CN103086946B - A kind of method of ropinirole hydrochloride purifying - Google Patents
A kind of method of ropinirole hydrochloride purifying Download PDFInfo
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- CN103086946B CN103086946B CN201310027249.7A CN201310027249A CN103086946B CN 103086946 B CN103086946 B CN 103086946B CN 201310027249 A CN201310027249 A CN 201310027249A CN 103086946 B CN103086946 B CN 103086946B
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Abstract
The present invention relates to a kind of ropinirole hydrochloride (4-2- di-n-propyl amine ethyl -1,3- dihydro -2H- indol-2-ones hydrochloride) purifying, and specific method is：Ropinirole hydrochloride containing oxidation impurities structure formula (I) is added to the water, and organic solvent is added, alkali is added after dissolved clarification is stirred at room temperature, stratification after stirring removes water layer；Obtained organic layer is dried with anhydrous magnesium sulfate, and activated carbon stirring is added and filters and concentrates later；After being concentrated to dryness, a certain amount of organic solvent is added into obtained grease, after being slowly added to a certain amount of concentrated hydrochloric acid stirring, feed liquid is cooled down, rejection filter, drying obtains ropinirole hydrochloride.The present invention can effectively remove the oxidation impurities (I) in ropinirole hydrochloride, can obtain ropinirole hydrochloride with preferable yield and purity, so that product purity is reached medicinal standard to control oxidation impurities.
Description
Technical field
The present invention relates to the methods of purifying ropinirole hydrochloride, particularly, are related to removing ropinirole hydrochloride oxidation impurities
Purification process.Its oxidation impurities structure (I) is：
Background technology
Ropinirole hydrochloride (ropinirole hydrochloride) is by Britain's SmithKLine-Beecham pharmacy
Company develops the second generation dopamine-receptor stimulant for treating Parkinson (PD), trade name Requip, different name
SKF101468.It can be used alone when treating Parkinson's disease, can also be used as adjuvant drug and reduce levodopa amine use
Amount, to reduce side effect.1996 for the first time Britain list, 1997 obtain U.S. FDA approval, at present Britain,
The listings such as the U.S. and France.Its structural formula is (II)：
The patent or document reported at present prepare the method for ropinirole hydrochloride mainly by five kinds.Respectively with 2- first
- 3 nitro-benzene acetic acid of base is raw material (US4452808), 3- bromoethyls aniline is raw material (WO94/15918), different benzo dihydro pyrrole
It is raw material (US2007032540), with adjacent bromo ethyl phenenyl formaldehyde to mutter as raw material (EP0300614, US4997954), 4- indolecarboxaldehydes
For raw material (US0156505) synthetic hydrochloric acid Ropinirole.
Specifically, patent US4452808, using borine hydrogenation, adds using -3 nitrobenzoic acid of 2- methyl as raw material
The acyl chlorides of thionyl chloride, nitrilation, hydrolysis obtain -3 nitrophenyl-acetic acid of 2- methyl, the amide then made again, hydrogenating reduction, contracting
It closes, oxydrolysis, last hydrogenating reduction obtains ropinirole hydrochloride at salt；For another example patent WO94/15918 is with 3- bromo ethyl phenenyls
Amine is raw material, and ropinirole hydrochloride is obtained by cyclization, oxidation, substitution, reduction；And patent EP0300614, US4997954 with
Isochroman is raw material, by bromination open loop, the nitrostyrene compound made under highly basic effect, using closing
Ring, reduction, substitution reaction obtain ropinirole hydrochloride；Also patent US2007032540 using 4- indolecarboxaldehydes as raw material, through with
Nitrostyrene compound is obtained by the reaction in nitromethane, and using hydrogenating reduction and propionic acid addition, reduction, finally oxidation obtains
Ropinirole hydrochloride；Finally there is patent US0156505 using adjacent bromo ethyl phenenyl formaldehyde as raw material, is substituted, is anti-with nitromethane
Nitrostyrene compound should be obtained, ropinirole hydrochloride is being obtained by cyclisation, oxidation, hydrolysis etc..
But above-mentioned document does not all refer to an important production problem, i.e. last one in ropinirole hydrochloride production
When technique, product is extremely oxidized easily, and is allowed to generate oxidation impurities, which is difficult to be realized to detach with conventional means.Especially
It to be proposed, which is the intermediate of patent WO94/15918 synthetic hydrochloric acid Ropiniroles, by adding hydrogen in Raney's nickel
Reduction obtains ropinirole hydrochloride at salt again.But since content is relatively low in the product for the impurity in other synthetic methods, if
It is too high using the method cost of reduction, and trouble is post-processed, and there is the possibility aoxidized again.Therefore, miscellaneous for this
Matter needs a kind of easy, cheap and effective purifying process to solve the problems, such as this.
