WO2011123654A1 - Compositions and methods of synthesis of pyridinoylpiperidine 5-ht1f agonists - Google Patents
Compositions and methods of synthesis of pyridinoylpiperidine 5-ht1f agonists Download PDFInfo
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- WO2011123654A1 WO2011123654A1 PCT/US2011/030740 US2011030740W WO2011123654A1 WO 2011123654 A1 WO2011123654 A1 WO 2011123654A1 US 2011030740 W US2011030740 W US 2011030740W WO 2011123654 A1 WO2011123654 A1 WO 2011123654A1
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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
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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
Definitions
- the present invention is directed to a certain polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l -methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide useful for activating 5-HTi F receptors and for the treatment or prevention of migraine.
- the present invention also relates to a process for the synthesis of pyridinoylpiperidine compounds of Formula I in high yield and high purity and in particular, a process to prepare 2,4,6-trifluoro- N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide, its hemisuccinate salt and polymorph (Form A).
- Sumatriptan and similar compounds previously advanced for the treatment of migraine had tended to be selected on the basis of this vasoconstrictive activity under the premises of the prior art models for migraine.
- Serotonin exhibits diverse physiological activity mediated by at least seven receptor classes, the most heterogeneous of which appears to be 5-HTi .
- 5-HT I F receptor agonists include compounds disclosed in the following:
- WO 98/46570 describing a family of 5-substituted indoles, pyrrolo[3,2-b]pyridines, benzofurans, and benzothiophenes, having the 3 -position substituted with octahydroindolizinyl, octahydro-2H-quinolizinyl, decahydropyrido[l,2- a]azepinyl, l,2,3,5,8,8a-hexahydroindolizinyl, l,3,4,6,9,9a-hexahydro-2H- quinolizinyl, or 1,4,6,7,8,9,10, 10a-octahydropyrido[l,2-a]azepinyl;
- WO 98/20875 and WO 99/25348 describing two families of 5 -substituted piperidin-3- yl-azaindoles and 5-substituted l,2,3,6-tetrahydropyridin-3-yl-azaindoles;
- WO 00/00487 describing a family of 5-substituted (piperidin-3-yl or 1 ,2,3,6- tetrahydropyridin-3-yl) indoles, azaindoles, benzofurans, and benzothiophenes;
- WO 98/08502 describing a family of 8-substituted-l,2,3,4-tetrahydro-2- dibenzofuranamines and 9-substituted-2-aminocyclohepta[b]benzofurans;
- WO 98/551 15 describing a family of 3-amino-l,2,3,4-tetrahydro-9H-carbazole-6- carboxamides and 4-amino-10H-cyclohepta[7,6-b]indole-7-carboxamides;
- WO 98/15545 describing a select family of 3,5-disubstituted indoles and benzofurans
- WO 00/00490 describing a family of 5-allyl-substituted (piperidin-3-yl or 1,2,3,6- tetrahydropyridin-3-yl)indoles, azaindoles, benzofurans, and benzothiophenes
- WO 00/47559 describing a family of 4-(3-substituted-benzoyl)piperidines;
- the present invention relates to a certain polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide useful for activating 5-HTi F receptors and for the treatment or prevention of migraine.
- the present invention also relates to the field of synthesizing pyridinoylpiperidine compounds.
- the present invention relates to a polymorph of the hemisuccinate salt of 2,4,6- trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide (Form A) characterized by an X-ray diffraction pattern substantially similar to that set forth in Figure 1A.
- the present invention relates to a polymorph of the
- the X-ray diffraction pattern using Cu-K march radiation includes peaks at about 15.3, 16.4, 19.3, 22.1, 23.6 and 25.9 degrees 2 ⁇ .
- the X-ray diffraction includes one or more additional peaks set forth in Table 1.
- the present invention relates to a polymorph of the
- the present invention relates to a polymorph of the
- the present invention relates to a polymorph of the
- the present invention relates to a polymorph of the
- the present invention relates to a polymorph of the
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4- carbonyl)-pyridin-2-yl] -benzamide (Form A) and a pharmaceutically acceptable carrier.
- the pharmaceutical composition comprises a polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]- benzamide (Form A) that is substantially free from impurities.
- the pharmaceutical composition comprises a polymorph of the hemisuccinate salt of 2,4,6- trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide (Form A) that has a chemical purity greater than 98.0% as determined by HPLC.
- the pharmaceutical comprises a polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l- methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide (Form A) that is substantially free from the impurity:
- the present invention relates to a method of treating migraine in a mammal comprising administering to a mammal in need of such treatment an effective amount of a polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4- carbonyl)-pyridin-2-yl]-benzamide (Form A).
- the mammal is a human.
- the present invention relates to a process for preparing 2,4,6-trifluoro-N-[6-(l- methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a salt thereof.
- the salt is a pharmaceutically acceptable salt thereof.
- the salt is the hemisuccinate salt.
