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Preparation method of p-hydroxy benzal propane diacid derivative

A technology of hydroxyphenylmalonic acid and hydroxyphenylacetic acid ester, which is applied in the field of preparation of p-hydroxyphenylmalonic acid derivatives, can solve problems such as difficult operation, high risk, and high price, and achieve low price and great competition Power, price, safe and easy to operate

Active Publication Date: 2013-04-17
SHANDONG RUIYING PIONEER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The n-butyllithium used in the above preparation reaction is a spontaneous combustion product, which has strict requirements on anhydrous environment, and has disadvantages such as difficult operation, great danger and high price in industrial production.

Method used

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  • Preparation method of p-hydroxy benzal propane diacid derivative
  • Preparation method of p-hydroxy benzal propane diacid derivative
  • Preparation method of p-hydroxy benzal propane diacid derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Add tetrahydrofuran (170ml), potassium tert-butoxide (15.0g, 134mmol) into a 500ml four-necked bottle, cool down to -20 degrees Celsius, add 4-hydroxyphenylacetic acid-(4-methoxyphenyl)-methyl ester (16.9g , 61mmol), stirred and heated up to 25°C, reacted for 5 hours, then cooled to -25°C, added 2.86 g of dry ice, followed by liquid chromatography analysis into the solution 4-hydroxyphenylacetic acid-(4-methoxyphenyl)- The methyl ester content is less than 2.5% as the reaction end point, the total reaction time is 6h, warm up to 0°C, add 200ml of water, 150ml of ethyl acetate, stir for 25 minutes, separate layers with a separatory funnel, add 150ml of ethyl acetate to the water phase , adjust the pH value to 0.5~1 with 5% hydrochloric acid, separate the layers with a separatory funnel, wash the organic phase once with 60ml of water, add 12g of anhydrous magnesium sulfate to dry for 30 minutes, filter, and concentrate to dryness under reduced pressure to obtain 17.0g 4-H...

Embodiment 2

[0027] Add tetrahydrofuran (170ml), potassium isopropoxide (134mmol, 13.3g) into a 500ml four-necked bottle, cool down to -20°C, add 4-hydroxyphenylacetic acid-(4-methoxyphenyl)-methyl ester (16.9g , 61mmol), stirred and heated to 25°C, reacted for 5 hours, then cooled to -25°C, added 2.86 grams of dry ice, followed by liquid chromatography analysis to 4-hydroxyphenylacetic acid-(4-methoxyphenyl) in the reaction liquid -Methyl ester content less than 8% is the reaction end point, the total reaction time is 8h, and the follow-up treatment is consistent with Example 1. Finally, 14.9g of 4-hydroxyphenylmalonate-4'-methoxybenzyl monoester white product was obtained, with a melting point of 92~93°C and a yield of 76.1%. 1 HNMR (CDCl 3 , 600MHz) δ : 6.95~7.00(m, H-Ph, 4H), 6.60~6.62 (m,H-Ph,4H), 4.81~4.93(m, -CH 2 -, 2H), 4.37~4.52(m, -CH-, 1H), 3.49(s, -OCH 3 , 3H).

Embodiment 3

[0029] Add tetrahydrofuran (170ml), potassium ethoxide (140mmol, 11.9g) into a 500ml four-necked bottle, cool down to -20°C, add 4-hydroxyphenylacetic acid-(4-methoxyphenyl)-methyl ester (16.9g, 61mmol ), stirred and heated to 25°C, reacted for 7 hours, added 2.86 grams of dry ice, followed by liquid chromatography analysis until the reaction liquid 4-hydroxyphenylacetic acid-(4-methoxyphenyl)-methyl ester was less than 10% was the end of the reaction , the total reaction time is 10h, and the follow-up treatment is consistent with Example 1. Finally, 14.5g of 4-hydroxyphenylmalonate-4'-methoxybenzyl monoester white product was obtained, with a melting point of 92~93°C and a yield of 74.2%. 1 HNMR (CDCl 3 , 600MHz) δ : 6.95~7.01(m, H-Ph, 4H), 6.65~6.67 (m,H-Ph,4H), 4.79~4.90(m, -CH 2 -, 2H), 4.36~4.51(m, -CH-, 1H), 3.53(s, -OCH 3 , 3H).

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Abstract

The invention belongs to the filed of chemical synthesis, and especially discloses a preparation method of a p-hydroxy benzal propane diacid derivative. According to the invention, p-hydroxy benzal acetic acid ester firstly reacts with an organic base to form carbanion on the alpha site of the ester group and then reacts with CO2, and finally undergoes acidification to produce the p-hydroxy benzal propane diacid derivative. The organic base used in the invention has a low price and is convenient to use, thus greatly reducing the cost and the risk of danger in industrial production. The preparation method provided by the invention has no requirement about the production equipment so as to reduce the investment in production equipment and possess large competitiveness in industrial production.

Description

(1) Technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a preparation method of p-hydroxyphenylmalonic acid derivatives. (2) Background technology [0002] P-hydroxyphenylmalonic acid derivatives are a class of important pharmaceutical intermediates, and they are important raw materials for the preparation of oxycephem antibiotics Latamoxef sodium. The compounds have high application value in pharmaceutical production. [0003] The preparation method provided in the "New Drug Synthesis" edited by Chen Fen'er is to first react with the alkyl derivative of lithium with the sodium p-hydroxyphenyl acetate, and then add dry ice to prepare it. The specific synthesis method is: control the temperature of the reaction solution at -10~-15°C, add n-butyllithium cyclohexane solution to the tetrahydrofuran solution containing diisopropylamine, stir for 15 minutes, and then dropwise add Tetrahydrofuran solution of the sodium salt of est...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/732C07C67/313
Inventor 杜彦峰李文宽付喜成曹利霞
Owner SHANDONG RUIYING PIONEER PHARMA