CN103130704A - Novel method for preparing 4-(2-ethoxy)-1,3-dihydro-2H-indole-2-ketone - Google Patents
Novel method for preparing 4-(2-ethoxy)-1,3-dihydro-2H-indole-2-ketone Download PDFInfo
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Abstract
The invention discloses a novel method for preparing a ropinirole hydrochloride key intermediate 4-(2-ethoxy)-1,3-dihydro-2H-indole-2-ketone (I). The reaction process comprises the following steps of: carrying out reduction reaction on 2-methyl-3-nitrobenzene acetic acid (III) to generate 2-methyl-3-nitrobenzene ethanol (IV); protecting the hydroxyl of the compound (IV) to generate 2-methyl-3-(2-alkoxy ethyl) nitrobenzene (V); reacting the compound (V) with diethyl oxalate to generate a 2-nitro-6-(2-alkoxy ethyl)-phenyl acetyl formic acid compound (VI); reacting the compound (VI) with hydrogen peroxide to generate 2-nitro-6-(2-alkoxy ethyl)-phenylacetic acid (VII); and carrying out oxidation reaction on the compound (VII) to obtain 4-(2-ethoxy)-1,3-dihydro-2H-indole-2-ketone (I).
Description
Technical field
The present invention relates to a kind of 4-of preparation (2-hydroxyethyl)-1, the novel method of 3-dihydro-2H-indol-2-one (I).
Background technology
Ropinirole hydrochloride (II), chemistry 4-[2-(dipropyl amido) ethyl by name]-1,3-dihydro-2H-indol-2-one hydrochloride is a kind of medicine by the exploitation of GSK company.This medicine is approved for the treatment Parkinson's disease at first, is found subsequently, and this medicine is also very effective in cure to the ekbom syndrome of severe in the treatment moderate.
Many documents and patent Introduction have been arranged at present Ropinirole hydrochloride (II) synthetic, but most popular or by the two lines of GSK exploitation.Wherein, document JMC, described article one route in 1985,1533:
This route is take the 2-methyl-3-nitrophenylacetic acid as initial feed, forms intermediate 2-methyl-3-nitro-N, N-diη-propyl phenylethylamine after acidylate, aminated and borane reduction.Form 2-nitro-6-[2-(N with the oxalic acid diethyl ester reaction subsequently under the effect of potassium ethylate, N-di-n-propylamine base) ethyl] phenyl-pyruvic acid, it first reacts under alkaline hydrogen peroxide, again under the hydrochloric acid effect, generate 2-nitro-6-[2-(N, N-di-n-propylamine base) ethyl] the phenylacetate hydrochlorate.Obtain Ropinirole hydrochloride (II) by catalytic hydrogenation at last.
But this route exists following defective: the at first essential large inflammable borane reagent again of expensive and toxicity of using, this also is unfavorable for suitability for industrialized production.Secondly, whole piece route yield is very low, only has 24% yield.
GSK has developed again a variation route afterwards, describes as patent US5336781:
This route is with heterochromatic full of starting raw material, first occur successively ring-opening reaction, Sommelet oxidizing reaction and and the Nitromethane 99Min. reaction after, obtain the intermediate nitrostyrene compound.By the cyclization of ferric trichloride catalytic, form the chloro Oxoindole subsequently.This compound then occurs to generate key intermediate 4-(2-hydroxyethyl)-1,3-dihydro-2H-indol-2-one (I) after dechlorination reaction and hydrolysis reaction successively.This compound can obtain Ropinirole hydrochloride (II) through salify after reacting with Tosyl chloride and di-n-propyl amine successively again.
This route has superiority than article one route, has avoided dangerous inflammable borine, and the reagent of use is more cheap.But still will use the large hydrazine hydrate of toxicity, Nitromethane 99Min. etc., and total recovery also only has 22%.We find after analyzing reason, and it is very low that this route shines into the synthesis yield that total recovery major cause on the low side is compound (I), only has 30%.
Therefore the many disadvantages that exists according to prior art has limited with technical scale and has prepared Ropinirole hydrochloride (II).
Summary of the invention
The present invention has overcome the defective of above-mentioned prior art, provides a kind of Ropinirole hydrochloride (II) key intermediate 4-(2-hydroxyethyl)-1 for preparing, the novel method of 3-dihydro-2H-indol-2-one (I).Present method has that route is short, cost is low, easy and simple to handle, whole process need not any intermediate is carried out purification operations, finally obtains compound (I) with high yield and high purity, is fit to suitability for industrialized production.