- the present invention relates to a process for preparing 2,4,6-trifluoro-N-[6-(l- methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a salt thereof comprising the step of: reacting (6-aminopyridin-2-yl)(l-methylpiperidin-4-yl)methanone or a salt thereof with 2,4,6-trifluorobenzoylchloride in the presence of chlorobenzene to yield 2,4,6-trifluoro-N-[6- (1 -methyl-piperidin-4-ylcarbonyl)-piperdin-2-yl]benzamide hydrochloride.
- the present invention relates to a process for preparing 2,4,6-trifluoro-N-[6-(l- methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a salt thereof, comprising the step of: reacting (6-bromopyridin-2-yl)(l-methylpiperidin-4-yl)methanone hydrobromide with >0.02 wt% copper(I)oxide at less than 80 °C to yield (6-aminopyridin-2-yl)(l- methylpiperidin-4-yl)methanone.
- the present invention relates to a process for preparing 2,4,6-trifluoro-N-[6-(l- methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a salt thereof, further comprising the step of: reacting N,N-diethyl-l-methylpiperidine-4-carboxamide with a solution of 2,6- dibromopyridine and Grignard reagent followed by the addition hydrobromic acid to yield (6- bromopyridin-2-yl)(l-methylpiperidin-4-yl)methanone hydrobromide.
- the present invention relates to a process for preparing 2,4,6-trifluoro-N-[6-(l- methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or salt thereof, further comprising the step of: reacting l-methylpiperidine-4-carboxylic acid with thionyl chloride and diethyl amine to yield N,N-diethyl-l-methylpiperidine-4-carboxamide.
- the present invention relates to a process for preparing 2,4,6-trifluoro-N-[6-(l- methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a salt thereof, further comprising the step of: converting piperidine-4-carboxylic acid to l-methylpiperidine-4-carboxylic acid using transfer hydrogenation conditions.
- the present invention relates to a process for preparing 2,4,6-trifluoro-N-[6-(l- methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate salt further comprising the step of: converting 2,4,6-trifluoro-N-[6-(l-methyl-piperidin-4-ylcarbonyl)- piperdin-2-yl]benzamide hydrochloride using succinic acid in the presence of ethanol to yield 2,4,6-trifluoro-N-[6-( 1 -methyl-piperidin-4-ylcarbonyl)-piperdin-2-yl]benzamide hemisuccinate salt.
- the present invention relates to a process for preparing a compound of formula I:
- R 1 is phenyl substituted with one to three halo substituents
- R 2 is C1-C3 alkyl
- R 3 is hydrogen or Q-C3 alkyl, comprising the steps of:
- Figure 1 shows X-ray diffraction patterns for various forms of the Compound VIII.
- Figure 1A Form A
- Figure IB Form B
- Figure IC Form C
- Figure ID amorphous material.
- Figure 2 shows a DSC thermogram of Compound VIII (Form A).
- FIG. 3 shows infra-red data for Compound VIII (Form A).
- Figure 4 shows a typical ⁇ NMR spectrum of 2,4,6-trifluoro-N-(6-(l- methylpiperidine-4-carbonyl)pyridine-2-yl)benzamide hemisuccinate, Form A (MeOD).
- Figure 5 shows a typical ⁇ NMR spectrum of l-methylpiperidine-4-carboxylic acid
- Figure 6 shows a typical 'H NMR spectrum of N,N-diethyl-l-methylpiperidine-4- carboxamide (MeOD).
- Figure 7 shows a typical ⁇ NMR spectrum of (6-bromopyridin-2-yl)(l- methylpiperidin-4-yl)methanone hydrobromide (MeOD).
- Figure 8 shows a typical ⁇ NMR spectrum of (6-aminopyridin-2-yl)(l- methylpiperidin-4-yl)methanone dihydrochloride (D20).
- Figure 9 shows a typical 1 HNMR spectrum of 2,4,6-trifluoro-N-(6-(l- methylpiperidine-4-carbonyl)pyridine-2-yl)benzamide hydrochloride (MeOD).
- Figure 10 shows an HPLC trace of 2,4,6-trifluoro-N-(6-(l-methylpiperidine-4- carbonyl)pyridine-2-yl)benzamide having a chemical purity of at least 99% (i.e. main peak normalisation / area % impurities).
- Form A is an anhydrous crystal form.
- the present invention is directed to a certain polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide characterized by its X-ray diffraction pattern and/or DSC thermogram, methods of making this polymorph, pharmaceutical compositions comprising this polymorph and methods of treating or preventing migraine by administering this polymorph to a subject.
- the present invention is directed to a certain polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide (Form A) characterized by the principal X-ray diffraction pattern peaks expressed in terms of 2 ⁇ and d- spacings, for example, as measured using Cu-K a radiation.
- the present invention is directed to a certain polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l -methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide (Form A) characterized by an X-ray diffraction pattern, using Cu-K a radiation, including peaks at about 15.3, 16.4, 19.3, 22.1, 23.6 and 25.9 degrees 2 ⁇ .
- this certain polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4- carbonyl)-pyridin-2-yl]-benzamide is also characterized by an X-ray diffraction pattern, using Cu-K a radiation, including one or more further peaks identified in Table 1.
- this certain polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6- (l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide (Form A) is also characterized by an X-ray diffraction pattern substantially similar to that set forth in Figure 1A.
