CN101906006B - Method for efficiently synthesizing cis-stilbene derivative and phosphate disodium salt predrug thereof - Google Patents

Method for efficiently synthesizing cis-stilbene derivative and phosphate disodium salt predrug thereof Download PDF

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CN101906006B
CN101906006B CN2009100526213A CN200910052621A CN101906006B CN 101906006 B CN101906006 B CN 101906006B CN 2009100526213 A CN2009100526213 A CN 2009100526213A CN 200910052621 A CN200910052621 A CN 200910052621A CN 101906006 B CN101906006 B CN 101906006B
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王建国
陈法贵
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Zhejiang Dade Pharmaceutical Group Co Ltd
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    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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Abstract

The invention discloses a preparation method of a compound shown in the formula II. The method comprises the following steps: (a) under the irradiation of 254nm of ultraviolet light, performing a Wittig reaction to obtain the compound shown in the formula II, wherein R represents CH3, C2H5, C3H7, CH2F, CHF2, CF3, CH2CF3, CF2CF3 or CF2CH3; and Rp represents Si(CH3)2t-Bu, C(C6H5)3, (CH3)3COCO or trityl resin. Further, the invention also discloses a preparation method of a phosphate disodium salt predrug of high-purity cis-stilbene derivative; and the method comprises the following steps: using oxygen to oxidize tetrabenzyl pyrophosphate or 2-chloro-1,3,2-dioxaphospholane and perform the phosphate esterification reaction, and using trimethylbromosilane and sodium methoxide to perform basic hydrolysis.

Description

The method of a kind of synthesizing cis-stilbene derivative and phosphate disodium salt predrug thereof
Technical field
It is synthetic to the present invention relates to compound, relates in particular to the high-efficiency synthesis method that tumor vascular targeting destroys the medicine cis-stilbene derivative.
Background technology
CombretastatinA-1 and A-4 (being abbreviated as CA-1 and CA-4) are tubulin growth inhibitor (pettit G R, SinghSB, Can.J.Chem. (1987) 652390-2396).
Though the discovery time of Combretastatins compounds is not long, but cause extensive studies interest.Current research shows that this class cis-stilbene derivative has the tumor vascular targeting destruction, and they are the new type antineoplastic medicines that have potentiality.
The committed step of synthetic this compounds is the Wittig reaction.To destroy the factor be cis-configuration to diphenylethylene the most effective unitary tumor vessel in Combretastatin, and the diphenylethylene compounds of transconfiguration is to very little of tumor vessel destruction.So in the complete synthesis process of this compounds, improve the stereoselectivity of Wittig reaction, increase the ratio of cis-isomeride, be to improve a crucial step of the efficient synthetic of productive rate.
Professor Pettit at first uses isovanillin and 3,4, and the 5-TMB is that raw material is through the synthetic CA-4 (J.Med.Chem of five steps reaction, 1995,38:1666), its ratio is Z/E=3/2, then, the method by column chromatography obtains purity greater than 98% CA-4, and overall yield is generally less than 30%.Calendar year 2001 OXigeneINC has proposed 3 hydroxyls with trityl chloride protection isovanillin, and with 3,4,5-trimethoxyphenyl methylene radical triphen base Phosphonium carries out the wittig reaction, sloughs trityl as protecting group then, thus synthetic CA-4 (WOO206279Al).To 3:1, overall yield is about 37% at 3:2 for the ratio of Z formula and E formula isomer.
In clinical use, CA-4 need be transformed into its disodic alkaliine water-soluble prodrug.Professor Pettit implements phosphating reaction (US4,996,237) with tetracol phenixin and dibenzyl phosphite.OxigeneINC company utilization carbon tetrabromide and dibenzyl phosphite carry out phosphating reaction (WOO206279Al).As everyone knows, tetracol phenixin is the very big chemical reagent of a kind of toxicity.
Therefore, this area presses for the high synthetic method of ratio that a kind of productive rate height and resulting CA-4Z formula and E formula isomer are provided.Simultaneously, this area also presses for provides a kind of easy and avoid using the method for synthesizing cis-stilbene derivative phosphate disodium salt predrug of the tetracol phenixin kind solvent of high poison.
Summary of the invention
The present invention aims to provide a kind of preparation method of formula II compound.
Another object of the present invention provides a kind of preparation method of formula IV compound.
A further object of the present invention provides a kind of preparation method of formula V compound.
The 4th purpose of the present invention provides a kind of preparation method of formula VI compound.
In a first aspect of the present invention, a kind of preparation method suc as formula the II compound is provided, described method comprises step:
(a) under the 254nm UV-irradiation, uncommon (Wittig) reaction of carrying out loving and respect one's elder brother Wei obtains formula II compound:
Figure G2009100526213D00021
Wherein: R is CH 3, C 2H 5, C 3H 7, CH 2F, CHF 2, CF 3, CH 2CF 3, CF 2CF 3, or CF 2CH 3Rp is Si (CH 3) 2T-Bu, C (C 6H 5) 3, (CH 3) 3COCO or trityl resin.
In another preference, described wittig reaction was carried out 4-12 hour at subzero 10 ℃ to subzero 40 ℃.
In another preference, in the described wittig reaction with tetrahydrofuran (THF) as solvent.
In a second aspect of the present invention, a kind of preparation method of formula III compound is provided, described method comprises step:
(a) under the 254nm UV-irradiation, uncommon (Wittig) reaction of carrying out loving and respect one's elder brother Wei obtains formula II compound:
Wherein: R is CH 3, C 2H 5, C 3H 7, CH 2F, CHF 2, CF 3, CH 2CF 3, CF 2CF 3, or CF 2CH 3Rp is Si (CH 3) 2T-Bu, C (C 6H 5) 3, (CH 3) 3COCO or trityl resin; With
(b) formula II compound and hydrochloric acid reaction are obtained the formula III compound:
Figure G2009100526213D00032
Wherein: R is CH 3, C 2H 5, C 3H 7, CH 2F, CHF 2, CF 3, CH 2CF 3, CF 2CF 3, or CF 2CH 3
In another preference, concentration of hydrochloric acid is 37v/v% in the reaction of step (b).
In another preference, add the trifluoroacetic acid of catalytic amount in the reaction of step (b), carry out crystallization at subzero 5 ℃ to 0 ℃.
In a third aspect of the present invention, a kind of preparation method of formula IV compound is provided, described method comprises step:
Formula III compound and tetra-sodium four benzyl esters are carried out phosphating reaction in the presence of organic bases, obtain formula IV compound:
Wherein: R is CH 3, C 2H 5, C 3H 7, CH 2F, CHF 2, CF 3, CH 2CF 3, CF 2CF 3, or CF 2CH 3
Described organic bases is selected from potassium tert.-butoxide, sodium tert-butoxide, triethylamine or diisopropylethylamine.
In another preference, described phosphating reaction carried out 40-80 minute at 50-70 ℃.
In another preference, described phosphating reaction with acetonitrile as solvent.
In another preference, described method comprises step:
(1) under the 254nm UV-irradiation, uncommon (Wittig) reaction of carrying out loving and respect one's elder brother Wei obtains formula II compound:
Figure G2009100526213D00042
Wherein: R is CH 3, C 2H 5, C 3H 7, CH 2F, CHF 2, CF 3, CH 2CF 3, CF 2CF 3, or CF 2CH 3Rp is Si (CH 3) 2T-Bu, C (C 6H 5) 3, (CH 3) 3COCO or trityl resin;
(2) formula II compound and hydrochloric acid reaction are obtained the formula III compound:
Figure G2009100526213D00043
(3) formula III compound and tetra-sodium four benzyl esters are carried out phosphating reaction in the presence of organic bases, obtain formula IV compound:
Figure G2009100526213D00051
Described organic bases is selected from potassium tert.-butoxide, sodium tert-butoxide, triethylamine or diisopropylethylamine.
In a fourth aspect of the present invention, a kind of preparation method of formula V compound is provided, described method comprises step:
With formula III compound and 2-chloro-1,3,2-two phosphine oxide heterocycle pentanes add oxygen in the presence of triethylamine or diisopropylethylamine, carry out phosphating reaction, obtain formula V compound:
Figure G2009100526213D00052
Wherein: R is CH 3, C 2H 5, C 3H 7, CH 2F, CHF 2, CF 3, CH 2CF 3, CF 2CF 3, or CF 2CH 3
In another preference, described phosphating reaction with tetrahydrofuran (THF) as solvent.
