WO2021023634A1 - PROCESS FOR THE SYNTHESIS OF PITOLISANT HCl - Google Patents
PROCESS FOR THE SYNTHESIS OF PITOLISANT HCl Download PDFInfo
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- WO2021023634A1 WO2021023634A1 PCT/EP2020/071581 EP2020071581W WO2021023634A1 WO 2021023634 A1 WO2021023634 A1 WO 2021023634A1 EP 2020071581 W EP2020071581 W EP 2020071581W WO 2021023634 A1 WO2021023634 A1 WO 2021023634A1
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- pitolisant
- process according
- tetrahydrofuran
- carbonate
- nonan
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
Definitions
- the present invention relates to a process for the preparation of pitolisant hydrochloride.
- the yields of said process are low on the whole: 60% for the first step and 56% for the second.
- One disadvantageous aspect relates to the use of crown ether (15-crown-5) to promote the deprotonation of compound (4) by sodium hydride during the second step; said reagent is rather expensive, and it can be difficult to remove during the work-up steps.
- the reagent 3-(4-chlorophenyl)propyl methanesulphonate (5) always used in the second step, has a very high cost.
- WO200684833 A1 discloses a synthesis of pitolisant HC1 (I) similar to that
- CN103435575 discloses the synthesis of pitolisant HC1 (I) and production of the intermediate 3-(4-chlorophenyl)propyl methanesulphonate (5), starting from 3-(4-chlorophenyl)propanoic acid, as indicated in Scheme 4.
- a further approach used in the synthesis of pitolisant HC1 (I) disclosed in CN104447620 involves the synthesis of a bromo- (9) or chloro-substituted intermediate (10), which is subsequently used to generate pitolisant base (6) by nucleophilic substitution reaction with 3-(4-chlorophenyl)propan-l-ol (11), followed by salification to give pitolisant HC1 (I) (Scheme 5).
- One of the drawbacks of said process relates to the first step, because the reaction of piperidine (2) with a bis-halogen derivative can lead to the formation of dimeric by products of the reaction which are difficult to remove during the work-up steps.
- a further drawback relates to the use of toxic solvents, such as dimethylformamide or dimethylacetamide, during the second step.
- the object of the present invention is a novel process for the synthesis of pitolisant HC1 (I) from piperidine (2) and l-bromo-3-chloropropane (8). Both reagents are commercially available, and were reacted in such a way as to obtain the bromide salt of
- Spiro derivative (12) undergoes selective opening by 3-(4-chlorophenyl)propan-l- ol (11), which is commercially available or easily obtainable by known procedures (CN103435575), in the presence of an inorganic base.
- the opening of spiro ring (12) is followed by a simple acid work-up that produces, in a single step with a high yield, pitolisant HC1 (I), which can subsequently be purified by crystallisation or trituration.
- the spiro derivative 4-azaspiro[3.5]nonan-4-ium bromide (12) is synthesised from piperidine (2) and l-bromo-3-chloropropane (8) with a high yield. The product is recovered by a simple work-up.
- the process is conducted in the presence of an inorganic base easily removed by filtration, preferably selected from hydroxides or carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, calcium carbonate, calcium bicarbonate, caesium carbonate, potassium
- bicarbonate and sodium bicarbonate preferably potassium carbonate.
- the process is conducted in an inert environment, preferably in a nitrogen or argon atmosphere, at temperatures ranging from 20°C to 120°C, preferably from 30 to 90°C.
- the solvents used can be aprotic apolar solvents such as n-heptane, toluene and xylene, or polar aprotic solvents such as acetone, acetonitrile, methyl isobutyl ketone, methyl ethyl ketone, dimethylformamide, dimethylsulphoxide, dimethylacetamide, n-butyl acetate, isobutyl acetate, tert-butyl acetate and tetrahydrofuran, preferably acetonitrile and xylene.
- aprotic apolar solvents such as n-heptane, toluene and xylene
- polar aprotic solvents such as acetone, acetonitrile, methyl
- Opening of the spiro ring 4-azaspiro[3.5]nonan-4-ium bromide (12) by 3-(4- chlorophenyl)propan-l-ol (11) is effected by means of a nucleophilic addition reaction.
- the process is conducted in the presence of an easily removable inorganic and/or organic base, preferably selected from hydroxides or carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, calcium carbonate, calcium bicarbonate, caesium carbonate, potassium bicarbonate and sodium bicarbonate, preferably potassium tert-butoxide.