- the present invention is also directed to a polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide (Form A) characterized by a Differential Scanning Calorimetry (DSC) thermogram having a maximum value at about 199 °C, as measured, for example, using a TA Instruments differential scanning calorimeter 2920 or Q2000.
- DSC Differential Scanning Calorimetry
- a further embodiment of the present invention is a polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide (Form A) characterized by an X-ray diffraction pattern substantially similar to that set forth in Figure 1A and a Differential Scanning Calorimetry (DSC) thermogram having a single maximum value at about 199 °C.
- DSC Differential Scanning Calorimetry
- the present invention is directed to a polymorph of the hemisuccinate salt of 2,4,6- trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide (Form A) produced by recrystallization with ethanol.
- the present invention is directed to a pharmaceutical composition
- a pharmaceutical composition comprising the a polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l -methyl-piperidine-4- carbonyl)-pyridin-2-yl]-benzamide (Form A) and a pharmaceutically acceptable carrier.
- the present invention is directed to a method of treating migraine in a mammal comprising administering to a mammal in need of such treatment an effective amount of a polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4- carbonyl)-pyridin-2-yl]-benzamide (Form A).
- the mammal is a human.
- the present invention is directed to a method of preventing migraine in a mammal comprising administering to a mammal in need of such treatment an effective amount of a polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4- carbonyl)-pyridin-2-yl]-benzamide (Form A).
- the mammal is a human.
- One embodiment of the present invention is a method for increasing activation of 5-
- HTIF receptors by administering a polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N- [6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide (Form A), while avoiding vasoconstrictive activity, for treating a variety of disorders that have been linked to decreased neurotransmission of serotonin in mammals.
- migraine migraine
- general pain trigeminal neuralgia
- dental pain or temperomandibular joint dysfunction pain anxiety, general anxiety disorder, panic disorder, depression, disorders of sleep, chronic fatigue syndrome, premenstrual syndrome or late luteal phase syndrome, post-traumatic syndrome, memory loss
- dementia including dementia of aging, social phobia, autism, attention deficit hyperactivity disorder, disruptive behavior disorders, impulse control disorders, borderline personality disorder, obsessive compulsive disorder, premature ejaculation, erectile dysfunction, bulimia, anorexia nervosa, alcoholism, tobacco abuse, mutism, and trichotillomania.
- the polymorph of this invention is also useful as a prophylactic treatment for migraine.
- Any of the described methods may employ a polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2- yl]-benzamide (Form A).
- the present invention is further directed to processes for the preparation of a compound having the formula I:
- R 1 is phenyl substituted with one to three halo substituents
- R 2 is C1-C3 alkyl
- R 3 is hydrogen or C1-C 3 alkyl.
- the present invention includes processes for the preparation of a polymorph of a compound of formula I.
- the present invention includes processes for the preparation of a pharmaceutically acceptable acid addition salt thereof.
- the present invention is directed to a process for the preparation of a compound of formula I or salt thereof comprising the steps of:
- the present invention is directed to a process for preparing the polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l -methyl-piperidine-4-carbonyl)-pyridin-2-yl]- benzamide (Form A).
- the present invention is directed to a process for preparing the polymorph the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l -methyl-piperidine-4-carbonyl)-pyridin-2-yl]- benzamide (Form A) comprising the step of: converting 2,4,6-trifluoro-N-[6-(l-methyl- piperidin-4-ylcarbonyl)-piperdin-2-yl]benzamide or a salt thereof using succinic acid in the presence of ethanol to yield 2,4,6-trifluoro-N-[6-(l-methyl-piperidin-4-ylcarbonyl)-piperdin- 2-yl]benzamide hemi-succinate salt.
- the starting salt is 2,4,6-trifluoro- N-[6-( 1 -methyl-piperidin-4-ylcarbonyl)-piperdin-2-yl]benzamide hydrochloride.
- the present invention is directed to a pharmaceutical composition
- a pharmaceutical composition comprising a polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4- carbonyl)-pyridin-2-yl]-benzamide (Form A), wherein said polymorph is substantially free from impurities.
- chemical purity means percentage of a particular compound in a sample. Unless stated otherwise, percentages stated throughout this specification are weight/weight (w/w) percentages.
- said polymorph has a chemical purity greater than 98.0% as determined by HPLC.
- said polymorph has a chemical purity of 99.0%.
- said polymorph has a chemical purity of 99.5%.
- said polymorph has a chemical purity of 99.6%.
- said polymorph has a chemi said is polymorph is substantially
- the impurity is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- crystalline means having a regularly repeating arrangement of molecules or external face planes.
- crystalline purity means percentage of a crystalline compound in a sample which may contain an amorphous form of the same compound, at least one other crystalline form of the compound or a mixture thereof. In one aspect, said polymorph has a crystalline purity of about 97.0%. In one aspect, said polymorph has a crystalline purity of about 99.0% crystalline purity. In one aspect, said polymorph has a crystalline purity of about 100% crystalline purity. In one aspect, differential scanning calorimetry (DSC) is used for determination of whether more than one phase is present.