In another preference, described method comprises step:
(i) under the 254nm UV-irradiation, uncommon (Wittig) reaction of carrying out loving and respect one's elder brother Wei obtains formula II compound:
Wherein: R is CH 3, C 2H 5, C 3H 7, CH 2F, CHF 2, CF 3, CH 2CF 3, CF 2CF 3, or CF 2CH 3Rp is Si (CH 3) 2T-Bu, C (C 6H 5) 3, (CH 3) 3COCO or trityl resin;
(ii) formula II compound and hydrochloric acid reaction are obtained the formula III compound:
Figure G2009100526213D00061
(iii) with formula III compound and 2-chloro-1,3,2-two phosphine oxide heterocycle pentanes add oxygen in the presence of triethylamine or diisopropylethylamine, carry out phosphating reaction, obtain formula V compound:
In a fifth aspect of the present invention, a kind of preparation method of formula VI compound is provided, described method comprises step:
With formula IV compound or formula V compound bromotrimethylsilane and sodium methylate hydrolysis, obtain formula VI compound:
Figure G2009100526213D00063
Wherein: R is CH 3, C 2H 5, C 3H 7, CH 2F, CHF 2, CF 3, CH 2CF 3, CF 2CF 3, or CF 2CH 3
In view of the above, the invention provides the high synthetic method of ratio of a kind of productive rate height and resulting CA-4Z formula and E formula isomer.Simultaneously, the present invention also provides a kind of easy and avoid using the method for synthesizing cis-stilbene derivative phosphate disodium salt predrug of the tetracol phenixin kind solvent of high poison.
Embodiment
The contriver is surprised to find under the 254nm ultraviolet radiation through extensive and deep research, implements the Wittig reaction, has changed reaction mechanism, can access high yield more and be about 90% and the ratio of Z/E be about 10 toluylene product.
Further, the contriver is with tetra-sodium four benzyl esters or 2-chloro-1,3, and 2-two phosphine oxide heterocycle pentanes carry out phosphating reaction, and purifying easily and have an advantage of big reagent such as the toxicity of avoiding using tetracol phenixin.
The invention provides a kind of preparation method suc as formula the II compound, is under the 254nm uv-radiation, carries out following Wittig reaction:
Figure G2009100526213D00071
Wherein: R is CH 3, C 2H 5, C 3H 7, CH 2F, CHF 2, CF 3, CH 2CF 3, CF 2CF 3, or CF 2CH 3Rp is Si (CH 3) 2T-Bu, C (C 6H 5) 3, (CH 3) 3COCO or trityl resin.
Above-mentioned reaction conditions is: subzero 40 ℃ of the subzero 10-of temperature of reaction, reaction times 4-12 hour, tetrahydrofuran (THF) was as solvent.
From the product II that above-mentioned Wittig reaction obtains, with the trifluoroacetic acid of 37% hydrochloric acid and catalytic amount, toluene is sloughed protecting group Rp as solvent, and under subzero 5-0 ℃ stirring, crystallization goes out cis-stilbene derivative III;
Figure G2009100526213D00072
Wherein: R is CH 3, C 2H 5, C 3H 7, CH 2F, CHF 2, CF 3, CH 2CF 3, CF 2CF 3, or CF 2CH 3
The present invention also provides a kind of preparation method of formula IV compound, is exactly cis-stilbene derivative III, under the effect of organic bases, carries out phosphating reaction with tetra-sodium four benzyl esters, obtains compound IV;
Wherein: R is CH 3, C 2H 5, C 3H 7, CH 2F, CHF 2, CF 3, CH 2CF 3, CF 2CF 3, or CF 2CH 3
Described organic bases is selected from: potassium tert.-butoxide, sodium tert-butoxide, triethylamine or diisopropylethylamine;
Described phosphating reaction carried out 40-80 minute at 50-70 ℃; Preferably carried out 50-70 minute at 55-65 ℃;
Described phosphating reaction with acetonitrile, tetrahydrofuran (THF), methylene dichloride as solvent; Preferred acetonitrile;
Described preparation method also comprises step: formula IV compound is carried out purifying; Described purifying can use method well known in the art to carry out, such as but not limited to, the combination of filtration, column chromatography, thermogravimetric crystallization, mixed solvent recrystallization or two or more mode.
The present invention also provides a kind of preparation method of formula V compound, is exactly cis-stilbene derivative III, under the effect of triethylamine or diisopropylethylamine, with 2-chloro-1,3,2-two phosphine oxide heterocycle pentanes, use dioxygen oxidation subsequently, implement phosphating reaction, obtain formula V compound;
Figure G2009100526213D00082
Wherein: R is CH 3, C 2H 5, C 3H 7, CH 2F, CHF 2, CF 3, CH 2CF 3, CF 2CF 3, or CF 2CH 3
Under the effect of triethylamine or diisopropylethylamine, cis-stilbene derivative III and 2-chloro-1,3,2-two phosphine oxide heterocycle pentanes be reflected at subzero 10 to subzero 5 ℃ carry out 15-60 minute after, being heated to 50-70 ℃ carried out 8-12 hour, aerating oxygen continues reaction 15-22 hour then, obtains formula V compound; Reaction solvent is selected from tetrahydrofuran (THF), acetonitrile, methylene dichloride; Preferred tetrahydrofuran (THF); The preferred high-purity dry oxygen of oxygen that feeds.
Described preparation method also comprises step: formula V compound is carried out purifying; Described purifying can use method well known in the art to carry out, such as but not limited to, the combination of filtration, column chromatography, thermogravimetric crystallization, mixed solvent recrystallization or two or more mode.
Formula IV or formula V compound can obtain cis-stilbene derivative phosphate disodium salt predrug formula VI compound with bromotrimethylsilane and sodium methylate hydrolysis;
Figure G2009100526213D00091
In a preference of the present invention, the preparation method of formula VI compound comprises step:
Formula III compound and tetra-sodium four benzyl esters are carried out phosphating reaction in the presence of organic bases, obtain formula IV compound:
Figure G2009100526213D00092
Described organic bases is selected from potassium tert.-butoxide, sodium tert-butoxide, triethylamine or diisopropylethylamine;
Perhaps, with formula III compound and 2-chloro-1,3,2-two phosphine oxide heterocycle pentanes add oxygen in the presence of triethylamine or diisopropylethylamine, carry out phosphating reaction, obtain formula V compound:
Figure G2009100526213D00093
Then, formula IV or formula V compound can obtain cis-stilbene derivative phosphate disodium salt predrug formula VI compound with bromotrimethylsilane and sodium methylate hydrolysis.
In another preference of the present invention, the preparation method of formula VI compound comprises step:
The first step, under the 254nm UV-irradiation, uncommon (Wittig) reaction of carrying out loving and respect one's elder brother Wei obtains formula II compound:
Figure G2009100526213D00101
Wherein: R is CH 3, C 2H 5, C 3H 7, CH 2F, CHF 2, CF 3, CH 2CF 3, CF 2CF 3, or CF 2CH 3Rp is Si (CH 3) 2T-Bu, C (C 6H 5) 3, (CH 3) 3COCO or trityl resin;
In second step, formula II compound and hydrochloric acid reaction are obtained the formula III compound:
Figure G2009100526213D00102
The 3rd step, formula III compound and tetra-sodium four benzyl esters are carried out phosphating reaction in the presence of organic bases, obtain formula IV compound:
Figure G2009100526213D00103
Described organic bases is selected from potassium tert.-butoxide, sodium tert-butoxide, triethylamine or diisopropylethylamine;
Perhaps, with formula III compound and 2-chloro-1,3,2-two phosphine oxide heterocycle pentanes add oxygen in the presence of triethylamine or diisopropylethylamine, carry out phosphating reaction, obtain formula V compound:
Figure G2009100526213D00104
In the 4th step, formula IV or formula V compound can obtain cis-stilbene derivative phosphate disodium salt predrug formula VI compound with bromotrimethylsilane and sodium methylate hydrolysis.
Figure G2009100526213D00111
The above-mentioned feature that the present invention mentions, or the feature that embodiment mentions can arbitrary combination.All features that this case specification sheets is disclosed can with any composition forms and usefulness, each feature that is disclosed in the specification sheets can anyly provide the alternative characteristics of identical, impartial or similar purpose to replace.Therefore removing has special instruction, and the feature that is disclosed only is the general example of equalization or similar features.
Major advantage of the present invention is:
1, use the 254nm ultraviolet radiation to implement the Wittig reaction, toluylene product productive rate height, the ratio of Z/E is big simultaneously;
2, use tetra-sodium four benzyl esters or 2-chloro-1,3,2-two phosphine oxide heterocycle pentanes carry out phosphating reaction, and purifying is convenient and avoided the big reagent of toxicity.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio, ratio, ratio or umber by weight.