Invention content
Present inventor has developed a kind of purification process of effective ropinirole hydrochloride and is particularly related to its oxidation
The purification process of impurity (structural formula I) removal.
Specifically, the present invention provides the methods for removing ropinirole hydrochloride oxidation impurities (structural formula I), including following
Step：
1) ropinirole hydrochloride (II) containing structure formula (I) is put into the mixed liquor of organic solvent and water, wherein
The volumetric usage of organic solvent is 8~12 times of ropinirole hydrochloride quality, and the volumetric usage of water is ropinirole hydrochloride quality
15~20 times, alkali is added after dissolved clarification is stirred at room temperature, and continue stir 20min or more.Layering removes water layer.
Above-mentioned organic solvent includes toluene, dichloromethane, n-hexane, hexamethylene, petroleum ether；The alkali can be selected from ethyl alcohol
Sodium, potassium ethoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, saleratus, tetramethylammonium hydroxide；Alkali
Mole dosage is 1.5~25 times of ropinirole hydrochloride mole dosage.
2) obtained organic layer is dried with anhydrous magnesium sulfate, and the work of ropinirole hydrochloride quality 5%~20% is added
Property charcoal persistently stirs 30min, filters and concentrates later.
3) after being concentrated to dryness, organic solvent is added into obtained grease, controls 15 ± 5 DEG C of reacting liquid temperature, slowly
A certain amount of concentrated hydrochloric acid is added, the dosage of concentrated hydrochloric acid is identical as ropinirole hydrochloride molecular equivalency, continues to stir 30min.It will material
Liquid, which is cooled to 5 ± 5 DEG C, to be continued to stir 1h, and for rejection filter to doing, drying obtains ropinirole hydrochloride.
Organic solvent can be selected from the lower alcohol of C1~C4, preferably isopropanol, ethyl alcohol and methanol in above-mentioned steps 3, more excellent
It is selected as isopropanol, the volumetric usage of lower alcohol is 6~15 times of ropinirole hydrochloride quality.
It is required to strictly carry out nitrogen protection in above each step.
Passing through above each step so that the present invention can effectively remove the oxidation impurities (I) in ropinirole hydrochloride (II),
Ropinirole hydrochloride can be obtained with preferable yield and purity, so that product purity is reached medicinal mark to control oxidation impurities
It is accurate.
Specific implementation mode
Embodiment below is that the present invention will be described in detail, is not intended to limit the present invention.
All processes are both needed to strictly carry out nitrogen protection, behind no longer explain over and over again.
Embodiment 1
Take 4-2- di-n-propyl amine ethyl -1,3- dihydro -2H- indol-2-ones hydrochloride (ropinirole hydrochloride, structural formula
II) (6.53g, 0.022mol), toluene 65ml, purified water 100ml are stirred in 250ml flasks.Continue to stir, and is slowly added to
10.7g sodium bicarbonates.Continue to stir 20min, stratification after finishing.Remove water layer, organic layer is dry with 2.5g anhydrous magnesium sulfates
It is dry, and 0.6g activated carbons are added in the drying process, continue to stir 30min.Organic layer is filtered, is concentrated to dryness, obtains grease.
90ml isopropanols are added into obtained grease, controls 15 ± 5 DEG C of reacting liquid temperature, is slowly added to the dense salt of 2.2g
Acid after addition, continues to stir 30min.Feed liquid is finally cooled to 5 ± 5 DEG C and continues to stir 1h, rejection filter is to dry.
Drying obtains ropinirole hydrochloride crude product, yield 85%.HPLC99.75%, oxidative impurity levels 0.03/2.1%.
The related substance HPLC analysis methods of ropinirole hydrochloride：
Instrument：High performance liquid chromatograph is equipped with UV detector
Chromatographic column：Waters XterraTMRP18250 × 4.6mm, 5 μm
2.84gNa2HPO4It is dissolved in 1000mL water, with the NaOH tune pH11.0 of 1mol/L
Mobile phase B：Acetonitrile
Dilution：Mobile phase A: Mobile phase B=70: 30 (%V/V)
Chromatographic column temperature：25 DEG C of Detection wavelengths：250nm
Flow velocity：1.0mL/min run time：35min
Sample size：20μL
Gradient table：
| Time (min) | Mobile phase A (%V/V) | Mobile phase B (%V/V) |
| 0→7.5 | 72 | 28 |
| 7.5→13 | 72→52 | 28→48 |
| 13→20 | 52 | 48 |
| 20→28 | 52→72 | 48→28 |
| 28→35 | 72 | 28 |
50mg ropinirole hydrochloride standard items are weighed, it is accurately weighed in 100mL volumetric flasks, it is dissolved and is diluted with dilution
To scale, mixing.(ropinirole hydrochloride concentration：500μg/mL)
Embodiment 2
Take 4-2- di-n-propyl amine ethyl -1,3- dihydro -2H- indol-2-ones hydrochloride (ropinirole hydrochloride, structural formula
II) (6.53g, 0.022mol), n-hexane 70ml, purified water 110ml are stirred in 250ml flasks.Continue to stir, and slowly adds
Enter 4.0g sodium ethoxides.Continue to stir 20min, stratification after finishing.Remove water layer, organic layer is dry with 2.5g anhydrous magnesium sulfates
It is dry, and 0.8g activated carbons are added in the drying process, continue to stir 30min.Organic layer is filtered, is concentrated to dryness, obtains grease.
