WO2007006708A1 - Process for preparing 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine - Google Patents
Process for preparing 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine Download PDFInfo
- Publication number
- WO2007006708A1 WO2007006708A1 PCT/EP2006/063927 EP2006063927W WO2007006708A1 WO 2007006708 A1 WO2007006708 A1 WO 2007006708A1 EP 2006063927 W EP2006063927 W EP 2006063927W WO 2007006708 A1 WO2007006708 A1 WO 2007006708A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- chlorophenyl
- propyl
- propoxy
- piperidine
- iii
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Definitions
- the present invention relates to a process for preparing 1- [3- [3- (4-chlorophenyl) propoxy] propyl] -piperidine .
- EP 982300 discloses the preparation of said compound in a heterogeneous phase, which comprises the use of crown ether phase transfer catalysts, resulting in an inappropriate industrial process because of its high cost and toxicity.
- compound (I) obtained according to the prior art method yields an improper purity profile to be used directly in the preparation of pharmaceutically acceptable salts thereof.
- the present invention discloses a process for preparing 1- [3- [3- (4-chlorophenyl) propoxy] propyl] -piperidine (I) which is more efficient than the process reported in the prior art.
- a sufficiently pure free base compound is obtained, which can then be used directly in the manufacturing of pharmacologically acceptable salts thereof, without any isolation or subsequent purification steps .
- the present invention also circumvents phase transfer catalysts thus providing a more convenient industrial process. Also, operating temperatures in the process of the present invention are lower than in the heterogeneous phase reaction disclosed in the prior art. In fact, in the present invention, reaction occurs at room temperature, i.e. 20-25°C, in contrast to 80-110°C needed in the prior art process. Such new smoother reaction conditions generate less impurities than those appearing in processes already described.
- the present invention comprises a process for the manufacture of 1- [3- [3- (4-chlorophenyl) propoxy] propyl] - piperidine (I) , which involves the formation of 3- piperidinopropanol (II) sodium salt in an aprotic polar solvent and subsequent reaction with 3- (4- chlorophenyl) propyl mesylate (III), according to Scheme 1.
- the aprotic polar solvent is selected from N,N-dimethylformamide, N, N- dimethylacetamide, l-methyl-2-pyrrolidone, l-methyl-2- piperidone, 1, 3-dimethyl-2-imidazolidinone, and the like, and mixtures thereof.
- molecular equivalents of both sodium hydride and 3- (4- chlorophenyl) propyl mesylate (III) are used in excess to the molecular equivalents of 3-piperidinopropanol (II) .
- the quantity of sodium hydride is from about 1.1 to about 2.0 molecular equivalents, more preferably from about 1.4 to about 1.7.
- 3- (4- chlorophenyl) propyl mesylate (III) the quantity thereof is from about 1.1 to about 2.0 molecular equivalents, preferably from about 1.2 to about 1.5. Accordingly, the excess of sodium hydride assures that 3- piperidinopropanol (II) remains as its reactive sodium salt specie.
- 3- (4-chlorophenyl) propyl mesylate (III) should be in excess because of its chemical lability.
- reaction of the sodium salt of compound (II) with compound (III) is performed at room temperature (i.e. 20-25°C) .
- the limiting reactant 3-piperidinopropanol (II) is fully converted, thus providing 1- [3- [3- (4-chlorophenyl) propoxy] propyl] - piperidine (I) as the unique nitrogen-bearing compound obtained.
- 3-piperidinopropanol (1 Kg, 6.98 mol) was dissolved in anhydrous N,N-dimethylacetamide (8.8 L) under a nitrogen atmosphere. Then sodium hydride 60% (0.449 Kg, 11.23 mol) was slowly added. The mixture was heated at 50°C for 1 hour with stirring. Then the mixture was cooled at 25°C and a solution of 3- (4-chlorophenyl) propyl mesylate (2.08 Kg, 8.36 mol) in anhydrous N,N-dimethylacetamide (3.5 L) was added for 2 hours . The mixture was stirred for 7 hours at 22°C.
Abstract
The present invention relates to a process for preparing 1- [3- [3- (4-chlorophenyl) propoxy] propyl] -piperidine (I) by reaction of 3-piperidinopropanol (II) with sodium hydride in an aprotic polar solvent and further reaction with 3- (4-chlorophenyl) propyl mesylate (III).
Description
Process for preparing 1- [3- [3- (4-chlorophenyl)propoxy] propyl] -piperidine
Field of the invention
The present invention relates to a process for preparing 1- [3- [3- (4-chlorophenyl) propoxy] propyl] -piperidine .
Background of the invention
1- [3- [3- (4-chlorophenyl) propoxy] propyl] -piperidine belongs to the pharmacological class of ligands of histamine H3 receptors and has the structural formula
(D :
The specification EP 982300 discloses the preparation of said compound in a heterogeneous phase, which comprises the use of crown ether phase transfer catalysts, resulting in an inappropriate industrial process because of its high cost and toxicity.
Moreover, compound (I) obtained according to the prior art method yields an improper purity profile to be used directly in the preparation of pharmaceutically acceptable salts thereof.
