WO2005040115A1 - Process for the preparation of ropinirole - Google Patents
Process for the preparation of ropinirole Download PDFInfo
- Publication number
- WO2005040115A1 WO2005040115A1 PCT/EP2004/011505 EP2004011505W WO2005040115A1 WO 2005040115 A1 WO2005040115 A1 WO 2005040115A1 EP 2004011505 W EP2004011505 W EP 2004011505W WO 2005040115 A1 WO2005040115 A1 WO 2005040115A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- process according
- reaction
- preparation
- Prior art date
Links
- XBARKDQKGSJDLG-UHFFFAOYSA-N NCCc1c(cc[nH]2)c2ccc1 Chemical compound NCCc1c(cc[nH]2)c2ccc1 XBARKDQKGSJDLG-UHFFFAOYSA-N 0.000 description 2
- UHSKFQJFRQCDBE-UHFFFAOYSA-N CCCN(CCC)CCc1c(CC(N2)=O)c2ccc1 Chemical compound CCCN(CCC)CCc1c(CC(N2)=O)c2ccc1 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 description 1
- DQVWAEMRCAYLKH-FNORWQNLSA-N [O-][N+](/C=C/c1c(cc[nH]2)c2ccc1)=O Chemical compound [O-][N+](/C=C/c1c(cc[nH]2)c2ccc1)=O DQVWAEMRCAYLKH-FNORWQNLSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
Definitions
- the section of technology which the invention refers to The present invention provides a new process for the preparation of Ropinirole useful in the treatment of Parkinson's disease.
- Description of the technical status The compound 4-[2-(dipropylamino)ethyl]-1,3-dihydro-indol-2-one represented by formula I, commonly known as Ropinirole has been used as an active constituent drug, as the hydrochloride salt.
- the compound of formula IV can be oxidised by any oxidising agent described in the literature for the conversion of indole into 2-oxindole.
- the oxidising agent can be selected from the group consisting of halogenating agents such as pyridinium tribromide (PTB), a ⁇ /-halosuccinimide such as ⁇ /-chlorosuccinimide (NCS) or ⁇ /-bromosuccinimide (NBS) in an acidic medium such as acetic acid or hydrochloric acid; or a sulphoxide such as dimethyl sulphoxide (DMSO) or a long chained alkylsulphoxide such as dodecylmethyl sulphoxide or decylmethyl sulphoxide in acidic medium such as for example hydrochloric acid can also be used.
- halogenating agents such as pyridinium tribromide (PTB), a ⁇ /-halosuccinimide such as ⁇ /-chloro
- This reaction is carried out in a suitable solvent depending on the oxidising agent, and at a temperature between room temperature and reflux temperature.
- the conversion of IV into I is carried out with pyridinium tribromide (PTB) and in the presence of an acid, preferentially aqueous acetic acid.
- the conversion of IV into I is carried out with N- chlorosuccinimide (NCS) and mineral acid, preferentially aqueous hydrochloric acid.
- NCS N- chlorosuccinimide
- the compound of formula I can be converted into its pharmaceutically acceptable salts, for example its hydrochloride, by means of the conventional methods already described in the literature as, for example processing with hydrochloric acid.
- the compound of formula IV can be prepared by alkylation of the compound III,
- an alkylating agent of formula CH 3 CH 2 CH 2 -L, wherein L is a leaving group, optionally in the presence of a base preferably halogen, methanesulphonate, toluenesulphonate, trifluoromethanesulphonate or benzenesulphonate.
- a wide variety of bases can be used, preferably sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate.
- the reaction is carried out in a suitable solvent, for example toluene.
- the leaving group is halogen and the reaction is carried out in the presence of a base.
- the leaving group is iodine or bromine and the reaction is carried out in the presence of sodium bicarbonate.
- the compound of formula IV can be prepared from the compound of formula III, by reaction with a carbonylic compound of formula CH 3 CH 2 COR 1 wherein R 1 can be OH or H, in the presence of a reducing agent and in normal reductive amination conditions.
- the carbonylic compound is CH 3 CH 2 COR 1 wherein R 1 is OH and the reducing agent is sodium borohydride.
- the compound of formula III can be prepared by reducing compound II,
- a reducing agent for example LiAIH 4 , NaBH -BF 3 ⁇ t 2 O, NaBH 4 -BH 3 , diisobutyl aluminium hydride, bis(2-methoxyethoxy)aluminium hydride or by means of hydrogenation in the presence of a catalyst, for example Pd/C, Pd(OH) 2 or PtO 2 ⁇ 2 O.
