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Method for synthesizing antitumor compound of diketopiperazine PJ147

A technology of PJ147 and diketopiperazine, which is applied in the field of synthesis of anti-tumor compound diketopiperazine PJ147, achieving the effect of high yield and low cost

Inactive Publication Date: 2008-09-03
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is no related patent for the synthesis of 4-geranyloxybenzaldehyde fragments, only the synthesis method of its analogue (application number 200510060319.4)

Method used

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  • Method for synthesizing antitumor compound of diketopiperazine PJ147
  • Method for synthesizing antitumor compound of diketopiperazine PJ147
  • Method for synthesizing antitumor compound of diketopiperazine PJ147

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Experimental program
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Effect test

Embodiment 1

[0025] Embodiment 1: the preparation of glycoside dipeptide

[0026] Dissolve L-alanine methyl ester (1.19g, 10mmol), triethylamine (1.01g, 10mmol) in dichloromethane (10ml), add N-benzyloxycarbonyl-L-glycine (2.09g, 10mmol) and HOBt (1-hydroxybenzotriazole) (1.35g, 10mmol), cooled to 0°C, added 10ml of DCC (N, N'-dicyclohexylcarbodiimide) (2.07g, 10mmol) Chloromethane solution, stirring and reacting at this temperature for 4 hours, continuing to react at room temperature for 8 hours, concentrating under reduced pressure, dissolving the residue in 20ml of ethyl acetate, diluting with 20ml of 2% hydrochloric acid, 20ml of 5% sodium bicarbonate solution and 20ml of Washed with water, dried over anhydrous sodium sulfate, distilled under reduced pressure, and recrystallized with ethyl acetate-petroleum ether-ether to obtain protected glycinyl methyl ester (N-benzyloxycarbonyl-L-glycerol-L-propan-OCH 3 ) 2.82g. N-Benzyloxycarbonyl-L-glycerin-L-propane-OCH 3 Dissolve in methanol ...

Embodiment 2

[0027] Embodiment 2: the preparation of 4-geranyloxybenzaldehyde

[0028] P-Hydroxybenzaldehyde (3.32g, 27mmol) and anhydrous potassium carbonate (4.42g, 32mmol) were dissolved in 10ml of anhydrous acetone, and bromogeraniol (5.40g, 25mmol) was slowly added dropwise under stirring at room temperature, and stirred for 5 hour, filter with suction, evaporate acetone under reduced pressure, add 50ml of ethyl acetate, wash the ethyl acetate layer with 50ml of 10% potassium hydroxide solution and water successively, dry over anhydrous sodium sulfate, filter overnight, and evaporate ethyl acetate under reduced pressure , 5.30 g of 4-geranyloxybenzaldehyde was obtained with a yield of 82%. 1 H-NMR (300MHz, DMSO-d 6 ): 1.62 (3H, s), 1.70 (3H, s), 1.76 (3H, s), 2.08 (2H, m), 2.13 (2H, m), 4.60 (2H, d, J=6.5Hz), 5.10 (1H, m), 5.50 (1H, t, J = 6.5Hz), 6.98 (2H, d, J = 8.7Hz), 7.78 (2H, d, J = 8.7Hz), 8.62 (1H, s).

Embodiment 3

[0029] Embodiment 3: the preparation of diketopiperazine PJ147

[0030] Take 128mg (1mmol) of proglycerin dipeptide, add it to 4ml of acetic anhydride, react overnight at 130°C, remove the acetic anhydride under reduced pressure, add a small amount of water to evaporate the remaining acetic anhydride under reduced pressure at low temperature, dissolve the product in 5ml of DMF, add 4 - 5ml of DMF solution of geranyloxybenzaldehyde (920mg, 4mmol), add dropwise 5ml of t-BuOK's tert-butanol solution (containing t-BuOK0.11g, 1mmol), stir at room temperature for 5 hours, filter, evaporate under reduced pressure Remove the solvent, dissolve in 10ml DMF, filter, add hydrazine hydrate (0.25ml, 4mmol) to the filtrate, stir at room temperature for 3 hours, and filter to obtain 280mg of white precipitate, which is the target product diketopiperazine PJ147, with a yield of 76%. 1 H-NMR (300MHz, DMSO-d 6 ): 1.32 (3H, d, J=6.9Hz), 1.57 (3H, s), 1.63 (3H, s), 1.71 (3H, s), 2.06 (2H, m), 2.0...

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Abstract

The invention relates to medicinal chemistry technic field, and relates to a synthetic method for diketopiperazine PJ147 of antineoplastic compounds, specifically comprising: (1) preparing propa gly clyclic dipeptide; (2) preparing 4-spiceleaf oxybenzaldehyde by stirring to make bromo geraniol, parahydroxybenzaldehyde and anhydrous potassium carbonate react in anhydrous propanone to obtain 4-spiceleaf oxybenzaldehyde, (3) preparing diketopiperazine PJ147 by acetylating the propa gly clyclic dipeptide obtained in the step 1 to obtain N, N- diacetyl propa gly clyclic dipeptide which is dissolved in a inert solvent, adding the inert solution of 4-spiceleaf oxybenzaldehyde prepared in the step 2, adding the t-butyl alcohol solution of potassium tert butoxide, stirring for reacting under room temperature, dissolving the reaction products in the inert solution, adding hydrazine hydrate to deacetylate to obtain diketopiperazine PJ147. Compared with the preparation method of micro organism fermentation binding abstraction for separating, the method has advantages of a low cost and a high yield, and is used for industrialization production for medicine.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and relates to a synthesis method of an antitumor compound diketopiperazine PJ147. Background technique [0002] The World Health Organization survey results show that the number of malignant tumor patients is increasing year by year, and its death toll reaches more than 6 million every year. It has become the second killer after cardiovascular and cerebrovascular diseases, and it greatly endangers human health. Chemotherapy is still the main treatment method at present. [0003] Diketopiperazine PJ147, chemical name (S, Z)-3-((E)-4-((E)-3,7-dimethylocta-2,6-dienyl-oxy)benzylidene)-6-methylpiperazine-2 , 5-dione, is a novel anti-tumor active compound isolated from the mycelium of the marine fungus Gliocaldium sp.YUP08, which has a great prospect of being developed into a new anti-tumor drug. Its chemical structure, strain source, fermentation process and extraction and separation met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/18A61P35/00
Inventor 裴月湖华会明李占林刘中刚
Owner SHENYANG PHARMA UNIVERSITY