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4-[1-(2-propinyl)-3, 4-dioxo-n-butyl] benzoate and preparation method thereof

A technology of dioxo-n-butyl and benzoate is applied in the field of organic synthesis route design and the preparation of raw materials and intermediates, which can solve the problems of difficulty in separation, hinder industrial production, rare raw materials, etc., and achieve a simple preparation process. , the effect of promoting economic and technological development, and beneficial to industrial production

Active Publication Date: 2013-09-04
临沂经开财金投资发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method can prepare the target compound pralatrexate, due to factors such as rare raw materials, many steps, and difficult separation, the industrial production of this product has been hindered.

Method used

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  • 4-[1-(2-propinyl)-3, 4-dioxo-n-butyl] benzoate and preparation method thereof
  • 4-[1-(2-propinyl)-3, 4-dioxo-n-butyl] benzoate and preparation method thereof
  • 4-[1-(2-propinyl)-3, 4-dioxo-n-butyl] benzoate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Under a dry nitrogen atmosphere, add 25 mL of a tetrahydrofuran solution containing 3.5 g of zinc bismuth into a three-necked flask. A solution consisting of 4-methoxycarbonylbenzaldehyde (II) (3.28 g, 20 mmol), 3-bromopropyne (III) (2.93 g, 25 mmol) and 25 mL of anhydrous tetrahydrofuran was added dropwise under vigorous stirring. Slowly raise the temperature to the reflux of the system, and maintain the reflux for 2 hours, and TLC detects that the reaction is complete. Cool down to room temperature, add dilute hydrochloric acid to quench the reaction, extract with ethyl acetate, and dry over anhydrous sodium sulfate. The solvent was collected under reduced pressure to obtain 3.48 g of light yellow oily product, methyl 4-(1-hydroxy-3-butyne)benzoate (IV), with a yield of 85.3%.

Embodiment 2

[0026] Under a dry and nitrogen atmosphere, 25 mL of a tetrahydrofuran solution containing 3.5 g of zinc-copper couple was added to a three-necked flask. A solution consisting of 4-ethoxycarbonylbenzaldehyde (II) (3.56 g, 20 mmol), 3-bromoendyne (III) (2.93 g, 25 mmol) and 25 mL of anhydrous tetrahydrofuran was added dropwise under vigorous stirring. Slowly raise the temperature until the system is in the same flow, and maintain the same flow for 2 hours, and TLC detects that the reaction is complete. Cool down to room temperature, add dilute hydrochloric acid to quench the reaction, extract with ethyl acetate, and dry over anhydrous sodium sulfate. The solvent was collected under reduced pressure to obtain 3.68 g of ethyl 4-(1-hydroxy-3-butyne)benzoate (IV) as a light yellow oil, with a yield of 84.4%.

Embodiment 3

[0028] Under nitrogen protection, methylglyoxal dimethyl acetal (V) (4.72 g, 40 mmol), triethylamine (5.5 g, 54 mmol) and 50 mL of tetrahydrofuran were added into a three-necked flask. The temperature was lowered to 0°C, and under stirring, trisilyl trifluoromethanesulfonate (10 mL, 50 mmol) was added dropwise. After the drop was completed, the mixture was reacted at room temperature for 4 hours, and the reaction was detected by TLC. After adding n-hexane and stirring for 15 minutes, the solid was removed by filtration. The mother liquor was washed with water, water and brine in sequence, dried over anhydrous magnesium sulfate, and the solvent was recovered by distillation under reduced pressure. The obtained pale yellow oil was dissolved in 100 mL of dichloromethane and placed in a dry three-necked flask, and methyl 4-(1-hydroxy-3-butyne)benzoate (IV) (2.04 g, 10 mmol) was added. The temperature was lowered to -65°C, under the protection of nitrogen, 7 mL of 1 M tin tetrachl...

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Abstract

The invention discloses a novel medical compound 4-[1-(2-propinyl)-3, 4-dioxo-n-butyl] benzoate (I) and a preparation method thereof. The preparation method comprises the following steps of carrying out an addition reaction on 4-carbalkoxy benzaldehyde (II) and 3-propargyl bromide (III) to generate 4-(1-hydroxyl-3-butyne) benzoate (IV); and carrying out a coupled reaction on an intermediate (IV) and pyruvaldehyde dialkyl acetal (V) after being subjected to enolization under the action of a metal catalyst to form the 4-[1-(2-propinyl)-3, 4-dioxo-n-butyl] benzoate (I). According to the intermediate (I) and the preparation method thereof, a novel preparation way for the antineoplastic pralatrexate is provided and the economic and technological development of the pralatrexate is promoted.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to a new compound 4-[1-(2-propynyl)-3,4-dioxo-n-butyl]benzyl Ester and its preparation method. Background technique [0002] Pralatrexate is a drug developed by Allos Therapeutics Inc in the United States for the treatment of relapsed and refractory peripheral T-cell lymphoma. Pralatrexate injection was approved by the US FDA on September 24, 2009 in the United States, with a trade name of Folotvn. The chemical name of pralatrexate is N-[4-(1-(2,4-diamino-6-pteridine)methyl-3-butynyl)benzoyl]-L-glutamic acid. [0003] [0004] U.S. Patent No. US6028071, No. US2010248249, No. US2011111436 and World Patent No. WO2012061469 originally developed by Aros Therapeutics reported the preparation method and pharmaceutical use of pralatrexate. The method is to use 4-methoxycarbonylphenylacetic acid methy...

Claims

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Application Information

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IPC IPC(8): C07C69/78C07C67/343C07D475/08
Inventor 许学农
Owner 临沂经开财金投资发展有限公司
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