CN1765878A - (1,3-dichlo-6-trifluomethyl-9-phenanthrene-yl)-3-hydroxylpropionamide derivative preparation method - Google Patents
(1,3-dichlo-6-trifluomethyl-9-phenanthrene-yl)-3-hydroxylpropionamide derivative preparation method Download PDFInfo
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- CN1765878A CN1765878A CN 200410067559 CN200410067559A CN1765878A CN 1765878 A CN1765878 A CN 1765878A CN 200410067559 CN200410067559 CN 200410067559 CN 200410067559 A CN200410067559 A CN 200410067559A CN 1765878 A CN1765878 A CN 1765878A
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- trifluomethyl
- dichlor
- phenanthrene
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Abstract
The invention discloses a preparation method for (1,3-dichlor-6- trifluoromethyl- 9- phenanthryl )-3-hydroxylpropionamide derivant, which uses 1,3- dichlor -6- trifluoromethyl -9- phenanthrylformaldehyde, alpha halogenated-N-alkylacetamide or alpha halogenated -N, N- dialkylacetamide for Reformatsky reaction with zinc powder in organic solution; adding acid for hydrolysis; filtering to remove residual zinc powder. This invention cuts reaction time with mild condition and less side reaction, and has high product purity and yield.
Description
Technical field
That the present invention relates to is preparation method about phenanthrene methanol class antimalarial agent intermediate (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxyl propanamide derivative.
Background technology
Phenanthrene methanol class antimalarial agent is the effective malaria treatment medicine of a class, as schizonticide, they for agamic erythrocytic phase plasmodium have the activity of killing of height.Clinically be used to treat because of cause single of plasmodium falciparum or plasmodium vivax infection or mix acute malaria.On behalf of medicine, it halofantrine, Monodesbutylhalofantrine etc. are arranged.
The structural formula of phenanthrene methanol class antimalarial agent is:
R
1=hydrogen, methyl, ethyl, propyl group, butyl, phenyl ,-CH
2CH (OH) CH
3,-CH
2CH (OH) CH (OH) ,-CH
2CH
2CH
2-phenyl ,-(CH
2)
X-Ar (X=0-4, Ar are the phenyl of six membered ring, pyridyl, the derivative that cyclohexyl and pyranyl and they replace through hydrophilic radical);
R
2=methyl, ethyl, propyl group, butyl, phenyl ,-CH
2CH (OH) CH
3,-CH
2CH (OH) CH (OH) ,-CH
2CH
2CH
2-phenyl ,-(CH
2)
X-Ar (X=0-4, Ar are the phenyl of six membered ring, pyridyl, the derivative that cyclohexyl and pyranyl and they replace through hydrophilic radical);
HX=hydrochloric acid, tartrate, oxalic acid, toxilic acid, quinic acid.
(1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxyl propanamide derivative (I) is the intermediate of synthetic phenanthrene methanol class antimalarial agent, and its structural formula is:
R
1=hydrogen, methyl, ethyl, propyl group, butyl, phenyl ,-CH
2CH (OH) CH
3,-CH
2CH (OH) CH (OH) ,-CH
2CH
2CH
2-phenyl ,-(CH
2)
X-Ar (X=0-4, Ar are the phenyl of six membered ring, pyridyl, the derivative that cyclohexyl and pyranyl and they replace through hydrophilic radical);
R
2=methyl, ethyl, propyl group, butyl, phenyl ,-CH
2CH (OH) CH
3,-CH
2CH (OH) CH (OH) ,-CH
2CH
2CH
2-phenyl ,-(CH
2)
X-Ar (X=0-4, Ar are the phenyl of six membered ring, pyridyl, cyclohexyl and pyranyl and their derivatives after hydrophilic radical replaces).
