CN1830955A

CN1830955A - Method for synthesizing O-ethoxy phenyl formamidine acetate

Info

Publication number: CN1830955A
Application number: CN 200510045045
Authority: CN
Inventors: 石志强; 马永山; 袁明鉴; 邢成芬; 于莹
Original assignee: Shandong Normal University
Current assignee: Shandong Normal University
Priority date: 2005-11-07
Filing date: 2005-11-07
Publication date: 2006-09-13

Abstract

A process for preparing o-ethoxybenzamidine acetate includes such steps as reflux reaction between o-ethoxy benzaldehyde and nitroethane to obtain o-ethoxy benzonitrile, reflux reacting on hydroxyammonium hydrochloride to obtain o-ethoxy benzamidoxime, and catalytic hydrogenating while stirring.

Description

The synthetic method of O-ethoxy phenyl formamidine acetate

Technical field:

The invention belongs to the synthetic field of medicine intermediate, relate to the synthetic method of O-ethoxy phenyl formamidine acetate.

Background technology:

Discover in many natural products and contain amidine compound, it plays important effect in vital process, and fragrant substituted amidine is the important medicine intermediate of a class, therefore existing various chemical synthesis process is in the news, and the most general synthetic method is by amides, nitrile and thioamide analog preparation.Wherein have the method for market outlook to have:

1, acid amides by the oxygen-alkylation of triethyl oxygen fluoroborate, generates amidine with the amine effect under the temperature condition of a gentleness.

2, Kakimoto has reported a synthetic method that is converted into amidine with Tripyrophosphoric acid trimethyl silane ester (PPSE) by carboxylic acid.

3, Pinner reaction is the classic methods that is prepared non-substituted amidine by nitrile.

O-ethoxy phenyl formamidine is a class newtype drug intermediate, above-mentioned synthetic the 2nd, 3 two kind of method is all inapplicable, and the 1st kind of method cost is too high.

Summary of the invention:

The invention provides that a kind of technology and equipment are simple, cost is low, purity is high, help the synthetic method of the O-ethoxy phenyl formamidine acetate that large-scale industrial produces.

Purpose of the present invention can realize by following technical measures

This method is carried out according to the following steps:

A, be raw material with O-ethoxyl formaldehyde, get the O-ethoxyl formonitrile HCN with the nitroethane back flow reaction, productive rate is 90-95%;

B, back flow reaction in ethanol makes adjacent ethoxy benzylidene amidoxime with O-ethoxyl formonitrile HCN and oxammonium hydrochloride, and productive rate is 91-96%;

C, with adjacent ethoxy benzylidene amidoxime catalyzer exist and stirring at room under normal pressure hydrogenation make O-ethoxy phenyl formamidine acetate, productive rate is 90-95%.

Purpose of the present invention also can realize by following technical measures

Reflux time described in the above-mentioned a operation is no less than 20 minutes, and the reflux time described in the b operation is no less than 1 hour; Hydrogenation time described in the C operation is no less than 4 hours; Wherein the reflux time described in a operation is to be scheme preferably in 4～8 hours with the reflux time described in 0.5～2 hour and the b operation with the hydrogenation time described in 1～5 hour and the C operation; Described hydrogenation is a solvent with acetate, and diacetyl oxide is as water-removal agent; Described hydrogenated products is used earlier dissolve with ethanol, is that solvent recrystallization is separated with ether again; Described catalyzer is selected from the palladium-carbon catalyst that palladium content is 5-20%.

Method of the present invention has following advantage:

1, technology is simple, equipment requirements is low, three-step reaction, and the first two steps reaction all is lower than 120 ℃, and is low to the thermal source requirement, and the 3rd step carried out at normal temperatures and pressures, did not need press device;

2, cost is low, and raw material is cheap, and catalyzer, solvent can reuse in the hydrogenation;

3, purity height, the three-step reaction productive rate all is higher than 90%, only relates to simple recrystallization and separates, and aftertreatment is simple.

Description of drawings:

Fig. 1 is a synthetic route synoptic diagram of the present invention;

Fig. 2 is a product mass spectrum of the present invention;

Fig. 3 is a product hydrogen nuclear magnetic resonance spectrogram of the present invention;

Fig. 4 is that product of the present invention is paid sharp leaf infrared spectrum.

