WO2008139484A2 - New process for the synthesis of loferpramine maleate: a stable salt of loferpramine - Google Patents
New process for the synthesis of loferpramine maleate: a stable salt of loferpramine Download PDFInfo
- Publication number
- WO2008139484A2 WO2008139484A2 PCT/IN2007/000195 IN2007000195W WO2008139484A2 WO 2008139484 A2 WO2008139484 A2 WO 2008139484A2 IN 2007000195 W IN2007000195 W IN 2007000195W WO 2008139484 A2 WO2008139484 A2 WO 2008139484A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lofepramine
- maleate
- base
- precipitates
- synthesis
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
- C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
- C07D223/28—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a single bond between positions 10 and 11
Definitions
- This invention relates to a stable salt of Lofepramine and a new process for the synthesis of Lofepramine Maleate.
- Lofepramine Hydrochloride is known to be a very good anti-depressant having interesting pharmacological activities. It has been synthesized in the early 1970's. Lofepramine as hydrochloride is known to be unstable. Its instability is mainly due to its ability to undergo air oxidation easily. Therefore, it was identified that Lofepramine Maleate is more stable and easy to prepare compare to the corresponding hydrochloride salt.
- Lofepramine hydrochloride prepared from all the reported procedure is stable only for few days ( ⁇ 7 days), unless it is stabilized.
- the Lofepramine Maleate is quite stable even after 6 months.
- Preliminary report shows that it also has similar bioavailability pattern compared to Lofepramine Hydrochloride.
- the stability of Lofepramine Maleate presents a major advantage in tablet formation and also in the shelf life of Lofepramine. There is no procedure reported till to date for the synthesis of Lofepramine Maleate. However, following literature is available for Lofepramine Hydrochloride synthesis.
- An object of this invention is to propose a process for the synthesis of Lofepramine Maleate.
- Another object of this invention is to propose a process for the synthesis of Lofepramine Maleate which is a stable Lofepramine salt.
- Further object of this invention is to propose a process for the synthesis of Lofepramine Maleate which is a substitute of Lofepramine hydrochloride.
- Lofepramine Maleate comprising; dissolving maleic acid in ethyl acetate by warming and the solution is then filtered hot; adding purified Lofepramine base to the said clear solution of maleic acid and heated upto about 40-60°C; filtering the precipitates of Lofepramine maleate; drying the said precipitates at 45 to 55°C to obtain Lofepramine maleate.
- Lofepramine is a tri-cyclic anti-depressant having interesting pharmacological properties. It has been helpful in treating broad spectrum of mental disorders. Though it has been synthesized from the above mentioned patented procedures, from almost similar reaction strategies, the product made from all these procedures are unstable leading to major problem in formulation and thus the shelf life of the product. The instability of this product is due to the air oxidation of the product. There are attempts to stabilize the Lofepramine hydrochloride by adding external stabilizers like tartaric acid (WO 92/19599) or ascorbic acid (USP 4061747). However no attempts have been made to stabilize the molecule with in itself.
- the present invention has taken a new approach in stabilizing the unstable Lofepramine by converting it as Maleate salt.
- the maleic acid counter ion acts as an internal stabilizer and blocks air oxidation of the product leading to stable Lofepramine.
- the Maleate counter ion dramatically increases the stability of the product. Its synthesis has been done as per the following reaction scheme-
- Lofepramine Base prepared as per the procedure described in US Patent no: 4,172074 (1979). Instead of ethyl acetate, t-butyl methyl, ether (1 :10-15 by Desipramine VWW) is used as solvent for the reaction and the Lofepramine base thus obtained is purified before use.
- Lofepramine obtained from the above method is dissolved in ethyl acetate/acetone (150-300 ml) and added to cooled methanol (500 mL) and stirred at 5-10°C for 1h. The crystals separated were filtered and dried at 35-45°C for 2-3 h to get 65-75 g pure white crystalline Lofepramine Base. Purity by HPLC: Min 99.5% (BP2004 method used for Lofepramine Hydrochloride). The above method removes both polar and non- polar impurities present in the crude Lofepramine Base obtained from the above procedure.