(1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-and the method for 3-hydroxyl propanamide derivative bibliographical information has: 1, United States Patent (USP) 5711966, with N-normal-butyl ethanamide, butyllithium is raw material, make the α lithium earlier for N-normal-butyl ethanamide, with the α lithium for N-normal-butyl ethanamide and 1, the reaction of 3-dichlor-6-trifluomethyl-9-phenanthrene formaldehyde obtains (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxy-n-(normal-butyl) propionic acid amide; 2, United States Patent (USP) 5250734, in the presence of ethyl bromoacetate and zinc powder, with 1, the 3-dichlor-6-trifluomethyl-9-phenanthrene formaldehyde obtains (1 through this base of row Buddhist Germania (English Reformatsky by name) reaction, 3-dichlor-6-trifluomethyl-9-phenanthrene base)-and 3-hydroxy-propionic acid ethyl ester, again (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxy-propionic acid ethyl ester and N-alkylamine are carried out the amine transesterify, obtain (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxy-n-(alkyl) propionic acid amide.
Above butyllithium route exists severe reaction conditions, anhydrous requirement height, and the shortcoming that the cost that costs an arm and a leg is high, and yield has only about 66%; Ethyl bromoacetate route amine transesterification reaction difficulty is big, and long reaction time needs 10 days, and total recovery is low.
Summary of the invention
Technical problem to be solved by this invention is to overcome the defective that above-mentioned prior art exists, provide a kind of simply, the method for one-step synthesis (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxyl propanamide derivative efficiently.
Technical scheme of the present invention is as follows: (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-preparation method of 3-hydroxyl propanamide derivative, it is characterized in that 1,3-dichlor-6-trifluomethyl-9-phenanthrene formaldehyde, α halo-N-alkyl ethanamide or α halo-N, the N-dialkyl acetamides is listed as the Fo Ermansi radical reaction in the presence of organic solvent and zinc powder, reaction finishes the back acid hydrolysis, removes by filter unreacted zinc powder.Reaction of the present invention is at first zinc powder and α halo-N-alkyl ethanamide or α halo-N, the effect of N-dialkyl acetamides obtains Reformatsky reagent, this Reformatsky reagent is at once with 1, the condensation of 3-dichlor-6-trifluomethyl-9-phenanthrene formaldehyde, hydrolysis gets (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxyl propanamide derivative again.
Described (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-preparation method of 3-hydroxyl propanamide derivative, organic solvent is sherwood oil, normal hexane, hexanaphthene, heptane, octane, ethers, tetrahydrofuran (THF), methyl-sulphoxide or aromatic hydrocarbon solvent, preferred tetrahydrofuran (THF), benzene,toluene,xylene.
Described (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-and the preparation method of 3-hydroxyl propanamide derivative, 1,3-dichlor-6-trifluomethyl-9-phenanthrene formaldehyde and α halo-N-alkyl ethanamide or α halo-N, the mol ratio of N-dialkyl acetamides consumption is 1: 1～5, be preferably 1: 1.1～and 2; α halo-N-alkyl ethanamide or α halo-N, the mol ratio of N-dialkyl acetamides and zinc powder consumption is 1: 1～5, be preferably 1: 1.5～2.
The preparation method of described (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxyl propanamide derivative, the temperature of reaction is-10～200 ℃, is preferably 20～130 ℃.
The preparation method of described (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxyl propanamide derivative, the time of row Fo Ermansi radical reaction is 0.5～6 hour.
The preparation method of described (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxyl propanamide derivative, described acid is tartrate, hydrochloric acid or acetic acid, is preferably tartrate, when the solution of reaction generation is cooled to below 50 ℃, adds 5～20% tartrate.
Raw material 1 of the present invention, the 3-dichlor-6-trifluomethyl-9-phenanthrene formaldehyde can be prepared by United States Patent (USP) 5711966 methods, also can buy to obtain.
The present invention has following beneficial effect: 1) adopt one-step synthesis, the required reaction times is 0.5～6 hour, has obviously shortened the reaction times, has improved production efficiency; 2) the reaction conditions gentleness is simple to operate; 3) side reaction is few, the purity of product and yield height (〉=70%); 4) raw material is easy to get, and production cost is low.
Embodiment
The invention will be further described below in conjunction with embodiment.