- DSC differential scanning calorimetry
- the present invention is directed to a pharmaceutical composition
- a pharmaceutical composition comprising a polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l -methyl-piperidine-4- carbonyl)-pyridin-2-yl]-benzamide (Form A), where the composition is a commercial scale composition.
- Scheme 1 illustrates a process for preparing the hemi-succinate salt of 2,4,6-trifluoro- N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide.
- the present invention is directed to a process as described below for preparing 2,4,6- trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a salt thereof.
- the salt thereof is a pharmaceutically acceptable salt.
- the salt thereof is 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)- pyridin-2-yl]-benzamide hemisuccinate salt.
- the present invention is directed to the process comprising the steps of:
- the pharmaceutically acceptable salt produced in step 5 is the hydrochloride salt.
- the present invention is directed to a process for the preparation of the hemi- succinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]- benzamide further comprising the step of converting 2,4,6-trifluoro-N-[6-(l-methyl- piperidin-4-ylcarbonyl)-piperdin-2-yl]benzamide hydrochloride using succinic acid in the presence of ethanol to yield 2,4,6-trifluoro-N-[6-(l-methyl-piperidin-4-ylcarbonyl)-piperdin- 2-yl]benzamide hemi-succinate salt.
- the present invention is directed to a process the preparation of the hemi-succinate salt of 2,4,6-trifluoro-N-[6-(l -methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide, where the process is a commercial scale process.
- the present invention is directed to a process for preparing 2,4,6-trifluoro-N-[6-(l- methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a pharmaceutically acceptable salt thereof e.g., the hemi-succinate salt comprising the step of: converting piperidine-4- carboxylic acid (I) to l-methylpiperidine-4-carboxylic acid (II) or a pharmaceutically acceptable salt thereof (e.g., to the hydrochloride salt) using transfer hydrogenation conditions.
- the present invention is directed to a process for preparing 2,4,6-trifluoro-N-[6-(l-methyI-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide
- hemisuccinate salt comprising the step of: reacting piperidine-4-carboxylic acid (I) with formaldehyde at ambient pressure to yield l-methylpiperidine-4-carboxylic acid (II). It is advantageous to convert the piperidine-4-carboxylic acid (isonipecotic acid) to 1- methylpiperidine-4-carboxylic acid using transfer hydrogenation conditions.
- Transfer hydrogenation is the addition of hydrogen to a molecule from a source other than gaseous H 2 . Transfer hydrogenation offers several advantages including ease of handling in a wide variety of reaction vessels and avoids the need for specialized high pressure equipment.
- transfer hydrogenation conditions include using formaldehyde.
- transfer hydrogenation conditions include ambient pressure.
- transfer hydrogenation conditions include a palladium catalyst e.g., palladium on charcoal, or platimum.
- transfer hydrogenation conditions include water and acid e.g., formic acid.
- the transfer hydrogenation conditions include heat.
- the reaction mixture is heated from ambient to about 90 to 95 °C.
- l-methylpiperidine-4-carboxylic acid (II) is converted to the hydrochloride salt.
- the hydrochloride salt of l-methylpiperidine-4-carboxylic acid (II) is formed using hydrochloric acid e.g., 1.5 equivalents.
- the present invention is directed to a process for preparing 2,4,6-trifluoro-N-[6-(l- methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a pharmaceutically acceptable salt thereof e.g., the hemisuccinate salt comprising the step of: reacting l-methylpiperidine-4- carboxylic acid (II) with thionyl chloride and diethyl amine to yield N,N-diethyl-l- methylpiperidine-4-carboxamide (III).
- the hydrochloride salt of II is reacted with thionyl chloride and diethyl amine.
- the present invention is directed to a process for preparing the hemi-succinate salt of 2,4,6-trifluoro-N-[6-(l -methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide, where in step 2, the use of diethylamine for the conversion of l-methylpiperidine-4-carboxylic acid (II) or a salt thereof to N,N-diethyl-l-methylpiperidine-4-carboxamide (III) is advantageous over the use and formation of other dialkylamines e.g., dimethylamine.
- ethylamine is a liquid at ambient temperature and thus, diethylamine offers ease of handling over dimethylamine.
- the present invention is directed to a process for preparing the hemi-succinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide, where the reagent used to activate the carboxylic acid moiety is thionyl chloride.
- thionyl chloride for the conversion of l-methylpiperidine-4-carboxylic acid (II) or a salt thereof to N,N-diethyl-l-methylpiperidine-4-carboxamide (III) is advantageous. Specifically, the use of
- thionyl chloride avoids the formation of dimethyl carbamoyl chloride: ; which is a carcinogen known to form as a result of the use of another alternative reagents such as oxalyl chloride and DMF.
- N,N-diethyl-l-methylpiperidine-4-carboxamide (III) is formed substantially free of dimethyl carbamoyl chloride.
- the present invention is directed to a process for preparing 2,4,6-trifluoro-N-[6-(l- methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a pharmaceutically acceptable salt thereof e.g., the hemi-succinate salt
- a pharmaceutically acceptable salt thereof e.g., the hemi-succinate salt
- the present invention is directed to a process for preparing the hemi-succinate salt of
- the Grignard reagent is Turbo Grignard reagent.