Unit in the percent weight in volume among the present invention is well-known to those skilled in the art, for example is meant the weight of solute in 100 milliliters solution.
Unless otherwise defined, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.
Embodiment 1
Preparation 3,4,5-trimethoxy-4 '-methoxyl group-3 '-dimethyl tertiary butyl siloxy-(Z)-toluylene (IIa)
Under argon shield; thermometer, mechanical stirring are being housed, and constant pressure funnel and ultraviolet lamp import in silica tube and the dry 500ml three-necked bottle of crossing, and add bromination 3; 4,5-trimethoxyphenyl methylene radical triphen base Phosphonium 15.1g (28.8mmol) and 300ml tetrahydrofuran (THF).System is cooled to-30 ℃ with the dry ice-propanone bath, slowly splashes into 19.6ml n-Butyl Lithium hexane solution (1.6M), still keep-30 ℃ to continue to stir 1.5 hours after dripping off.Open ultraviolet lamp then, under uv-radiation, splash into 4-methoxyl group-3-dimethyl tertiary butyl siloxy phenyl aldehyde 7.7g (28.8mmol) tetrahydrofuran solution (50ml), dripped off in about 30 minutes, temperature still remains on-30 ℃, continues to stir 4.5 hours, at room temperature stirs then 10 hours.Close ultraviolet lamp, add the 70ml frozen water, and then add the 80ml ether, tell the ether layer.Water layer extracts with ether 300ml * 2; The combined ether layer is with distilled water 300ml * 3 washings, anhydrous magnesium sulfate drying; The pressure reducing and steaming solvent obtains the beige solid.This solid with acetic acid ethyl dissolution after, through rapid column chromatography instrument chromatographic separation, obtain faint yellow oily thing Z formula isomer 10.3g at last 1H-NMR (CDCl 3δ); 6.85 (dd, J=8Hz, 2Hz, 1H, 6 '-H); 6.80 (d, J=2Hz, 1H, 2 '-H); 6.74 (d, J=8Hz, 1H, 5 '-H); 6.53 (s, 2H, 2,6-H); 6.46 (AB J=12Hz, 1H, 1a-H); 6.42 (ABJ=12Hz, 1H, 1a '-H); 3.80 (s, 3H, 4-OCH 3); 3.77 (s, 3H, 4 '-OCH 3); 3.68 (s, 6H, 3,5-OCH 3); 0.92 (s, 9H, SiC (CH 3) 3); 0.06 (s, 6H, Si (CH 3) 2). ultimate analysis: C66.68; H 8.26 theoretical value (C 24H 34O 5Si) C 66.95; H 7.96.
Mp:127-128 ℃ of white crystal E formula isomer 1.0g; 1H-NMR (CDCl 3δ): 7.34 (dd, J=8﹠2Hz, 1H, 6 '-H); 7.22 (d, J=8Hz, 1H, 5 '-H); 6.90 (d, J=2Hz, 1H, 2 '-H); 6.88 (AB, J=16Hz, 1H, 1a-H); 6.82 (AB, J=16Hz, 1H, 1a '-H); 6.69 (s, 2H, 2,6-H); 3.92 (s, 6H, 3,5-OCH 3); 3.85 (s, 3H, 4-OCH 3); 3.81 (s, 3H, 4 '-OCH 3); 0.99 (s, 9H, SiC (CH 3) 3); 0.17 (s, 6H, Si (CH 3) 2); Ultimate analysis, experimental value: C 67.08; H 8.19, theoretical value (C 24H 34O 5Si): C 66.95; H 7.96.
Wittig reaction yield 91%, the ratio of Z/E is 10.3: 1.
Embodiment 2
Preparation 3,4,5-trimethoxy-4 '-oxyethyl group-3 '-dimethyl tertiary butyl siloxy-(Z)-toluylene (IIb)
Undertaken by embodiment one, replace 4-methoxyl group-3-dimethyl tertiary butyl siloxy phenyl aldehyde with 4-oxyethyl group-3-dimethyl tertiary butyl siloxy phenyl aldehyde 8.1g (28.8mmol) tetrahydrofuran solution (50ml).Obtain faint yellow oily thing Z formula isomer 10.1g 1H-NMR (CDCl 3δ); 6.81 (dd, J=8Hz, 2Hz, 1H, 6 '-H); 6.77 (d, J=2Hz, 1H, 2 '-H); 6.71 (d, J=8Hz, 1H, 5 '-H); 6.49 (s, 2H, 2,6-H); 6.42 (AB, J=12Hz, 1H, 1a-H); 6.37 (AB, J=12Hz, 1H, 1a '-H); 4.01 (q, J=7Hz, 2H ,-OCH 2-); 3.80 (s, 3H, 4-OCH 3); 3.68 (s, 6H, 3,5-OCH 3); 1.36 (t, J=7Hz, 3H ,-OCH 2CH 3); 0.90 (s, 9H, SiC (CH 3) 3); 0.05 (s, 6H, Si (CH 3) 2). ultimate analysis: C 67.50; H 8.32 theoretical value (C 25H 36O 5Si) C 67.57; H 8.11.
Mp:125-127 ℃ of white crystal E formula isomer 1.1g; 1H-NMR (CDCl 3δ): 7.41 (dd, J=8﹠2Hz, 1H, 6 '-H); 7.26 (d, J=8Hz, 1H, 5 '-H); 6.93 (d, J=2Hz, 1H, 2 '-H); 6.89 (AB, J=16Hz, 1H, 1a-H); 6.83 (AB, J=16Hz, 1H, 1a '-H); 6.69 (s, 2H, 2,6-H); 4.00 (q, J=7Hz, 2H ,-OCH 2-); 3.92 (s, 6H, 3,5-OCH 3); 3.85 (s, 3H, 4-OCH 3); 1.38 (t, J=7Hz, 3H ,-OCH 2CH 3); 0.95 (s, 9H, SiC (CH 3) 3); 0.12 (s, 6H, Si (CH 3) 2); Ultimate analysis, experimental value: C 67.86; H 8.43, theoretical value (C 25H 36O 5Si): C 67.57; H 8.11.
Wittig reaction yield 88%, the ratio of Z/E is 9.2: 1.
Embodiment 3
Preparation 3,4,5-trimethoxy-4 '-trifluoro ethoxy-3 '-dimethyl tertiary butyl siloxy-(Z)-toluylene (IIc)
Undertaken by embodiment one, replace 4-methoxyl group-3-dimethyl tertiary butyl siloxy phenyl aldehyde with 4-trifluoro ethoxy-3-dimethyl tertiary butyl siloxy phenyl aldehyde 9.6g (28.8mmol) tetrahydrofuran solution (50ml).Obtain faint yellow oily thing Z formula isomer 11.5g 1H-NMR (CDCl 3δ); 6.71 (m, 1H, 6 '-H); 6.55 (m, 2H, 2 ', 5 '-H); 6.46 (s, 2H, 2,6-H); 6.42 (m, 2H, alkene-H); 4.34 (q, J=8Hz, 2H ,-OCH 2CF 3); 3.83 (s, 3H, 4-OCH 3); 3.69 (s, 6H, 3,5-OCH 3); 0.96 (s, 9H, SiC (CH 3) 3); 0.07 (s, 6H, Si (CH 3) 2). ultimate analysis: C 61.02; H 7.21 theoretical value (C 25H 33F 3O 5Si) C 60.24; H 6.63.
White crystal E formula isomer 1.2g. 1H-NMR (CDCl 3δ): 7.61 (dd, J=8﹠2Hz, 1H, 6 '-H); 7.36 (d, J=8Hz, 1H, 5 '-H); 7.03 (d, J=2Hz, 1H, 2 '-H); 6.92 (d, J=16Hz, 1H, 1a-H); 6.88 (d, J=16Hz, 1H, 1a '-H); 6.70 (s, 2H, 2,6-H); 4.38 (q, J=8Hz, 2H ,-OCH 2CF 3); 3.98 (s, 6H, 3,5-OCH 3); 3.89 (s, 3H, 4-OCH 3); 0.97 (s, 9H, SiC (CH 3) 3); 0.14 (s, 6H, Si (CH 3) 2); Ultimate analysis, experimental value: C 60.78; H 7.03, theoretical value (C 25H 33F 3O 5Si) C 60.24; H 6.63.
Wittig reaction yield 88.6%, the ratio of Z/E is 9.6: 1.