- hydroxides or carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, calcium carbonate, calcium bicarbonate, caesium carbonate, potassium bicarbonate and sodium bicarbonate, preferably potassium tert-butoxide.
- the process is conducted in an inert environment, preferably in a nitrogen or argon atmosphere, at temperatures ranging from 5°C to 70°C, preferably from 15 to 50°C.
- the solvents used can be aprotic apolar solvents such as n-heptane, toluene and xylene, or polar aprotic solvents such as acetone, acetonitrile, methyl isobutyl ketone, methyl ethyl ketone, dimethylformamide, dimethylsulphoxide, dimethylacetamide, n-butyl acetate, isobutyl acetate, tert-butyl acetate, tetrahydrofuran and 2-methyl-tetrahydrofuran, preferably tetrahydrofuran.
- l-bromo-3-chloropropane (8) is dissolved in 2-50 volumes, preferably 2-25 volumes, of a suitable aprotic apolar solvent, preferably acetonitrile.
- a suitable aprotic apolar solvent preferably acetonitrile.
- the mixture is left under stirring for a time ranging from 0.5 to 2.5 hours, preferably from 0.5 to 2 hours, at a temperature ranging from +10 to +100°C, preferably from +30 to +90°C.
- the process disclosed is advantageous because it enables pitolisant HC1 (I) to be obtained in only two steps; the process is easily scaled-up to an industrial scale, and is preferable to the known processes in terms of cost-effectiveness.
Abstract
Disclosed is a process for the synthesis of pitolisant HCl of formula (I), from piperidine and 1-bromo-3-chloropropane. The process according to the invention is economically efficient and easily industrially scalable.
Description
PROCESS FOR THE SYNTHESIS OF PITOLISANT HC1
The present invention relates to a process for the preparation of pitolisant hydrochloride.
BACKGROUND TO THE INVENTION
The known processes for the preparation of pitolisant HC1 (I) are mainly characterised by multi-step reactions involving a number of drawbacks, such as poor cost-effectiveness and low yield (Eur. J. Pharm. Sci. 13 (2001) 249-259;
WO200684833A1; W0200706708A1; CN103435575; CN104447620).
Eur. J. Pharm. Sci. 13 (2001) 249-259 describes a method for obtaining pitolisant base (6) from piperidine (2) and 3-chloropropanol (3), in the presence of potassium iodide, to give the intermediate 3-(piperidin-l-yl)propan-l-ol (4), which is used in the reaction with the commercially available compound 3-(4-chlorophenyl)propyl methanesulphonate (5) to obtain pitolisant base (6) (Scheme 1).
The yields of said process are low on the whole: 60% for the first step and 56% for the second. One disadvantageous aspect relates to the use of crown ether (15-crown-5) to promote the deprotonation of compound (4) by sodium hydride during the second step; said reagent is rather expensive, and it can be difficult to remove during the work-up steps. Moreover, the reagent 3-(4-chlorophenyl)propyl methanesulphonate (5), always used in the second step, has a very high cost. These two aspects make the process particularly disadvantageous.
WO200684833 A1 discloses a synthesis of pitolisant HC1 (I) similar to that
reported in Eur. J. Pharm. Sci. 13 (2001) 249-259. The process involves three steps, starting with piperidine (2) and 3-chloropropanol (3), to give the intermediate 3-(piperidin-l-yl)propan-l-ol (4), which is reacted with 3-(4-chlorophenyl)propyl methanesulphonate (5) to give pitolisant base (6), which is finally salified with gaseous hydrochloric acid to give pitolisant HC1 (I), as reported in Scheme 2.
The economic drawbacks deriving from the use of crown ether (15-crown-5) and 3-(4-chlorophenyl)propyl methanesulphonate (5), as described above, are also present in this process, which is even more disadvantageous because of the low yield of the last step, not exceeding a total of 40%. W0200706708 discloses the production of pitolisant base (6) in a very similar way to that reported in the two references cited above; the process involves a nucleophilic substitution reaction between 3-(piperidin-l-yl)propan-l-ol (4) and 3-(4-chlorophenyl)propyl methanesulphonate (5), to give pitolisant base (6) (Scheme 3).
The significant drawbacks of this process relate to the use of the very expensive reagent 3-(4-chlorophenyl)propyl methanesulphonate (5) and the use of dimethylacetamide, the toxicity of which makes its use inadvisable during the final synthesis steps in the production of an active ingredient. CN103435575 discloses the synthesis of pitolisant HC1 (I) and production of the intermediate 3-(4-chlorophenyl)propyl methanesulphonate (5), starting from 3-(4-chlorophenyl)propanoic acid, as indicated in Scheme 4.
