CN103145604A - Method for preparing ropinirole key intermediate - Google Patents
Method for preparing ropinirole key intermediate Download PDFInfo
- Publication number
- CN103145604A CN103145604A CN2013100887932A CN201310088793A CN103145604A CN 103145604 A CN103145604 A CN 103145604A CN 2013100887932 A CN2013100887932 A CN 2013100887932A CN 201310088793 A CN201310088793 A CN 201310088793A CN 103145604 A CN103145604 A CN 103145604A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- methyl
- nitro
- sodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 *COCCc1c(CC(O)=O)c([N+]([O-])=O)ccc1 Chemical compound *COCCc1c(CC(O)=O)c([N+]([O-])=O)ccc1 0.000 description 3
- QRTHVOUKWCEPKJ-UHFFFAOYSA-N OCCc1cccc(N2)c1CC2=O Chemical compound OCCc1cccc(N2)c1CC2=O QRTHVOUKWCEPKJ-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Indole Compounds (AREA)
Abstract
The invention discloses a novel method of ropinirole key intermediate, namely 4-(2-hydroxyethyl)-1,3-dihydro-2H-indole-2-ketone (I). The method comprises the following steps of: reacting 2-methyl-3-nitrophenyl-acetic acid (III) with chloro-carbonic ester to generate mixed anhydride, then reducing the mixed anhydride to obtain 2-methyl-3-nitrophenyl alcohol (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 2-nitro-6-(2-alkoxy ethyl) phenacetyl formic acid compound (VI), reacting the compound (VI) with hydrogen peroxide to generate 2-nitro-6-(2-alkoxy ethyl) phenylacetic acid (VII), reducing the compound (VII) through nitro and carrying out ring closing reaction on the compound (VII) to obtain 4-(2-alkoxy ethyl)-1,3-dihydro-2H-indole-2-ketone (VIII); and carrying out hydrogenation reaction on the compound (VIII) to obtain 4-(2-hydroxyethyl)-1,3-dihydro-2H-indole-2-ketone (I). The route is low in cost, simple in operation and environmental-friendly, and the yield and purity of products are greatly improved, so that the method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of Ropinirole key intermediate 4-(2-hydroxyethyl)-1 for preparing, the method for 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 that commodity were called Requip first in Britain's listing in 1996 by a kind of medicine of GSK company exploitation.FDA ratified the initial treatment that these product are used for Parkinson's disease sign and symptom in 1998, and was used for the Parkinsonian in late period as the ancillary drug of L-dopa, ratified its restless leg syndrome that is used for the treatment of moderate or severe (RLS) in 2004.
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.JMC19851533 has described article one route:
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.It 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, with the key intermediate 4-(2-hydroxyethyl)-1 of a variation route synthetic preparation Ropinirole hydrochloride (II), the method for 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) first generates to restore after mixed acid anhydride with the chloro-formic ester reaction and obtains 2-methyl-3-
Oil of mirbane ethanol (IV);
(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) is through nitroreduction and ring closure reaction occurs obtain 4-(2-alkoxyethyl)-1,3-dihydro-2H-indol-2-one (VIII);
(6) compound (VIII) 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:
R in formula
1The expression 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; R
2Expression 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 chloro-formic ester, and chloro-formic ester used is selected from: methyl-chloroformate, Vinyl chloroformate, isopropyl chlorocarbonate, isobutyl chlorocarbonate, phenyl chloroformate, chloroformic acid benzyl ester.
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 selected reductive agent is selected from sodium borohydride, lithium borohydride, zinc borohydride, POTASSIUM BOROHYDRIDE.
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, solvent used is the mixing of following one or both: dimethyl sulfoxide (DMSO), N, dinethylformamide, N,N-dimethylacetamide, tetrahydrofuran (THF), toluene, acetonitrile, 2-methyltetrahydrofuran, water.
