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2-amino-5-hydroxypropiophenone preparation method

A technology of hydroxypropiophenone and amino, which is applied in the field of preparation of intermediate 2-amino-5-hydroxypropiophenone, can solve the problems of inability to realize industrial production, pollution of three wastes, harsh reaction conditions, etc., and achieve good industrialization prospects and environmental friendliness , the effect of easy operation

Inactive Publication Date: 2009-02-11
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] This method has poor nitration regioselectivity, and the ratio of para-position main product to ortho-position by-product is: 3:2. It is difficult to obtain high-purity compound (I), and industrial production cannot be realized. At the same time, the reaction conditions are harsh and the equipment is highly corrosive. The three wastes are seriously polluted

Method used

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Experimental program
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Effect test

Embodiment 1

[0083] Compound 2-nitro-5-hydroxybenzaldehyde (II) 10.0g (59.88mmol), dimethyl sulfate 18.86g (0.15mol) and water (80ml) were placed in a reaction flask, under normal pressure, below 40 React at ℃, continuously add 30% potassium hydroxide solution dropwise during the reaction to control the pH of the reaction solution to 9~10 (the molar ratio of compound (II) to NaOH is 1:1.2~8.5), after the pH of the reaction solution is stable, The temperature was raised to 40° C. to continue the reaction for 4 hours (the total reaction time was 5-10 hours). The reactant was filtered, the filter cake was washed with water until neutral, and dried to obtain 9.53 g of white needle-like solid 2-nitro-5-methoxybenzaldehyde (III), melting point 83.1-83.8°C, yield 85.1%, content ≥ 93.9 %(GC / MS)(m / z)=181.

Embodiment 2

[0085] Compound 2-nitro-5-hydroxybenzaldehyde (II) 10.0g (59.88mmol) and acetone (150ml) were placed in a reaction flask, and potassium carbonate 9.93g (0.1mol ), and then gradually added 10.21 g (71.86 mmol) of iodomethane dropwise. After the dropwise addition, the temperature rose to 60° C. to continue the reaction for 4.5 hours (the total reaction time was 5 to 10 hours). After the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure, 135ml of ethyl acetate was added, and the organic layer was washed with 10% sodium hydroxide solution (10ml×2) and water (15ml×2). After drying over anhydrous sodium sulfate, ethyl acetate was recovered to obtain 9.87 g of white solid 2-nitro-5-methoxybenzaldehyde (III), with a melting point of 84.0-84.9° C., a yield of 91.8%, and a content of ≥96.9% (GC / MS) (m / z) = 181.

[0086] (two) the preparation of 2-nitro-5-methoxybenzonitrile (V):

[0087] Example 1

[0088] Method A is a two-step meth...

Embodiment 3

[0096] Method B is a one-step method, 2-nitro-5-methoxybenzaldehyde (III) directly produces 2-nitro-5-methoxybenzonitrile (V) through step C:

[0097] Compound 2-nitro-5-methoxybenzaldehyde (III) 7.0g (38.67mmol), hydroxylamine hydrochloride 2.9g (42.54mmol), sodium formate 6.16g (0.15mol) and 85% formic acid 40ml were placed in the reaction flask, The reaction temperature was 70-135°C, and the reaction was stirred under reflux for 0.5 hours. After the reaction was completed, the reaction solution was cooled and poured into ice water, neutralized with 10% sodium hydroxide solution, extracted with ethyl acetate (30ml×3), the organic layer was washed with water (15ml×2), and dried over anhydrous sodium sulfate Afterwards, reclaim ethyl acetate, obtain compound 2-nitro-5-methoxybenzonitrile (V) 5.03g, fusing point 148.6~149.5 ℃, yield 75.4%, content≥93.8% (GC / MS) (m / z)=178.

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Abstract

The invention relates to a method for preparing an intermediate 2-amino-5-hydroxy propiophenone (I) that is relevant to camptothecin drug synthesizing, which comprises the following steps in sequence: firstly, with the existence of inorganic alkali, 2-nitryl-5-hydroxy benzaldehyde (II) and methylation reagent carry out the O-methylation reaction in solvent to obtain 2-nitryl-5-methoxy benzaldehyde (III); secondly, the compound (III) and hydroxylamine hydrochloride react by a two-step method or a one-step method to obtain 2-nitryl-5-methoxy cyanobenzene (V); thirdly, with the catalysis of the palladium catalyst, the compound (V) carries out the hydrogenation reaction in organic solvent to obtain 2-amino-5-methoxy cyanobenzene (VI); fourthly, under the protection of inert gases, the compound (VI) and format reaction reagent carry out the Grignard reaction in the organic solvent to obtain 2-amino-5-methoxy propiophenone (VII); and fifthly, the compound (VII) and the demethylating reagent carry out the demethylating reaction to obtain 2-amino-5-hydroxy propiophenone (I).

Description

technical field [0001] The invention belongs to the field of organic chemistry, in particular to a preparation method of an intermediate 2-amino-5-hydroxypropiophenone (I) related to the synthesis of camptothecin drugs. [0002] Background technique [0003] 2-Amino-5-hydroxypropiophenone (I) is an important key intermediate in the synthesis of irinotecan (X) precursor 7-ethyl-10-hydroxycamptothecin (IX), which has antitumor activity body. From compound (I) and (5'S)-1,5-dioxo-5'-ethyl-5'-hydroxyl-2'H, 5'H, 6'H-6'-oxo-pyran-[ 3', 4', f]-△ 6(8) -tetrahydroindolizine (VIII) can make (X) through Friedlander condensation reaction, and its reaction formula is as follows: [0004] [0005] U.S. Patent US2004 / 0106830A1 takes 2-nitro-5-hydroxybenzaldehyde (II) as raw material, obtains 2-amino-5-hydroxypropiophenone (I) through benzylation protection, Grignard reaction, oxidation reaction, catalytic reduction ). The method has harsh reaction conditions, complicated operati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C225/22C07C221/00
Inventor 陈芬儿熊小东
Owner FUDAN UNIV
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