WO2015186138A1 - Improved process for the preparation of crystalline form ii of rotigotine - Google Patents
Improved process for the preparation of crystalline form ii of rotigotine Download PDFInfo
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- WO2015186138A1 WO2015186138A1 PCT/IN2015/000223 IN2015000223W WO2015186138A1 WO 2015186138 A1 WO2015186138 A1 WO 2015186138A1 IN 2015000223 W IN2015000223 W IN 2015000223W WO 2015186138 A1 WO2015186138 A1 WO 2015186138A1
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- KFQYTPMOWPVWEJ-INIZCTEOSA-N CCCN(CCc1ccc[s]1)[C@@H]1Cc2cccc(O)c2CC1 Chemical compound CCCN(CCc1ccc[s]1)[C@@H]1Cc2cccc(O)c2CC1 KFQYTPMOWPVWEJ-INIZCTEOSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
The present invention relates to an improved, environment friendly and cost effective process for the preparation of crystalline Form II of Rotigotine. Rotigotine, i.e. (6S)-6-{propyl[2-(2-thienyl) ethyl]amino}-5,6,7,8-tetrahydro-l-naphthalenol represented by structural formula (I), is used for the treatment of Parkinson's disease and Willis-Ekbom disease.
Description
Improved process for the preparation of crystalline Form II of Rotigotine
Field of the invention
The present invention relates to an improved process for the preparation of crystalline Form II of Rotigotine.
Background of the invention
Rotigotine [(6S)-6-{propyl[2-(2-thienyl)ethyl]amino}-5,6,7,8-tetrahydro-l-naphthalenol] is represented by the following structural formula (I).
Rotigotine is used for the treatment of Parkinson's disease and Wills-Ekbom disease.
Rotigotine was commercially developed by Schwarz Biosciences under the trademark name of Neupro.
The preparation and therapeutic uses of Rotigotine were first disclosed in US 4,564,628 and US 4,885,308. US 4,564,628 and US 4,885,308 disclosed procedures for the preparation of Rotigotine free base in an oil form, this form is not desirable form. US 6,372,920 disclosed five examples for the preparation of Rotigotine hydrochloride salt from Rotigotine free base, none of the examples describe the physical state of the Rotigotine. US 8,232,414 disclosed Rotigotine polymorphic Form I and Form II obtained from the tempering process or from ethanolic precipitation. US 8,344, 165 describe the. crystallization of Rotigotine from various solvents in multiple purification methods.
Therefore, there is a need to develop environment friendly and cost effective process for the preparation of crystalline Form II of Rotigotine.
Summary of the invention
The present invention provides an improved process for the preparation of crystalline Form II of Rotigotine, which comprises:
a) adding of Rotigotine acid salt in water and in presence of base at 25-35 °C;
b) stirring the reaction mass for 1-4 hours;
c) filtering the precipitated compound and washing with water;
d) drying the obtained wet compound in vacuum oven at 60-65 °C for 10-15 hours to get the crystalline Form II of Rotigotine.
Brief Description of Drawing
Figure 1: PXRD of crystalline Form II of Rotigotine.
Detailed Description of the Invention
The present invention provides an improved process for the preparation of crystalline Form II of Rotigotine, which comprises:
a) adding of Rotigotine acid salt in water and in presence of base, at 25-35 °C;
b) stirring the reaction mass for 1-4 hours;
c) filtering the precipitated compound and washing with water;
d) drying the obtained wet compound in vacuum oven at 60-65 °C for 10-15 hours to get the crystalline Form II of Rotigotine.
The base employed in step a) of reaction can be selected from organic or inorganic base wherein the organic base is selected from the group comprising of primary amine, secondary amines and tertiary amines such as ammonia, methyl amine, ethanolamine, diethanolamine, triethanolamine, triethyl amine, tromethamine, N-methylglucamine. Inorganic base is selected from the group comprising of alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, alkali metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide and metal alkoxides such as alkoxides of sodium, lithium or potassium and sodium tert-butoxide.
Experimental Procedure
Example 1: Preparation of (6S)-6-{propyl[2-(2-thienyI)ethyl]amino}-5,6,7,8,-tetrahydro-l- naphthalenol Hydrochloride (Rotigotine HC1)
Step (i) : Preparation of (S)-5-Methoxy-2-(N-propylamino) tetralin dibenzoyl-L-tartaric acid salt.
To the mixture of 5-methoxy-2-tetralone (500 grams, 1 equivalent) and toluene (2500 mL, 5volumes) acetic acid was added (485 mL, 3 equivalents) and followed by n-propyl amine (184.5 grams, 1.1 equivalent) at 25-35 °C, stirred for 30 minutes at 25-35 °C. The reaction mixture was cooled to 10 °C and
sodium borohydride (NaBHt) was added (105.2 grams, 1 equivalent) lot wise at 10-20 °C, stirred for 1 to 2 hours at 25-35 °C. Progress of the reaction was monitored by HPLC. Filtered the reaction mass and washed bed with toluene (1000 mL, 2 volumes). To the filtrate aqueous hydrochloride (400 mL, 0.8 volumes) was added and cooled to 10-15 °C and stirred for 1 hour and filtered the solid compound and washed with acetone (2000 mL, 4 volumes).