Reaction from 2-methyl-3-nitrophenylacetic acid (III) preparation 2-methyl-3-nitro phenylethyl alcohol (IV) of the present invention is carried out under alkaline condition, and alkali used is selected from: salt of wormwood, sodium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, diisopropyl ethyl amine, pyridine.
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:
Add compound (III), solvent, alkali in reaction flask, then add chloro-formic ester, following reaction 1-10h, mixed acid anhydride prepares complete.Add the aqueous solution of reductive agent in reaction solution, then stir 1-5h.Add entry and organic solvent extracts, tell organic layer, drying, after concentrated oily matter (IV), directly drop into 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 compound (IV), solvent in reaction flask, then add successively alkali, the methyl halogenated thing of substituted-phenyl, following reaction 1-48h.Add entry and organic solvent extracts, tell organic layer after drying, the concentrated oily matter (V) that to get directly drops into 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 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 to carry out suitable solvent; solvent used is selected from: tetrahydrofuran (THF), acetone, ethanol, methyl alcohol, 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, solvent, alkali in reaction flask, then add compound (V), following reaction 1-48h.After reaction finishes, get oily matter (VI) after removal of solvent under reduced pressure, directly drop into next step reaction.
Reaction needed 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 used superoxol.
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 compound (VI), aqueous sodium hydroxide solution in reaction flask, add aqueous hydrogen peroxide solution, following reaction 1-24h.Add S-WAT cancellation reaction, add hydrochloric acid to solid to separate out, suction filtration gets compound (VII) after the solid oven dry, directly drops into next step reaction.
Of the present invention from 2-nitro-6-(2-alkoxyethyl) toluylic acid (VII) preparation 4-(2-alkoxyethyl)-1, the reaction of 3-dihydro-2H-indol-2-one (VIII) is carried out under the reductive agent effect, and reductive agent used is selected from: iron powder, zinc powder, hydrazine hydrate, Raney's nickel.
Of the present invention from 2-nitro-6-(2-alkoxyethyl) toluylic acid (VII) preparation 4-(2-alkoxyethyl)-1,3-dihydro-the reaction of 2H-indol-2-one (VIII) is to carry out under suitable solvent, and solvent used is selected from the mixing of following one or both: acetic acid, ethanol, methyl alcohol, Virahol, the trimethyl carbinol, ethyl acetate, tetrahydrofuran (THF), water.
Above-mentioned from 2-nitro-6-(2-alkoxyethyl)-toluylic acid (VII) preparation 4-(2-alkoxyethyl)-1, the operating process of the reaction of 3-dihydro-2H-indol-2-one (VIII) is roughly as follows:
Add compound (VII), solvent in reaction flask, add reductive agent, following reaction 1-48h.After the filtering reductive agent, add entry and organic solvent extracts, tell organic layer, after concentrated oily matter (VIII), directly drop into next step reaction.
Of the present invention from 4-(2-alkoxyethyl)-1,3-dihydro-2H-indol-2-one (VIII) 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, palladium, Palladous chloride and Raney's nickel.
Of the present invention from 4-(2-alkoxyethyl)-1,3-dihydro-2H-indol-2-one (VIII) preparation 4-(2-hydroxyethyl)-1, the reaction of 3-dihydro-2H-indol-2-one (I) is carried out under hydrogen atmosphere, 1～20 normal atmosphere of pressure.
Of the present invention from 4-(2-alkoxyethyl)-1,3-dihydro-2H-indol-2-one (VIII) 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 following one or both mixing: methyl alcohol, ethanol, Virahol, ethyl acetate, acetic acid, tetrahydrofuran (THF), water.