The present invention specifically comprises the steps:
(1) 2-methyl-3-nitrophenylacetic acid (III) generates 2-methyl-3-nitro phenylethyl alcohol (IV) through reduction reaction;
(2) hydroxyl of compound (IV) is protected generation 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V);
(3) compound (V) and oxalic acid diethyl ester reaction, generate 2-nitro-6-(2-alkoxyethyl)-phenylacetyl formic acid cpds (VI);
(4) compound (VI) generates 2-nitro-6-(2-alkoxyethyl)-toluylic acid (VII) with the hydrogen peroxide reaction;
(5) compound (VII) obtains 4-(2-hydroxyethyl)-1 through hydrogenation, 3-dihydro-2H-indol-2-one (I).
Involved in the present invention to reaction can represent with following reaction formula:
In formula, R represents phenyl, can replace by one or more following bases on phenyl: halogen, hydroxyl, nitro, C
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-alkylamino radical; P represents ethyl or hydrogen.
Reaction needed from 2-methyl-3-nitrophenylacetic acid (III) preparation 2-methyl-3-nitro phenylethyl alcohol (IV) of the present invention is used reductive agent, and reductive agent used is selected from sodium borohydride, lithium borohydride, zinc borohydride, lithium aluminium hydride, borine.
Reaction needed from 2-methyl-3-nitrophenylacetic acid (III) preparation 2-methyl-3-nitro phenylethyl alcohol (IV) of the present invention is used additive, and additive used is selected from boron trifluoride ethyl ether complex, boron trifluoride tetrahydrofuran complex, methylsulfonic acid, Phenylsulfonic acid, tosic acid, formic acid, acetic acid, trifluoracetic acid.
Reaction from 2-methyl-3-nitrophenylacetic acid (III) preparation 2-methyl-3-nitro phenylethyl alcohol (IV) of the present invention is to carry out under suitable solvent, and solvent used is selected from ether, tetrahydrofuran (THF), methyl alcohol, ethanol.
The operating process of above-mentioned reaction from 2-methyl-3-nitrophenylacetic acid (III) preparation 2-methyl-3-nitro phenylethyl alcohol (IV) is roughly as follows:
With after 2-methyl-3-nitrophenylacetic acid (III), reductive agent, additive and solvent, reaction is 1-24 hour at suitable temperature in reaction flask.Water and ethyl acetate are carried out extracting and demixing, separating obtained organic phase after drying, decompression is removed organic solvent and is namely got 2-methyl-3-nitro phenylethyl alcohol (IV), directly carries out next step reaction.
Reaction needed from 2-methyl-3-nitro phenylethyl alcohol (IV) preparation 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V) of the present invention is used the phenyl methyl halides that replaces, and the phenyl methyl halides of replacement used is selected from phenyl and replaces by one or more following bases: halogen, hydroxyl, nitro, C
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-alkylamino radical, halogen is the phenyl methyl halides of chlorine, bromine or iodine.
Reaction from 2-methyl-3-nitro phenylethyl alcohol (IV) preparation 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V) of the present invention is to carry out under suitable solvent, solvent used is selected from tetrahydrofuran (THF), isopropyl ether, first uncle's ether, acetone, espeleton, mibk, methylene dichloride, chloroform, toluene, acetonitrile, methyl alcohol, ethanol, DMF.
Reaction from 2-methyl-3-nitro phenylethyl alcohol (IV) preparation 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V) of the present invention is carried out under the alkali effect, and alkali used is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium hydride, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, butyllithium, triethylamine, diisopropyl ethyl amine, pyridine.
The operating process of above-mentioned reaction from 2-methyl-3-nitro phenylethyl alcohol (IV) preparation 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V) is roughly as follows:
Add 2-methyl-3-nitro phenylethyl alcohol (IV), alkali and solvent in reaction flask.The phenyl methyl halides that adds subsequently replacement, and reacted 1-48 hour at suitable temperature.Water and ethyl acetate are carried out extracting and demixing, separating obtained organic phase after drying, decompression is removed organic solvent and is namely got 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V), directly carries out next step reaction.