The main drawback of said process relates to the large number of steps, a total of five, which make the process unproductive and poorly cost-effective. Moreover, dimethylacetamide is also used in this case.
A further approach used in the synthesis of pitolisant HC1 (I) disclosed in CN104447620 involves the synthesis of a bromo- (9) or chloro-substituted intermediate (10), which is subsequently used to generate pitolisant base (6) by nucleophilic substitution reaction with 3-(4-chlorophenyl)propan-l-ol (11), followed by salification to give pitolisant HC1 (I) (Scheme 5).
One of the drawbacks of said process relates to the first step, because the reaction of piperidine (2) with a bis-halogen derivative can lead to the formation of dimeric by products of the reaction which are difficult to remove during the work-up steps. A further drawback relates to the use of toxic solvents, such as dimethylformamide or dimethylacetamide, during the second step.
DESCRIPTION OF THE INVENTION
The object of the present invention is a novel process for the synthesis of pitolisant HC1 (I) from piperidine (2) and l-bromo-3-chloropropane (8). Both reagents are commercially available, and were reacted in such a way as to obtain the bromide salt of
the spiro intermediate 4-azaspiro[3.5]nonan-4-ium (12; Scheme 6). Intermediate (12) is novel, and constitutes a further object of the invention.
Spiro derivative (12) undergoes selective opening by 3-(4-chlorophenyl)propan-l- ol (11), which is commercially available or easily obtainable by known procedures (CN103435575), in the presence of an inorganic base. The opening of spiro ring (12) is followed by a simple acid work-up that produces, in a single step with a high yield, pitolisant HC1 (I), which can subsequently be purified by crystallisation or trituration.
The process is cost-effective because piperidine and l-bromo-3-chloropropane are readily available and very cheap. Moreover, the process according to the invention, unlike the procedures reported in WO200684833 and W0200706708, does not require the use of the extremely expensive compound 3-(4-chlorophenyl)propyl methanesulphonate (5); the process involves the use of 3-(4-chlorophenyl)propan-l-ol (11), which is not only much less expensive, but used in the last step with excellent yields.
DETAILED DESCRIPTION OF THE INVENTION
The spiro derivative 4-azaspiro[3.5]nonan-4-ium bromide (12) is synthesised from piperidine (2) and l-bromo-3-chloropropane (8) with a high yield. The product is recovered by a simple work-up.
The process is conducted in the presence of an inorganic base easily removed by filtration, preferably selected from hydroxides or carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, calcium carbonate, calcium bicarbonate, caesium carbonate, potassium
bicarbonate and sodium bicarbonate, preferably potassium carbonate.
The process is conducted in an inert environment, preferably in a nitrogen or argon atmosphere, at temperatures ranging from 20°C to 120°C, preferably from 30 to 90°C. The solvents used can be aprotic apolar solvents such as n-heptane, toluene and xylene, or polar aprotic solvents such as acetone, acetonitrile, methyl isobutyl ketone, methyl ethyl ketone, dimethylformamide, dimethylsulphoxide, dimethylacetamide, n-butyl acetate, isobutyl acetate, tert-butyl acetate and tetrahydrofuran, preferably acetonitrile and xylene. Opening of the spiro ring 4-azaspiro[3.5]nonan-4-ium bromide (12) by 3-(4- chlorophenyl)propan-l-ol (11) is effected by means of a nucleophilic addition reaction.
The process is conducted in the presence of an easily removable inorganic and/or organic base, preferably selected from hydroxides or carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, calcium carbonate, calcium bicarbonate, caesium carbonate, potassium bicarbonate and sodium bicarbonate, preferably potassium tert-butoxide.
The process is conducted in an inert environment, preferably in a nitrogen or argon atmosphere, at temperatures ranging from 5°C to 70°C, preferably from 15 to 50°C. The solvents used can be aprotic apolar solvents such as n-heptane, toluene and xylene, or polar aprotic solvents such as acetone, acetonitrile, methyl isobutyl ketone, methyl ethyl ketone, dimethylformamide, dimethylsulphoxide, dimethylacetamide, n-butyl acetate, isobutyl acetate, tert-butyl acetate, tetrahydrofuran and 2-methyl-tetrahydrofuran, preferably tetrahydrofuran. Typically, 1 mole of l-bromo-3-chloropropane (8) is dissolved in 2-50 volumes, preferably 2-25 volumes, of a suitable aprotic apolar solvent, preferably acetonitrile. 0.8-6 equivalents, preferably 0.8-4 equivalents, of an inorganic base, preferably potassium carbonate, are added to the resulting solution. The mixture is left under stirring for a time
ranging from 0.5 to 2.5 hours, preferably from 0.5 to 2 hours, at a temperature ranging from +10 to +100°C, preferably from +30 to +90°C.