- Lofepramine base 420 g was added all at once and warmed up to 40-60°C. Lofepramine base initially dissolves and re-precipitates as Lofepramine Maleate in about 5 min., which is stirred at room temperature for 1 h and filtered. Dried at 45-55°C for 5-6 h to get 500-520 g, about 95% of Lofepramine Maleate.
- Lofepramine Base prepared as per the procedure described in US Patent no: 4,172074 (1979). Instead of ethyl acetate, t-butyl methyl ether (1:10-15 by Desipramine W/W) is used as solvent for the reaction and the Lofepramine base thus obtained is purified before use.
- 100 g Lofepramine obtained from the above method is dissolved in ethyl acetate/acetone (150-300 ml) and added to cooled methanol (500 mL) and stirred at 5-1O°C for 1h. The crystals separated were filtered and dried at 35-45°C for 2-3 h to get 65-75 g pure white crystalline Lofepramine Base. Purity by HPLC: Min 99.5% (BP2004 method used for Lofepramine Hydrochloride). The above method removes both polar and non- polar impurities present in the crude Lofepramine Base obtained from the above procedure.
- Lofepramine base 420 g was added all at once and warmed up to 40-60°C. Lofepramine base initially dissolves and re-precipitates as Lofepramine Maleate in about 5 min., which is stirred at room temperature for 1 h and filtered. Dried at 45-55°C for 5-6 h to get 500-520 g, about 95% of Lofepramine Maleate.
Abstract
This invention relates to a stable salt of Lofepramine and A process for the synthesis of stable Lofepramine maleate comprising; dissolving maleic acid in ethyl acetate by warming and the solution is then filtered hot; adding purified Lofepramine base to the said clear solution of maleic acid and heated upto about 40-60°C; filtering the precipitates of Lofepramine maleate; drying the said precipitates at 45 to 55°C to obtain Lofepramine maleate.
Description
TITLE
New process for the synthesis of loferpramine maleate: a stable salt of loferpramine
FIELD OF INVENTION:
This invention relates to a stable salt of Lofepramine and a new process for the synthesis of Lofepramine Maleate.
BACKGROUND OF THE INVENTION:
Lofepramine Hydrochloride is known to be a very good anti-depressant having interesting pharmacological activities. It has been synthesized in the early 1970's. Lofepramine as hydrochloride is known to be unstable. Its instability is mainly due to its ability to undergo air oxidation easily. Therefore, it was identified that Lofepramine Maleate is more stable and easy to prepare compare to the corresponding hydrochloride salt.
The Lofepramine hydrochloride prepared from all the reported procedure is stable only for few days (< 7 days), unless it is stabilized. However, the Lofepramine Maleate is quite stable even after 6 months. Preliminary report shows that it also has similar bioavailability pattern compared to Lofepramine Hydrochloride. The stability of Lofepramine Maleate presents a major advantage in tablet formation and also in the shelf life of Lofepramine. There is no procedure reported till to date for the synthesis of Lofepramine Maleate. However, following literature is available for Lofepramine Hydrochloride synthesis.
OBJECTS OF THE INVENTION:
An object of this invention is to propose a process for the synthesis of Lofepramine Maleate.
Another object of this invention is to propose a process for the synthesis of Lofepramine Maleate which is a stable Lofepramine salt.
Further object of this invention is to propose a process for the synthesis of Lofepramine Maleate which is a substitute of Lofepramine hydrochloride.
BRIEF DESCRIPTION OF THE INVENTION:
According to this invention there is provided a stable salt of Lofepramine.
According to this invention there is also a process for the synthesis of stable
Lofepramine Maleate comprising; dissolving maleic acid in ethyl acetate by warming and the solution is then filtered hot; adding purified Lofepramine base to the said clear solution of maleic acid and heated upto about 40-60°C; filtering the precipitates of Lofepramine maleate; drying the said precipitates at 45 to 55°C to obtain Lofepramine maleate.