The purification of compound (I) obtained according to the prior art process would require an additional column chromatography and/or a molecular distillation process. Column chromatography techniques are not widely used in manufacturing processes, partly because of the large
quantities of solvents needed, which may result in environmental problems . On the other hand, fractioned distillation of compound (I) is not convenient because of its high boiling point (180°C / 0.01 mmHg) . This fact forces to use a molecular distillation equipment, which limits its industrial feasibility.
Description of the invention
The present invention discloses a process for preparing 1- [3- [3- (4-chlorophenyl) propoxy] propyl] -piperidine (I) which is more efficient than the process reported in the prior art. Thus, by using reaction conditions in a homogeneous phase, a sufficiently pure free base compound is obtained, which can then be used directly in the manufacturing of pharmacologically acceptable salts thereof, without any isolation or subsequent purification steps .
The present invention also circumvents phase transfer catalysts thus providing a more convenient industrial process. Also, operating temperatures in the process of the present invention are lower than in the heterogeneous phase reaction disclosed in the prior art. In fact, in the present invention, reaction occurs at room temperature, i.e. 20-25°C, in contrast to 80-110°C needed in the prior art process. Such new smoother reaction conditions generate less impurities than those appearing in processes already described.
The present invention comprises a process for the manufacture of 1- [3- [3- (4-chlorophenyl) propoxy] propyl] - piperidine (I) , which involves the formation of 3- piperidinopropanol (II) sodium salt in an aprotic polar solvent and subsequent reaction with 3- (4-
chlorophenyl) propyl mesylate (III), according to Scheme 1.
Scheme 1
In another embodiment, the aprotic polar solvent is selected from N,N-dimethylformamide, N, N- dimethylacetamide, l-methyl-2-pyrrolidone, l-methyl-2- piperidone, 1, 3-dimethyl-2-imidazolidinone, and the like, and mixtures thereof.
In another embodiment of the present invention process, molecular equivalents of both sodium hydride and 3- (4- chlorophenyl) propyl mesylate (III) are used in excess to the molecular equivalents of 3-piperidinopropanol (II) . Thus, the quantity of sodium hydride is from about 1.1 to about 2.0 molecular equivalents, more preferably from about 1.4 to about 1.7. Regarding 3- (4- chlorophenyl) propyl mesylate (III), the quantity thereof is from about 1.1 to about 2.0 molecular equivalents, preferably from about 1.2 to about 1.5. Accordingly, the excess of sodium hydride assures that 3- piperidinopropanol (II) remains as its reactive sodium salt specie. Likewise, 3- (4-chlorophenyl) propyl mesylate (III) should be in excess because of its chemical lability.
In another embodiment, the reaction of the sodium salt of compound (II) with compound (III) is performed at room temperature (i.e. 20-25°C) .
In the process of the present invention, the limiting reactant 3-piperidinopropanol (II) is fully converted, thus providing 1- [3- [3- (4-chlorophenyl) propoxy] propyl] - piperidine (I) as the unique nitrogen-bearing compound obtained.
Further washes of the aqueous phase containing the formed salt of 1- [3- [3- (4-chlorophenyl) propoxy] propyl] - piperidine (I) with an organic solvent removes all non nitrogen by-products, yielding a product (I) with a quality good enough to be used in subsequent process steps without any kind of purification.
Example 1: 1- [3- [3- (4-chlorophenyl) propoxy] propyl] - piperidine (I)
3-piperidinopropanol (1 Kg, 6.98 mol) was dissolved in anhydrous N,N-dimethylacetamide (8.8 L) under a nitrogen atmosphere. Then sodium hydride 60% (0.449 Kg, 11.23 mol) was slowly added. The mixture was heated at 50°C for 1 hour with stirring. Then the mixture was cooled at 25°C and a solution of 3- (4-chlorophenyl) propyl mesylate (2.08 Kg, 8.36 mol) in anhydrous N,N-dimethylacetamide (3.5 L) was added for 2 hours . The mixture was stirred for 7 hours at 22°C. Then the mixture was cooled at 10°C and a solution of sodium chloride (1.1 Kg) in water (13.3 L) was slowly added. After extraction of the aqueous phase several times with toluene, the organic extracts were combined and extracted with HCl (7 L, 2N) . The aqueous phase was then washed with toluene (1.75 L) . The aqueous phase was treated with sodium hydroxide (6N, 2.5 L) and taken to pH 12, and then extracted twice with 7 L of toluene. The toluene extracts were washed thrice with 7 L of water. Toluene was distilled at reduced pressure to
yield 1.99 Kg of 1- [3- [3- (4-chlorophenyl) propoxy] propyl] ■ piperidine (I) as an oil. Yield 99.3%. Purity (GC) 99.2%.
Claims
1. A process for the preparation of l-[3-[3-(4- chlorophenyl) propoxy] propyl] -piperidine (I) :
which comprises reaction of 3-piperidinopropanol (II) :
HO N
π
with sodium hydride to form the sodium salt of (II) wherein the quantity of sodium hydride is from about 1.1 to about 2.0 molecular equivalents, in an aprotic polar solvent and subsequent reaction with 3- (4- chlorophenyl) propyl mesylate (III) :
III
wherein the quantity of (III) is from about 1.1 to about 2.0 molecular equivalents .
