 post); EI-MS (m/e): 302 (M); IR (cm -1): 3463,3300 and 3197 (acromions), 2963,2925,2867,1869,1611,1527,1517,1443,1394,1382,1292,1239,1194,960,938. 1H NMR (600MHz, CD 3COCD 3) δ ppm:0.812 (6H, d, J=13.2Hz), 1.723 (2H, m), 2.176 and 2.198 (2H, dd, J 1=13.2Hz, J 2=9Hz), 2.687 and 2.666 (2H, dd, J 1=5.1Hz, J 2=12.9Hz), 3..124 (4H, br); 6.506 and 6.494 (2H, dd, J 1=1.8Hz, J 2=7.8Hz), 6.680 (2H, d, J=1.8Hz); 6.733 and 6.720 (2H, d, J=7.8Hz); 13C NMR (600MHz, CD 3COCD 3) 16.517,39.239,40.158,115.756,116.850,121.068,134.246,143.748,145.614; Ultimate analysis (C 18H 22O 4) calculated value: C:71.50%, H:7.33%; Measured value: C:71.15%, H:7.28%.

Claims (18)

1. the high-efficient solid method for selective synthesis of a diphenyl butane lignans compound, wherein, R 1, R 2, R 3, R 4, R 5, R 1', R 2', R 3', R 4' and R 5' be methoxyl group, OH, H independently of one another; R 6And R 6' be α-or Beta-methyl, ethyl, propyl group independently of one another, it is characterized in that with following method synthetic:
Figure C021337000002C1
(1) in organic solvent, phenyl aldehyde compound 1 and nitro-compound reflux water-dividing 3～5 hours under organic bases and organic acid catalysis, condensation changes phenyl nitro vinyl compound 2 into, the recrystallization separation and purification of reaction products therefrom, described organic solvent is a benzene, toluene, tetrahydrofuran (THF) or dioxane, described organic alkali catalyst is 4-N, the N-dimethyl aminopyridine, pyridine, n-Butyl Amine 99, triethylamine, quadrol or Diisopropylamine, described organic acid catalyst is a formic acid, Glacial acetic acid, propionic acid, phenylformic acid or tosic acid, recrystallization solvent are sherwood oil, pentane, ether, isopropyl ether, acetone, ethyl acetate, methylene dichloride, trichloromethane, benzene, the single solvent of toluene or mixed solvent;
(2) phenyl nitro vinyl compound 2 is dissolved in benzene, toluene, tetrahydrofuran (THF), methyl alcohol, ethanol or the dioxane organic solvent, with iron powder, iron trichloride, distilled water and concentrated hydrochloric acid effect, reflux 3～5 hours, be transformed into phenyl ketone compounds 3, products therefrom is through recrystallization or underpressure distillation purifying, and described recrystallization solvent is the single solvent or the mixed solvent of sherwood oil, pentane, methyl alcohol, ethanol, Virahol, ether, isopropyl ether, acetone, butanone ethyl acetate, methylene dichloride, trichloromethane, benzene, toluene;
(3) phenyl ketone compounds 3 generates phenylbenzene tetramethyl ethylene ketone compounds 4 with titanium tetrachloride, zinc powder effect reduction in tetrahydrofuran solvent, reaction gained phenylbenzene tetramethyl ethylene ketone compounds 4 is through recrystallization purifying, reinforced sequencing is followed successively by raw material, titanium tetrachloride, zinc powder, or be followed successively by zinc powder, titanium tetrachloride, raw material, reaction conditions is anhydrous, and recrystallization solvent is the single solvent or the mixed solvent of sherwood oil, pentane, methyl alcohol, ethanol, Virahol, ether, isopropyl ether, acetone, ethyl acetate, methylene dichloride, trichloromethane, benzene, toluene;
(4) phenylbenzene tetramethyl ethylene ketone compounds 4 is under the phenylformic acid effect, be transformed into cis (Z)-phenylbenzene butylene compounds 5a and trans (E)-phenylbenzene butylene compounds 5b with triethyl orthoformate dehydration under 85 ℃～190 ℃, gained cis (Z)-phenylbenzene butylene compounds 5a and trans (E)-phenylbenzene butylene compounds 5b mixture after the recrystallization separation and purification respectively pure cis (Z)-phenylbenzene butylene compounds 5a and pure trans (E)-phenylbenzene butylene compounds 5b, the two is the needle-like crystal compound, and described recrystallization solvent is a pentane, hexane, sherwood oil, methyl alcohol, ethanol, Virahol, ether, isopropyl ether, ethyl acetate, methylene dichloride, trichloromethane, benzene, the single solvent of toluene or mixed solvent;
(5) in organic solvent, at room temperature, trans (E)-phenylbenzene butylene compounds 5b is under catalysis of iodine, be transformed into cis (Z)-phenylbenzene butylene compounds 5a in 0.5～5 hour through UV-irradiation, behind recrystallization, obtain cis (Z)-phenylbenzene butylene compounds 5a stereospecificity, wherein organic solvent is a pentane, sherwood oil, ethyl acetate, methyl alcohol, ethanol, Virahol, ether or isopropyl ether, described ultraviolet source is 50～200W low-voltage mercury arc lamp, and described recrystallization solvent is a pentane, hexane, sherwood oil, methyl alcohol, ethanol, Virahol, ether, isopropyl ether, ethyl acetate, methylene dichloride, trichloromethane, benzene, the single solvent of toluene or mixed solvent;
(6) in organic solvent, cis (Z)-phenylbenzene butylene compounds 5a is under the organic acid acidic conditions, under the normal temperature and pressure, synthesizing Soviet Union's formula through platinum dioxide catalysis cis hydrogenation stereospecificity ground (is meso, meso) the diphenyl butane compounds 6, get pure product behind the recrystallization, described organic solvent is a methyl alcohol, ethanol, ethyl acetate or tetrahydrofuran (THF), described organic acid is an acetate, and described recrystallization solvent is a pentane, hexane, sherwood oil, methyl alcohol, ethanol, Virahol, ether, isopropyl ether, ethyl acetate, methylene dichloride, trichloromethane, benzene, the single solvent of toluene or mixed solvent;