Embodiment 4
Preparation 3,4,5-trimethoxy-4 '-difluoro-methoxy-3 '-dimethyl tertiary butyl siloxy-(Z)-toluylene (IId)
Undertaken by embodiment one, replace 4-methoxyl group-3-dimethyl tertiary butyl siloxy phenyl aldehyde with 4-difluoro-methoxy-3-dimethyl tertiary butyl siloxy phenyl aldehyde 8.7g (28.8mmol) tetrahydrofuran solution (50ml).Obtain faint yellow oily thing Z formula isomer 10.8g 1H-NMR (CDCl 3δ); 6.94 (d, J=8Hz, 1H, 5 '-H); 6.73 (d, J=2Hz, 1H, 2 '-H); 6.65 (dd, J=8Hz﹠2Hz, 1H, 6 '-H); 6.48 (s, 2H, 2,6-H); 6.47 (m 2H, alkene-H); 6.45 (t, J=74Hz, 1H ,-OCHF 2); 3.84 (s, 3H, 4-OCH 3); 3.69 (s, 6H, 3,5-OCH 3); 0.91 (s, 9H, SiC (CH 3) 3); 0.06 (s, 6H, Si (CH 3) 2). ultimate analysis: C 62.05; H 7.08 theoretical value (C 24H 32F 2O 5Si) C 61.80; H 6.87.
White crystal E formula isomer 1.1g. 1H-NMR (CDCl 3δ): 7.49 (d, J=8Hz, 1H, 5 '-H); 7.11 (m, 2H, 2 ', 6 '-H); 6.97 (s, 2H, 2,6-H); 6.73 (m 2H, alkene-H); 6.53 (t, J=74Hz, 1H ,-OCHF 2); 3.92 (s, 6H, 3,5-OCH 3); 3.88 (s, 3H, 4-OCH 3); 0.92 (s, 9H, SiC (CH 3) 3); 0.07 (s, 6H, Si (CH 3) 2). ultimate analysis, experimental value: C 62.21; H 7.11, theoretical value (C 24H 32F 2O 5Si) C 61.80; H 6.87.
Wittig reaction yield 88.8%, the ratio of Z/E is 9.8: 1.
Embodiment 5
Preparation 3,4,5-trimethoxy-4 '-methoxyl group-3 '-three benzyloxy-(Z)-toluylene (IIe)
Undertaken by embodiment one, replace 4-methoxyl group-3-dimethyl tertiary butyl siloxy phenyl aldehyde with 4-methoxyl group-3-triphen methoxybenzaldehyde 11.3g (28.8mmol) tetrahydrofuran solution (50ml).Obtain faint yellow solid, obtain white crystal Z formula isomer 13.1g with ethyl alcohol recrystallization 1H-NMR (CDCl 3δ); 7.28 (m, 15H, OC (C 6H 5) 3) 7.14 (d, J=2Hz, 1H, 2 '-H); 7.06 (dd, J=8Hz, 2Hz, 1H, 6 '-H); 6.79 (d, J=8Hz, 1H, 5 '-H); 6.49 (s, 2H, 2,6-H); 6.44 (AB J=12Hz, 1H, 1a-H); 6.40 (AB J=12Hz, 1H, 1a '-H); 3.80 (s, 3H, 4-OCH 3); 3.77 (s, 3H, 4 '-OCH 3); 3.68 (s, 6H, 3,5-OCH 3). ultimate analysis: C 80.01; H6.32 theoretical value (C 37H 34O 5) C 79.57; H 6.09.
White crystal E formula isomer 1.3g 1H-NMR (CDCl 3δ): 7.51 (m, 15H, OC (C 6H 5) 3); 7.31 (dd, J=8﹠2Hz, 1H, 6 '-H); 7.22 (d, J=8Hz, 1H, 5 '-H); 6.90 (d, J=2Hz, 1H, 2 '-H); 6.83 (AB, J=16Hz, 1H, 1a-H); 6.79 (AB, J=16Hz, 1H, 1a '-H); 6.69 (s, 2H, 2,6-H); 3.92 (s, 6H, 3,5-OCH 3); 3.85 (s, 3H, 4-OCH 3); 3.81 (s, 3H, 4 '-OCH 3); Ultimate analysis, experimental value: C 79.91; H 6.21, theoretical value (C 37H 34O 5) C 79.57; H 6.09.
Wittig reaction yield 89.6%, the ratio of Z/E is 10.1: 1.
Embodiment 6
Preparation 3,4,5-trimethoxy-4 '-oxyethyl group-3 '-three benzyloxy-(Z)-toluylene (IIf)
Undertaken by embodiment one, replace 4-methoxyl group-3-dimethyl tertiary butyl siloxy phenyl aldehyde with 4-oxyethyl group-3-triphen methoxybenzaldehyde 11.8g (28.8mmol) tetrahydrofuran solution (50ml).Obtain faint yellow solid, obtain white crystal Z formula isomer 13.1g with ethyl alcohol recrystallization 1H-NMR (CDCl 3δ); 7.31 (m, 15H, OC (C 6H 5) 3) 7.15 (d, J=2Hz, 1H, 2 '-H); 7.09 (dd, J=8Hz, 2Hz, 1H, 6 '-H); 6.80 (d, J=8Hz, 1H, 5 '-H); 6.49 (s, 2H, 2,6-H); 6.44 (AB J=12Hz, 1H, 1a-H); 6.40 (AB J=12Hz, 1H, 1a '-H); 4.07 (q, J=7Hz, 2H ,-OCH 2-); 3.83 (s, 3H, 4-OCH 3); 3.68 (s, 6H, 3,5-OCH 3) .1.35 (t, J=7Hz, 3H ,-OCH 2CH 3). ultimate analysis: C80.10; H6.33 theoretical value (C 38H 36O 5) C 79.72; H 6.29.
White crystal E formula isomer 1.3g 1H-NMR (CDCl 3δ): 7.55 (m, 15H, OC (C 6H 5) 3); 7.43 (dd, J=8﹠2Hz, 1H, 6 '-H); 7.30 (d, J=8Hz, 1H, 5 '-H); 6.96 (d, J=2Hz, 1H, 2 '-H); 6.91 (AB, J=16Hz, 1H, 1a-H); 6.85 (AB, J=16Hz, 1H, 1a '-H); 6.70 (s, 2H, 2,6-H); 4.06 (q, J=7Hz, 2H ,-OCH 2-); 3.94 (s, 6H, 3,5-OCH 3); 3.89 (s, 3H, 4-OCH 3); 1.40 (t, J=7Hz, 3H ,-OCH 2CH 3); Ultimate analysis, experimental value: C 79.93; H 6.33, theoretical value (C 38H 36O 5) C 79.72; H6.29.
Wittig reaction yield 86.8%, the ratio of Z/E is 9.2: 1.
Embodiment 7
Preparation 3,4,5-trimethoxy-4 '-trifluoro ethoxy-3 '-three benzyloxy-(Z)-toluylene (IIg)
Undertaken by embodiment one, replace 4-methoxyl group-3-dimethyl tertiary butyl siloxy phenyl aldehyde with 4-trifluoro ethoxy-3-triphen methoxybenzaldehyde 13.3g (28.8mmol) tetrahydrofuran solution (50ml).Obtain faint yellow solid, obtain white crystal Z formula isomer 13.9g with ethyl alcohol recrystallization 1H-NMR (CDCl 3δ); 7.27 (m, 15H, OC (C 6H 5) 3) 6.74 (m, 1H, 6 '-H); 6.58 (m, 2H, 2 ', 5 '-H); 6.46 (s, 2H, 2,6-H); 6.40 (m, 2H, alkene-H); 4.31 (q, J=8Hz, 2H ,-OCH 2CF 3); 3.83 (s, 3H, 4-OCH 3); 3.69 (s, 6H, 3,5-OCH 3); Ultimate analysis: C72.97; H5.68 theoretical value (C 38H 33F 3O 5) C72.84; H 5.27.
White crystal E formula isomer 1.5g 1H-NMR (CDCl 3δ); 7.58 (m, 15H, OC (C 6H 5) 3); 7.63 (dd, J=8﹠2Hz, 1H, 6 '-H); 7.36 (d, J=8Hz, 1H, 5 '-H); 7.03 (d, J=2Hz, 1H, 2 '-H); 6.92 (d, J=16Hz, 1H, 1a-H); 6.88 (d, J=16Hz, 1H, 1a '-H); 6.70 (s, 2H, 2,6-H); 4.38 (q, J=8Hz, 2H ,-OCH 2CF 3); 3.98 (s, 6H, 3,5-OCH 3); 3.89 (s, 3H, 4-OCH 3). ultimate analysis, experimental value: C 72.90; H 5.64, theoretical value (C 38H 33F 3O 5) C72.84; H 5.27.
Wittig reaction yield 85.4%, the ratio of Z/E is 9.3: 1.