The above wet material was taken in another round bottom flask (RB flask), added water (2500 mL, 5 volumes) and methylene dichloride (MDC) (2500 mL, 5 volumes) at 25-35 °C, later triehylamine (400 mL, 0.8 volumes) was added, stirred for 5 minutes at 25-35 °C. Organic layer was separated and aqueous layer was again extracted with MDC (1500 mL, 3 volumes), both MDC layers was combined and washed with water (1000 mL, 2 volumes), Distilled off the MDC solvent below 40 °C under vacuum. Cooled the reaction mixture to 25-35 °C and added ethanol (1500 mL, 3 volumes) and followed by Dibenzoyl-L- tartaric acid solution (750 grams dissolved in ethanol 3000 mL) at 25-35°C, stirred for 2.0 hours at 25 to 35 °C. Filtered the solid and washed the material with ethanol (500 mL, 1 volume). The obtained material was again purified in ethanol up to R-isomer is below 2%, dried the compound. Yield:25%
HPLC purity: 99%.
Step (ii) : Preparation of (S)-5-Hydroxy-2-(N-propylamino) tetralin hydrobromide
To the mixture of (S)-5-Methoxy-2-(N-Propylamino) tetralin dibenzoyl-L-tartaric acid (100 grams, 1 equivalent) and MDC (500 mL, 5 volumes) water was added (500 mL, 5 volumes) at 25-35 °C. The reaction mixture was cooled to the below 10 °C and aqueous sodium hydroxide solution was added (17 grams, sodium hydroxide dissolved in 400 mL water). Stirred the reaction mixture for 10 minutes at 25- 35 °C. Organic layer was separated and aqueous layer was again extracted with MDC (200 mL, 2 volumes), both MDC layers were combined and washed with water (200 mL, 2 volumes). Distilled off the MDC solvent below 40 °C under vacuum. Cooled the reaction mixture to 25-35 °C and aqueous hydro bromide solution (250 mL, 2.5 volumes) was added to the reaction mixture at 25-35 °C, Heated the reaction mixture to 110-120 °C and maintained for 4-6 hours, the progress of the reaction was monitored by HPLC. Reaction mixture was cooled to 0 -10 °C and maintained the mixture for 2- 3 hours at 0-10 °C. Filtered the solid and washed with cool water (100 mL, 1 volume), dried the compound at 60-65 °C for 6- 8 hours. Yield: 90% , HPLC purity: 98%.
Step (iii):Preparation of (6S)-6-{Propyl[2-(2-thienyl)ethyl]amino}-5,6,7,8,-tetrahydro-l- naphthalenol hydrochloride (Rotigotine HC1)
To the mixture of (S)-5-Hydroxy-2n-propyl amino) tetralin hydrobromide (100 grams, 1 equivalent) and MDC (700 mL, 7 volumes) water was added (500 mL, 5 volumes) and followed by triethylamine (80 mL,
0.8 volumes) at 25-35 °C, stirred for 10 minutesat 25-35 °C. Organic layer was separated and aqueous layer was again extracted with MDC (200 mL, 2 volumes), both MDC layers were combined and washed with 10% brine solution (400 mL, 4 volumes). Distilled off the MDC below 40 °C under vacuum. Cooled the reaction mixture to 25-35 °C and toluene (1000 mL, 10 volumes) was added to the reaction mixture at 25-35 °C. Stirred for 5 minutes to get clear solution at 25-35 °C.
Meanwhile in another RB flask 2-thiopheneacetic acid (310 grams, 6.25 equivalents) was dissolved in toluene (1000 mL, 10 volumes) at 25-35 °C, then it was cooled to 15 °C, sodium borohydride was (42 grams, 3.25 equivalents) added to the reaction mixture at 15-20 °C slowly lot wise. Stirred for 60 minutes at 25-35 °C. After that above prepared free base solution was added to the reaction mixture at 25-35 °C. Heated to internal temperature 90-100 °C and stirred for 6- 8 hours at 90-100 °C. Progress of the reaction was monitored by HPLC. Cooled to 0 °C. Water (200 mL, 2 volumes) was added to the reaction mixture at 0-10 °C and stirred for 5-10 minutes at 25-35 °C, then reaction mass was washed with 10% potassium carbonate solution (2x8 volumes) followed by water (500 mL, 5 volumes). Distilled off the toluene solvent below 65 °C under vacuum 630-700 mmHg. Crude residue was dissolved in methylene chloride (600 mL, 6 volumes) at 25-35 °C and HC1 gas was passed through the reaction mass for 10 minutes at 25 -35 °C (RM pH should be below 2). Stirred the reaction mixture for 30 minutes at 25-35 °C. Filtered the solid compound and washed with methylene chloride (2 x 200 mL, 4 volumes), dried the solid compound at 55-60 °C for 2 hours, to get Rotigotine HC1 (98.5 grams). HPLC purity:98%.