- Turbo Grignard reagent is lithium chloride plus Grignard reagent.
- the Turbo Grignard is isopropylmagnesium chloride/lithium chloride.
- chlorinated by-product is: a). This chlorinated by-product does not displace with ammonia in the subsequent step 4, thus lowering yield in conversion of IV to V.
- the use of the HBr salt of (6-bromopyridin-2-yl)(l-methylpiperidin-4-yl)methanone (IV) circumvents this side reaction and thus increases yields and purity in conversion of IV to V.
- (6-aminopyridin-2-yl)(l-methylpiperidin-4-yl)methanone is formed substantially free from the chlorinated by-product Va. Step 4.
- the present invention is directed to a process for preparing 2,4,6-trifluoro-N-[6-(l- methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a pharmaceutically acceptable salt thereof e.g., the hemi-succinate salt
- a process for preparing 2,4,6-trifluoro-N-[6-(l- methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a pharmaceutically acceptable salt thereof e.g., the hemi-succinate salt comprising the step of: reacting (6-bromopyridin-2- yl)(l-methylpiperidin-4-yl)methanone (IV) hydrobromide with >0.02 wt% copper(I)oxide at less than 80 °C to yield (6-aminopyridin-2-yl)(l-methylpiperidin-4-yl)methanone(V) or a pharmaceutically acceptable salt thereof
- the present invention is directed to a process for preparing the hemi-succinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide, where the conversion of (6-bromopyridin-2-yl)(l-methylpiperidin-4-yl)methanone (IV) hydrobromide to (6-aminopyridin-2-yl)(l-methylpiperidin-4-yl)methanone (V) using ammonia and greater than 0.02 wt% copper(I)oxide is advantageous.
- a catalyst loading of >0.02 wt% allows for the reaction to be conducted at a lower temperature, a temperature below 80 °C e.g., about 60-70 °C, preferably about 70 °C.
- the use of a lower temperature avoids discoloration of the product of step 4, (6-aminopyridin-2-yl)(l-methylpiperidin-4- yl)methanone (V), and ultimately affords the final product, 2,4,6-trifluoro-N-[6-(l-methyl- piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate salt, as a white crystalline solid.
- step 4 is carried out at higher temperatures such as 80-110 °C and lower catalyst loadings ⁇ 0.02 wt%.
- the resulting product at step 4 is yellow to brown in color and this undesired discoloration carries over to the final product which results in an off-white to brown colored final product, 2,4,6-trifluoro-N-[6-( 1 -methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate salt (VIII).
- a white active ingredient is preferred over a colored active ingredient because a white active ingredient does not require any dye additives prior to formulation of the drug product.
- the present invention is directed to a process for preparing 2,4,6-trifluoro-N-[6-(l- methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a pharmaceutically acceptable salt thereof e.g., the hemi-succinate salt comprising the step of: reacting (6-aminopyridin-2-yl)(l- methylpiperidin-4-yl)methanone (V) with 2,4,6-trifluorobenzoylchloride in the presence of chlorobenzene to yield 2,4,6-trifluoro-N-[6-(l -methyl-piperidin-4-ylcarbonyl)-piperdin-2- yl]benzamide (VI) hydrochloride.
- the present invention is directed to a process for preparing the hemi-succinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide, where it is advantageous to react (6-aminopyridin-2-yl)(l-methylpiperidin-4-yl)methanone (V) with 2,4,6-trifluorobenzoylchloride in the presence of the solvent chlorobenzene.
- V 6-aminopyridin-2-yl)(l-methylpiperidin-4-yl)methanone
- V 2,4,6-trifluorobenzoylchloride
- the dihydrochloride salt of V is used in step 5.
- an alternative solvent such as dichloromethane (DCM)
- the present invention is directed to a process for preparing 2,4,6-trifluoro-N-[6-(l- methyl-piperidin-4-ylcarbonyl)-piperdin-2-yl]benzamide hemisuccinate salt comprising the step of: converting 2,4,6-trifluoro-N-[6-(l-methyl-piperidin-4-ylcarbonyl)-piperdin-2- yl]benzamide (VI) hydrochloride using succinic acid in the presence of ethanol to yield 2,4,6- trifluoro-N-[6-(l-methyl-piperidin-4-ylcarbonyl)-piperdin-2-yl]benzamide hemi-succinate salt.
- the present invention is directed to a process for preparing the hemi-succinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide, where it is advantageous to convert 2,4,6-trifluoro-N-[6-( 1 -methyl-piperidin-4-ylcarbonyl)-piperdin-2- yl]benzamide hydrochloride to the free base and then to the hemi-succinate salt in ethanol.
- ethanol as a crystallization solvent is preferred over solvents such as acetone and provides reproducibly a single polymorph Form A.
- alkyl refers to a branched or unbranched saturated hydrocarbon group.
- n- alkyl refers to an unbranched alkyl group.
- C x -C y alkyl refers to an alkyl group having between x and y carbon atoms, inclusively, in the branched or unbranched hydrocarbon group.
