Synthesis method of indobufen key intermediate 2-(4-nitrophenyl) butyric acid

A technology of indobufen and nitrophenyl, which is applied in the field of synthesis of 2-butyric acid, the key intermediate of indobufen, can solve problems such as the impact of environmental impact, and achieve the effect of convenient operation, high safety and low pollution

Pending Publication Date: 2022-05-20
HANGZHOU ZHONGMEI HUADONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, affected by the environmental impact, the production involving nitration reaction is strictly controlled. In order to reduce the risk, it is necessary to develop a new preparation method for the key intermediate of indobufen, 2-(4-nitrophenyl)butanoic acid.

Method used

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  • Synthesis method of indobufen key intermediate 2-(4-nitrophenyl) butyric acid
  • Synthesis method of indobufen key intermediate 2-(4-nitrophenyl) butyric acid
  • Synthesis method of indobufen key intermediate 2-(4-nitrophenyl) butyric acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024]

[0025] SM1 (1.62g, 10.00mmol) and sodium hydroxide (1.20g, 30.00mmol) were added to the reaction flask, dissolved in DMF, bromoethane (1.63g, 15.00mmol) was added dropwise with stirring, and reacted at room temperature for 12h. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, purified by column chromatography, eluent n-hexane: ethyl acetate = 10:1, 1.50 g of pale yellow oily liquid A00 was obtained, with a yield of 79%. 1 H NMR (60MHz, CDCl 3 )δ8.47–8.03(m,2H),7.78–7.35(m,2H),3.89(t,J=7.0Hz,1H),2.34–1.73(m,2H),1.31–0.93(m,3H) .HRMS(ESI):found 189.0765[M+H] -

Embodiment 2

[0027]

[0028] Add SM1 (1.62g, 10.00mmol) to the reaction flask and dissolve it in DMF, cool to 0°C, add NaH (0.28g, 12.00mmol) under ice bath, stir for half an hour and drop bromoethane (1.63g, 15.00 mmol), remove the ice bath, and react at room temperature for 12h. After the reaction was completed, the reaction liquid was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, purified by column chromatography, and the eluent was n-hexane:ethyl acetate=10:1 to obtain Pale yellow oily liquid A00 1.56g, yield 85%.

[0029] 1 H NMR (60MHz, CDCl 3 )δ8.47–8.03(m,2H),7.78–7.35(m,2H),3.89(t,J=7.0Hz,1H),2.34–1.73(m,2H),1.31–0.93(m,3H) .HRMS(ESI):found 189.0765[M-H] -

Embodiment 3

[0031] The sodium hydroxide in Example 1 was replaced with triethylamine (4.09mL, 30.00mmol), and the other condition parameters remained unchanged, no reaction occurred, and the target product A00 could not be obtained.

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Abstract

The invention discloses a synthesis method of an indobufen key intermediate 2-(4-nitrophenyl) butyric acid, which comprises the following steps: in an organic solvent, under the action of an alkaline substance, reacting a compound as shown in a formula I with bromoethane to obtain a compound as shown in a formula II, and hydrolyzing the compound as shown in the formula II under an acidic condition to obtain a target product as shown in a formula III. The method provided by the invention has the advantages of simple steps, convenience in operation, no nitration process in reaction, high safety, small pollution and high product yield.

Description

technical field [0001] The invention belongs to the field of compound synthesis, and in particular relates to a method for synthesizing 2-(4-nitrophenyl)butyric acid, a key intermediate of indobufen. Background technique [0002] Indobufen (indobufen) chemical name is 2-[4-(1-oxo 2-isoindolinyl) phenyl] butyric acid, which is a racemic mixture developed by Pfizer of the United States. It can selectively act on circulating platelets, block thrombus formation, inhibit the release of platelet factors and exert anti-platelet aggregation effect, this inhibition is reversible, does not change plasma parameters, does not damage platelet function, and restores abnormal platelet function to normal . Compared with similar drugs, indobufen inhibits platelet factors, and the anti-platelet aggregation effect is 2 to 5 times that of salicylic acid, and the bleeding time is shorter than that of slight duration. [0003] Gao Xuemin, etc. in "The Synthesis of Anticoagulant Indobufen" (Jour...

Claims

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Application Information

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IPC IPC(8): C07C201/12C07C205/56
CPCC07C201/12C07C253/30C07C205/56C07C255/35Y02P20/55
Inventor靳浩吴沣王含光
OwnerHANGZHOU ZHONGMEI HUADONG PHARMA