N, the preparation of N-di-n-butyl bromoacetamide
In 500 milliliters of there-necked flasks that have mechanical stirring, thermometer, dropping funnel, add 150ml ethylene dichloride and 25.8 gram Di-n-Butyl Amines, be cooled to-10 ℃, under this temperature, drip the mixture of 20.2 gram bromoacetyl bromides and 25ml ethylene dichloride, reacted 5 minutes, and filtered, filtrate is washed with dilute hydrochloric acid, use anhydrous magnesium sulfate drying, remove solvent, collect bp101-102 ℃ of component (under vacuum tightness 0.22mmHg), be N, N-di-n-butyl bromoacetamide, yield 90%.
Embodiment 1
In having 250 milliliters of there-necked flasks of mechanical stirring, thermometer, add 6.9 grams 1,3-dichlor-6-trifluomethyl-9-phenanthrene formaldehyde (0.02 mole), 6.2 gram N, N-di-n-butyl bromoacetamide (0.03 mole), 3.9 gram zinc powder (0.06 mole) and 100 milliliters of dry-out benzene, temperature rising reflux reaction 2 hours.Reaction finishes, and is cooled to below 40 ℃, adds 20ml 10% tartrate, stirs hydrolysis, removes by filter unreacted zinc powder.Filtrate layering, benzene layer water, 10% sodium hydrogen carbonate solution, water are respectively washed successively, reclaim under reduced pressure benzene, and residue obtains 7.8 gram (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxy-ns, N-(di-n-butyl) propionic acid amide, yield 76% through silica gel column chromatography.
Embodiment 2
In having 250 milliliters of there-necked flasks of mechanical stirring, thermometer, add 6.9 grams 1,3-dichlor-6-trifluomethyl-9-phenanthrene formaldehyde (0.02 mole), 3.9 gram zinc powder (0.06 mole) and 100 milliliters of dry-out benzene, be warming up to backflow, drip 6.2 gram N, N-di-n-butyl bromoacetamide (0.03 mole), drip off half an hour, continued back flow reaction 2 hours.Reaction finishes, and is cooled to below 40 ℃, adds 20ml 10% tartrate, stirs hydrolysis, removes by filter unreacted zinc powder.Filtrate layering, benzene layer water, 10% sodium hydrogen carbonate solution, water are respectively washed successively, reclaim under reduced pressure benzene, and residue obtains 8.4 gram (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxy-ns, N-(di-n-butyl) propionic acid amide, yield 82% through silica gel column chromatography.
Embodiment 3
Repeat the operation of embodiment 1, change the solvent benzol among the embodiment 1 into toluene, in 1 hour reaction times, get product yield 78%.
Embodiment 4
Repeat the operation of embodiment 2, change the solvent benzol among the embodiment 2 into toluene, in 1 hour reaction times, get product yield 83%.
Embodiment 5
In having 250 milliliters of there-necked flasks of mechanical stirring, thermometer, add 6.9 grams 1,3-dichlor-6-trifluomethyl-9-phenanthrene formaldehyde (0.02 mole), 4.3 gram N-n-butyl chloride ethanamides (0.04 mole), 5.2 gram zinc powders (0.08 mole), 0.9 gram iodine and 100 milliliters of dry-out benzene, temperature rising reflux reaction 3 hours.Reaction finishes, and is cooled to below 40 ℃, adds 20ml 10% tartrate, stirs hydrolysis, removes by filter unreacted zinc powder.Filtrate layering, benzene layer water, 10% sodium hydrogen carbonate solution, water are respectively washed successively, reclaim under reduced pressure benzene, and residue obtains 6.8 gram (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxy-n-(normal-butyl) propionic acid amides, yield 74% through silica gel column chromatography.
Embodiment 6
In having 250 milliliters of there-necked flasks of mechanical stirring, thermometer, add 6.9 grams 1,3-dichlor-6-trifluomethyl-9-phenanthrene formaldehyde (0.02 mole), 5.2 gram zinc powders (0.08 mole), 0.9 gram iodine and 100 milliliters of dry-out benzene, be warming up to backflow, drip 4.3 gram N-n-butyl chloride ethanamide (0.04 mole) temperature rising reflux reactions 3 hours.Reaction finishes, and is cooled to below 40 ℃, adds 20ml 10% tartrate, stirs hydrolysis, removes by filter unreacted zinc powder.Filtrate layering, benzene layer water, 10% sodium hydrogen carbonate solution, water are respectively washed successively, reclaim under reduced pressure benzene, and residue obtains 7.0 gram (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxy-n-(normal-butyl) propionic acid amides, yield 76% through silica gel column chromatography.
