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Preparation method of 2-aryl-pentyne-4-olic acid ester compounds

A compound and alkyl technology, applied in the field of preparation of 2-aryl-pent-4-ynoic acid ester compounds, can solve the problems of harsh reaction conditions, unsuitable for large-scale industrial production, and difficult to separate, and achieves easy industrialization production effect

Active Publication Date: 2013-07-31
QILU PHARMA HAINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] There are following defects in this preparation method: 1. the used starting raw material homodimethyl terephthalate is difficult to obtain; 2. reaction easily produces by-product α-dipropargyl homo dimethyl terephthalate, and this by product will be produced in the future Difficult to separate in the reaction, HPLC shows target product α-propargyl homodimethyl terephthalate and the mass ratio of by-product α-dipropargyl homo dimethyl terephthalate is about 3: 1, namely It can be considered that the product purity is about 75%; ③The reaction conditions are harsh, the reaction requires anhydrous operation, and the dangerous reagent sodium hydride needs to be used, which is not suitable for large-scale industrial production

Method used

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  • Preparation method of 2-aryl-pentyne-4-olic acid ester compounds

Examples

Experimental program
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Effect test

Embodiment 1

[0050] Preparation of 2-(4-(ethoxycarbonyl)phenyl)-2-(prop-2-ynyl)-malonate (III)

[0051] Dissolve 2-(4-(ethoxycarbonyl)phenyl)-malonic acid diethyl (IV) (12.3g, 40mmol) and 3-bromopropyne (5.72g, 48mmol) in acetone (100mL) Add potassium carbonate (22.1g, 160mmol), heat to reflux, stir for 2 hours, cool to room temperature, add a large amount of water to dilute, adjust pH to 3-4 with 2N dilute hydrochloric acid, extract with ethyl acetate (300mL*3), and combine The organic phase was washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, the filtrate was evaporated to dryness, 200-300 mesh silica gel column chromatography (petroleum ether: ethyl acetate = 20:1), and the solvent was evaporated to obtain a yellow oil 物9.7g.

Embodiment 2

[0053] Preparation of 2-(4-(methoxycarbonyl)phenyl)-2-(prop-2-ynyl)-malononitrile (III)

[0054] Dissolve 2-(4-(methoxycarbonyl)phenyl)-malononitrile (IV) (10.0g, 50mmol) and 3-bromopropyne (8.92g, 75mmol) in acetone (120mL), add carbonic acid Potassium (17.3g, 125mmol), heat and stir to reflux, after 2 hours, cool to room temperature, add a large amount of water to dilute, adjust the pH to 3-4 with 2N dilute hydrochloric acid, extract with ethyl acetate (300mL*3), combine the organic phases, Wash with water, saturated brine, dry with anhydrous magnesium sulfate, filter, evaporate the filtrate, 200-300 mesh silica gel column chromatography (petroleum ether: ethyl acetate = 20:1), evaporate the solvent to obtain 8.9 g of yellow solid.

Embodiment 3

[0056] Preparation of 2-[(4-carboxy)phenyl]-pent-4-ynoic acid (II)

[0057] The 2-(4-(ethoxycarbonyl)phenyl)-2-(prop-2-ynyl)-malonic acid diethyl (III) (9.7g, 28.0mmol) obtained in Example 1 was dissolved in In methanol (30mL), add potassium hydroxide (15.8g, 280mmol) aqueous solution (30mL), warm to reflux, stir for 2 hours, cool to room temperature, add water to dilute, evaporate methanol under reduced pressure, ethyl acetate (100mL*3 ) Extract, combine the organic phases, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, evaporate the filtrate, and recrystallize (petroleum ether: ethyl acetate = 1:1) to obtain 5.8 g of white solid.

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Abstract

The invention relates to a preparation method of 2-aryl-pentyne-4-olic acid ester compounds with a structure shown in a formula I, wherein R is described in the specification. The preparation method has the advantages of low cost and availability of raw materials, mild reaction conditions, simpleness in operation and suitability for industrial production.

Description

Technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a method for preparing 2-aryl-pent-4-ynoate compounds. Background of the invention [0002] Pralatrexate (PDX) is an anti-metabolic antineoplastic drug developed by Allos Therapeutics of the United States. It is a dihydrofolate reductase (DHFR) inhibitor. It is used to treat NSCLC, mesothelioma and non-Hodgkin’s lymphoma. Its injection has It was approved by the FDA in September 2009 to be marketed in the United States for the treatment of T cell lymphoma. By combining with dihydrofolate reductase, the drug prevents dihydrofolate from being converted into tetrahydrofolate, thereby interfering with the synthesis of DNA, RNA and protein, and hindering the growth of tumor cells. [0003] The chemical name of Pralatrexate (PDX) is N-(4-{1-[(2,4-Diaminopteridine-6-yl)methyl]-3-butyn-1-yl}benzoyl)-L -Glutamic acid, molecular formula is C 23 H 23 N 7 O 5 , The molecular weight is 477, and its...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/78C07C67/08C07C67/10
Inventor 王晶翼王金远白俊生范传文朱屹东张明会
Owner QILU PHARMA HAINAN
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