Embodiment:

Embodiment 1:

Get 7.5 gram (0.05mol) O-ethoxyl formaldehyde, 4.31 gram (0.0575mol) nitroethanes and 6.64 gram (0.0575mol) anhydrous pyridine hydrochlorides in container, be heated to 114 ℃, back flow reaction 1 hour, be chilled to the hydrochloric acid soln that adds 100 milliliters of chloroforms and 100 milliliters of 0.1M after the room temperature, fully isolate organic layer behind the mixing, water chloroform extraction 3 times, each 20 milliliters, organic phase washes each 50 milliliters with water three times after merging.Product is by the silicagel column of 2.5 centimetres of long 6 centimetres, diameters, is that leacheate separates and obtains the O-ethoxyl eyeball with the chloroform, and productive rate is 92%.

In 5.9 gram (0.04mol) O-ethoxyl eyeballs, 4.2 gram (0.06mol) oxammonium hydrochlorides, 4.2 gram salt of wormwood, add 15 milliliters of ethanol, stir and add 15 ml waters down in batches, no bubble generates post-heating to 78 ℃, refluxed 3 hours, steam and remove ethanol, naturally cooling is collected the white crystal of separating out, cold water washing; Solution is partly removed solvent, and water recrystallization behind the cold water washing merges the white crystal of gained, dry adjacent ethoxy benzylidene amidoxime, and productive rate is 90%.

7.2 gram (0.04mol) adjacent ethoxy benzylidene amidoximes are dissolved in 200 milliliters of acetate, add 6 ml acetic anhydride, 1.5 gram palladium-carbon catalysts.Mixture normal pressure hydrogenation 6 hours under stirring at room.Filtered and recycled palladium carbon, solution reclaims solvent with Rotary Evaporators, and jelly adds 10 ml n-hexanes and is spin-dried for, and three times to remove a small amount of high-boiling-point impurity repeatedly.Add the small amount of ethanol lysate, add ether again and obtain white, needle-shaped crystals, with ether washing, the dry O-ethoxy phenyl formamidine acetate that gets, productive rate is 92%.

Embodiment 2:

Get 7.5 gram (0.05mol) O-ethoxyl formaldehyde, 4.31 gram (0.0575mol) nitroethanes and 6.64 gram (0.0575mol) anhydrous pyridine hydrochlorides in container, be heated to 114 ℃, back flow reaction 0.5 hour, be chilled to the hydrochloric acid soln that adds 100 milliliters of chloroforms and 100 milliliters of 0.1M after the room temperature, fully isolate organic layer behind the mixing, water chloroform extraction 3 times, each 20 milliliters, organic phase washes each 50 milliliters with water three times after merging.Product is by the silicagel column of 2.5 centimetres of long 6 centimetres, diameters, is that leacheate separates and obtains the O-ethoxyl eyeball with the chloroform, and productive rate is 92%.

In 5.9 gram (0.04mol) O-ethoxyl eyeballs, 4.2 gram (0.06mol) oxammonium hydrochlorides, 4.2 gram salt of wormwood, add 15 milliliters of ethanol, stir and add 15 ml waters down in batches, no bubble generates post-heating to 78 ℃, refluxed 5 hours, steam and remove ethanol, naturally cooling is collected the white crystal of separating out, cold water washing; Solution is partly removed solvent, and water recrystallization behind the cold water washing merges the white crystal of gained, dry adjacent ethoxy benzylidene amidoxime, and productive rate is 90%.

7.2 gram (0.04mol) adjacent ethoxy benzylidene amidoximes are dissolved in 200 milliliters of acetate, add 6 ml acetic anhydride, 1.5 gram palladium-carbon catalysts.Mixture normal pressure hydrogenation 4 hours under stirring at room.Filtered and recycled palladium carbon, solution reclaims solvent with Rotary Evaporators, and jelly adds 10 ml n-hexanes and is spin-dried for, and three times to remove a small amount of high-boiling-point impurity repeatedly.Add the small amount of ethanol lysate, add ether again and obtain white, needle-shaped crystals, with ether washing, the dry O-ethoxy phenyl formamidine acetate that gets, productive rate is 92%.