Embodiment 7
Repeat the operation of embodiment 5, change the solvent benzol among the embodiment 5 into toluene, in 1.5 hours reaction times, get product yield 76%.
Embodiment 8
Repeat the operation of embodiment 6, change the solvent benzol among the embodiment 6 into toluene, in 1.5 hours reaction times, get product yield 79%.
Embodiment 9
Repeat the operation of embodiment 6, change the solvent benzol among the embodiment 6 into dimethylbenzene, in 1.0 hours reaction times, get product yield 78%.
Claims (10)
1, (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-preparation method of 3-hydroxyl propanamide derivative, it is characterized in that 1,3-dichlor-6-trifluomethyl-9-phenanthrene formaldehyde, α halo-N-alkyl ethanamide or α halo-N, the N-dialkyl acetamides is listed as the Fo Ermansi radical reaction in the presence of organic solvent and zinc powder, reaction finishes the back acid hydrolysis, removes by filter unreacted zinc powder.
2, according to claim 1 (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-and the preparation method of 3-hydroxyl propanamide derivative, it is characterized in that organic solvent is sherwood oil, normal hexane, hexanaphthene, heptane, octane, ethers, tetrahydrofuran (THF), methyl-sulphoxide or aromatic hydrocarbon solvent.
3, the preparation method of (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxyl propanamide derivative according to claim 2 is characterized in that the preferred tetrahydrofuran (THF) of organic solvent, benzene,toluene,xylene.
4, according to claim 1 (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-preparation method of 3-hydroxyl propanamide derivative, it is characterized in that 1,3-dichlor-6-trifluomethyl-9-phenanthrene formaldehyde and α halo-N-alkyl ethanamide or α halo-N, the mol ratio of N-dialkyl acetamides consumption is 1: 1～5, α halo-N-alkyl ethanamide or α halo-N, the mol ratio of N-dialkyl acetamides and zinc powder consumption is 1: 1～5.
5, according to claim 4 (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-preparation method of 3-hydroxyl propanamide derivative, it is characterized in that 1, the 3-dichlor-6-trifluomethyl-9-phenanthrene formaldehyde, α halo-N-alkyl ethanamide or α halo-N, the mol ratio of N-dialkyl acetamides consumption is preferably 1: 1.1～and 2, every mole of α halo-N-alkyl ethanamide or α halo-N, the mol ratio of N-dialkyl acetamides and zinc powder consumption is preferably 1: 1.5～and 2.
6, the preparation method of (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxyl propanamide derivative according to claim 1 is characterized in that the temperature of reacting is-10～200 ℃.
7, the preparation method of (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxyl propanamide derivative according to claim 6 is characterized in that the temperature of reacting is preferably 20～130 ℃.
8, the preparation method of (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxyl propanamide derivative according to claim 1, the time that it is characterized in that being listed as the Fo Ermansi radical reaction is 0.5～6 hour.
9, the preparation method of (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-3-hydroxyl propanamide derivative according to claim 1 is characterized in that described acid is tartrate, hydrochloric acid or acetic acid.
10, according to claim 9 (1,3-dichlor-6-trifluomethyl-9-phenanthrene base)-preparation method of 3-hydroxyl propanamide derivative, it is characterized in that used acid is preferably tartrate, when the solution of reaction generation is cooled to below 50 ℃, add 5～20% tartrate.
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| CNB2004100675592A CN100398514C (en) | 2004-10-28 | 2004-10-28 | (1,3-dichlo-6-trifluomethyl-9-phenanthrene-yl)-3-hydroxylpropionamide derivative preparation method |
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| CNB2004100675592A CN100398514C (en) | 2004-10-28 | 2004-10-28 | (1,3-dichlo-6-trifluomethyl-9-phenanthrene-yl)-3-hydroxylpropionamide derivative preparation method |
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| CN100398514C CN100398514C (en) | 2008-07-02 |
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Granted publication date: 20080702 Termination date: 20181028 |