Embodiment 8
Preparation 3,4,5-trimethoxy-4 '-difluoro-methoxy-3 '-three benzyloxy-(Z)-toluylene (IIh)
Undertaken by embodiment one, replace 4-methoxyl group-3-dimethyl tertiary butyl siloxy phenyl aldehyde with 4-difluoro-methoxy-3-triphen methoxybenzaldehyde 12.4g (28.8mmol) tetrahydrofuran solution (50ml).Obtain faint yellow solid, obtain white crystal Z formula isomer 13.5g with ethyl alcohol recrystallization 1H-NMR (CDCl 3δ); 7.35 (m, 15H, OC (C 6H 5) 3) 6.98 (d, J=8Hz, 1H, 5 '-H); 6.77 (d, J=2Hz, 1H, 2 '-H); 6.69 (dd, J=8Hz﹠2Hz, 1H, 6 '-H); 6.51 (s, 2H, 2,6-H); 6.48 (m 2H, alkene-H); 6.45 (t, J=74Hz, 1H ,-OCHF 2); 3.84 (s, 3H, 4-OCH 3); 3.69 (s, 6H, 3,5-OCH 3); Ultimate analysis: C 74.96; H5.66 theoretical value (C 37H 32F 2O 5) C 74.75; H 5.39.
White crystal E formula isomer 1.4g 1H-NMR (CDCl 3δ): 7.55 (m, 15H, OC (C 6H 5) 3); 7.50 (d, J=8Hz, 1H, 5 '-H); 7.11 (m, 2H, 2 ', 6 '-H); 6.98 (s, 2H, 2,6-H); 6.75 (m 2H, alkene-H); 6.53 (t, J=74Hz, 1H ,-OCHF 2); 3.92 (s, 6H, 3,5-OCH 3); 3.88 (s, 3H, 4-OCH 3); . ultimate analysis, experimental value: C 74.89; H 5.58, theoretical value (C 37H 32F 2O 5) C 74.75; H5.39.
Wittig reaction yield 87.1%, the ratio of Z/E is 9.6: 1.
Embodiment 9
Preparation 3,4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene-O '-trityl resin (IIi)
Undertaken by embodiment one, restrain (aldehyde group content 1.89mmol./g) (28.8mmol) tetrahydrofuran solution (50ml) replacement 4-methoxyl group-3-dimethyl tertiary butyl siloxy phenyl aldehyde with the immobilized isovanillin 15.3 of trityl chloride resin.After adding the water termination reaction, filter, filtrate is under agitation poured in 3 liters of ethanol, is settled out polymkeric substance.Filter, it is white 3,4 that vacuum-drying gets, 5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene-O '-trityl resin 19.6 grams.Turnover ratio 91.4%.Double bond content: 1.34mmol./g.
Embodiment 10
Preparation 3,4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene CA-4 (IIIa)
Method one; Thermometer, mechanical stirring are being housed, in the 500ml three-necked bottle of constant pressure funnel, are adding 3,4,5-trimethoxy-4 '-methoxyl group-3 '-three benzyloxy-(Z)-toluylene (IIe) 100g (0.18mol) and 200ml toluene.Under the room temperature, stirring and dissolving. splash into 40 milliliters of 37% hydrochloric acid (wherein being added with 1 gram trifluoroacetic acid) then, follow the tracks of reaction, disappear until reaction raw materials point with the thin plate chromatography.Add distilled water 100ml, reaction system is cooled to 0-5 ℃, stir down, crystallization goes out white solid, filters, washing, get white crystal 48.9 grams after the vacuum-drying, productive rate 86.0%. gets 3 with ethyl acetate/normal hexane recrystallization, 4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene CA-4 (IIIa).
Method two; Get 3,4,5-trimethoxy-4 '-methoxyl group-(Z)-toluylene-O '-trityl resin (IIi) 30g (containing CA-4 amount 40.2mmol.) is dissolved in 200 milliliters of tetrahydrofuran (THF)s, adds 37% concentrated hydrochloric acid 30ml, under 40 ℃-45 ℃, stirs 1 hour.After adding the 200ml anhydrous diethyl ether, filter and remove insolubles, tell organic phase, the saturated common salt water washing, anhydrous magnesium sulfate drying boils off solvent, gets thick product.With ethyl acetate/normal hexane recrystallization.Get the white particulate crystal 3,4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene CA-4 (IIIa) 11.3 grams.Productive rate 89%.116-117 ℃; TOF-MS (ES+): 317.1390[M+H +]; 339.1207[M+Na +] (theoretical molecular mass: molecular formula: C 18H 20O 5316.13).UVλ max(logε)in?CHCl 3：238(1.429)，298(0.7975)nm。FT-IR(KBr)v max3506s，2994m，2939m，2838m，1618m，1581s，1507s，1456s，1285s，1222s，1125vs，1030m，1011m，995m，cm -1。 1H-NMR (CDCl 3δ): 3.691 (s, 6H, 3,5-OCH 3); 3.835 (s, 3H, 4 '-OCH 3); 3.852 (s, 3H, 4-OCH 3); 5.529 (broad, 1H, OH); 6.389,6.419,6.448,6.479 (AB system, 2H, J=12Hz, cis-HC=CH-); 6.524 (s, 2H, 2,6-ArH); 6.7265 (d, 1H, J=8.4Hz, 5 '-ArH); 6.787 (d-d, 1H, J=8.4Hz, J=1.6Hz, 6 '-ArH); 6.913 (d, 1H, J=1.6Hz, 2 '-ArH) ppm. 13C-NMR(400MHz，CDCl 3)δ55.995(3，4，5-OCH 3)；60.827(4’-OCH 3)；106.458(2，6-ArC)；110.462(5’-ArC)；115.124(2’-ArC)；121.071(6’-ArC)；129.088(＝C 1a’)；129.460(C 1a＝)；130.789(1’-ArC)；132.657(1-ArC)；137.552(4-ArC)；145.368(4’-ArC)；45.835(3’-ArC)；152.940(3，5-ArC)ppm。Ultimate analysis, experimental value: C68.11; H 6.51, theoretical value: (C 18H 20O 5): C 68.35; H 6.37.
Embodiment 11
Preparation 3,4,5-trimethoxy-4 '-oxyethyl group-3 '-hydroxyl-(Z)-toluylene (IIIb)
Undertaken by embodiment ten methods one, with 3,4,5 trimethoxies-4 '-oxyethyl group-3 '-three benzyloxy-(Z)-toluylene (IIf) 100g (0.175mol) replacement 3,4,5-trimethoxy-4 '-methoxyl group-3 '-three benzyloxy-(Z)-toluylene (IIe).Obtain 51.4 gram white crystal IIIb, productive rate 89%. 1H-NMR (CDCl 3δ); 7.17 (d, J=2Hz, 1H, 2 '-H); 7.10 (dd, J=8Hz, 2Hz, 1H, 6 '-H); 6.80 (d, J=8Hz, 1H, 5 '-H); 6.50 (s, 2H, 2,6-H); 6.44 (AB J=12Hz, 1H, 1a-H); 6.40 (ABJ=12Hz, 1H, 1a '-H); 5.12 (s, 1H, OH); 4.07 (q, J=7Hz, 2H ,-OCH 2-); 3.83 (s, 3H, 4-OCH 3); 3.68 (s, 6H, 3,5-OCH 3) .1.35 (t, J=7Hz, 3H ,-OCH 2CH 3). ultimate analysis, experimental value: C 69.21; H 6.79, theoretical value: (C 19H 22O 5): C69.09; H 6.67.
Embodiment 12
Preparation 3,4,5-trimethoxy-4 '-trifluoro ethoxy-3 '-hydroxyl-(Z)-toluylene (IIIc)
Undertaken by embodiment ten methods one, with 3,4,5-trimethoxy-4 '-trifluoro ethoxy-3 '-three benzyloxy-(Z)-toluylene (IIg) 100g (0.160mol) replacement 3,4,5-trimethoxy-4 '-methoxyl group-3 '-three benzyloxy-(Z)-toluylene (IIe).Obtain 52.2 gram white crystal IIIc, productive rate 85%. 1H-NMR (CDCl 3δ); 6.77 (m, 1H, 6 '-H); 6.61 (m, 2H, 2 ', 5 '-H); 6.46 (s, 2H, 2,6-H); 6.40 (m, 2H, alkene-H); 5.37 (s, 1H, OH); 4.31 (q, J=8Hz, 2H ,-OCH 2CF 3); 3.83 (s, 3H, 4-OCH 3); 3.69 (s, 6H, 3,5-OCH 3); Ultimate analysis, experimental value: C 59.75; H 5.07, theoretical value: (C 19H 19F 3O 5): C59.38; H 4.95.