Rotigotine HC1 stirred in acetone (690 mL, 7volumes) at 50-55°C and water was added (74 mL, 0.75 volumes). Stirred the reaction mixture for 5-10 minutes at 50-55°C. Clear solution was observed. Reaction mixture was cooled to 0 °C, stirred for 60 minutes, filtered the solid and washed with acetone (197 mL, 2 volumes), dried the compound for 6-10 hours at 55- 65 °C to get Rotigotine HC1. Yield : 65% HPLC purity: 99.5%.
Example 2: Preparation of (6S)-6-{Propyl [2-(2-thienyl) ethyl] amino}-5,6,7,8-tetrahydro-l- naphthalenol (Rotigotine Form-II)
To the mixture of Rotigotine hydrochloride (10 grams, 1 equivalent) and water (70 mL, 7 volumes) was added sodium bicarbonate (2.86 grams, 1.2 equivalents) at 25-35 °C and stirred the reaction mixture for 1-4 hours. Then precipitated compound was filtered and washed with water (70 mL, 10 volumes). The obtained wet compound was dried in vacuum oven at 60 °C for 10-15 hours to get the crystalline Rotigotine (8.2 grams). Yield: 91.5%.
Example-3: Preparation of (6S)-6- {Propyl [2-(2-thienyl) ethyl] amino}-5,6,7,8-tetrahydro-l- naphthalenol (Rotigotine Form-II)
To the mixture of Rotigotine hydrochloride (5, grams, 1 equivalent) and water (25 mL, 5 volumes) was added ammonia solution (2.5 mL, 0.5 volumes) at 25-35 °C. Stirred the reaction mixture for 1-3 hours. Then precipitated compound was filtered and dried in vacuum oven at 60 °C for 10-15 hours to get the crystalline Rotigotine (3.6 grams). Yield: 80.3%.
Example-4: Preparation of (6S)-6- {Propyl [2-(2-thienyl) ethyl] amino}-5,6,7,8-tetrahydro-l- naphthalenol (Rotigotine Form-II)
To the mixture of Rotigotine hydrochloride (5 grams, 1 equivalent) and water (25 mL, 5 volumes) was added triethylamine (4.0 mL, 0.8 volumes) at 25-35 °C. Stirred for 1-3 hours. Then precipitated compound was filtered and dried in vacuum oven at 60 °C for 10-15 hours to get the crystalline Rotigotine (3.8 grams). Yield: 84.8%.
Example-5: Preparation of (6S)-6- {Propyl [2-(2-thienyl) ethyl] amino}-5, 6, 7, 8,-tetrahydro-l- naphthalenol (Rotigotine Form-II)
To the mixture of Rotigotine hydrochloride (5 grams, 1 equivalent) and water (25 mL, 5 volumes) was added sodium hydroxide solution (680 mg, 1.2 equivalent)) at 25-35 °C. Stirred for 1-3 hours. Then precipitated compound was filtered and dried in vacuum oven at 60 °C for 10-15 hours to get the crystalline Rotigotine (3.2 grams). Yield: 71.4%.
Example-6: Preparation of (6S)-6-{Propyl [2-(2-thienyl) ethyl] amino}-5, 6, 7, 8,-tetrahydro-l- naphthalenol (Rotigotine Form-II)
To the mixture of Rotigotine hydrochloride (5 grams, 1 equivalent) and water (25 mL, 5 volumes) was added sodium methoxide solution (921 mg, 1.2 equivalents) at 25-35 °C. Stirred the reaction mixture for 1-3 hours. Then precipitated compound was filtered and dried in vacuum oven at 60 °C for 10-15 hours to get the crystalline Rotigotine (3.0 grams). Yield:67%.
