NZ783764B2 - Processes and intermediate for the large-scale preparation of 2,4,6-trifluoro-n-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate, and preparation of 2,4,6-trifluoro-n-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide acetate - Google Patents
Processes and intermediate for the large-scale preparation of 2,4,6-trifluoro-n-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate, and preparation of 2,4,6-trifluoro-n-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide acetateInfo
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- NZ783764B2 NZ783764B2 NZ783764A NZ78376420A NZ783764B2 NZ 783764 B2 NZ783764 B2 NZ 783764B2 NZ 783764 A NZ783764 A NZ 783764A NZ 78376420 A NZ78376420 A NZ 78376420A NZ 783764 B2 NZ783764 B2 NZ 783764B2
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- New Zealand
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- treatment
- subsequent
- water
- methanone
- trifluoro
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/08—Acetic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/10—Succinic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The embodiments of present invention provide processes and an intermediate for the large-scale preparation of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate, and formulations and product forms made by these processes. The embodiments of the present invention further provide for the preparation of lasmiditan acetate, 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate salt, and/or pharmaceutical compositions thereof, and/or uses of lasmiditan acetate and formulations thereof in subcutaneous drug delivery.
Claims (19)
1. A process for preparing a compound of the formula: 5 comprising the steps of: i.) Treatment of piperidinecarboxylic acid under reductive amination conditions comprising formaldehyde and formic acid in water with subsequent treatment with aqueous HCl followed by water distillation and acetonitrile addition, with repeated dilution/distillation until the water 10 content is not more than 0.2% by Karl-Fischer analysis, to obtain solid 1- methylpiperidinecarboxylic acid hydrochloride; ii.) Treatment of 1-methylpiperidinecarboxylic acid hydrochloride with a chlorinating agent to obtain 1-methylpiperidinecarboxylic acid chloride; iii.) Treatment of 1-methylpiperidinecarboxylic acid chloride with N,N- diethylamine in chlorobenzene containing triethylamine with subsequent base wash and subsequent treatment with aqueous HCl in isopropanol to obtain solid N,N-diethylmethyl-piperidinecarboxamide hydrate 20 hydrochloride; iv.) Treatment of N,N-diethylmethyl-piperidinecarboxamide hydrate hydrochloride with a mineral base in a non-polar solvent with subsequent water wash, phase separation, and distillation of the organic solvent until the water content is not more than 0.1 weight t% by Karl Fischer analysis to obtain N,N-diethylmethyl-piperidinecarboxamide; v.) Subsequent treatment of N,N-diethylmethyl-piperidinecarboxamide 5 with (6-bromopyridyl)lithium in a non-polar organic solvent with subsequent extraction of the resulting mixture with water and a suitable organic solvent, phase separation, and repeated distillation of the organic solvent until the water content is not more than 0.2 weight % by Karl- Fischer analysis, to obtain (6-bromopyridyl)-(1-methyl 10 piperidyl)methanone; vi.) Treatment of (6-bromopyridyl)-(1-methylpiperidyl)methanone with aqueous HBr and subsequent extraction with n-butanol followed by repeated distillation of the organic solvent until the water content is not 15 more than 0.3% by Karl-Fischer analysis, to obtain solid (6-bromo pyridyl)-(1-methylpiperidyl)methanone hydrobromide; vii.) Treatment of (6-bromopyridylmethylpiperidyl)methanone hydrobromide with a solution of NH in ethylene glycol in the presence of 20 Cu O catalyst at about 80 C for about 2 hr, with subsequent washes with water, saturated aqueous NaCl, and 20% aqueous NaOH and subsequent extraction with a non-polar