Above-mentioned from 4-(2-alkoxyethyl)-1,3-dihydro-2H-indol-2-one (VIII) preparation 4-(2-hydroxyethyl)-1, the operating process of the reaction of 3-dihydro-2H-indol-2-one (I) is roughly as follows:
Add compound (VIII), solvent in reaction flask, add metal catalyst, be replaced as hydrogen atmosphere, react 1-48h subsequently at suitable temperature.After filtration catalizer, removal of solvent under reduced pressure is to certain volume, and solid is separated out, and filtering drying namely gets compound (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 special purification operations, only needs can directly carry out next step reaction through operations such as simple filtration and extractions, 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)
Add 1.95kg compound (III), 20L tetrahydrofuran (THF) and 1.21kg triethylamine in reaction flask, control 0～10 ℃ of temperature, drip the 1.04kg methyl-chloroformate in reaction system, drip rear room temperature reaction 2h.Filter, filtrate is cooled to 0～10 ℃, add the 3L aqueous solution of 0.57kg sodium borohydride in the filtrate.Rise to room temperature reaction 3h after dripping, react complete.Add the extraction of 10L ethyl acetate and 10L saturated aqueous common salt, tell organic layer.Organic layer is dry, obtains the oily matter crude product of 1.85kg2-methyl-3-nitro phenylethyl alcohol (IV) after concentrating, and directly carries out next step reaction.
1H?NMR(CDCl
3,400MHz)δ:2.40(s,3H),2.89(br?s,1H),2.95(t,J=6.8Hz,2H),3.80(q,J=6.4Hz,2H),7.24(t,J=7.6Hz,1H),7.41(d,J=7.6Hz,1H),7.59(d,J=8.0Hz,1H)
Synthesizing of embodiment two 2-methyl-3-(2-benzyloxy ethyl) oil of mirbane (V)
The compound (IV), 1.68kg potassium hydroxide and the 10L acetone that add preparation in embodiment one in reaction flask are controlled 0～10 ℃ of temperature, drip the 1.87kg bromobenzyl in reaction system, rise to room temperature reaction 24h after dripping.After concentrated desolventizing, add 10L ethyl acetate and 10L water in system.Tell organic layer, organic layer with the saturated common salt water washing once.Organic layer is dry, and removal of solvent under reduced pressure gets the oily matter crude product of 2.59kg2-methyl-3-(2-benzyloxy ethyl) oil of mirbane (V), directly drops into next step reaction.Get the 1.0g column chromatography and purify, get yellow oil.
1H?NMR(CDCl
3,400MHz)δ:2.44(s,3H),3.06(t,J=7.2Hz,2H),3.72(t,J=7.2Hz,2H),4.56(s,2H),7.27-7.46(m,6H),7.45(d,J=7.2Hz,1H),7.64(dd,J=8.0,J=0.8Hz,1H)。
Synthesizing of embodiment three 2-nitro-6-(2-benzyloxy ethyl) phenylacetyl formic acid cpds (VI)
Add 1.68kg sodium ethylate and 15L ethanol in reaction flask, the disposable 2.1kg oxalic acid diethyl ester that adds is controlled 0～10 ℃ of temperature, drips the 5L ethanolic soln of the compound (V) for preparing in embodiment two in the reaction system.Rise to 50 ℃ of reaction 24h after dripping.Be cooled to room temperature, the oily matter crude product that ethanol gets 4.03kg2-nitro-6-(2-benzyloxy ethyl) phenylacetyl formic acid cpds (VI) is removed in decompression, directly drops into next step reaction.Get the 1.0g column chromatography and purify, get yellow oil.