Example-7: Preparation of (6S)-6-{Propyl< [2-(2-thienyI) ethyl] amino}-5,6,7,8-tetrahydro-l- naphthalenol (Rotigotine Form-II)
To the mixture of (6S)-6- {Propyl [2-(2-thienyl) ethyl] amino}-5,6,7,8-tetrahydro-l-naphthalenol hydrochloride (100 grams, 1 equivalent) and ethyl acetate (500 mL, 5 volumes) was added water (500 mL, 5 volumes) at 25-35 °C, later ammonia solution (80 mL, 0.8 volumes) was added to the reaction mixture at 25-35 °C. Stirred for 5 minutes. Organic layer was separated and aqueous layer was again
extracted with ethyl acetate (200 mL, 2 volumes), combined both organic layers, acidic carbon (5 grams, 5% w/w) was added to the reaction mixture and heated to 70-75 °C, stirred for 30 minutes at 70-75 °C, later the reaction mixture was cooled to 30-35 °C, filtered and washed the bed with Ethyl acetate (100 mL, 1 volume), distilled-off the solvent under vacuum at 40 °C to get residue. Cyclohexane (200 mL, 2volumes) was added to the residue and distilled-off the solvent under vacuum at 40 °C, cyclohexane (800 mL, 8 volumes) was added to the residue at 25-35 °C, Heated the contents to 65-70 °C and stirred for 5 minutes at 65-70 °C (clear solution was observed). The reaction mixture was cooled to 10-15 °C and stirred for 30 minutes at 10-15 °C. Filtered the solid and washed with cyclohexane (50 mL, 0.5 volumes). Dried the product under vacuum at 60-65 °C for 10-15 hours to get Rotigotine Form-II. Yield: 90%.
HPLC purity: 99.5%.
Example-8: Preparation of (6S)-6- {Propyl [2-(2-thienyl) ethyl] amino}-5, 6, 7, 8,-tetrahydro-l- naphthalenol (Rotigotine Form-II)
To the mixture of Rotigotine hydrochloride (25 grams, 1 equivalent) and water (125 mL, 5 volumes) was added MDC (150 mL, 6volumes) at 25-35°C, later 25% ammonia solution (12.5 mL, 0.5 volumes) was added to the reaction mixture and stirred for 10 minutes at 25-35 °C, organic layer was separated and distilled off at 40 °C under vacuum, cyclohexane (50 mL, 2 volumes) was added to the residue and distilled off at 40 °C. After that cyclohexane (125 mL, 5 volumes) was added to the residue and heated to 60-65 °C and stirred for 10 minutes.Clear solution was observed. The reaction mixture was cooled to 10
°C and stirred for 60 minutes. Filtered the solid compound and dried in vacuum oven 60-65 °C for 10-15 hours to get crystalline Rotigotine (19 grams). Yield: 85%.
Claims
1. An improved process for the preparation of crystalline Form II of Rotigotine, which comprises:
a) adding Rotigotine acid salt in water and in presence of base at 25-35 °C;
b) stirring the reaction mass for 1-4 hours;
c) filtering the precipitated compound and washing with water;
d) drying the obtained wet compound in vacuum oven at 60-65 °C for 10-15 hours to get the crystalline Form II of Rotigotine.
2. The process as claimed in claim 1, wherein base used in step a) is organic or inorganic base.
3. The process as claimed in claim 2, wherein organic base used in step a) is selected from ammonia, methyl amine, ethanolamine, diethanolamine, triethanolamine, triethylamine, tromethamine or N- methylglucamine.
4. The process as claimed in claim 2, where in inorganic base used in step a) is selected from sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, calcium hydroxide, potassium hydroxide, sodium methoxide, lithium methoxide, potassium methoxide or sodium tert-butoxide.
5. The process as claimed in claim 1, wherein the solvent used in step a) is water.
6. The process as claimed in claim 1, wherein the reaction of step a) takes place at temperature 25-35 °C.
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| Application Number | Priority Date | Filing Date | Title |
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| IN2722/CHE/2014 | 2014-06-03 | ||
| IN2722CH2014 | 2014-06-03 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2215072B1 (en) | 2007-11-28 | 2015-09-02 | UCB Pharma GmbH | Polymorphic form of rotigotine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010073124A2 (en) * | 2008-12-26 | 2010-07-01 | Actavis Group Ptc Ehf | Processes for preparing highly pure rotigotine or a pharmaceutically acceptable salt thereof |
| US8232414B2 (en) * | 2007-11-28 | 2012-07-31 | Ucb Pharma Gmbh | Polymorphic form of rotigotine and process for production |
| US8344165B2 (en) * | 2007-05-30 | 2013-01-01 | Chemagis Ltd. | Crystalline rotigotine base and preparation process therefor |
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2015
- 2015-05-28 WO PCT/IN2015/000223 patent/WO2015186138A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8344165B2 (en) * | 2007-05-30 | 2013-01-01 | Chemagis Ltd. | Crystalline rotigotine base and preparation process therefor |
| US8232414B2 (en) * | 2007-11-28 | 2012-07-31 | Ucb Pharma Gmbh | Polymorphic form of rotigotine and process for production |
| WO2010073124A2 (en) * | 2008-12-26 | 2010-07-01 | Actavis Group Ptc Ehf | Processes for preparing highly pure rotigotine or a pharmaceutically acceptable salt thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2215072B1 (en) | 2007-11-28 | 2015-09-02 | UCB Pharma GmbH | Polymorphic form of rotigotine |
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