aprotic solvent, phase separation, and treatment of the organic phase with 5 weight % carbon; 25 viii.) Filtration of the above mixture, dilution with a suitable polar alcoholic solvent, and repeated distillation of the organic solvent until the water content is not more than 0.2% by Karl-Fischer analysis, with subsequent treatment of the resulting residue with isopropanol, water, and 20 weight % HCl, wherein the water concentration of the resulting slurry is at least 30 2%, filtration of the resulting slurry, and drying under vacuum at 40 C for 16-24 hr to obtain solid (6-aminopyridyl)-(1-methyl piperidyl)methanone dihydrate dihydrochloride; ix.) Treatment of (6-aminopyridyl)-(1-methylpiperidyl)methanone 5 dihydrate dihydrochloride in chlorobenzene with 6 weight/weight % NaOH in water at about 54 C for about 30 min, with subsequent phase separation and vacuum distillation of the aqueous solution to obtain (6- aminopyridyl)-(1-methylpiperidyl)methanone; 10 x.) Subsequent treatment of (6-aminopyridyl)-(1-methyl piperidyl)methanone with 2,4,6-trifluorobenzoic acid chloride in chlorobenzene at about 100 C for about 4 hr, with subsequent cooling, charging with acetonitrile and heating the resulting slurry to 80 C for about 1 hr, and subsequent collection of the resulting solid by filtration, to 15 obtain solid 2,4,6-trifluoro-N-[6-(1-methylpiperidinecarbonyl) pyridyl]benzamide hydrochloride; xi.) Treatment of 2,4,6-trifluoro-N-[6-(1-methylpiperidinecarbonyl) pyridyl]benzamide hydrochloride with saturated aqueous Na CO in 20 methyl-tert-butyl ether; xii.) Treatment of the mixture of step xi above with SiO with subsequent filtration, treatment with carbon, filtration, and evaporation, dilution with ethanol, and distillation until the water content is not more than 1% by 25 Karl-Fischer analysis, to obtain 2,4,6-trifluoro-N-[6-(1-methylpiperidine- 4-carbonyl)pyridyl]benzamide; xiii.) Treatment of 2,4,6-trifluoro-N-[6-(1-methylpiperidinecarbonyl) pyridyl]benzamide in ethanol with a solution of 0.5 equivalents succinic 30 acid in ethanol at about 55 C for not less than 3 hr at RT, and subsequent collection of the solid by filtration, to obtain solid 2,4,6-trifluoro-N-[6-(1- methylpiperidinecarbonyl)pyridyl]benzamide hemisuccinate.
2. A process for preparing a compound of the formula: comprising the steps of: i.) Treatment of piperidinecarboxylic acid under reductive amination conditions comprising formaldehyde and formic acid in water with 10 subsequent treatment with aqueous HCl followed by water distillation and acetonitrile addition, with repeated dilution/distillation until the water content is not more than 0.2% by Karl-Fischer analysis, to obtain solid 1- methylpiperidinecarboxylic acid hydrochloride; 15 ii.) Treatment of 1-methylpiperidinecarboxylic acid hydrochloride with a chlorinating agent to obtain 1-methylpiperidinecarboxylic acid chloride; iii.) Treatment of 1-methylpiperidinecarboxylic acid chloride with N,N- diethylamine in chlorobenzene containing triethylamine with subsequent 20 base wash and subsequent treatment with aqueous HCl in isopropanol to obtain solid N,N-diethylmethyl-piperidinecarboxamide hydrate hydrochloride; iv.) Treatment of N,N-diethylmethyl-piperidinecarboxamide hydrate hydrochloride with a mineral base in a non-polar solvent with subsequent water wash, phase separation, and distillation of the organic solvent until the water content is not more than 0.1 weight % by Karl Fischer analysis 5 to obtain N,N-diethylmethyl-piperidinecarboxamide; v.) Subsequent treatment of N,N-diethylmethyl-piperidinecarboxamide with (6-bromopyridyl)lithium in a non-polar organic solvent with subsequent extraction of the resulting mixture with water and a suitable 10 organic solvent, phase separation, and repeated distillation of the organic solvent until the water content is not more than 0.2 weight % by Karl- Fischer analysis, to obtain (6-bromopyridyl)-(1-methyl piperidyl)methanone; 15 vi.) Treatment of (6-bromopyridyl)-(1-methylpiperidyl)methanone with aqueous HBr and subsequent extraction with n-butanol followed by repeated distillation of the organic solvent until the water content is not more than 0.3% by Karl-Fischer analysis, to obtain solid (6-bromo pyridyl)-(1-methylpiperidyl)methanone hydrobromide; vii.) Treatment of (6-bromopyridylmethylpiperidyl)methanone hydrobromide in a biphasic mixture of water and toluene with solid KOH for about 3 hr with subsequent separation of the organic layer and evaporation of the solvent to obtain of (6-bromopyridylmethyl 25 piperidyl)methanone; viii.) Treatment of (6-bromopyridylmethylpiperidyl)methanone with 2,4,6-trifluorobenzamide in toluene containing K CO , water, Pd(OAc) , 2 3 2 and Xantphos at about 70 C for about 12 hr, until the (6-bromo 30 pyridyl)-(1-methylpiperidyl)methanone content is not more than 0.1% by HPLC, with subsequent dilution of the reaction mixture with water and EtOAc, subsequent treatment with thiourea-modified silica gel at 60 C for about 8 hr, with subsequent filtration to obtain a solution of 2,4,6-trifluoro- N-[6-(1-methylpiperidinecarbonyl)pyridyl]benzamide; ix.) Treatment of a solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine carbonyl)pyridyl]benzamide in EtOAc with a solution of about 0.5 equivalents of succinic acid dissolved in EtOH at 55 C for about 3 hr, with subsequent cooling to RT over about 10 hr, and collection of the 10 resulting solids by filtration, to obtain solid 2,4,6-trifluoro-N-[6-(1- methylpiperidinecarbonyl)pyridyl]benzamide hemisuccinate.
3. A process of Claim 1 or Claim 2 wherein the chlorinating agent in step ii.) is thionyl chloride in chlorobenzene. 15
4. A process of any one of Claims 1 to 3 wherein the mineral base in step iv.) is aqueous NaOH.
5. A process of any one of Claims 1 to 4 wherein the non-polar solvent in step iv.) is methyl-tert-butyl ether.
6. A process of any one of Claims 1 to 5 wherein the non-polar organic solvent in 20 step v.) is methyl-tert-butyl ether.
7. A process of any one of Claims 1 to 6 wherein the organic solvent in step v.) is n- butanol.
8. A process of Claim 1 wherein the non-polar aprotic solvent in step vii.) is methyl- tert-butyl ether. 25
9. A process of Claim 1 wherein the polar alcoholic solvent in step viii.) is isopropanol.
10. A process of any one of Claims 1 to 9 wherein the reactions are performed using batch processing methodology.
11. A process of Claim 10 wherein the batch produced is at process scale.
12. A process of Claim 11 wherein the batch produced is at least 1 kilogram. 5
13. A process of Claim 11 wherein the batch produced is at least 10 kilograms.
14. A process of Claim 11 wherein the batch produced is at least 100 kilograms.
15. A compound of the formula: 2 HCl 2 H O
16. The compound of Claim 15 which is crystalline. 10
17. The compound according to claim 16 characterized by an X-ray powder diffraction pattern using CuK a radiation having an intense peak at diffraction angle 2-theta of 8.3° in combination with one or more of the peaks selected from the group consisting of 16.6°, 23.5°, and 33.7° (± 0.2° respectively).
18. The process of any one of Claims 1 to 14, substantially as herein described with 15 reference to any example thereof.
19. The compound of any one of Claims 15 to 17, substantially as herein described with reference to any example thereof. SUBSTITUTE SHEET (RULE 26)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962871965P | 2019-07-09 | 2019-07-09 | |
| PCT/US2020/040881 WO2021007155A1 (en) | 2019-07-09 | 2020-07-06 | Processes and intermediate for the large-scale preparation of 2,4,6-trifluoro-n-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate, and preparation of 2,4,6-trifluoro-n-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide acetate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ783764A NZ783764A (en) | 2025-03-28 |
| NZ783764B2 true NZ783764B2 (en) | 2025-07-01 |
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