Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/12—Oxygen or sulfur atoms
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
  • C07C57/13—Dicarboxylic acids
  • C07C57/15—Fumaric acid
• • 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
  • C07B2200/11—Compounds covalently bound to a solid support
• • 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

Definitions

• the present disclosure concerns a process for preparing the compound (+)-3-(2,3- difluorophenyl)-3-methoxypyrrolidine, or a pharmaceutically acceptable salt thereof, in high chemical and/or enantiomeric purity.
• the present disclosure also concerns a combination of (-)-dibenzoyl-Z. -tartaric acid and 3-(2,3-difluorophenyl)-3- methoxypyrrolidine as an intermediate in the synthesis of (+)-3-(2,3-difluorophenyl)-3- methoxypyrrolidine.
• the present disclosure concerns a fumaric acid salt of the compound (+)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine, a method for preparation thereof as well as uses thereof.
• the cerebral cortex encompasses several major regions that are involved in higher functions such as thought, feelings, memory and planning.
• Biogenic amines i.e.
• dopamine, norepinephrine and serotonin are important for mammalian cortical function.
• the ascending dopamine and norepinephrine pathways innervate the cortex.
• the serotonergic neurons of the CNS project to virtually all regions of the brain including the cerebral cortex.
• Primary or secondary dysfunctions in the activity of these pathways lead to dysregulation of the activity at dopamine and norepinephrine and serotonin receptors in these brain areas and subsequently to manifestations of psychiatric and neurological symptoms.
• the biogenic amines of the cortex modulate several aspects of cortical functions controlling affect, anxiety, motivation, cognition, attention, arousal and wakefulness.
• the catecholamines dopamine and norepinephrine exert strong influence on the prefrontal cortical areas, the integrity of which is essential for the so-called executive cognitive functions, related to e.g. attention, planning of actions and impulse control.
• Norepinephrine is a major part in the circuitry regulating anxiety and fear and is thus believed to be dysregulated in anxiety disorders such as panic disorders, generalized anxiety disorder (GAD) and specific phobias.
• GAD generalized anxiety disorder
• specific phobias Concerning mood and affective functions, the usefulness of compounds facilitating particularly norepinephrine and serotonin neurotransmission in the treatment of depression and anxiety has strongly contributed to the widely-accepted concept that these neurotransmitters are both involved in the regulation of affective functions.
• the monoamine systems in the cortex are known to be directly or indirectly involved in the core symptoms of schizophrenia.
• this disorder emerges as various pathological etiologies converge upon cortical function leading to dysregulation of the cortical micro-circuitry, which is clinically manifested as the symptoms of schizophrenia.
• This cortical micro-circuitry is regulated by several neurotransmitters, including glutamate, GABA, and dopamine.
• WO 2010/058018 discloses 3-phenyl-3-methoxy-pyrrolidine derivatives useful for modulating extracellular levels of catecholamines, dopamine and norepinephrine, in cerebral cortical areas of the mammalian brain, and more specifically for the treatment of central nervous system disorders.
• the compound 3-(2,3-difluorophenyl)-3- methoxypyrrolidine is disclosed in the form as a racemate, and as the corresponding (+)- and (-) enantiomers, respectively.
• the racemate is disclosed in its non-salt form
• enantiomers of chiral drugs frequently interact differently with chiral macromolecules such as receptors and/or enzymes in the human body, and therefore may exhibit differences in biological activities such as pharmacology, toxicology, and pharmacokinetics. Consequently, it is desirable to develop and launch a new drug as 5 a single enantiomer rather than as a racemic mixture so as to fully take advantage of the pharmacodynamic and pharmacokinetic properties of the drug and/or avoid possible drawbacks associated with the racemic mixture. Further, it is desirable to have knowledge of the three-dimensional arrangement of a chiral molecule such as an enantiomer of an investigational drug in order to increase the understanding of its interaction with enzymes, 10 receptors etc.
• the drug has to be provided in a form making it suitable for handling during, for instance, storage and transportation.
• (+)-3-(2,3-difluorophenyl)-3- 35 methoxypyrrolidine, or a pharmaceutically acceptable salt thereof, and/or enable industrial production thereof there remains a need for alternative methods. Further, there is a need for a form of (+)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine exhibiting satisfactory pharmaceutical properties as well as satisfactory handling and drug properties, in particular on an industrial scale.