DETAILED DESCRIPTION OF THE INVENTION:
Lofepramine is a tri-cyclic anti-depressant having interesting pharmacological properties. It has been helpful in treating broad spectrum of mental disorders. Though it has been synthesized from the above mentioned patented procedures, from almost similar reaction strategies, the product made from all these procedures are unstable leading to major problem in formulation and thus the shelf life of the product. The instability of this product is due to the air oxidation of the product. There are attempts to stabilize the Lofepramine hydrochloride by adding external stabilizers like tartaric acid (WO 92/19599) or ascorbic acid (USP 4061747). However no attempts have been made to stabilize the molecule with in itself.
The present invention has taken a new approach in stabilizing the unstable Lofepramine by converting it as Maleate salt. The maleic acid counter ion acts as an internal stabilizer and blocks air oxidation of the product leading to stable Lofepramine. The Maleate counter ion dramatically increases the stability of the product. Its synthesis has been done as per the following reaction scheme-
The instability problem of Lofepramine has been over come by converting it to Maleate salt. Maleate counter ion dramatically increases the stability of Lofepramine by blocking the air oxidation pathway, a main cause of stability. Lofepramine Base prepared as per the procedure described in US Patent no: 4,172074 (1979). Instead of ethyl acetate, t-butyl methyl, ether (1 :10-15 by Desipramine VWW) is used as solvent for the reaction and the Lofepramine base thus obtained is purified before use. Thus 100 g Lofepramine obtained from the above method is dissolved in ethyl acetate/acetone (150-300 ml) and added to cooled methanol (500 mL) and stirred at 5-10°C for 1h. The crystals separated were filtered and dried at 35-45°C for 2-3 h to get 65-75 g pure white crystalline Lofepramine Base. Purity by HPLC: Min 99.5% (BP2004 method used for Lofepramine Hydrochloride). The above method removes both polar and non- polar impurities present in the crude Lofepramine Base obtained from the above procedure.
Maleic acid (116 g) dissolved in ethyl acetate (1500 mL) by warming up to 50- 60°C and filtered hot. To this clear solution of maleic acid in ethyl acetate (under nitrogen atmosphere), Lofepramine base (420 g) was added all at once and warmed up to 40-60°C. Lofepramine base initially dissolves and re-precipitates as Lofepramine Maleate in about 5 min., which is stirred at room temperature for 1 h and filtered. Dried at 45-55°C for 5-6 h to get 500-520 g, about 95% of Lofepramine Maleate.
EXAMPLE 1 : Preparation of Lofepramine Base:
Lofepramine Base prepared as per the procedure described in US Patent no: 4,172074 (1979). Instead of ethyl acetate, t-butyl methyl ether (1:10-15 by Desipramine W/W) is used as solvent for the reaction and the Lofepramine base thus obtained is purified before use. Thus 100 g Lofepramine obtained from the
above method is dissolved in ethyl acetate/acetone (150-300 ml) and added to cooled methanol (500 mL) and stirred at 5-1O°C for 1h. The crystals separated were filtered and dried at 35-45°C for 2-3 h to get 65-75 g pure white crystalline Lofepramine Base. Purity by HPLC: Min 99.5% (BP2004 method used for Lofepramine Hydrochloride). The above method removes both polar and non- polar impurities present in the crude Lofepramine Base obtained from the above procedure.
EXAMPLE 2: Preparation of Lofepramine Maleate:
Maleic acid (116 g) dissolved in ethyl acetate (1500 mL) by warming up to 50- 6O°C and filtered hot. To this clear solution of maleic acid in ethyl acetate (under nitrogen atmosphere), Lofepramine base (420 g) was added all at once and warmed up to 40-60°C. Lofepramine base initially dissolves and re-precipitates as Lofepramine Maleate in about 5 min., which is stirred at room temperature for 1 h and filtered. Dried at 45-55°C for 5-6 h to get 500-520 g, about 95% of Lofepramine Maleate.