- the reducing agent is bis(2-methoxyethoxy)aluminium hydride and the reaction is carried out in toluene, tetrahydrofuran or their mixtures at a temperature between room temperature and reflux temperature of the solvent.
- the compound of formula II can be prepared by treatment of 4- indolecarboxaldehyde V
- the compound of formula II can be prepared from compound of formula V by reaction with nitromethane in the presence of ammonium acetate at the reflux temperature of nitromethane.
- the compound of formula V is known and can be prepared by processes already described in the literature, for example the method described by Joseph M. Muchowski in the Journal of Heterocyclic Chemistry 2000, 37(5), 1293. The following examples are only given by way of illustration of the invention and not to be understood as limiting. The following abbreviations have been used in the examples: AcOEt: ethyl acetate THF: tetrahydrofuran DIBAH: diisobutyl aluminium hydride
- Method A A solution of 4-(2-nitrovinyl)indole (II) (10g, 53.2mmol) in THF (200mL) was added to a suspension of LiAIH 4 (12.1g, 319.2mmol) in THF (600mL) at 0°C and under inert atmosphere. When the temperature reached room temperature, the reaction mixture was heated at the reflux temperature and stirred at this temperature for 3 hours. Ice-water was added to the resultant suspension, which was filtered through Celite, concentrated and extracted with AcOEt. The organic layer was dried, filtered and concentrated to obtain, 6.9g (81%) of 4-[(2-amino)ethyl]indole (III).
- 1 H-RMN (200MHz, CDCI 3 /CD 3 OD), ⁇ : 2,06 (broad, 2H, NH 2 ), 3,06 (m, 4H, Ar-CH 2 - CH 2 -NH 2 ), 6,55 (m, 1 H, 3-H), 6,90-7,30 (m, 4H, Ar), 9,0 (broad, 1 H, NH).
- Method B A solution of 4-(2-nitrovinyl)indole (II) (3g, 15.9 mmol) in THF (10 ml) was added to a suspension of DIBAH (1M THF, 159 ml, 159 mmol) under an inert atmosphere and was stirred at room temperature for 30min, then it was heated at 60°C and stirred for ⁇ hours. The obtained mixture was cooled to 0°C, AcOEt, water and KOH 10% were added and the ontained product was filtered. The aqueous layer was extracted with AcOEt and the organic layer was dried and evaporated to obtain 4-[(2-amino)ethy.]indole (III).
- Method C A solution of 4-(2-nitrovinyl)indole (II) (25g, 132.8mmol) in THF (325mL) was added to a solution of bis(2-methoxy)aluminium hydride in toluene 70% (385g, 1333mmol) in toluene (325mL), the reaction mixture was heated to 60-70°C and at this temperature the THF was distilled. Then toluene (325mL) was added and stirred at a temperature between 60-70°C for 2 hours. Once the reaction mixture had reached room temperature, it was cooled to 5-10°C and then NaOH 5% (600mL) was slowly added.
- Method B A mixture of 4-[(2-amino)ethyl]indole (III) (2.0g, 12.48mmol), 1-iodopropane (8.5g, ⁇ Ommol), NaHCO 3 (2.3g, 27.4mmol) in toluene (40mL) was stirred at reflux temperature for 21 h. NaHCO 3 (1.15g, 13.7mmol) in water (20mL) and 1-iodopropane (2.12g,
- Method A A solution of pyridinium tribromide 90% (8.72g, 24.5mmol) in acetic acid 50% (50mL) was added to a solution of 4-[2-(dipropylamino)ethyl]indol (IV) (5g, 20.5 mmol) in acetic acid 50% (100mL) and was stirred at 50°C for 3h. When the resultant mixture reached room temperature, it was stirred at this temperature for 16h. The reaction mixture was concentrated to obtain an aqueous residue, which was diluted with water (100mL), basified with an aqueous solution of NaOH 10% and extracted with AcOEt.