Reaction needed from 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V) preparation 2-nitro-6-(2-alkoxyethyl)-phenylacetyl formic acid cpds (VI) of the present invention is used oxalic acid diethyl ester.
Reaction needed from 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V) preparation 2-nitro-6-(2-alkoxyethyl)-phenylacetyl formic acid cpds (VI) of the present invention is used alkali, and alkali used is selected from sodium ethylate, potassium ethylate, sodium methylate, potassium methylate, sodium tert-butoxide, potassium tert.-butoxide, butyllithium, methyl-magnesium-bromide, sodium hydride, sodium hydroxide, potassium hydroxide.
Reaction needed from 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V) preparation 2-nitro-6-(2-alkoxyethyl)-phenylacetyl formic acid cpds (VI) of the present invention is used solvent; solvent used is selected from tetrahydrofuran (THF), acetone, methyl alcohol, ethanol, the trimethyl carbinol, DMF.
Of the present invention from the reaction of 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V) preparation 2-nitro-6-(2-alkoxyethyl)-phenylacetyl formic acid cpds (VI), 2-nitro-6-(2-alkoxyethyl)-phenylacetyl formic acid cpds is selected from a kind of or mixing in 2-nitro-6-(2-alkoxyethyl)-phenylacetyl ethyl formate, 2-nitro-6-(2-alkoxyethyl)-phenylacetyl formic acid.
The operating process of above-mentioned reaction from 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V) preparation 2-nitro-6-(2-alkoxyethyl)-phenylacetyl formic acid cpds (VI) is roughly as follows:
Add oxalic acid diethyl ester, alkali and solvent in reaction flask.Add subsequently 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V), and reacted 1-48 hour at suitable temperature.After reaction finishes, get 2-nitro-6-(2-alkoxyethyl)-phenylacetyl formic acid cpds (VI) after removal of solvent under reduced pressure, directly carry out next step reaction.
Reaction from 2-nitro-6-(2-alkoxyethyl)-phenylacetyl formic acid cpds (VI) preparation 2-nitro-6-(2-alkoxyethyl)-toluylic acid (VII) of the present invention is carried out under hydrogen peroxide.
The operating process of above-mentioned reaction from 2-nitro-6-(2-alkoxyethyl)-phenylacetyl formic acid cpds (VI) preparation 2-nitro-6-(2-alkoxyethyl)-toluylic acid (VII) is roughly as follows:
Add 2-nitro-6-(2-alkoxyethyl)-phenylacetyl formic acid cpds (VI) and aqueous sodium hydroxide solution in reaction flask, add subsequently hydrogen peroxide, and reacted 1-24 hour at suitable temperature.After reaction finishes, add S-WAT cancellation reaction, add acid to separate out to solid, namely get 2-nitro-6-(2-alkoxyethyl)-toluylic acid (VII) after the abundant drying of separate solid, directly carry out next step reaction.
Of the present invention from 2-nitro-6-(2-alkoxyethyl)-toluylic acid (VII) preparation 4-(2-hydroxyethyl)-1, the reaction of 3-dihydro-2H-indol-2-one (I) is carried out under the metal catalyst effect, and metal catalyst used is selected from palladium carbon, palladium calcium carbonate, palladium barium sulfate, Raney's nickel.
Of the present invention from 2-nitro-6-(2-alkoxyethyl)-toluylic acid (VII) preparation 4-(2-hydroxyethyl)-1, the reaction of 3-dihydro-2H-indol-2-one (I) is carried out under nitrogen atmosphere.
Of the present invention from 2-nitro-6-(2-alkoxyethyl)-toluylic acid (VII) preparation 4-(2-hydroxyethyl)-1,3-dihydro-the reaction of 2H-indol-2-one (I) is to carry out under suitable solvent, and solvent used is selected from methyl alcohol, ethanol, ethyl acetate, acetic acid, tetrahydrofuran (THF), water.
Above-mentioned from 2-nitro-6-(2-alkoxyethyl)-toluylic acid (VII) preparation 4-(2-hydroxyethyl)-1, the operating process of the reaction of 3-dihydro-2H-indol-2-one (I) is roughly as follows:
Add 2-nitro-6-(2-alkoxyethyl)-toluylic acid (VII) in reaction flask, metal catalyst and solvent pass into hydrogen subsequently, and react 1-48 hour at suitable temperature.Remove by filter catalyzer, removal of solvent under reduced pressure is to certain volume, and solid is separated out, and filtering drying namely gets compound 4-(2-hydroxyethyl)-1,3-dihydro-2H-indol-2-one (I).