Claims
1. A stable salt of Lofepramine.
2. The stable salt as claimed in claim 1 wherein the salt is Lofepramine Maleate.
3. A process for the synthesis of stable Lofepramine maleate comprising; dissolving maleic acid in ethyl acetate by warming and the solution is then filtered hot; adding purified Lofepramine base to the said clear solution of maleic acid and heated upto about 40-60°C; filtering the precipitates of Lofepramine maleate; drying the said precipitates at 45 to 55°C to obtain Lofepramine maleate.
4. The process as claimed in claim 3, wherein said purified Lofepramine base is obtained comprising; dissolving Lofepramine base in an organic solvent; adding the said Lofepramine base solution to cooled methanol and stirred; subjecting the mixture to the step of filtration and drying to obtain purified
Lofepramine base;
5. The process as claimed in claim 4 wherein the organic solvent is selected from any ester and aliphatic Keton.
6. The process as claimed in claim 5 wherein said organic solvent is selected form ethyl acetate and acetone.
7. The process as claimed in claim 4, wherein said mixture is stirred for about 1 hour at 5 to 10°C.
8. The process as claimed in claim 3, wherein said Lofepramine base is dried at 35 to 45°C for 2 to 3 hours.
9. The process as claimed in claim 3, wherein Lofepramine base initially dissolves in the ethyl acetate and maleic acid solution and then precipitates as Lofepramine Maleate is about 5 minutes.
1O.The process as claimed in claim 3, wherein said Lofepramine Maleate precipitates is dried at 45-55°C for 5-6 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2007/000195 WO2008139484A2 (en) | 2007-05-16 | 2007-05-16 | New process for the synthesis of loferpramine maleate: a stable salt of loferpramine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2007/000195 WO2008139484A2 (en) | 2007-05-16 | 2007-05-16 | New process for the synthesis of loferpramine maleate: a stable salt of loferpramine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2008139484A2 true WO2008139484A2 (en) | 2008-11-20 |
| WO2008139484A3 WO2008139484A3 (en) | 2009-09-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2007/000195 WO2008139484A2 (en) | 2007-05-16 | 2007-05-16 | New process for the synthesis of loferpramine maleate: a stable salt of loferpramine |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020061649A1 (en) | 2018-09-28 | 2020-04-02 | Griffith University | Agents and methods for modulating pathogen activity |
| WO2022093904A1 (en) * | 2020-10-27 | 2022-05-05 | Trevena, Inc. | Crystalline and amorphous forms of a delta-opioid modulator |
| US11912713B2 (en) | 2017-02-17 | 2024-02-27 | Trevena, Inc. | 7-membered aza-heterocyclic containing delta-opioid receptor modulating compounds, methods of using and making the same |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0575370B1 (en) * | 1991-03-13 | 1996-04-24 | SCHULER, Wilhelm | Process for the purification of lofepramine by crystallisation |
| WO2003015699A2 (en) * | 2001-08-17 | 2003-02-27 | Epicept Corporation | Topical compositions and methods for treating pain |
-
2007
- 2007-05-16 WO PCT/IN2007/000195 patent/WO2008139484A2/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0575370B1 (en) * | 1991-03-13 | 1996-04-24 | SCHULER, Wilhelm | Process for the purification of lofepramine by crystallisation |
| WO2003015699A2 (en) * | 2001-08-17 | 2003-02-27 | Epicept Corporation | Topical compositions and methods for treating pain |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11912713B2 (en) | 2017-02-17 | 2024-02-27 | Trevena, Inc. | 7-membered aza-heterocyclic containing delta-opioid receptor modulating compounds, methods of using and making the same |
| WO2020061649A1 (en) | 2018-09-28 | 2020-04-02 | Griffith University | Agents and methods for modulating pathogen activity |
| EP4295864A2 (en) | 2018-09-28 | 2023-12-27 | Research Institute at Nationwide Children's Hospital | Phenylpropionic acid derivatives for modulating pathogen activity |
| WO2022093904A1 (en) * | 2020-10-27 | 2022-05-05 | Trevena, Inc. | Crystalline and amorphous forms of a delta-opioid modulator |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008139484A3 (en) | 2009-09-24 |
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