60ml isopropanols are added into obtained grease, controls 15 ± 5 DEG C of reacting liquid temperature, is slowly added to the dense salt of 2.2g
Acid after addition, continues to stir 30min.Feed liquid is finally cooled to 5 ± 5 DEG C and continues to stir 1h, rejection filter is to dry.
Drying obtains ropinirole hydrochloride crude product, yield 92%.HPLC99.65%, oxidative impurity levels 0.06/2.1%.
Embodiment 3
Take 4-2- di-n-propyl amine ethyl -1,3- dihydro -2H- indol-2-ones hydrochloride (ropinirole hydrochloride, structural formula
II) (6.53g, 0.022mol), dichloromethane 65ml, purified water 120ml are stirred in 250ml flasks.Continue to stir, and slowly
5.8g sodium hydroxides are added.Continue to stir 20min, stratification after finishing.Remove water layer, organic layer 2.5g anhydrous magnesium sulfates
It is dry, and 0.9g activated carbons are added in the drying process, continue to stir 30min.Organic layer is filtered, is concentrated to dryness, obtains oily
Object.
70ml isopropanols are added into obtained grease, controls 15 ± 5 DEG C of reacting liquid temperature, is slowly added to the dense salt of 2.2g
Acid after addition, continues to stir 30min.Feed liquid is finally cooled to 5 ± 5 DEG C and continues to stir 1h, rejection filter is to dry.
Drying obtains ropinirole hydrochloride crude product, yield 89%.HPLC99.71%, oxidative impurity levels 0.05/2.1%.
Embodiment 4
Take 4-2- di-n-propyl amine ethyl -1,3- dihydro -2H- indol-2-ones hydrochloride (ropinirole hydrochloride, structural formula
II) (6.53g, 0.022mol), hexamethylene 75ml, purified water 100ml are stirred in 250ml flasks.Continue to stir, and slowly adds
Enter 5.7g sodium carbonate.Continue to stir 20min, stratification after finishing.Remove water layer, organic layer is dry with 2.5g anhydrous magnesium sulfates
It is dry, and 0.8g activated carbons are added in the drying process, continue to stir 30min.Organic layer is filtered, is concentrated to dryness, obtains grease.
70ml methanol is added into obtained grease, controls 15 ± 5 DEG C of reacting liquid temperature, is slowly added to the dense salt of 2.2g
Acid after addition, continues to stir 30min.Feed liquid is finally cooled to 5 ± 5 DEG C and continues to stir 1h, rejection filter is to dry.
Drying obtains ropinirole hydrochloride crude product, yield 66%.HPLC99.70%, oxidative impurity levels 0.06/2.1%.
Embodiment 5
Take 4-2- di-n-propyl amine ethyl -1,3- dihydro -2H- indol-2-ones hydrochloride (ropinirole hydrochloride, structural formula
II) (6.53g, 0.022mol), petroleum ether 65ml, purified water 120ml are stirred in 250ml flasks.Continue to stir, and slowly adds
Enter 3.0g tetramethylammonium hydroxides.Continue to stir 20min, stratification after finishing.Remove water layer, organic layer 2.5g anhydrous slufuric acids
Magnesium is dried, and 0.7g activated carbons are added in the drying process, continues to stir 30min.Organic layer is filtered, is concentrated to dryness, obtains oil
Shape object.
60ml ethyl alcohol is added into obtained grease, controls 15 ± 5 DEG C of reacting liquid temperature, is slowly added to the dense salt of 2.2g
Acid after addition, continues to stir 30min.Feed liquid is finally cooled to 5 ± 5 DEG C and continues to stir 1h, rejection filter is to dry.
Drying obtains ropinirole hydrochloride crude product, yield 71%.HPLC99.78%, oxidative impurity levels 0.07/2.1%.