2. A process according to claim 1 wherein the quantity of sodium hydride is from about 1.4 to about 1.7 molecular equivalents.
3. A process according to claim 1 wherein the quantity of compound (III) is from about 1.2 to about 1.5 molecular equivalents .
4. A process according to claim 1 wherein the aprotic polar solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, l-methyl-2-pyrrolidone, 1-methyl- 2-piperidone, 1, 3-dimethyl-2-imidazolidinone and mixtures thereof.
5. A process according to claim 4 wherein the aprotic polar solvent is N,N-dimethylacetamide .
6. A process according to claim 1 wherein the reaction of the sodium salt of (II) with (III) is performed at room temperature .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06764080A EP1910323A1 (en) | 2005-07-08 | 2006-07-05 | Process for preparing 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05106263.6 | 2005-07-08 | ||
| EP05106263 | 2005-07-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2007006708A1 true WO2007006708A1 (en) | 2007-01-18 |
Family
ID=36997559
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2006/063927 WO2007006708A1 (en) | 2005-07-08 | 2006-07-05 | Process for preparing 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1910323A1 (en) |
| AR (1) | AR054530A1 (en) |
| TW (1) | TWI382975B (en) |
| WO (1) | WO2007006708A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103435575A (en) * | 2013-08-06 | 2013-12-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Preparation method of 1-(3-(3-(4-chlorphenyl) propoxy) propyl) piperidine hydrochloride |
| CN104447620A (en) * | 2014-11-28 | 2015-03-25 | 瑞阳制药有限公司 | Preparation method of 1-[3-[3-(4-chlorphenyl) propoxy] propyl]-piperidine hydrochloride |
| EP3239138A1 (en) | 2016-04-25 | 2017-11-01 | Sandoz Ag | Hydrogen fumarate salt of 1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine |
| IT201900013941A1 (en) | 2019-08-05 | 2021-02-05 | Procos Spa | PROCESS FOR THE SYNTHESIS OF PITOLISANT HCl |
| US11623920B2 (en) | 2021-06-07 | 2023-04-11 | Nuray Chemicals Private Limited | Process for preparing pitolisant hydrochloride and solid-state forms thereof |
| US11945788B2 (en) | 2021-06-07 | 2024-04-02 | Nuray Chemicals Private Limited | Process for preparing pitolisant hydrochloride and solid-state forms thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000006254A2 (en) * | 1998-07-29 | 2000-02-10 | Societe Civile Bioprojet | Non-imidazole alkylamines as histamine h3-receptor ligands and their therapeutic applications |
-
2006
- 2006-07-03 AR ARP060102863 patent/AR054530A1/en not_active Application Discontinuation
- 2006-07-04 TW TW95124239A patent/TWI382975B/en active
- 2006-07-05 EP EP06764080A patent/EP1910323A1/en not_active Withdrawn
- 2006-07-05 WO PCT/EP2006/063927 patent/WO2007006708A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000006254A2 (en) * | 1998-07-29 | 2000-02-10 | Societe Civile Bioprojet | Non-imidazole alkylamines as histamine h3-receptor ligands and their therapeutic applications |
Non-Patent Citations (1)
| Title |
|---|
| MEIER GALINA ET AL: "Influence of imidazole replacement in different structural classes of histamine H3-receptor antagonists", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, ELSEVIER, AMSTERDAM, NL, vol. 13, no. 3, June 2001 (2001-06-01), pages 249 - 259, XP002269929, ISSN: 0928-0987 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103435575A (en) * | 2013-08-06 | 2013-12-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Preparation method of 1-(3-(3-(4-chlorphenyl) propoxy) propyl) piperidine hydrochloride |
| CN104447620A (en) * | 2014-11-28 | 2015-03-25 | 瑞阳制药有限公司 | Preparation method of 1-[3-[3-(4-chlorphenyl) propoxy] propyl]-piperidine hydrochloride |
| EP3239138A1 (en) | 2016-04-25 | 2017-11-01 | Sandoz Ag | Hydrogen fumarate salt of 1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine |
| IT201900013941A1 (en) | 2019-08-05 | 2021-02-05 | Procos Spa | PROCESS FOR THE SYNTHESIS OF PITOLISANT HCl |
| WO2021023634A1 (en) | 2019-08-05 | 2021-02-11 | Procos S.P.A. | PROCESS FOR THE SYNTHESIS OF PITOLISANT HCl |
| US11623920B2 (en) | 2021-06-07 | 2023-04-11 | Nuray Chemicals Private Limited | Process for preparing pitolisant hydrochloride and solid-state forms thereof |
| US11945788B2 (en) | 2021-06-07 | 2024-04-02 | Nuray Chemicals Private Limited | Process for preparing pitolisant hydrochloride and solid-state forms thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| TWI382975B (en) | 2013-01-21 |
| TW200736238A (en) | 2007-10-01 |
| AR054530A1 (en) | 2007-06-27 |
| EP1910323A1 (en) | 2008-04-16 |
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