(7) in organic solvent, trans (E)-phenylbenzene butylene compounds 5b is under the organic acid acidic conditions, under the normal temperature and pressure, synthesizing erythro form through platinum dioxide catalysis cis hydrogenation stereospecificity ground (is racemize, d1) the diphenyl butane compounds 6, recrystallization gets the pure product in back, described organic solvent is a methyl alcohol, ethanol, ethyl acetate or tetrahydrofuran (THF), described organic acid is an acetate, and described recrystallization solvent is a pentane, hexane, sherwood oil, methyl alcohol, ethanol, Virahol, ether, isopropyl ether, ethyl acetate, methylene dichloride, trichloromethane, benzene, the single solvent of toluene or mixed solvent;
(8) Soviet Union's formula (be meso, meso) diphenyl butane compounds 6 or erythro form (be racemize, d1) diphenyl butane compounds 6 (R 1, R 2, R 3, R 3, R 5, R 1', R 2', R 3', R 4' and R 5' be methoxyl group independently of one another) under acidic conditions ,-78 ℃ to reflux temperature, de-methoxy protect the compound 6 (R of hydroxyl 1, R 2, R 3, R 3, R 5, R 1', R 2', R 3', R 4' and R 5' be OH independently of one another), getting pure product through recrystallization, recrystallization solvent is water, 10%～80% acetic acid, acetic acid, formic acid, 10%～80% formic acid, methyl alcohol, methanol-water, ethanol or alcohol-water.
2. synthetic method as claimed in claim 1 is characterized in that wherein the phenyl aldehyde compound 1 described in the method for (1) is 1: 2～5: 0.01～0.50: 0～0.1 with nitro-compound, organic bases, organic acid mol ratio.
3. synthetic method as claimed in claim 1 is characterized in that wherein the phenyl nitro vinyl compound 2 described in the method for (2) and the mol ratio of iron powder, iron trichloride, concentrated hydrochloric acid are 1: 2～5: 0.01～0.50: 0～0.1.
4. synthetic method as claimed in claim 1 is characterized in that wherein the phenyl ketone compounds 3 described in the method for (3) and the mol ratio of titanium tetrachloride, zinc powder are 1: 1.5～3: 3～6.
5. synthetic method as claimed in claim 1 is characterized in that wherein the phenylbenzene tetramethyl ethylene ketone compounds 4 described in the method for (4) is 1: 1.5～5: 0.1～1.5 with triethyl orthoformate, benzoic mol ratio.
6. synthetic method as claimed in claim 1 is characterized in that wherein the trans phenylbenzene butylene compounds 5b described in the method for (5) and the mass ratio of iodine are 1: 0.01～0.20.
7. synthetic method as claimed in claim 1 is characterized in that wherein cis (the Z)-phenylbenzene butylene compounds 5a described in the method for (6) and (7) or the mass ratio of trans (E)-phenylbenzene butylene compounds 5b and platinum dioxide are 1: 0.01～1; Described organic solvent and organic acid volume ratio are 1: 0.01～0.05.
8. synthetic method as claimed in claim 1 is characterized in that wherein the acid described in the method for (8) is to be selected from the protonic acid of Hydrogen bromide or acetic acid or to be selected from boron tribromide or the Lewis acid of aluminum chloride; When using Lewis acid, with methylene dichloride solubilizing reaction thing; Reaction conditions is room temperature or reflux.
9. synthetic method as claimed in claim 1 is characterized in that wherein the reaction product described in the method for (1) is 1-(3, the 4-Dimethoxyphenyl)-2-nitro-1-propylene.
10. synthetic method as claimed in claim 1 is characterized in that wherein the reaction product described in the method for (2) is 1-(3, the 4-Dimethoxyphenyl)-1-acetone.
11. a synthetic method as claimed in claim 1 is characterized in that wherein the reaction product described in the method for (3) is 1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2,3-butyleneglycol.
12. a synthetic method as claimed in claim 1 is characterized in that wherein one of reaction product described in the method for (4) is (Z)-1,4-two (3,4 ,-Dimethoxyphenyl)-2,3-dimethyl-2-butylene.
13. a synthetic method as claimed in claim 1 is characterized in that wherein two of the reaction product described in the method for (4) are (E)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butylene.
14. a synthetic method as claimed in claim 1 is characterized in that wherein the reaction product described in the method for (5) is (Z)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butylene.
15. a synthetic method as claimed in claim 1 is characterized in that wherein the reaction product described in the method for (6) is (meso)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butane.
16. a synthetic method as claimed in claim 1 is characterized in that wherein the reaction product described in the method for (7) is (d1)-1,4-two (3, the 4-Dimethoxyphenyl)-2,3-dimethyl-2-butane.
17. a synthetic method as claimed in claim 1 is characterized in that wherein the reaction product described in the method for (8) is (meso)-1,4-two (3,4 ,-dihydroxy phenyl)-2,3-dimethyl-2-butane.
18. a synthetic method as claimed in claim 1 is characterized in that wherein the reaction product described in the method for (8) is (d1)-1,4-two (3,4 ,-dihydroxy phenyl)-2,3-dimethyl-2-butane.
CNB021337004A 2002-09-04 2002-09-04 Method for synthesizing stereoselectively and efficiently diphenyl butane lignan compound Expired - Fee Related CN1193980C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CNB021337004A CN1193980C (en) 2002-09-04 2002-09-04 Method for synthesizing stereoselectively and efficiently diphenyl butane lignan compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CNB021337004A CN1193980C (en) 2002-09-04 2002-09-04 Method for synthesizing stereoselectively and efficiently diphenyl butane lignan compound