Following table is the table of comparisons with the ropinirole hydrochloride containing different oxidation impurities after purification：
In table, the oxidative impurity levels xx/2.1 listed is indicated：Xx means the content of HPLC detections, and 2.1 are
The correction factor of its oxidation impurities.For example, its oxidation impurities actual content of 0.66/2.1% is 0.314%.
Claims (7)
1. a kind of purifying of ropinirole hydrochloride (4-2- di-n-propyl amine ethyl -1,3- dihydro -2H- indol-2-ones hydrochloride)
Method, which is characterized in that include the following steps：
(1) ropinirole hydrochloride containing oxidation impurities structure formula (I) is added to the water, and organic solvent is added, at room temperature
Alkali is added after stirring dissolved clarification, stratification after stirring removes water layer；The wherein described organic solvent is selected from toluene, dichloromethane, just
Hexane, hexamethylene, petroleum ether；The alkali is selected from sodium ethoxide, potassium ethoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, hydroxide
Potassium, potassium carbonate, saleratus, tetramethylammonium hydroxide；
(2) obtained organic layer is dried with anhydrous magnesium sulfate, and activated carbon stirring is added and filters and concentrates later；
(3) after being concentrated to dryness, a certain amount of organic solvent is added into obtained grease, is slowly added to a certain amount of concentrated hydrochloric acid
After stirring, feed liquid is cooled down, rejection filter, drying obtains ropinirole hydrochloride.
2. purification process according to claim 1, it is characterised in that wherein the volumetric usage of organic solvent is hydrochloric acid in step (1)
8~12 times of Ropinirole quality, the volumetric usage of water are 15~20 times of ropinirole hydrochloride quality.
3. purification process according to claim 1, it is characterised in that the mole dosage of alkali is rubbed for ropinirole hydrochloride in step (1)
1.5-25 times of that dosage.
4. purification process according to claim 1, it is characterised in that the quality of activated carbon is ropinirole hydrochloride matter in step (2)
The 5%~20% of amount.
5. purification process according to claim 1, it is characterised in that the organic solvent in step (3) is selected from the lower alcohol of C1-C4.
6. purification process according to claim 5, it is characterised in that lower alcohol is selected from isopropanol, methanol, ethyl alcohol in step (3),
Its volumetric usage is 6~15 times of ropinirole hydrochloride quality.
7. purification process according to claim 5, it is characterised in that lower alcohol is isopropanol in step (3).
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| CN104904862A (en) * | 2015-06-02 | 2015-09-16 | 安徽省虹升生物科技有限公司 | Double-skin milk and ropinirole mixed nutrient solution and preparation method thereof |
| WO2018155390A1 (en) * | 2017-02-24 | 2018-08-30 | 久光製薬株式会社 | Adhesive skin patch and packaged product thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005080333A1 (en) * | 2004-02-19 | 2005-09-01 | Torrent Pharmaceuticals Ltd | Process for purification of ropinirole |
| CN1909901A (en) * | 2004-01-20 | 2007-02-07 | Usv有限公司 | A process for the preparation of 4-(2-dipropylaminoethyl)-1,3-dihydro-2H-indol-2-one hydrochloride |
| WO2007110880A2 (en) * | 2006-03-29 | 2007-10-04 | Alembic Limited | A process for the purification of ropinirole hydrochloride |
| WO2007110879A2 (en) * | 2006-03-29 | 2007-10-04 | Alembic Limited | A process for the purification of ropinirole hydrochloride |
| WO2008075169A2 (en) * | 2006-12-15 | 2008-06-26 | Orchid Chemicals & Pharmaceuticals Limited | A process for the purification of ropinirole hydrochloride |
-
2013
- 2013-01-17 CN CN201310027249.7A patent/CN103086946B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1909901A (en) * | 2004-01-20 | 2007-02-07 | Usv有限公司 | A process for the preparation of 4-(2-dipropylaminoethyl)-1,3-dihydro-2H-indol-2-one hydrochloride |
| WO2005080333A1 (en) * | 2004-02-19 | 2005-09-01 | Torrent Pharmaceuticals Ltd | Process for purification of ropinirole |
| WO2007110880A2 (en) * | 2006-03-29 | 2007-10-04 | Alembic Limited | A process for the purification of ropinirole hydrochloride |
| WO2007110879A2 (en) * | 2006-03-29 | 2007-10-04 | Alembic Limited | A process for the purification of ropinirole hydrochloride |
| WO2008075169A2 (en) * | 2006-12-15 | 2008-06-26 | Orchid Chemicals & Pharmaceuticals Limited | A process for the purification of ropinirole hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 盐酸罗匹尼罗合成工艺的改进;余长泉,等;《高校化学工程学报》;20101231;第24卷(第6期);第1011-1016页，第1014页2.2.8部分 * |
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