Embodiment 13
Preparation 3,4,5-trimethoxy-4 '-difluoro-methoxy-3 '-hydroxyl-(Z)-toluylene (IIId)
Undertaken by embodiment ten methods one, with 3,4,5-trimethoxy-4 '-difluoro-methoxy-3 '-three benzyloxy-(Z)-toluylene (IIh) 100g (0.168mol) replacement 3,4,5-trimethoxy-4 '-methoxyl group-3 '-three benzyloxy-(Z)-toluylene (IIe).Obtain 50.9 gram white crystal IIId, productive rate 86.1%. 1H-NMR (CDCl 3δ); 6.92 (d, J=8Hz, 1H, 5 '-H); 6.71 (d, J=2Hz, 1H, 2 '-H); 6.63 (dd, J=8Hz﹠2Hz, 1H, 6 '-H); 6.50 (s, 2H, 2,6-H); 6.42 (m 2H, alkene-H); 6.45 (t, J=74Hz, 1H ,-OCHF 2); 5.77 (s, 1H, OH); 3.84 (s, 3H, 4-OCH 3); 3.69 (s, 6H, 3,5-OCH 3); Ultimate analysis, experimental value: C 61.71; H 5.56, theoretical value: (C 18H 18F 2O 5): C61.36; H5.11.
Embodiment 14
Preparation 3,4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene-O '-phosphate dibenzyl ester (IVa)
At one through putting into 40 grams 3 in thorough drying and 1 liter of three-necked bottle by argon gas, 4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene CA-4 (IIIa) (0.126mol) and potassium tert.-butoxide 15.5 grams (0.139mol) with the dry acetonitrile dissolving of 400mL, be heated to 60 ℃, splash into 67.8 gram (0.126mol) tetra-sodiums, four benzyl ester 200ml acetonitrile solutions, continue to stir after 60 minutes cooling, elimination white depositions.Filtrate decompression boils off solvent, and as the drip washing solvent, silicagel column (1200 * 180) chromatography separated obtaining the lurid oily matter of 80 grams fast with 3: 2 sherwood oil (60-90 ℃)/ethyl acetate.Obtain colourless acicular crystal IVa 72 grams through ethyl acetate-normal hexane recrystallization.Productive rate 98%. fusing points: 73 ℃.Rf 0.26 (n-hexane/ethyl acetate V/V 3: 2).TOF-MS (ES +): 577.2004[M+H +]; 599.181[M+Na +] (theoretical molecular mass: molecular formula: C 32H 33O 8P; 576.19).UVλ max(logε)in?CHCl 3：237.5(1112)，259(0.5845)，291(0.4906)nm。FT-IR(KBr)v max3060m，3033m，2935m，1605w，1579m，1512m，1491m，1445s，1277s，1130s，1010s，cm -1。 1H-NMR (CDCl 3δ); 3.65 (s, 6H, 3,5-OCH 3); 3.74 (s, 3H, 4 '-OCH 3); 3.79 (s, 3H, 4-OCH 3); 5.10 (d, 4H, 3J P-H=7.8Hz, POCH 2); 6.37,6.40,6.42,6.45 (AB system, 2H, J=12Hz, cis-HC=CH-); 6.47 (s, 2H, 2,6-ArH); 6.769 (d, 1H, J=8.4Hz, 5 '-ArH); 7.049 (d-m, 1H, J=8.4Hz, 6 '-ArH); 7.15 (m, 1H, 2 '-ArH); 7.32-7.22 (m, 10H, POBzH) ppm. 13C-NMR (400MHz, CDCl 3) δ 55.995 (3,4,5-OCH 3); 60.773 (4 '-OCH 3); 69.726 (POCH 2); 82.002 (POCH 2); 106.310 (2,6-ArC); 112.490 (5 '-ArC); 122.207 (2 '-ArC); 126.497 (6 '-ArC); (127.177-128.462 10 tertiary carbons of phosphate dibenzyl ester phenyl ring); 128.515 (=C 1a '); 129.736 (C 1a=); 130.331 (1 '-ArC); 132.404 (1-ArC); 135.747,135.821 (2 quaternary carbons of phosphate dibenzyl ester phenyl ring); 137.552 (4-ArC); 146.950 (3 ', 4 '-ArC); 153.046 (3,5-ArC) ppm.
Embodiment 15
Preparation 3,4,5-trimethoxy-4 '-oxyethyl group-3 '-hydroxyl-(Z)-toluylene-O '-phosphate dibenzyl ester (IVb)
Undertaken by embodiment 14, with 3,4,5-trimethoxy-4 '-oxyethyl group-3 '-hydroxyl-(Z)-and toluylene (IIIb) 40g (0.121mol) replacement 3,4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene CA-4 (IIIa).Obtain 67.8 gram white crystal IVb, productive rate 95%. 1H-NMR (CDCl 3δ); 1.38 (t, J=7Hz, 3H ,-OCH 2CH 3); 3.68 (s, 6H, 3,5-OCH 3); 3.81 (s, 3H, 4-OCH 3); 4.09 (q, J=7Hz, 2H ,-OCH 2-); 5.14 (d, 4H, 3J P-H=7.8Hz, POCH 2); 6.37,6.40,6.42,6.45 (AB system, 2H, J=12Hz, cis-HC=CH-); 6.49 (s, 2H, 2,6-ArH); 6.79 (d, 1H, J=8.4Hz, 5 '-ArH); 7.07 (d-m, 1H, J=8.4Hz, 6 '-ArH); 7.19 (m, 1H, 2 '-ArH); 7.33-7.24 (m, 10H, POBnH).
Embodiment 16
Preparation 3,4,5-trimethoxy-4 '-trifluoro ethoxy-3 '-hydroxyl-(Z)-toluylene-O '-phosphate dibenzyl ester (IVc)
Undertaken by embodiment 14, with 3,4,5-trimethoxy-4 '-trifluoro ethoxy-3 '-hydroxyl-(Z)-and toluylene (IIIc) 40g (0.104mol) replacement 3,4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene CA-4 (IIIa).Obtain 61.6 gram white crystal IVc, productive rate 92%. 1H-NMR (CDCl 3δ); 3.69 (s, 6H, 3,5-OCH 3); 3.83 (s, 3H, 4-OCH 3); 4.31 (q, J=8Hz, 2H ,-OCH 2CF 3); 5.15 (d, 4H, 3J P-H=7.8Hz, POCH 2); 6.37,6.40,6.42,6.45 (AB system, 2H, J=12Hz, cis-HC=CH-); 6.49 (s, 2H, 2,6-ArH); 6.79 (d, 1H, J=8Hz, 5 '-ArH); 7.07 (d-m, 1H, J=8Hz, 6 '-ArH); 7.19 (m, 1H, 2 '-ArH); 7.33-7.24 (m, 10H, POBnH).
Embodiment 17
Preparation 3,4,5-trimethoxy-4 '-difluoro oxygen base-3 '-hydroxyl-(Z)-toluylene-O '-phosphate dibenzyl ester (IVd)
Undertaken by embodiment 14, with 3,4,5-trimethoxy-4 '-difluoro-methoxy-3 '-hydroxyl-(Z)-and toluylene (IIId) 40g (0.114mol) replacement 3,4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene CA-4 (IIIa).Obtain 64.9 gram white crystal IVd, productive rate 93%. 1H-NMR (CDCl 3δ); 3.71 (s, 6H, 3,5-OCH 3); 3.85 (s, 3H, 4-OCH 3); 5.18 (d, 4H, 3J P-H=7.8Hz, POCH 2); 6.35,6.38,6.40,6.43 (AB system, 2H, J=12Hz, cis-HC=CH-); 6.45 (t, J=74Hz, 1H ,-OCHF 2); 6.49 (s, 2H, 2,6-ArH); 6.79 (d, 1H, J=8Hz, 5 '-ArH); 7.07 (d-m, 1H, J=8Hz, 6 '-ArH); 7.19 (m, 1H, 2 '-ArH); 7.38-7.42 (m, 10H, POBnH).