- Method B ⁇ /-chlorosuccinimide (2.52g, 18.9mmol) was added to a solution of 4-[2- (dipropylamino)ethyl]indole (IV) (3g, 12.28mmol) in toluene (10mL) and was stirred at room temperature for 1h. The resultant mixture was washed with an aqueous solution of NaOH 5% and then an aqueous solution of HCI 1N (30mL) was added to the organic layer and was heated at reflux temperature for 1h. When the mixture reached room temperature, the organic layer was separated and the aqueous layer was basified with an aqueous solution of NaOH and extracted with AcOEt. The organic layer was dried, filtered and concentrated to obtain 2.1g (66%) of 4-[2-(dipropylamino)ethyl]indol-2-one (I), which was purified and converted into its hydrochloride salt.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04790372A EP1673340A1 (en) | 2003-10-14 | 2004-10-13 | Process for the preparation of ropinirole |
US10/572,210 US7230118B2 (en) | 2003-10-14 | 2004-10-13 | Process for the preparation of ropinirole |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES200302382A ES2237307B1 (en) | 2003-10-14 | 2003-10-14 | PROCEDURE FOR THE PREPARATION OF ROPINIROL. |
ES200302382 | 2003-10-14 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2005040115A1 true WO2005040115A1 (en) | 2005-05-06 |
WO2005040115A8 WO2005040115A8 (en) | 2005-07-07 |
Family
ID=34507892
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2004/011505 WO2005040115A1 (en) | 2003-10-14 | 2004-10-13 | Process for the preparation of ropinirole |
Country Status (4)
Country | Link |
---|---|
US (1) | US7230118B2 (en) |
EP (1) | EP1673340A1 (en) |
ES (1) | ES2237307B1 (en) |
WO (1) | WO2005040115A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108993496A (en) * | 2018-10-30 | 2018-12-14 | 泰山医学院 | A kind of preparation method for treating dyskinesia drug ropinirole intermediate |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2009356855A1 (en) | 2009-12-16 | 2012-08-09 | Pharmathen S.A. | Process for the preparation of Ropinirole and salts thereof |
CN110621660B (en) | 2017-06-16 | 2022-06-28 | 浙江华海立诚药业有限公司 | Purification method of ropinirole hydrochloride |
CN111499514A (en) * | 2019-01-31 | 2020-08-07 | 连云港润众制药有限公司 | Preparation method of intermediate of roxasistat |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0113964A1 (en) * | 1982-12-07 | 1984-07-25 | Smithkline Beckman Corporation | 4-Aminoalkyl-2(3H)-indolones |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4378368A (en) * | 1981-11-04 | 1983-03-29 | Purdue Research Foundation | Use of 4-(2-di-n-propylaminoethyl)indole or a salt thereof as a presynaptic dopamine autoreceptor stimulant |
GB9300309D0 (en) * | 1993-01-08 | 1993-03-03 | Smithkline Beecham Plc | Process |
-
2003
- 2003-10-14 ES ES200302382A patent/ES2237307B1/en not_active Expired - Lifetime
-
2004
- 2004-10-13 US US10/572,210 patent/US7230118B2/en not_active Expired - Fee Related
- 2004-10-13 WO PCT/EP2004/011505 patent/WO2005040115A1/en not_active Application Discontinuation
- 2004-10-13 EP EP04790372A patent/EP1673340A1/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0113964A1 (en) * | 1982-12-07 | 1984-07-25 | Smithkline Beckman Corporation | 4-Aminoalkyl-2(3H)-indolones |
Non-Patent Citations (1)
Title |
---|
STJERNLÖF P ET AL: "Structure-activity relationships in the 8-amino- 6,7,8,9-tetrahydro-3H-benz[e]indole ring system. 1. Effects of substituents in the aromatic system on serotonin and dopamine receptor subtypes", JOURNAL OF MEDICINAL CHEMISTRY, vol. 38, no. 12, 1995, pages 2202 - 2216, XP002036487 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108993496A (en) * | 2018-10-30 | 2018-12-14 | 泰山医学院 | A kind of preparation method for treating dyskinesia drug ropinirole intermediate |
CN108993496B (en) * | 2018-10-30 | 2021-01-15 | 山东第一医科大学(山东省医学科学院) | Preparation method of ropinirole intermediate for treating dyskinesia |
Also Published As
Publication number | Publication date |
---|---|
US7230118B2 (en) | 2007-06-12 |
ES2237307A1 (en) | 2005-07-16 |
ES2237307B1 (en) | 2006-11-01 |
EP1673340A1 (en) | 2006-06-28 |
US20070032540A1 (en) | 2007-02-08 |
WO2005040115A8 (en) | 2005-07-07 |
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