0.8-2 Equivalents, preferably 1.0-1.75 equivalents, of piperidine (2) are added, and the mixture thus obtained is conditioned until the reaction is complete. The resulting mixture is filtered and concentrated under vacuum until 4-azaspiro[3.5]nonan-4-ium bromide (12) is obtained.
1 mole of 3-(4-chlorophenyl)propan-l-ol (11) is then dissolved in 2-50 volumes, preferably 2-30 volumes, of a suitable polar aprotic solvent, preferably tetrahydrofuran. 0.8-6 equivalents, preferably 0.8-4.5 equivalents, of a suitable organic base, preferably potassium tert-butoxide, are added to the resulting mixture, followed by 0.8-5 equivalents, preferably 1-3 equivalents, of 4-azaspiro[3.5]nonan-4-ium bromide (12). The resulting mixture is conditioned to a temperature ranging from +10 to +100°C, preferably from +15 to 50°C, until the reaction is complete. The mixture undergoes a mild acid work-up, and the organic phase is concentrated under vacuum to obtain crude pitolisant HC1, which is purified by known methods.
Pitolisant HC1 (I) is prepared during the work-up steps, and the end product can be purified by known crystallisation or trituration procedures.
The process disclosed is advantageous because it enables pitolisant HC1 (I) to be obtained in only two steps; the process is easily scaled-up to an industrial scale, and is preferable to the known processes in terms of cost-effectiveness.
The invention will now be illustrated in detail by the following examples.
The order of addition of the solvents and reagents may differ from that reported below.
Example 1 - 4-azaspiro[3.5]nonan-4-ium bromide (12)
25.0 g of l-bromo-3-chloropropane (0.165 moles) is dissolved in acetonitrile (100 mL). 22.7 g of potassium carbonate (0.165 moles) is then added. The resulting mixture is heated to 60°C, and left under stirring for 10 minutes. 10 g of piperidine (0.117 moles) is then added, and the mixture is left under stirring until the reaction is
complete. The mixture is cooled and filtered under vacuum, and the solid filtrate is washed with acetonitrile (100 mL).
The organic phase is concentrated under vacuum to give 22 g of 4-azaspiro[3.5]nonan-4-ium bromide (12) (orange oil; yield: 92%). ¾ NMR (DMSO-d6) d: 4.31 - 4.12 (m, 4H, 7, 9), 3.50 (t, J = 5.7 Hz, 4H, 4, 6),
2.47 (p, J = 8.3 Hz, 2H, 8), 1.67 (p, J = 5.7 Hz, 4H, 1, 3), 1.46 (p, J = 6.0 Hz, 2H, 2)
13NMR (DMSO-d6) d: 62.1, 59.8, 26.0, 20.8, 13.8.
Example 2 - Pitolisant HC1 (I)
1.0 g of 3-(4-chlorophenyl)propan-l-ol (11) (5.8 mmols) is dissolved in tetrahydrofuran (10 mL). 0.72 g of potassium tert-butoxide (6.4 mmols) is then added. The resulting solution is stirred for 30 minutes, after which 1.8 g of 4-azaspiro[3.5]nonan- 4-ium bromide (12) (8.8 mmol) is added, and the mixture is left under stirring until the reaction is complete. The mixture is cooled and diluted with dichloromethane (50 mL). The organic phase is then washed three times with IN aqueous hydrochloric acid. The organic phase is concentrated under vacuum to give 1.75 g of crude pitolisant HC1 (I) (pale yellow solid; yield: 90%). The crude pitolisant HC1 (I) is purified by known methods.
¾ (chloroform-d) d: 11.93 (s, 1H), 7.26 - 7.20 (m, 2H), 7.13 - 7.06 (m, 2H), 3.55 - 3.45 (m, 4H), 3.39 (t, J = 6.3 Hz, 2H), 3.06 - 2.94 (m, 2H), 2.70 - 2.55 (m, 4H), 2.35 - 2.10 (m, 4H), 1.83 (dddd, J = 12.9, 8.8, 5.3, 2.5 Hz, 5H), 1.41 (qt, J = 11.4, 3.1 Hz, 1H).