- C1-C3 alkyl refers to a straight chain or branched hydrocarbon moiety having from 1 to 3 carbon atoms, including methyl, ethyl, «-propyl, and isopropyl.
- Ci-C 3 rc-alkyl refers to straight chain hydrocarbon moieties having from 1 to 3 carbon atoms including methyl, ethyl, and n- propyl.
- halo refers to fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro, chloro, and bromo. More preferred halo groups are fluoro and chloro.
- DMF means ⁇ , ⁇ -dimethylformamide.
- XRPD means X-Ray Powder Diffraction.
- DSC means Differential Scanning Calorimetry.
- DCM means dichloromethane.
- TBME means tert-butyl methyl ether.
- AKX or AX reagent means Karl Fischer analysis reagent.
- THF means tetrahydrofuran.
- HPLC means high performance liquid chromatography.
- IPA means isopropyl alcohol.
- RH means Relative Humidity.
- polymorphs of the invention means the Form A polymorph of the hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l -methyl-piperidine-4-carbonyl)-pyridin-2-yl]- benzamide.
- pharmaceutical or “pharmaceutically acceptable” when used herein as an adjective, means substantially non-toxic and substantially non-deleterious to the recipient.
- excipients and salt must be compatible with the active ingredient of the formulation (e.g. a compound of formula I). It is understood by those of ordinary skill in this art that the terms “pharmaceutical formulation” and “pharmaceutical composition” are generally
- acid addition salt refers to a salt of a compound e.g., 2,4,6-trifluoro-N-[6- (l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide prepared by reaction of a the free base of the compound with a mineral or organic acid.
- hemi-salts can be formed by reacting a compound with the desired acid in a 2: 1 ratio, compound to acid.
- the reactants are generally combined in a mutual solvent such as diethylether, tetrahydrofuran, methanol, ethanol, isopropanol, benzene, or the like.
- the salts normally precipitate out of solution within about one hour to about ten days and can be isolated by filtration or other conventional methods.
- Inorganic acids commonly employed to form such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like.
- Organic acids commonly employed to form such salts include p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
- salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, hemisuccinate, suberate, sebacate, fumarate, maleate, butyne-1,4- dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylprop
- commercial scale process and “commercial scale composition” refer to a process and composition, respectively, which is run or produced as a single batch of at least about 100 grams.
- an effective amount means an amount of the polymorph of the invention which is capable of activating 5-HTJF receptors and/or inhibiting neuronal protein
- treating includes any effect e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc.
- Treating or “treatment” of a disease state means the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting an existing disease-state, i.e., arresting its development or its clinical symptoms; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
- preventing means causing the clinical symptoms of the disease state not to develop i.e., inhibiting the onset of disease, in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
- suitable solvent refers to any solvent, or mixture of solvents, inert to the ongoing reaction that sufficiently solubilizes the reactants to afford a medium within which to effect the desired reaction.
- amorphous as used herein, means essentially without a regularly repeating arrangement of molecules or external face planes.
- peak heights in a powder x-ray diffraction pattern may vary and will be dependent on variables such as the temperature, crystal size, crystal habit, sample preparation or sample height in the analysis well. It is meant to be understood that the peak labels in the images in Figures 1 and 3 are meant as a visual aid. Consult the corresponding Table for accurate 20 and cm "1 positions.
- peak positions may vary when measured with different radiation sources.
- the type of formulation used for the administration of the polymorph employed in the methods of the present invention may be dictated by the type of pharmacokinetic profile desired from the route of administration and the state of the patient.
- Formulations amenable to oral, sublingual, nasal or injectable administration are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
- a formulation of the present invention includes an active ingredient (the polymorph of the invention) and is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
- an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
- the formulations can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, gels, suppositories, sterile injectable solutions, and sterile packaged powders.
- the active polymorph In preparing a formulation, it may be necessary to mill the active polymorph to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh. In one embodiment of the present invention, the particle size range is between about 0.1 ⁇ to about 100 ⁇ .
- excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
- the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
- the compounds of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
- active ingredient refers to a polymorph of the invention.
- the polymorph is usually administered in the form of pharmaceutical formulations comprising a pharmaceutically acceptable excipient and at least one active ingredient.
- These formulations can be administered by a variety of routes including oral, buccal, rectal, intranasal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
- the polymorph employed in the methods of this invention are effective as both injectable and oral compositions.
- transdermal delivery device In order to administer transdermally, a transdermal delivery device ("patch") is needed. Such transdermal patches may be used to provide continuous or discontinuous infusion of a polymorph of the present invention in controlled amounts.
- the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent No. 5,023,252. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
- Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier.
- a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier.
- One such implantable delivery system used for the transport of biological factors to specific anatomical regions of the body, is described in U.S. Patent 5,011,472, which is herein incorporated by reference.
- the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
- a pharmaceutical formulation comprising at lest one active polymorph as described above in a formulation adapted for buccal and/or sublingual, or nasal administration.
- This embodiment provides administration of the active polymorph in a manner that avoids gastric complications, such as first pass metabolism by the gastric system and/or through the liver. This administration route may also reduce adsorption times, providing more rapid onset of therapeutic benefit.
