CN101230074A - Phosphate derivative of oxazole compounds and preparation method thereof - Google Patents
Phosphate derivative of oxazole compounds and preparation method thereof Download PDFInfo
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- CN101230074A CN101230074A CNA2008100145077A CN200810014507A CN101230074A CN 101230074 A CN101230074 A CN 101230074A CN A2008100145077 A CNA2008100145077 A CN A2008100145077A CN 200810014507 A CN200810014507 A CN 200810014507A CN 101230074 A CN101230074 A CN 101230074A
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- oxazole
- phosphoric acid
- phosphate derivative
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- benzyl
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Abstract
The invention discloses a phosphate derivative of an oxazole compound. During the preparation, 4-(3,4,5-Trimethoxyphenyl)-5-(3-hydroxyl-4-methoxyl phenyl) oxazole is dissolved into the mixed solvent of acetonitrile and N, N-dimethyl formamide to react with carbon tetrachloride, dimethylin pyridine and dibenzyl phosphoric acid, for preparing benzyl phosphate ester of the oxazole compound; then the benzyl of benzyl phosphate ester is removed by utilizing trimethyl silicon bromide to obtain the phosphoric acid derivative of oxazole; finally, the phosphoric acid derivative of the oxazole reacts with sodium methoxide, lithium hydroxide, potassium hydroxide, ammonia water or calcium acetale, to obtain the phosphate derivative of the oxazole compound. The preparation method is simple, highly effective and universal. The phosphate derivative of the prepared series of oxazole compounds can be applied as antineoplastic medicine inhibiting microtubule assembly and selectively targeting tumor blood vessels and having novel structure.
Description
Technical field
The present invention relates to phosphate derivative of Yi Zhong oxazole compounds and preparation method thereof.
Background technology
Lamellarins is that sponge, the Ascidian from the ocean separates the polyaromatic alkaloid compound of extended familys that obtain, and its constitutional features is that a pyrroles center is replaced by poly-hydroxy or Polymethoxylated phenyl ring.Studies show that Lamellarins has extremely strong cytotoxic activity to various tumor cell strains, but its synthetic complicacy makes its patent medicine become very difficult.
Antitumor drug Combretastatin A-4 (being called for short CA-4) is the diphenylethylene compounds of separating from the plant Combretum caffrum of South Africa, and it is to the ED of P388 cell strain
50Value is 0.0034 μ g/mL, and tubulin polymerization suppresses active IC
50Be 2-3 μ M.It has with 3,4 of cis-double bonds connection, the B ring that A ring that the 5-trimethoxy replaces and 3-hydroxyl 4-methoxyl group replace.CA-4 is a kind of new type antineoplastic medicine of many target spots, can effectively suppress the polymerization of tubulin, also is effective growth inhibitor for tumor vessels.But because CA-4 is water-soluble bad, cause the pharmacokinetics poor-performing, limited its application clinically; The easy isomery of cis-double bonds in the structure turns to the more stable trans double bond of thermodynamics in addition, thus active the reduction.Wang Le etc. utilizes heterocycles such as imidazoles, oxazole and pyrazoles to replace two keys to be connected A, B and encircles and obtained the CA-4 heterocyclic analogs, has solved the problem of CA-4 double-bond isomerization.CA-4 heterocyclic analogs Zhong De oxazole analogue 4-(3,4, the 5-trimethoxyphenyl)-5-(3-hydroxyl-4-p-methoxy-phenyl) oxazole [English name 4-(3,4,5-trimethoxyphenyl)-and 5-(3-hydroxy-4-methoxyphenyl) oxazole] tumour cell is had better inhibited activity, but still have lipotropy height, water-soluble bad, defective that bioavailability is low.
Summary of the invention
The purpose of this invention is to provide phosphate derivative of Yi Zhong oxazole compounds and preparation method thereof, can overcome nitrogenous polynuclear aromatic hydrocarbons compounds Lamellarins synthetic difficulty, and this phosphate derivative good water solubility, the bioavailability height can be as the antitumor drug that suppresses micropipe aggregation, selectivity target tumor blood vessel.
The phosphate derivative of Yi Zhong oxazole compounds is characterized in that its structural formula is as follows:
In the formula R be P (O) (ONa)
2, P (O) (OK)
2, P (O) (OLi)
2, P (O) (ONH
4)
2Or P (O) O
2Ca.