Embodiment 3:

Get 7.5 gram (0.05mol) O-ethoxyl formaldehyde, 4.31 gram (0.0575mol) nitroethanes and 6.64 gram (0.0575mol) anhydrous pyridine hydrochlorides in container, be heated to 114 ℃, back flow reaction 2 hours, be chilled to the hydrochloric acid soln that adds 100 milliliters of chloroforms and 100 milliliters of 0.1M after the room temperature, fully isolate organic layer behind the mixing, water chloroform extraction 3 times, each 20 milliliters, organic phase washes each 50 milliliters with water three times after merging.Product is by the silicagel column of 2.5 centimetres of long 6 centimetres, diameters, is that leacheate separates and obtains the O-ethoxyl eyeball with the chloroform, and productive rate is 92%.

In 5.9 gram (0.04mol) O-ethoxyl eyeballs, 4.2 gram (0.06mol) oxammonium hydrochlorides, 4.2 gram salt of wormwood, add 15 milliliters of ethanol, stir and add 15 ml waters down in batches, no bubble generates post-heating to 78 ℃, refluxed 1 hour, steam and remove ethanol, naturally cooling is collected the white crystal of separating out, cold water washing; Solution is partly removed solvent, and water recrystallization behind the cold water washing merges the white crystal of gained, dry adjacent ethoxy benzylidene amidoxime, and productive rate is 90%.

7.2 gram (0.04mol) adjacent ethoxy benzylidene amidoximes are dissolved in 200 milliliters of acetate, add 6 ml acetic anhydride, 1.5 gram palladium-carbon catalysts.Mixture normal pressure hydrogenation 8 hours under stirring at room.Filtered and recycled palladium carbon, solution reclaims solvent with Rotary Evaporators, and jelly adds 10 ml n-hexanes and is spin-dried for, and three times to remove a small amount of high-boiling-point impurity repeatedly.Add the small amount of ethanol lysate, add ether again and obtain white, needle-shaped crystals, with ether washing, the dry O-ethoxy phenyl formamidine acetate that gets, productive rate is 92%.

Claims

1, the synthetic method of O-ethoxy phenyl formamidine acetate is characterized in that this method carries out according to the following steps:

A, be raw material, get the O-ethoxyl formonitrile HCN with the nitroethane back flow reaction with O-ethoxyl formaldehyde;

B, back flow reaction in ethanol makes adjacent ethoxy benzylidene amidoxime with O-ethoxyl formonitrile HCN and oxammonium hydrochloride;

C, with adjacent ethoxy benzylidene amidoxime catalyzer exist and stirring at room under normal pressure hydrogenation make O-ethoxy phenyl formamidine acetate.

2, the synthetic method of O-ethoxy phenyl formamidine acetate according to claim 1 is characterized in that the reflux time described in a operation is no less than 20 minutes, and the reflux time described in the b operation is no less than 1 hour.

3, the synthetic method of O-ethoxy phenyl formamidine acetate according to claim 1 is characterized in that the hydrogenation time described in the C operation is no less than 4 hours.

4, the synthetic method of O-ethoxy phenyl formamidine acetate according to claim 1 is characterized in that the reflux time described in a operation is 0.5～2 hour, and the reflux time described in the b operation is 1～5 hour.

5, the synthetic method of O-ethoxy phenyl formamidine acetate according to claim 1 is characterized in that the hydrogenation time described in the C operation is 4～8 hours.

6, the synthetic method of O-ethoxy phenyl formamidine acetate according to claim 1 is characterized in that described hydrogenation is a solvent with acetate, and diacetyl oxide is as water-removal agent.

7, the synthetic method of O-ethoxy phenyl formamidine acetate according to claim 1 is characterized in that the first dissolve with ethanol of using of described hydrogenated products, is that solvent recrystallization is separated with ether again.

8, the synthetic method of O-ethoxy phenyl formamidine acetate according to claim 1 is characterized in that described catalyzer is selected from the palladium-carbon catalyst that palladium content is 5-20%.