- the compounds of the present invention may provide particularly favorable solubility profiles to facilitate sublingual/buccal formulations.
- Such formulations typically require relatively high concentrations of active ingredients to deliver sufficient amounts of active ingredients to the limited surface area of the sublingual/buccal mucosa for the relatively short durations the formulation is in contact with the surface area, to allow the absorption of the active ingredient.
- the very high activity of the polymorph of the invention combined with its high solubility, facilitates its suitability for sublingual/buccal formulation.
- the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising an amount of a polymorph of the invention ranging up to 1000 mg per dose administered once, two, or three times daily and a pharmaceutically acceptable diluent or carrier.
- the invention relates to a pharmaceutical composition for oral or rectal administration comprising an amount of a polymorph of the invention ranging up to 1000 mg per dose administered once, two or three times daily and a pharmaceutically acceptable diluent or carrier.
- the invention relates to a pharmaceutical composition comprising an amount of a polymorph of the invention wherein the amount is from 50 mg to 500 mg per dose.
- the invention relates to a pharmaceutical composition comprising an amount of a polymorph of the invention wherein the amount is from 50 mg to 400 mg per dose.
- the invention relates to a pharmaceutical composition comprising an amount of a polymorph of the invention wherein the amount is 50 mg per dose.
- the invention relates to a pharmaceutical composition comprising an amount of a polymorph of the invention wherein the amount is 100 mg per dose. In one aspect, the invention relates to a pharmaceutical composition comprising an amount of a polymorph of the invention wherein the amount is 200 mg per dose. In one aspect, the invention relates to a pharmaceutical composition comprising an amount of a polymorph of the invention wherein the amount is 400 mg per dose.
- the invention relates to a pharmaceutical composition comprising a polymorph of the invention or a pharmaceutically acceptable salt, wherein the administration is oral. In one aspect, the invention relates to a pharmaceutical composition comprising an amount of a polymorph of the invention wherein the administration is rectal.
- the invention relates to a pharmaceutical composition for buccal, sublingual, nasal/intranasal, transdermal, subcutaneous, injectable, intravenous, or intramuscular administration comprising an amount of a polymorph of the invention ranging up to 200 mg per dose administered once, two or three times daily and a pharmaceutically acceptable diluent or carrier.
- the invention relates to a pharmaceutical composition comprising a polymorph of the invention wherein the amount is from 2 to 100 mg per dose. In one aspect, the invention relates to a pharmaceutical composition comprising an amount of a polymorph of the invention wherein the amount is about 10, 15, 25, 30, 45 50, 60, 75, 90 or 100 mg per dose.
- the invention relates to a pharmaceutical composition, wherein the administration is buccal. In one aspect, the invention relates to a pharmaceutical composition, wherein the administration is sublingual. In one aspect, the invention relates to a pharmaceutical composition, wherein the administration is nasal or intranasal. In one aspect, the invention relates to a pharmaceutical composition, wherein the administration is transdermal. In one aspect, the invention relates to a pharmaceutical composition, wherein the administration is subcutaneous. In one aspect, the invention relates to a pharmaceutical composition, wherein the administration is injectable. In one aspect, the invention relates to a pharmaceutical composition, wherein the administration is intravenous. In one aspect, the invention relates to a pharmaceutical composition, wherein the administration is
- the invention relates to a pharmaceutical composition, wherein the administration of a polymorph of the invention is intravenous. In one aspect, the invention relates to a pharmaceutical composition, wherein the administration of a polymorph of the invention is intravenous over time. In one aspect, the invention relates to a pharmaceutical composition, wherein the administration of a polymorph of the invention is intravenous over a period of about 20 minutes. In one aspect, the invention relates to a pharmaceutical composition, wherein the administration of a polymorph of the invention is intravenous over a period of 20 minutes.
- the invention relates to a pharmaceutical composition, wherein the dose of a polymorph of the invention is administered one time daily. In one aspect, the invention relates to a pharmaceutical composition, wherein the dose of a polymorph of the invention is administered two times daily. In one aspect, the invention relates to a pharmaceutical composition, wherein the dose of a polymorph of the invention is administered three times daily.
- succinic acid (0.16 wt, 0.53 equiv, 29.3 g) followed by ethanol (3.0 vol, 2.4 wt, 550 mL) and stir under nitrogen for 40 to 50 minutes at 20 to 25°C, confirm dissolution by visual examination.
- Form A is a crystalline, non-hygroscopic anhydrate which melts at 198 °C.
- Form A is characterized the X-ray diffraction pattern set forth in Figure 1A. Further, Form A is also characterized by differential calorimetry (DSC).
- DSC differential calorimetry
- Form A has an onset of melting transition/decomposition point at about 199°.
- Figure 3 shows a typical infrared spectrum of Form A and Figure 4 shows a typical 'HNMR spectrum of Form A(MeOD).
- aqueous hydrobromic acid solution (0.70 vol, 1.04 wt, 292 mL) to the combined filtrates at up to 30°C followed by a n-butanol (2.0vol, 1.6wt) line rinse.
- Check the pH of the mixture with a damp pH strip (pass criterion pH ⁇ 2).