The preparation method of the phosphate derivative of Shang Shu De oxazole compounds, it is characterized in that 4-(3,4, the 5-trimethoxyphenyl)-(3-hydroxyl-4-p-methoxy-phenyl) oxazole dissolves in acetonitrile and N to 5-, in the mixed solvent of dinethylformamide, with tetracol phenixin, Dimethylamino pyridine and dibenzyl phosphatase reaction, the benzyl phosphoric acid ester of Zhi Bei oxazole compounds; Utilize the trimethylammonium silicon bromide to remove the phosphoric acid derivatives of the benzyl De of benzyl phosphoric acid ester then Dao oxazole; The phosphoric acid derivatives of last Shi oxazole and sodium methylate, lithium hydroxide, potassium hydroxide, ammoniacal liquor or calcium acetate reaction, De is Dao the phosphate derivative of oxazole compounds.
Phosphate derivative good water solubility of the present invention can be improved the bioavailability of guide's thing and the target tumor vascular of raising drug molecule, and the preparation method is easy, and route is shorter, and condition is easy to control, has improved synthetic efficient greatly.
Embodiment
Simple in structure and have the Lamellarin 1C and a CA-4 De oxazole analogue 4-(3 of remarkable anti-tumor activity, 4, the 5-trimethoxyphenyl)-(3-hydroxyl-4-p-methoxy-phenyl) oxazole structurally has certain skeleton similarity to 5-, and CA-4 De oxazole analogue is equivalent to the pyrrole ring of Yong oxazole ring displacement Lamellarin frame center.Therefore the present invention simulates Lamellarins as lead compound with CA-4 De oxazole analogue, carry out structural modification, prepare the high-activity compound that suppresses micropipe aggregation, has selectivity target inner skin cell function, the microtubule association class antitumor drug that obtains existing tumor vessel in the body is had the novel structure of tangible destruction on this basis is significant.
The present invention links to each other drug molecule and forms phosphate derivative with phosphate group, help drug molecule to intracellular transport, and has before entering drug target good stability and long transformation period; Phosphate prodrug can be hydrolyzed to female medicine by endogenic Phosphoric acid esterase in vivo and discharge, and the higher hydrolytic action that makes of cancer cells surface phosphoric acid esterase activity has selectivity.Can improve water-soluble, the selectivity of drug molecule and toxic side effect and the untoward reaction that reduces medicine by the phosphate prodrug administration.
The preparation of the phosphate derivative of oxazole compounds, its concrete steps are as follows:
4-(3 with 0.5mmol; 4; the 5-trimethoxyphenyl)-(3-hydroxyl-4-p-methoxy-phenyl) oxazole dissolves in the mixed solvent of 10mL acetonitrile and N, dinethylformamide 5-; under argon shield;-10 ℃ drip the 0.3mmol tetracol phenixin down; stir after 10 minutes; add the 0.1mmol Dimethylamino pyridine; after 5 minutes; slowly drip 1.5mmol dibenzyl phosphoric acid ,-10 ℃ of reactions are after 2 hours, and (3 * 30mL) extract reaction solution with ethyl acetate; organic phase anhydrous sodium sulfate drying, silica gel column chromatography obtain white solid benzyl phosphoric acid ester.0.3mmol benzyl phosphoric acid ester is dissolved in the 5mL methylene dichloride, drips 1.0mmol trimethylammonium silicon bromide under argon shield, ice bath, stir after 45 minutes, underpressure distillation obtains the phosphoric acid derivatives of Bai look Gu Ti oxazole compounds.Without separation, add the 5mL dehydrated alcohol, add alkali then, reaction is spent the night under the room temperature, and underpressure distillation removes and desolvates, and obtains white solid with the acetone recrystallization, is phosphate derivative of the present invention.
(mol ratio of 3-hydroxyl-4-p-methoxy-phenyl) oxazole, tetracol phenixin, Dimethylamino pyridine, dibenzyl phosphoric acid is 1 to 4-described in the above-mentioned reaction (3,4, the 5-trimethoxyphenyl)-5-: 0.3-0.7: 0.1-0.2: 1-5; When adopting the trimethylammonium silicon bromide to remove benzyl protecting group, the mol ratio of described benzyl phosphoric acid ester and trimethylammonium silicon bromide is 1: 3.0-5.0; Described alkali is that sodium methylate, lithium hydroxide, potassium hydroxide, ammoniacal liquor or the phosphoric acid derivatives of calcium acetate ， oxazole compounds and the mol ratio of alkali are 1.0: 2.0-4.0.