Publications (2)

Publication Number Publication Date
CN1405142A CN1405142A (en) 2003-03-26
CN1193980C true CN1193980C (en) 2005-03-23

Family

ID=4747344

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB021337004A Expired - Fee Related CN1193980C (en) 2002-09-04 2002-09-04 Method for synthesizing stereoselectively and efficiently diphenyl butane lignan compound

Country Status (1)

Country Link
CN (1) CN1193980C (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102126933B (en) * 2010-12-20 2013-03-20 湖南大学 Diphenyl propane lignan compound and preparation method thereof
CN103113223B (en) * 2013-01-23 2016-01-20 安徽医科大学 Scabrous Patrinia Root A prime, B prime and preparation method thereof and the application on antitumor drug
CN111205171A (en) * 2020-01-13 2020-05-29 晋城天成科创股份有限公司 New synthetic method of nordihydroguaiaretic acid (NDGA)

Also Published As

Publication number Publication date
CN1405142A (en) 2003-03-26

Similar Documents

Publication Publication Date Title
CH657615A5 (en) ARYLIC DERIVATIVES OF PIPERAZINE, THEIR PREPARATION PROCESS.
JPS59144780A (en) Manufacture of chroman derivative
JPS6019908B2 (en) 1,3-dioxolen-2-one derivative
HU183108B (en) Process for preparing new acetophenone derivatives
JP6310612B2 (en) Filigenin ibuprofen ester, its preparation method and its application
US4218567A (en) Process for aromatic ethers
CN103755541B (en) One class chalcone derivative and its production and use
CN1193980C (en) Method for synthesizing stereoselectively and efficiently diphenyl butane lignan compound
CN101066912A (en) Process of preparing trans-polyhydroxy diphenyl ethylene
HU203515B (en) Process for producing new calcon derivatives and pharmaceutical compositions containing them as active components
CN101066919A (en) Process of synthesizing shikolin dimethyl ether derivative
NO174848B (en) Analogous Process for Preparing Therapeutically Active Substitutes
DE2059985B2 (en) Right-handed, basic substituted phenylacetonitriles, processes for their preparation and pharmaceuticals containing these compounds
Wells et al. Synthesis of 2-azetidinones
WO2019100786A1 (en) Method for synthesizing 3-ethoxy-4-methoxybenzaldehyde
CN110183371B (en) Preparation process of zafirlukast intermediate
EP0588797A1 (en) N- 4,5-dihydroxy- and 4,5,8-trihydroxy-9,10-dihydro-9,10-dioxo-2-anthracene-yl]carbonyl]amino acids useful in the therapy of osteoarticular affections.
CN111087356B (en) Preparation method of Iguratimod
CN108440460B (en) Preparation method of perillene and analogues thereof
CN1882523B (en) Novel phenol derivative, and anti-trypanosomiasis medicine with the phenol derivative as effective ingredient
CN1280248C (en) Method for preparing 3-hydroxy-4,3',4',5' tetramethoxy bibenzil
CN101265246A (en) Trifluoromethyl substituted benzofuran derivatives and preparation method thereof
CN113214199B (en) Synthetic method of benzofuran-3-oxocarboxylate compound
CN1566116A (en) Process for preparing wedelia lactone and application thereof
NZ544155A (en) Carboxylic acid compound and medicine containing the same

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20050323

Termination date: 20120904