- Concentrate to ca.lO vol by atmospheric distillation (expected temperature 108 to 112 °C).
- ethylene glycol (8.0 vol, 8.9 wt, 3.3 L) to vessel A and adjust the temperature as necessary to 1 to 25°C. Bubble ammonia gas through vessel A at 15 to 25 °C until a saturated ammonia solution is achieved by titration (pass criterion is >14.3%w/w ammonia).
- vessel B charge (6-Bromopyridin-2-yl)(l-methylpiperidin-4-yl)methanone Hydrobromide (1.0 wt, 1.0 eq, 414 g).
- Charge copper(I)oxide (0.05 eq, 0.02 wt, 8.3 g) to vessel B. Transfer the contents of vessel A to vessel B. Seal vessel B and heat the contents to 70 to 75°C.
- reaction mixture at 70 to 75 °C at ca 4 to 5barA until complete by HPLC analysis (pass criterion ⁇ 2.0%area starting material, reaction expected to take up to 10 hours). Cool the reaction mixture to 15 to 25°C. Charge aqueous sodium hydroxide (16%w/w, 3.0 vol, 1.2 L) to the vessel at 15 to 25°C. Charge aqueous sodium chloride solution (30%w/w, 20.0 vol, 8.3 L) to the vessel at 15 to 25°C. Charge TBME (5.0 vol, 3.7 wt, 2.1 L) to the vessel at 15 to 25°C. Stir the resulting mixture at 15 to 25°C for 15 to 30 minutes then separate the layers.
- aqueous sodium hydroxide (16%w/w, 3.0 vol, 1.2 L) to the vessel at 15 to 25°C.
- aqueous sodium chloride solution (30%w/w, 20.0 vol, 8.3 L) to the vessel at 15 to 25°C.
- TBME 5.0 vol, 3.7 wt,
- the vial with solution was parafilmed, wrapped in aluminum foil, and placed in the refrigerator at approximately 2 °C. Colorless solid crystallized within approximately 3 weeks of storage in the refrigerator. The remaining solution was decanted and the solid air-dried for approximately 1 hour and analyzed.
- Amorphous hemisuccinate salt of 2,4,6-trifluoro-N-[6-(l-methyl-piperidine-4- carbonyl)-pyridin-2-yl]-benzamide was stressed at 75% Relative Humidity (RH) and ambient temperature by placing a vial with solid material inside a sealed chamber at the controlled relative humidity conditions. The vial was wrapped in aluminum foil to minimize exposure to light. After 1 day, the resulting dry and dense solid was subsampled and analyzed by polarized light microscopy and XRPD. No changes were noted by visual observation of the sample after 2 and 3 days at 75% RH.
- RH Relative Humidity
- X-ray powder diffraction analyses were performed using an Inel XRG-3000 X-ray powder diffractometers with Cu K a radiation.
- the Inel XRG-3000 diffractometer is equipped with a CPS (Curved Position Sensitive) detector with a 2 ⁇ range of 120°.
- Real time data were collected using Cu-K a radiation starting at approximately 4 °2 ⁇ at a resolution of 0.03 °2 ⁇ .
- the tube voltage and amperage were set to 40 kV and 30 mA, respectively.
- FIG. 1 depicts X-ray diffraction patterns for various forms of the Compound VIII.
- Figure 1 A is an X-ray diffraction pattern of Form A, with the data for the observed peaks and representative peaks presented in Tables 1 and 2, respectively.
- Figure IB is an X-ray diffraction pattern of Form B, with the data for the observed peaks and prominent peaks presented in Tables 3 and 4, respectively.
- Figure 1C is an X-ray diffraction pattern of Form C, with the data for the observed peaks and prominent peaks presented in Tables 5 and 6, respectively.
- Figure ID amorphous material.
- Figure ID is an X-ray diffraction pattern of a sample of amorphous 2,4,6-Trifluoro-N-(6-( 1 -methylpiperidine-4-carbonyl)pyridine-2-yl)benzamide Hemisuccinate (VIII).
- Differential scanning calorimetry was performed using a TA Instruments differential scanning calorimeter 2920. The sample was placed into an aluminum DSC pan, and the weight accurately recorded. Reported temperatures are at the transition maxima.
- Figure 2 shows a DSC thermogram of Form A of Compound VIII.
- the thermogram has a single maximum value at about 199°C.
- the rate of heating i.e., the scan rate at which the DSC is conducted
- the calibration standard used, instrument calibration, the relative humidity and upon the purity the endotherms may vary.
- the observed endotherms may also differ from instrument to instrument; however, it will generally be within the ranges defined herein provided the instruments are calibrated similarly.
- EXAMPLE 6 Infrared Analysis of the title compound 2,4,6-Trifluoro-N-(6-(l- methyIpiperidine-4-carbonyl)pyridine-2-yl)benzamide Hemisuccinate (VIII).
- IR infrared
- FT-IR Fourier transform infrared
- DTGS deuterated triglycine sulfate
- ATR attenuated total reflectance
- ThunderdomeTM Thermo Spectra-Tech
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Abstract
Description
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US8697876B2 (en) | 2014-04-15 |
CA2795062A1 (en) | 2011-10-06 |
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