The structural formula of the phosphate derivative of the De oxazole compounds of the present invention that above-mentioned reaction obtains is:
R=P in the structural formula (O) (ONa)
2The time be the sodium phosphate salt derivative; R=P in the structural formula (O) (OK)
2The time be the potassium phosphate salt derivative; R=P (O) (OLi)
2The time be the Trilithium phosphate salt derivative; R=P (O) (ONH
4)
2The time be the phosphate amine salt derivative; R=P (O) O
2It during Ca the calcium phosphate salt derivative.
The phosphate derivative of the oxazole compounds of Ben Faming has good water solubility, high excellent of bioavilability Point can be used as the antineoplastic that suppresses micropipe aggregation, selective target tumor blood vessel.
Claims (5)
1. the phosphate derivative of Yi Zhong oxazole compounds is characterized in that its structural formula is as follows:
In the formula R be P (O) (ONa)
2, P (O) (OK)
2, P (O) (OLi)
2, P (O) (ONH
4)
2Or P (O) O
2Ca.
2. the preparation method of the phosphate derivative of claim 1 Suo Shu De oxazole compounds, it is characterized in that 4-(3,4, the 5-trimethoxyphenyl)-(3-hydroxyl-4-p-methoxy-phenyl) oxazole dissolves in acetonitrile and N to 5-, in the mixed solvent of dinethylformamide, with tetracol phenixin, Dimethylamino pyridine and dibenzyl phosphatase reaction, the benzyl phosphoric acid ester of Zhi Bei oxazole compounds; Utilize the trimethylammonium silicon bromide to remove the phosphoric acid derivatives of the benzyl De of benzyl phosphoric acid ester then Dao oxazole; The phosphoric acid derivatives of last Shi oxazole and sodium methylate, lithium hydroxide, potassium hydroxide, ammoniacal liquor or calcium acetate reaction, De is Dao the phosphate derivative of oxazole compounds.
3. as the preparation method of the phosphate derivative of claim 2 Suo Shu De oxazole compounds, it is characterized in that described 4-(3,4, the 5-trimethoxyphenyl)-(mol ratio of 3-hydroxyl-4-p-methoxy-phenyl) oxazole, tetracol phenixin, Dimethylamino pyridine, dibenzyl phosphoric acid is 1 to 5-: 0.3-0.7: 0.1-0.2: 1-5.
4. as the preparation method of the phosphate derivative of claim 2 Suo Shu De oxazole compounds, it is characterized in that the mol ratio of described benzyl phosphoric acid ester and trimethylammonium silicon bromide is 1: 3.0-5.0.
5. as the preparation method of the phosphate derivative of claim 2 Suo Shu De oxazole compounds, it is characterized in that the phosphoric acid derivatives of Suo Shu De oxazole and the mol ratio of sodium methylate, lithium hydroxide, potassium hydroxide, ammoniacal liquor or calcium acetate are 1.0: 20-4.0.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2008100145077A CN101230074A (en) | 2008-01-29 | 2008-01-29 | Phosphate derivative of oxazole compounds and preparation method thereof |
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| CNA2008100145077A CN101230074A (en) | 2008-01-29 | 2008-01-29 | Phosphate derivative of oxazole compounds and preparation method thereof |
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| CN101230074A true CN101230074A (en) | 2008-07-30 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102863472A (en) * | 2012-10-15 | 2013-01-09 | 中国海洋大学 | Combretastatin A-4 analogue, preparation method of combretastatin A-4 analogue and application of combretastatin A-4 analogue in preparing anti-tumor drugs |
| JP2014523885A (en) * | 2011-07-05 | 2014-09-18 | 南京聖和薬業有限公司 | Tumor targeting drug combretastatin A4 derivative |
-
2008
- 2008-01-29 CN CNA2008100145077A patent/CN101230074A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014523885A (en) * | 2011-07-05 | 2014-09-18 | 南京聖和薬業有限公司 | Tumor targeting drug combretastatin A4 derivative |
| US9139574B2 (en) | 2011-07-05 | 2015-09-22 | Nanjing Sanhome Pharmaceutical Co., Ltd. | Tumor targeted drug combretastatin A4 derivative |
| CN102863472A (en) * | 2012-10-15 | 2013-01-09 | 中国海洋大学 | Combretastatin A-4 analogue, preparation method of combretastatin A-4 analogue and application of combretastatin A-4 analogue in preparing anti-tumor drugs |
| CN102863472B (en) * | 2012-10-15 | 2015-05-13 | 中国海洋大学 | Combretastatin A-4 analogue, preparation method of combretastatin A-4 analogue and application of combretastatin A-4 analogue in preparing anti-tumor drugs |
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| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
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Open date: 20080730 |