1H?NMR(CDCl
3,400MHz)δ:1.40(J=7.0Hz,3H),2.98(t,J=6.4Hz,2H),3.67(t,J=6.4Hz,2H),4.36(q,J=6.8Hz,2H),4.58(s,2H),7.23-7.42(m,6H),7.54(d,J=7.6Hz,1H),7.90(dd,J=8.4,J=1.6Hz,1H)。
Synthesizing of embodiment four 2-nitro-6-(2-benzyloxy ethyl) toluylic acid (VII)
Add the compound (VI) of preparation in embodiment three, the aqueous sodium hydroxide solution of 20L7% in reaction flask, control 0～10 ℃ of temperature, drip the 2.5kg30% superoxol in reaction system, drip rear continuation reaction 3h.Add 1.8kg S-WAT cancellation reaction.PH to 3 with 6N hydrochloric acid regulation system separates out solid.Suction filtration, filter cake is washed with massive laundering, dries to get the yellow solid crude product of 2.69kg2-nitro-6-(2-benzyloxy ethyl) toluylic acid (VII), yield 85% (in III), HPLC detects purity 93%, directly drops into next step reaction.
1H?NMR(CDCl
3,400MHz)δ:3.00(t,J=6.8Hz,2H),3.66(t,J=7.2Hz,2H),4.03(s,2H),4.46(s,2H),7.21-7.37(m,6H),7.49(d,J=7.2Hz,1H),7.84(d,J=8.0Hz,1H),10.10(br?s,1H).
Embodiment five 4-(2-benzyloxy ethyl)-1,3-dihydro-2H-indol-2-one (VIII) synthetic
Add compound (VII), 12L Glacial acetic acid and the 5L water of preparation in embodiment four in reaction flask, add the 2.0kg activated zinc powder under room temperature in batches, add post-heating to 50～60 ℃ continuation reaction 3h.Filter, filtrate is concentrated.Add the 10L ethyl acetate, extremely alkaline with the pH of ammoniacal liquor regulation system, tell organic layer.Organic layer with the saturated common salt water washing once.Organic layer is dry, and removal of solvent under reduced pressure gets 2.3kg4-(2-benzyloxy ethyl)-1, and the yellow solid crude product of 3-dihydro-2H-indol-2-one (VIII) directly drops into next step reaction.Get the 1.0g column chromatography and purify, get the pale asphyxia solid.
1H?NMR(CDCl
3,400MHz)δ:2.87(t,J=6.6Hz,2H),3.48(s,2H),3.70(t,J=6.6Hz,2H),4.52(s,2H),6.75(d,J=7.2Hz,1H),6.89(d,J=7.6Hz,1H),7.17(t,J=7.8Hz,1H),7.25-7.37(m,5H),8.50(br?s,1H).
Embodiment six 4-(2-hydroxyethyl)-1,3-dihydro-2H-indol-2-one (I) synthetic
Add compound (VIII), 200g10% palladium carbon, 40L ethyl acetate and the 500g Glacial acetic acid of preparation in embodiment five in reaction flask, be replaced as hydrogen atmosphere, in 40 ℃ of reaction 36h.Filter, filtrate is washed (10L*2) with saturated sodium carbonate.Tell organic layer, organic layer is dry, is concentrated into residue 4L, has solid to separate out.Under 0～10 ℃, stir 20h.Suction filtration, filter cake is dried to get pale asphyxia solid 1.11kg with the washing of glacial acetic acid ethyl ester, total recovery 63% (in III), HPLC purity is greater than 99%.
1H?NMR(DMSO-d
6,400MHz)δ:2.64(t,J=6.8Hz,2H),3.44(s,2H),3.59(q,J=6.8Hz,2H),6.64(d,J=7.6Hz,1H),6.78(d,J=7.6Hz,1H),7.08(t,J=7.2Hz,1H),10.30(s,1H).