13NMR (chloroform-d) d: 140.3, 131.4, 129.8, 128.4, 70.2, 7.5, 55.5, 53.3, 31.8, 30.9, 24.1, 22.5, 22.
Claims
1. A process for the synthesis of pitolisant HC1 (I) which comprises: a) reacting piperidine and l-bromo-3-chloropropane in the presence of an inorganic base to give 4-azaspiro[3.5]nonan-4-ium bromide (12); b). reacting 4-azaspiro[3.5]nonan-4-ium bromide (12) with
3-(4-chlorophenyl)propan-l-ol in the presence of an inorganic base and treating with hydrochloric acid.
2. The process according to claim 1 wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, calcium carbonate, calcium bicarbonate, caesium carbonate, potassium bicarbonate and sodium bicarbonate, preferably potassium carbonate.
3. The process according to claim 1 or 2 wherein step a is effected under nitrogen or argon atmosphere at temperatures ranging from 20°C to 120°C, preferably from 30 to 90°C, in an apolar or polar aprotic solvent.
4. The process according to claim 3 wherein the solvents are selected from n-heptane, toluene, xylene, acetone, acetonitrile, methyl isobutyl ketone, methyl ethyl ketone, dimethylformamide, dimethylsulphoxide, dimethylacetamide, n-butyl acetate, isobutyl acetate, tert-butyl acetate and tetrahydrofuran, preferably acetonitrile and xylene.
5. The process according to any one of claims 1-4 wherein step b) is effected under nitrogen or argon atmosphere at temperatures ranging from 5°C to 70°C, preferably from
15 to 50°C, in an apolar or polar aprotic solvent.
6. The process according to claim 5 wherein the solvents are selected from n-heptane, toluene, xylene, acetone, acetonitrile, methyl isobutyl ketone, methyl ethyl ketone, dimethylformamide, dimethylsulphoxide, dimethylacetamide, n-butyl acetate, isobutyl acetate, tert-butyl acetate, tetrahydrofuran and 2-methyl-tetrahydrofuran, preferably tetrahydrofuran.
7. 4-Azaspiro[3.5]nonan-4-ium bromide (12).
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IT102019000013941A IT201900013941A1 (en) | 2019-08-05 | 2019-08-05 | PROCESS FOR THE SYNTHESIS OF PITOLISANT HCl |
IT102019000013941 | 2019-08-05 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11623920B2 (en) | 2021-06-07 | 2023-04-11 | Nuray Chemicals Private Limited | Process for preparing pitolisant hydrochloride and solid-state forms thereof |
WO2023214431A1 (en) * | 2022-05-04 | 2023-11-09 | Msn Laboratories Private Limited, R&D Center | A pharmaceutical composition of pitolisant hydrochloride and their process for the preparation |
US11945788B2 (en) | 2021-06-07 | 2024-04-02 | Nuray Chemicals Private Limited | Process for preparing pitolisant hydrochloride and solid-state forms thereof |
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WO2006084833A1 (en) | 2005-02-10 | 2006-08-17 | Bioprojet | Monohydrochloride salt of 1- [3- [3- (4-chlorophenyl) propoxy] propyl] -piperidine |
WO2007006708A1 (en) | 2005-07-08 | 2007-01-18 | Bioprojet | Process for preparing 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine |
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 |
-
2019
- 2019-08-05 IT IT102019000013941A patent/IT201900013941A1/en unknown
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2020
- 2020-07-30 WO PCT/EP2020/071581 patent/WO2021023634A1/en active Application Filing
Patent Citations (4)
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WO2006084833A1 (en) | 2005-02-10 | 2006-08-17 | Bioprojet | Monohydrochloride salt of 1- [3- [3- (4-chlorophenyl) propoxy] propyl] -piperidine |
WO2007006708A1 (en) | 2005-07-08 | 2007-01-18 | Bioprojet | Process for preparing 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine |
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 |
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EUR. J. PHARM. SCI., vol. 13, 2001, pages 249 - 259 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
WO2023214431A1 (en) * | 2022-05-04 | 2023-11-09 | Msn Laboratories Private Limited, R&D Center | A pharmaceutical composition of pitolisant hydrochloride and their process for the preparation |
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