Embodiment 18
Preparation 3,4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-and toluylene-O '-1,3,2-dioxy phosphine oxide heterocycle pentane ester (Va)
At one through putting into 0.63 gram (2mmol) 3 in thorough drying and 100 milliliters of three-necked bottles by argon gas, 4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene CA-4 (IIIa) 40mL dry tetrahydrofuran dissolving, under the room temperature, drip 0.33ml (2mmol) diisopropyl ethyl amine.Then, be cooled to subzero 10 and spend subzero 5 degree, drip 0.28 gram (2mmol) 2-chloro-2-1,3, the tetrahydrofuran solution 10ml of the assorted alkane of 2-dioxy ring phosphine.Dropwise, sustained reaction half an hour be heated to 60 ℃ then, continue to stir 10 hours.TLC feeds high-purity dry oxygen after following the tracks of the reaction end, continues reaction 18 hours, behind the stopped reaction, and the elimination white depositions.Filtrate decompression boils off solvent, and as the drip washing solvent, silicagel column (1200 * 180) chromatography separated obtaining the lurid oily matter Va of 0.75 gram fast with 3: 2 sherwood oil (60-90 ℃)/ethyl acetate.Productive rate 88.9%. 1H-NMR (CDCl 3δ): 3.70 (s, 6H, 3,5-OCH 3); 3.85 (s, 3H, 4 '-OCH 3); 3.87 (s, 3H, 4-OCH 3); 4.61 (m, 2H ,-2CH e); 4.54 (m, 2H ,-2CH a); 6.39,6.42,6.45,6.48 (AB system, 2H, J=12Hz, cis-HC=CH-); 6.52 (s, 2H, 2,6-ArH); 6.73 (d, 1H, J=8Hz, 5 '-ArH); 6.79 (d-d, 1H, J=8Hz, J=2Hz, 6 '-ArH); 6.91 (d, 1H, J=2Hz, 2 '-ArH) ppm.
Embodiment 19
Preparation 3,4,5-trimethoxy-4 '-oxyethyl group-3 '-hydroxyl-(Z)-and toluylene-O '-1,3,2-dioxy phosphine oxide heterocycle pentane ester (Vb)
Undertaken by embodiment 18, with 3,4,5-trimethoxy-4 '-oxyethyl group-3 '-hydroxyl-(Z)-toluylene (IIIb) 0.66 gram (2mmol) replaced C A-4 (IIIa).Obtain the lurid oily matter Vb of 0.77 gram.Productive rate 88.3%. 1H-NMR (CDCl 3δ): 1.38 (t, J=7Hz, 3H ,-OCH 2CH 3); 3.70 (s, 6H, 3,5-OCH 3); 3.87 (s, 3H, 4-OCH 3); 4.09 (q, J=7Hz, 2H ,-OCH 2-); 4.54 (m, 2H ,-2CH e); 4.61 (m, 2H ,-2CH a); 6.39,6.42,6.45,6.48 (AB system, 2H, J=12Hz, cis-HC=CH-); 6.52 (s, 2H, 2,6-ArH); 6.73 (d, 1H, J=8Hz, 5 '-ArH); 6.79 (d-d, 1H, J=8Hz, J=2Hz, 6 '-ArH); 6.91 (d, 1H, J=2Hz, 2 '-ArH) ppm.
Embodiment 20
Preparation 3,4,5-trimethoxy-4 '-trifluoro ethoxy-3 '-hydroxyl-(Z)-and toluylene-O '-1,3,2-dioxy phosphine oxide heterocycle pentane ester (Vc)
Undertaken by embodiment 18, with 3,4,5-trimethoxy-4 '-trifluoro ethoxy-3 '-hydroxyl-(Z)-toluylene (IIIc) 0.77 gram (2mmol) replaced C A-4 (IIIa).Obtain the lurid oily matter Vc of 0.80 gram.Productive rate 81.6%. 1H-NMR (CDCl 3δ): 6.77 (m, 1H, 6 '-H); 6.61 (m, 2H, 2 ', 5 '-H); 6.46 (s, 2H, 2,6-H); 6.40 (m, 2H, alkene-H); 4.61 (m, 2H ,-2CH a); 4.54 (m, 2H ,-2CH e); 4.31 (q, J=8Hz, 2H ,-OCH 2CF 3); 3.83 (s, 3H, 4-OCH 3); 3.69 (s, 6H, 3,5-OCH 3) ppm.
Embodiment 21
Preparation 3,4,5-trimethoxy-4 '-difluoro-methoxy-3 '-hydroxyl-(Z)-and toluylene-O '-1,3,2-dioxy phosphine oxide heterocycle pentane ester (Vd)
Undertaken by embodiment 18, with 3,4,5-trimethoxy-4 '-difluoro-methoxy-3 '-hydroxyl-(Z)-toluylene (IIId) 0.71 gram (2mmol) replaced C A-4 (IIIa).Obtain the lurid oily matter Vd of 0.76 gram.Productive rate 83%. 1H-NMR (CDCl 3δ): 6.92 (d, J=8Hz, 1H, 5 '-H); 6.71 (d, J=2Hz, 1H, 2 '-H); 6.63 (dd, J=8Hz﹠2Hz, 1H, 6 '-H); 6.50 (s, 2H, 2,6-H); 6.42 (m 2H, alkene-H); 6.45 (t, J=74Hz, 1H ,-OCHF 2); 4.61 (m, 2H ,-2CH a); 4.54 (m, 2H ,-2CH e); 3.84 (s, 3H, 4-OCH 3); 3.69 (s, 6H, 3,5-OCH 3) ppm.
Embodiment 22
Preparation 3,4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene-O '-Di-Sodium Phosphate CA-4P (VIa)
Thermometer, mechanical stirring are being housed, in 1 liter of four neck flask of airway, add exsiccant 3,4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene-O '-phosphate dibenzyl ester (IVa) 57.6 grams (0.1mol), the dry anhydrous acetonitrile of measuring 225ml is slowly poured in the four-necked bottle, feeds argon gas, 15 ℃ of stirrings.Measure 40ml bromotrimethylsilane (TMBS) and add the exsiccant dropping funnel, be added drop-wise to fast in the four-necked bottle, after 5-10 minute, add the solution of 16.3g sodium methylate and 62.5ml anhydrous methanol preparation, reaction system becomes milky suspension liquid immediately.After half an hour, add the 33ml anhydrous methanol, 33ml acetone, stirring is spent the night.Suction filtration obtains white solid, with anhydrous methanol and washing with acetone, vacuum-drying.Obtain crude product 40.8 gram of CA-4P, with dissolving crude product in the water of 20ml, the furnishing starchiness, the methanol solution that with mass ratio is 25% sodium methylate is regulated pH value about 10-12, continues to add the methanol solution of 20ml in solution, stirring, a small amount of insolubles is arranged, filter.Filtrate is with ethyl acetate (20ml * 3) extraction 3 times, divide go ethyl acetate after, filtrate was 35-40 ℃ of heated and stirred 1 hour.Cool to room temperature, the acetone of adding 20ml has a large amount of white precipitates to generate, and stirs 2 hours, adds 20ml acetone again, and stirring is spent the night, and adds 20ml acetone next day, filters.Twice of filter cake water and washing with acetone.After the vacuum-drying, obtain 38 gram white powder VIa.Productive rate 86.2%.Fusing point: 192-195 ℃ (decomposition).Rf 0.64 (propyl carbinol/methanol/ammoniacal liquor V/V 4: 3: 2: 1).HPLC detects: 〉=99.5%; TOF-MS (ES +): 441.0689[M]; 442.0747[M+H +] (theoretical molecular mass: molecular formula: C 18H 20O 8Na 2P; 441.0691).FT-IR (KBr pressed disc method): v P-O-H3423 (s, broad); v Ar-H ,=C-H3005 (m); v CH32969 (m), 2939 (m), 2841 (m); v -C=C-1604 (m); v C6H5-1577 (m), 1514 (s), 1453 (m); v C-O-C1265 (s), 1108 (vs), 996 (s). 1H-NMR(CDCl 3；δ)：3.691(s，6H，3，5-OCH 3)；3.835(s，3H，4’-OCH 3)；3.852(s，3H，4-OCH 3)；6.389，6.419，6.448，6.479(AB，2H，J＝12Hz，cis-HC＝CH-)；6.524(s，2H，2，6-ArH)；6.7265(d，1H，J＝8.4Hz，5’-ArH)；6.787(d-d，1H，J＝8.4Hz，J＝1.6Hz，6’-ArH)；6.913(d，1H，J＝1.6Hz，2’-ArH)ppm。 13C-NMR(400MHz，CDCl 3)δ55.995(3，4，5-OCH 3)；60.827(4’-OCH 3)；106.458(2，6-ArC)；?110.462(5’-ArC)；115.124(2’-ArC)；121.071(6’-ArC)；129.088(＝C 1a’)；129.460(C 1a＝)；130.789(1’-ArC)；132.657(1-ArC)；137.552(4-ArC)；145.368(4’-ArC)；45.835(3’-ArC)；152.940(3，5-ArC)ppm。
In addition, with 3,4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene-O '-1,3,2-dioxy phosphine oxide heterocycle pentane ester (Va) 42.2 grams (0.1mol) replace 3,4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene-O '-phosphate dibenzyl ester (IVa) carries out alkaline hydrolysis by said process, can get CA-4P (VIa) equally.