Claims (10)
1. a synthetic Ropinirole key intermediate 4-(2-hydroxyethyl)-1, the method for 3-dihydro-2H-indol-2-one (I),
Comprise following steps:
(a), 2-methyl-3-nitrophenylacetic acid (III) first generates to restore after mixed acid anhydride with the chloro-formic ester reaction and obtains 2-methyl-3-nitro phenylethyl alcohol (IV),
(b), the hydroxyl of compound (IV) protected generated 2-methyl-3-(2-alkoxyethyl) oil of mirbane (V),
(c), the reaction of compound (V) and oxalic acid diethyl ester generates 2-nitro-6-(2-alkoxyethyl) phenylacetyl formic acid cpds (VI),
(d), the reaction of compound (VI) and hydrogen peroxide generates 2-nitro-6-(2-alkoxyethyl) toluylic acid (VII),
(e), compound (VII) is through nitroreduction and ring closure reaction occurs obtain 4-(2-alkoxyethyl)-1,3-dioxy-2H-indol-2-one (VIII),
(f), compound (VIII) obtains 4-(2-hydroxyethyl)-1 through hydrogenation, 3-dioxy-ZH-indol-2-one (I),
R in formula
1The expression phenyl can replace by one or more following bases on phenyl: halogen, alkyl, nitro, C
1-C
6-alkyl, C
1-C
6-alkoxyl group, C
1-C
6-alkylamino radical; R
2Expression ethyl or hydrogen.
2. preparation method according to claim 1, it is characterized in that preparing the reaction needed use chloro-formic ester of compound (IV), chloro-formic ester used is selected from: methyl-chloroformate, Vinyl chloroformate, isopropyl chlorocarbonate, isobutyl chlorocarbonate, phenyl chloroformate, chloroformic acid benzyl ester.
3. preparation method according to claim 1 is characterized in that preparing the reaction needed reductive agent of compound (IV), and reductive agent used is selected from: sodium borohydride, lithium borohydride, zinc borohydride, POTASSIUM BOROHYDRIDE.
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 the replacement of using 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, it is characterized in that the reaction for preparing compound (V) carries out under alkaline condition, the alkali that uses 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.
6. preparation method according to claim 1, it is characterized in that the reaction for preparing compound (VI) carries out under the alkalescence effect, 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.
7. preparation method according to claim 1 is characterized in that the reaction for preparing compound (VIII) carries out under the reductive agent effect, reductive agent used is selected from iron powder, zinc powder, hydrazine hydrate, Raney's nickel.
8. preparation method according to claim 1, is characterized in that the hydrogenation for preparing compound (I) carries out under catalyzer exists, and used catalyst is selected from palladium carbon, palladium calcium carbonate, palladium barium sulfate, palladium, Palladous chloride and Raney's nickel.
9. a synthetic 2-methyl-3-nitro phenylethyl alcohol (IV) method,
It is characterized in that 2-methyl-3-nitrophenylacetic acid (III) first generates to restore after mixed acid anhydride with the chloro-formic ester reaction obtains 2-methyl-3-nitro phenylethyl alcohol (IV).
10. a synthetic 4-(2-hydroxyethyl)-1, the method for 3-dihydro-2H-indol-2-one (I),
It is characterized in that compound (VIII) obtains 4-(2-hydroxyethyl)-1 through oxidizing reaction, 3-dioxy-ZH-indol-2-one (I), R in formula
1The expression 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013100887932A CN103145604A (en) | 2013-03-19 | 2013-03-19 | Method for preparing ropinirole key intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013100887932A CN103145604A (en) | 2013-03-19 | 2013-03-19 | Method for preparing ropinirole key intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103145604A true CN103145604A (en) | 2013-06-12 |
Family
ID=48543986