The invention has the advantages that by brief route, simple operation, with high yield effect and high purity prepared the key intermediate 4-(2-hydroxyethyl)-1 of Ropinirole hydrochloride (II), 3-dihydro-2H-indol-2-one (I).Particularly, the intermediate of whole piece route all need not to carry out purification operations, can directly carry out next step reaction, has greatly simplified operation.Than other route, this route is not only with low cost, and is simple to operate, and environmental friendliness and greatly improved product yield and purity is fit to suitability for industrialized production.
Embodiment
The below further illustrates technical scheme of the present invention with specific embodiment, but protection scope of the present invention is not limited to this:
Synthesizing of embodiment one 2-methyl-3-nitro phenylethyl alcohol (IV)
Under room temperature, 694g2-methyl-3-nitrophenylacetic acid (III), 676g sodium borohydride are mixed mutually with the 15L tetrahydrofuran (THF), add the 4.5L boron trifluoride diethyl etherate under fully stirring.Back flow reaction 5h subsequently.Under 0 degree, slowly drip the 3L concentrated hydrochloric acid, add rear stirring at room 6h.Filter, filtrate is after anhydrous sodium sulfate drying, and organic solvent is removed in decompression, obtains 640g2-methyl-3-nitro phenylethyl alcohol (IV) oily matter crude product, directly carries out next step reaction.
Synthesizing of embodiment two 2-methyl-3-nitro phenylethyl alcohols (IV)
Under room temperature, 500g2-methyl-3-nitrophenylacetic acid (III), 200g sodium borohydride are mixed mutually with the 5L tetrahydrofuran (THF), add subsequently the 250g methylsulfonic acid, after stirring at room 24h, add successively 3L ethyl acetate and 5L concentrated hydrochloric acid.Separatory gets organic phase, and after anhydrous sodium sulfate drying, organic solvent is removed in decompression, obtains 420g2-methyl-3-nitro phenylethyl alcohol (IV) oily matter crude product, directly carries out next step reaction.
Synthesizing of embodiment three 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V)
Compound (IV) crude product and the 275g sodium hydroxide of gained in embodiment two are added in 2L acetone, then drip 430g benzyl bromine.After dripping off stirring at room 24 hours.After removal of solvent under reduced pressure, add 1.5L ethyl acetate and 1.5L water.Separatory, organic phase are used the water washing of 1.5L saturated common salt again.Separatory gets organic phase, and after anhydrous sodium sulfate drying, decompression is removed organic solvent and got 590g2-methyl-3-(2-alkoxyethyl) oil of mirbane (V) oily matter crude product, is directly used in next step reaction.
Synthesizing of embodiment four 2-nitro-6-(2-alkoxyethyl)-phenylacetyl formic acid cpds (VI)
Under room temperature, 500g oxalic acid diethyl ester, 370g sodium ethylate are added in 4L ethanol.The 1L ethanolic soln that adds subsequently compound (V) crude product in embodiment three.Mixture reacts 24h under 50 degree, be cooled to room temperature, and decompression is removed ethanol and got 1Kg2-nitro-6-(2-alkoxyethyl)-phenylacetyl formic acid cpds (VI) crude product, is directly used in next step reaction.
Synthesizing of embodiment five 2-nitro-6-(2-alkoxyethyl)-toluylic acid (VII)
Compound (VI) crude product of embodiment four gained is added in the 3L aqueous solution of being prepared by 200g sodium hydroxide, slowly drips the 800g30% hydrogen peroxide solution with backward system.After stirring 2h under room temperature, add the 500g S-WAT.Then add the 1L concentrated hydrochloric acid to system again, solid is separated out.Filter to get solid, water washing 2 times (each 2L).Obtain 640g yellow solid 2-nitro-6-(2-alkoxyethyl)-toluylic acid (VII) crude product after oven dry, be directly used in next step reaction.
Embodiment six 4-(2-hydroxyethyl)-1,3-dihydro-2H-indol-2-one (I) synthetic
Compound (VII) crude product and the 64g10% palladium carbon of embodiment five gained are added in the 20L ethyl acetate, pass into hydrogen.React at normal temperatures and pressures subsequently stopped reaction after 48h.Remove by filter palladium carbon, the underpressure distillation desolventizing.Also surplus approximately 10% the time when solvent, stop distillation, standing, solid is separated out.Filter to get solid, ethyl acetate washing post-drying gets 285g white solid 4-(2-hydroxyethyl)-1,3-dihydro-2H-indol-2-one (I), purity 99%, total recovery 62.5%.