Embodiment 23
Preparation 3,4,5-trimethoxy-4 '-oxyethyl group-3 '-hydroxyl-(Z)-toluylene-O '-Di-Sodium Phosphate (VIb)
Undertaken by embodiment 22, with 3,4,5-trimethoxy-4 '-oxyethyl group-3 '-hydroxyl-(Z)-toluylene-O '-phosphate dibenzyl ester (IVb) 59.0g (0.1mol) replacement 3,4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene-O '-phosphate dibenzyl ester (IVa).Obtain 38.7 gram white powder VIb, productive rate 85.1%.HPLC detects: 〉=99%; 1H-NMR (CDCl 3δ); 7.16 (d, J=2Hz, 1H, 2 '-H); 7.13 (dd, J=8Hz, 2Hz, 1H, 6 '-H); 6.80 (d, J=8Hz, 1H, 5 '-H); 6.50 (s, 2H, 2,6-H); 6.44 (AB, J=12Hz, 1H, a-H); 6.40 (AB, J=12Hz, 1H, 1a '-H); 4.07 (q, J=7Hz, 2H ,-OCH 2-); 3.85 (s, 3H, 4-OCH 3); 3.68 (s, 6H, 3,5-OCH 3) .1.33 (t, J=7Hz, 3H ,-OCH 2CH 3) ppm.
Embodiment 24
Preparation 3,4,5-trimethoxy-4 '-trifluoro ethoxy-3 '-hydroxyl-(Z)-toluylene-O '-Di-Sodium Phosphate (VIc)
Undertaken by embodiment 22, with 3,4,5-trimethoxy-4 '-trifluoro ethoxy-3 '-hydroxyl-(Z)-toluylene-O '-phosphate dibenzyl ester (IVc) 64.4g (0.1mol) replacement 3,4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene-O '-phosphate dibenzyl ester (IVa).Obtain 41.7 gram white powder VIc, productive rate 81.9%.HPLC detects: 〉=99%; 1H-NMR (CDCl 3δ); 6.77 (m, 1H, 6 '-H); 6.63 (m, 2H, 2 ', 5 '-H); 6.44 (s, 2H, 2,6-H); 6.40 (m, 2H, alkene-H); 4.31 (q, J=8Hz, 2H ,-OCH 2CF 3); 3.84 (s, 3H, 4-OCH 3); 3.71 (s, 6H, 3,5-OCH 3) ppm.
Embodiment 25
Preparation 3,4,5-trimethoxy-4 '-difluoro-methoxy-3 '-hydroxyl-(Z)-toluylene-O '-Di-Sodium Phosphate (VId)
Undertaken by embodiment 22, with 3,4,5-trimethoxy-4 '-difluoro-methoxy-3 '-hydroxyl-(Z)-toluylene-O '-phosphate dibenzyl ester (IVd) 61.2g (0.1mol) replacement 3,4,5-trimethoxy-4 '-methoxyl group-3 '-hydroxyl-(Z)-toluylene-O '-phosphate dibenzyl ester (IVa).Obtain 38.2 gram white powder VId, productive rate 80.1%.HPLC detects: 〉=99%; 1H-NMR (CDCl 3δ); 6.95 (d, J=8Hz, 1H, 5 '-H); 6.74 (d, J=2Hz, 1H, 2 '-H); 6.67 (dd, J=8Hz﹠2Hz, 1H, 6 '-H); 6.52 (s, 2H, 2,6-H); 6.46 (m 2H, alkene-H); 6.45 (t, J=74Hz, 1H ,-OCHF 2); 3.87 (s, 3H, 4-OCH 3); 3.72 (s, 6H, 3,5-OCH 3) ppm.
The above only is preferred embodiment of the present invention, be not in order to limit essence technology contents scope of the present invention, essence technology contents of the present invention is broadly to be defined in the claim scope of application, any technology entity or method that other people finish, if it is defined identical with the claim scope of application, also or a kind of change of equivalence, all will be regarded as being covered by among this claim scope.

Claims (7)

1. the preparation method suc as formula the II compound is characterized in that, described method comprises step:
(a) under the 254nm UV-irradiation, uncommon (Wittig) reaction of carrying out loving and respect one's elder brother Wei obtains formula II compound
Wherein: R is-CH 3,-C 2H 5,-C 3H 7,-CH 2F ,-CHF 2,-CF 3,-CH 2CF 3,-CF 2CF 3, or-CF 2CH 3;
Rp is-S i (CH 3) 2T-Bu ,-C (C 6H 5) 3, or (CH 3) 3COCO-.
2. preparation method as claimed in claim 1 is characterized in that, described wittig reaction was carried out 4-12 hour to subzero 40 ° of C at subzero 10 ° of C.
3. the preparation method of a formula III compound is characterized in that, described method comprises step:
(a) under the 254nm UV-irradiation, uncommon (Wittig) reaction of carrying out loving and respect one's elder brother Wei obtains formula II compound:
Figure FDA00003084625300014
Wherein: R is-CH 3,-C 2H 5,-C 3H 7,-CH 2F ,-CHF 2,-CF 3,-CH 2CF 3,-CF 2CF 3, or-CF 2CH 3
Rp is-Si (CH 3) 2T-Bu ,-C (C 6H 5) 3, or (CH 3) 3COCO-; With
(b) formula II compound and hydrochloric acid reaction are obtained the formula III compound:
Figure FDA00003084625300021
4. the preparation method of a formula IV compound is characterized in that, described method comprises step:
(1) under the 254nm UV-irradiation, uncommon (Wittig) reaction of carrying out loving and respect one's elder brother Wei obtains formula II compound:
Figure FDA00003084625300022
Figure FDA00003084625300023
Wherein: R is-CH 3,-C 2H 5,-C 3H 7,-CH 2F ,-CHF 2,-CF 3,-CH 2CF 3,-CF 2CF 3, or-CF 2CH 3,
Rp is-Si (CH 3) 2T-Bu ,-C (C 6H 5) 3, or (CH 3) 3COCO-;
(2) formula II compound and hydrochloric acid reaction are obtained the formula III compound:
Figure FDA00003084625300024
With
(3) formula III compound and tetra-sodium four benzyl esters are carried out phosphating reaction in the presence of organic bases, obtain formula IV compound:
Figure FDA00003084625300025
Described organic bases is selected from potassium tert.-butoxide, sodium tert-butoxide, triethylamine or diisopropylethylamine.
5. preparation method as claimed in claim 4 is characterized in that, described phosphating reaction carried out 40-80 minute at 50-70 ° of C.
6. the preparation method of a formula V compound is characterized in that, described method comprises step:
(i) under the 254nm UV-irradiation, uncommon (Wittig) reaction of carrying out loving and respect one's elder brother Wei obtains formula II compound:
Figure FDA00003084625300031
Figure FDA00003084625300032
Wherein: R is-CH 3,-C 2H 5,-C 3H 7,-CH 2F ,-CHF 2,-CF 3,-CH 2CF 3,-CF 2CF 3, or-CF 2CH 3;
Rp is-S i (CH 3) 2T-Bu ,-C (C 6H 5) 3, or (CH 3) 3COCO-;
(ii) formula II compound and hydrochloric acid reaction are obtained the formula III compound:
Figure FDA00003084625300033
With
(iii) with formula III compound and 2-chloro-1,3, the 2-dioxaphospholane adds oxygen in the presence of triethylamine or diisopropylethylamine, carry out phosphating reaction, obtains formula V compound:
Figure FDA00003084625300034
7. preparation method as claimed in claim 6 is characterized in that, described phosphating reaction with tetrahydrofuran (THF) as solvent.
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Citations (2)

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Publication number Priority date Publication date Assignee Title
CN101070274A (en) * 2007-06-14 2007-11-14 复旦大学 Diphenylethene compound with anti-tumor activity and preparing method
CN101186563A (en) * 2007-12-13 2008-05-28 江苏省原子医学研究所 3,5-dimethoxyl or 3,5-dihydroxy diphenylethene compounds and preparation method thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101070274A (en) * 2007-06-14 2007-11-14 复旦大学 Diphenylethene compound with anti-tumor activity and preparing method
CN101186563A (en) * 2007-12-13 2008-05-28 江苏省原子医学研究所 3,5-dimethoxyl or 3,5-dihydroxy diphenylethene compounds and preparation method thereof

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