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013100887932A Pending CN103145604A (en) | 2013-03-19 | 2013-03-19 | Method for preparing ropinirole key intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103145604A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1056686A (en) * | 1990-04-17 | 1991-12-04 | 史密丝克莱恩及法国实验所 | Improving one's methods of the indolone derivatives that preparation replaces |
| WO2006123356A1 (en) * | 2005-02-15 | 2006-11-23 | Alembic Limited | Process for the preparation of indolone derivative |
| CN1887853A (en) * | 2005-06-27 | 2007-01-03 | 上海奥博生物医药技术有限公司 | Prepn of 2-methyl-3-nitrophenylalkylamine derivative or its salt |
| CN102267934A (en) * | 2010-06-02 | 2011-12-07 | 金凯美(大连)医药科技有限公司 | Method for preparing 6-carbomethoxy indolone |
| CN102964259A (en) * | 2012-12-11 | 2013-03-13 | 上海奥博生物医药技术有限公司 | Preparation method of related substance E of metoprolol |
-
2013
- 2013-03-19 CN CN2013100887932A patent/CN103145604A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1056686A (en) * | 1990-04-17 | 1991-12-04 | 史密丝克莱恩及法国实验所 | Improving one's methods of the indolone derivatives that preparation replaces |
| WO2006123356A1 (en) * | 2005-02-15 | 2006-11-23 | Alembic Limited | Process for the preparation of indolone derivative |
| CN1887853A (en) * | 2005-06-27 | 2007-01-03 | 上海奥博生物医药技术有限公司 | Prepn of 2-methyl-3-nitrophenylalkylamine derivative or its salt |
| CN102267934A (en) * | 2010-06-02 | 2011-12-07 | 金凯美(大连)医药科技有限公司 | Method for preparing 6-carbomethoxy indolone |
| CN102964259A (en) * | 2012-12-11 | 2013-03-13 | 上海奥博生物医药技术有限公司 | Preparation method of related substance E of metoprolol |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9856215B2 (en) | Preparation method of Nintedanib | |
| JP6441478B2 (en) | Process for preparing disubstituted 1,4-benzenediamine and salts thereof | |
| AU2011281421A1 (en) | Process for preparing aminobenzoylbenzofuran derivatives | |
| CN112062767B (en) | Preparation method and intermediate of rumepilone | |
| WO2013080215A1 (en) | An improved process for the preparation of flupirtine and pharmaceutically acceptable salts thereof | |
| CN110437124B (en) | Preparation method of indoloquinone derivative | |
| CN110981782A (en) | Method for efficiently preparing 5, 6-dihydroxyindole | |
| CN108610279B (en) | Novel method for synthesizing cis-1-benzyl-3-methylamino-4-methyl-piperidine | |
| CN116284031A (en) | Preparation method of R-glabridin | |
| CN105884746B (en) | The synthetic method of fluorine imatinib | |
| CN103145604A (en) | Method for preparing ropinirole key intermediate | |
| CN108623602A (en) | A method of prepare and purify and replaces Buddhist nun according to Shandong | |
| CN102633802B (en) | Intermediate for synthesizing 2-chloro-7H-pyrrolo (2, 3-d) pyrimidine and preparation method thereof | |
| CN115417816A (en) | Preparation method of 3,6-dibromo-1-chloro-isoquinoline | |
| KR20160027536A (en) | Process for preparing an intermediate useful for the synthesis of silodosin | |
| CN107021930A (en) | Synthesize 1H, 1`H（2,2` bisbenzimidazoles）The method of 5,5` diamines | |
| CN103130704B (en) | It is a kind of to prepare 4- (2- ethoxy) -1,3- dihydro -2H- indol-2-one new method | |
| CN110724098A (en) | Synthetic method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid hydrochloride | |
| CA3132399A1 (en) | Synthesis of 4-amino-5-methyl-1h-pyridin-2(1h)-on (intermediate compound for the synthesis of the mr antagonist finerenone) from 2-chloro-5-methyl-4-nitro-pyridine-1-oxide using the intermediate compound 2-chloro-5-methyl-4-pyridinamine | |
| CN102491954B (en) | Preparation method of linezolid | |
| CN116178239B (en) | Synthesis method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde | |
| Rozhkov et al. | Transformations of 2-aryl-4, 6-dinitroindoles | |
| CN111763198B (en) | Preparation method of 5-substituted cyclopropyl formylaminoindole derivative | |
| CN109748885B (en) | Ceritinib intermediate and preparation method of ceritinib | |
| CN109293627B (en) | Recovery method of ketotifen intermediate mother liquor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130612 |