• Figure 1 shows an XRPD spectrum of the salt of Formula lib.
• Figure 2 shows the chemical structure of haloperidol.
• the present disclosure provides a salt of Formula lib:
• the present disclosure also provides a process for manufacturing a salt of Formula lib said process comprising:
• the present disclosure also provides a process for manufacturing a compound of Formula II:
• the present disclosure also provides a method for manufacturing a compound of Formula I as described herein:
• said method comprising the steps of:
• M represents an alkali metal or an alkaline earth metal halide
• PG represents a protecting group such as ief-butoxycarbonyl
• the present disclosure also provides a pharmaceutical composition
• a pharmaceutical composition comprising:
• the present disclosure also provides
• a disease, disorder and/or condition which is at least one of the following: dementia, age-related cognitive impairment, Autism spectrum disorder, ADHD, Cerebral Palsy, Huntington's disease, Gilles de la Tourette's syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, generalized anxiety disorder (GAD), specific phobia, panic disorder, sleep disorder, bipolar disorder, drug induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinosis, non- iatrogenic psychosis, non-iatrogenic hallucinose, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, emotional disturbances related to ageing, Alzheimer's disease, Parkinson ' s disease dementia, behavioural and psychological symptoms of dementia, substance abuse, disorders characterized by misuse of food, sexual disorders, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, movement disorder, Parkinson's disease, Parkinsonism, parkinsonian syndromes, dyskines
• neurodevelopmental disorder neurodegenerative disorder, tics, tremor, restless legs, narcolepsy, behavioural disorder.
• the present disclosure also provides use of a salt of Formula Ila, Formula Ila ' , Formula lib or Formula lib ' as described herein; or
• a disease, disorder and/or condition which is at least one of the following: dementia, age- related cognitive impairment, Autism spectrum disorder, ADHD, Cerebral Palsy,
• the present disclosure also provides a method for treatment and/or prevention of a disease, disorder and/or condition which is at least one of the following: dementia, age- related cognitive impairment, Autism spectrum disorder, ADHD, Cerebral Palsy,
• the present disclosure provides a salt of Formula lib:
• the salt of Formula lib is a combination of a compound of Formula II and fumaric acid in a 1 :1 ratio.
• the salt of Formula lib is a fumaric acid salt of the compound of Formula II wherein the ratio of the fumaric acid and the compound of Formula II is 1 :1.
• Formula II Fumaric acid The salt of Formula lib is pharmaceutically acceptable and has unexpectedly been found to exhibit properties of high crystallinity (i.e. being substantially crystalline), not being hygroscopic, not changing in its crystalline phase at any tested relative humidity, high melting point and/or acceptable aqueous solubility profile. Furthermore, the salt of Formula lib can be isolated in good chemical yield with a high purity.
• a salt of Formula lib as described herein characterized by being crystalline.
• the crystallinity may be determined by XRPD or any other appropriate method.
• the high crystallinity of the salt of Formula lib which makes it well-defined with respect to, for instance, melting point and XRPD, is a benefit in making tablets and is believed to enhance storage stability.
• high crystallinity intends a degree of crystallinity of about 80% or more such as about 85%, about 90%, about 95%, about 99% or about 100% as measured by XPRD or any other appropriate method of measurement.
• the salt of Formula lib is not hygroscopic since it allows for storage without being changed by surrounding humidity. It has been found that the salt of Formula l ib changes its weight by ⁇ 0.2 % by weight or less at any humidity such as any relative humidity as described herein, i.e. it is not hygroscopic or substantially not hygroscopic. In an example, the salt of Formula l ib does not change its weight at any humidity such as any tested relative humidity.
• the salt of Formula l ib does not change its crystalline phase at any humidity such as any relative humidity as described herein making it storage stable.
• the high melting point of the salt of Formula l ib of about 164.1°C is a benefit in, for instance, tablet making.
• the water solubility of the salt of Formula l ib has been found to be 34 mg/mL and/or 74.1 mg/mL at room temperature as measured in a regular water solubility test and flask method water solubility test, respectively, as described in the Examples section of this document making it suitable for any administration to a human, such as oral administration.