Claims (10)
1. one kind prepares 4-(2-hydroxyethyl)-1, the novel method of 3-dihydro-2H-indol-2-one (I),
Its feature comprises:
(1) 2-methyl-3-nitrophenylacetic acid (III) generates 2-methyl-3-nitro phenylethyl alcohol (IV) through reduction reaction,
(2) hydroxyl of compound (IV) is protected generation 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V),
(3) compound (V) generates 2-nitro-6-(2-alkoxyethyl)-phenylacetyl formic acid cpds (VI) with the oxalic acid diethyl ester reaction,
(4) compound (VI) generates 2-nitro-6-(2-alkoxyethyl)-toluylic acid (VII) with the hydrogen peroxide reaction,
(5) compound (VII) obtains 4-(2-hydroxyethyl)-1 through hydrogenation, 3-dihydro-2H-indol-2-one (I),
In formula, R represents phenyl, can replace by one or more following bases on phenyl: halogen, hydroxyl, nitro, C
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-alkylamino radical; P represents ethyl or hydrogen.
2. preparation method according to claim 1 is characterized in that the reaction needed for preparing compound (IV) uses reductive agent, and reductive agent used is selected from sodium borohydride, lithium borohydride, zinc borohydride, lithium aluminium hydride, borine.
3. preparation method according to claim 1, it is characterized in that preparing the reaction needed use additive of compound (IV), additive used is selected from boron trifluoride ethyl ether complex, boron trifluoride tetrahydrofuran complex, methylsulfonic acid, Phenylsulfonic acid, tosic acid, formic acid, acetic acid, trifluoracetic acid.
4. preparation method according to claim 1, the reaction needed that it is characterized in that preparing compound (V) is used the phenyl methyl halides that replaces, and the phenyl methyl halides of replacement used is selected from phenyl and replaces by one or more following bases: halogen, hydroxyl, nitro, C
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-alkylamino radical, halogen is the phenyl methyl halides of chlorine, bromine or iodine.
5. preparation method according to claim 1, the reaction that it is characterized in that preparing compound (V) is to carry out under suitable solvent, solvent used is selected from tetrahydrofuran (THF), isopropyl ether, first uncle's ether, acetone, espeleton, mibk, methylene dichloride, chloroform, toluene, acetonitrile, methyl alcohol, ethanol, DMF.
6. preparation method according to claim 1, the reaction that it is characterized in that preparing compound (V) is to carry out under suitable alkali effect, and alkali used is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium hydride, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, butyllithium, triethylamine, diisopropyl ethyl amine, pyridine.
7. preparation method according to claim 1, it is characterized in that preparing the reaction needed use alkali of compound (VI), alkali used is selected from sodium ethylate, potassium ethylate, sodium methylate, potassium methylate, sodium tert-butoxide, potassium tert.-butoxide, butyllithium, methyl-magnesium-bromide, sodium hydride, sodium hydroxide, potassium hydroxide.
8. preparation method according to claim 1 is characterized in that the reaction for preparing compound (I) carries out under the metal catalyst effect, metal catalyst used is selected from palladium carbon, palladium calcium carbonate, palladium barium sulfate, Raney's nickel.
9. method for preparing 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V),
It is characterized in that reacting and be to carry out under suitable solvent, solvent used is selected from tetrahydrofuran (THF), isopropyl ether, first uncle's ether, acetone, espeleton, mibk, methylene dichloride, chloroform, toluene, acetonitrile, methyl alcohol, ethanol, DMF.
10. preparation method according to claim 9, the reaction that it is characterized in that preparing compound (V) is to carry out under suitable alkali effect, and alkali used is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium hydride, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert.-butoxide, butyllithium, triethylamine, diisopropyl ethyl amine, pyridine.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418482A (en) * | 2015-11-23 | 2016-03-23 | 东南大学 | Improved preparation method for ropinirole hydrochloride |
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| CN105418482A (en) * | 2015-11-23 | 2016-03-23 | 东南大学 | Improved preparation method for ropinirole hydrochloride |
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