• the humidity such as any relative humidity may be within the range of from about 0 to about 100%.
• the humidity such as the relative humidity may be within the range of from about 0 to about 97%.
• the humidity such as the relative humidity may be equal to or above at least one of the following: about 0%, about 6%, about 1 1 %, about 22%, about 32%, about 43%, about 56%, about 73%, about 84%, about 97%.
• the humidity such as the relative humidity may be measured at a temperature within the range of from about 20°C to about 50°C.
• the humidity such as the relative humidity may be about 30°C.
• the weight of the salt of Formula lib may be determined after storage for about one week at a humidity such as a relative humidity as described herein and/or at a temperature as described herein.
• a salt of Formula lib as described herein having a melting point of from about 163°C to about 165°C such as about 164.1 °C.
• the melting point may be determined by differential scanning calorimethry (DSC).
• the salt of Formula lib described herein may have a a water solubility from about 30mg/ml_ to about 80 mg/mL as determined by the regular water solubility test method and/or the flask method water solubility test described in the Examples section of this document.
• the water solubility of the salt of Formula lib may be 34 mg/mL as determined by the regular water solubility method described herein and/or 74.1 mg/mL as determined by the flask method water solubility test described herein.
• the water solubility may be measured at room temperature, i.e. a temperature within the range of from about 22°C to about 25°C.
• the relative humidity intends the ratio of the partial pressure of water vapour to the equilibrium pressure of water at a given temperature and at atmospheric pressure.
• the salt of Formula lib may be characterized by an XRPD diffractogram comprising a peak at about 23.16 2 ⁇ , and optionally at least one further peak selected from the following: about 6.66 such as about 6.7, about 13.41 such as about 13.4, about 27.79 such as about 27.8, about 29.38 such as about 29.4 2 ⁇ .
• the salt of Formula lib may also be characterized by an XRPD diffractogram comprising a peak at about 6.66, about 13.41 , about 23.16, about 27.79, about 29.38 2 ⁇ , and optionally at least one further peak selected from the following: about 16.27, about 34.02 2 ⁇ .
• the XRPD diffractogram may comprise peaks at about 6.7, about 13.4, about 23.2, about 27.8 and about 29.4 2 ⁇ .
• the salt of Formula lib may also be characterized by an XRPD diffractogram comprising a peak at about about 6.66, about 13.41 , about 16.27, about 23.16, about 27.79, about 29.38, about 34.02 2 ⁇ , and optionally at least one further peak selected from the following: about 16.42, about 21.69 2 ⁇ .
• the salt of Formula lib may be characterized by an XRPD diffractogram substantially as shown in Figure 1.
• the compound of Formula II may be combined with fumaric acid in a 2:1 ratio thereb forming a salt of Formula lib ' :
• the salt of Formula lib ' may be manufactured using a process as described herein.
• the present disclosure provides a process for manufacturing the salt of Formula lib:
• the salt of Formula lib may also be prepared by combining fumaric acid with a compound of Formula II, which compound of Formula II has been prepared using a chiral resolution process different from the one described herein.
• the compound of Formula II may be prepared by fractional crystallization of a diastereomeric salt of a compound of Formula I which is different from the salt with (-)- dibenzoyl-Z.
• -tartaric acid such as for instance a salt with other tartrate derivatives such as (-)-di-p-toluyl-Z- -tartaric acid.
• resolution procedures for preparing the compound of Formula II may be a resolution procedure utilizing a derivative of the compound of Formula I rather than the compound of Formula I itself such as for instance utilizing an N- benzyl derivative of a compound of Formula I.
• Such a procedure may comprise a fractional crystallization step utilizing a diastereomeric salt such as for instance a salt with (-)-dibenzoyl-Z- -tartaric acid, and/or the procedure may comprise a chromatographic separation step as depicted in Scheme 1.
• a resolution procedure comprising a chromatographic separation step may be a process where the two enantiomers of a compound of Formula I are directly separated on a chiral column for chromatography.
• the compound of Formula II may be prepared using asymmetric synthesis or by any other method known in the art.
• the present disclosure also provides a process for manufacturing a compound of Formula
• the compound of Formula I described herein is an enantiomeric mixture.
• the enantiomeric mixture may be a racemate, i.e. a 50:50 mixture of
• the compound of Formula I is also denominated 3-(2,3- difluorophenyl)-3-methoxypyrrolidine.
• the compound of Formula II described herein is the (+)- enantiomer of the compound of Formula I and is substantially enantiomerically pure, i.e. it is substantially free of the (-)-enantiomer of the compound of Formula I and may have an enantiomeric excess of about 95% or more such as 96%, 97%, 98% or 99%.
• the compound of Formula II is also denominated (+)-3-(2,3-difluorophenyl)-3- methoxypyrrolidine.
• the pharmaceutically acceptable salts of the compound of Formula II may be acid addition salts selected from the group consisting of: hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate,
• the pharmaceutically acceptable salt may be a fumarate salt formed from fumaric acid and the compound of Formula II.
• the compound of Formula II, or a pharmaceutically acceptable salt thereof comprise chiral resolution, wherein said chiral resolution may include the steps of:
• step a) may be performed during heating in order to dissolve the (-)- dibenzoyl-Z. -tartaric acid in the at least one solvent.
• step b) may then be performed while the first solution is warm.
• the salt of Formula Ila will precipitate from said second solution.
• the salt of Formula Ila may precipitate from said second solution using other known crystallization techniques known in the art such as addition of a seed crystal.
• the salt of Formula Ila may subsequently be washed with the at least one further solvent and/or dried.
• the at least one solvent and/or the at least one further solvent as described herein may be selected from the group consisting of: methanol, ethanol, 1 -propanol, 2-propanol, 1 - butanol, 2-butanol, and any combination thereof.
• the at least one solvent and/or the at least one further solvent may consist of or comprise ethanol.
• the treatment with the base of the process described herein may comprise the steps of: - mixing the compound of Formula Ila with a mixture of a first water-insoluble solvent and an aqueous solution comprising a base, thereby forming:
• a water-insoluble solvent intends an organic solvent or mixture of organic solvents that is/are substantially immiscible with water.
• water- insoluble solvents include dichloromethane and methyl tert-butyl ether.
• the base described herein may consist of or comprise a carbonate such as sodium carbonate and/or potassium carbonate, and/or
• the first water-insoluble solvent and/or the second water-insoluble solvent consist(s) of or comprise(s) dichloromethane.
• the molar ratio between the compound of Formula I and the (-)-dibenzoyl-Z- -tartaric acid may be within the range of from about 1.9:1 to about 2.1 : such as 2:1 .
• the salt of Formula Ilb ' may be precipitated from an ethanol solution comprising the compound of Formula II and (-)-dibenzoyl-L-tartaric acid.
• the process described herein may provide the salt of Formula lib, and/or the compound of Formula II, or a pharmaceutically acceptable salt thereof , in high enantiomeric purity.
• the enantiomeric excess may be 95% or higher such as 96, 97, 98 or 99 %.
• enantiomeric excess (ee) intends the percentage of the (+)-enantiomer of Formula I or a salt thereof minus the percentage of the (-)- enantiomer of Formula I or a salt thereof. For example, if a mixture contains 98 mole % of a (+)-enantiomer and 2 mole % of a (-)-enantiomer the enantiomeric excess is 96%.
• the present disclosure provides for manufacturing the salt of Formula lib and/or the compound of Formula II, or a pharmaceutically acceptable salt thereof, such as a salt in high chemical purity, such as 95% or more as measured by HPLC or any other appropriate method, by incorporating into the process described herein the following method steps for preparing the compound of Formula I:
• M represents an alkali metal or an alkaline earth metal halide
• PG represents a protecting group such as ief-butoxycarbonyl
• the method steps above substantially prevent the formation of impurities such as a compound of Formula VIII thereby avoiding or minimizing the need for additional purification steps.
• impurities such as a compound of Formula VIII
• the compound of Formula VIII formed when ief-butyl 3-oxopyrrolidine-1-carboxylate was subjected to harsh basic conditions such as n-hexyllithium and was difficult to remove.
• the method described herein allows for providing the compound of Formula I in a chemical purity of about 98% or more as measured by, for instance, HPLC or NMR.
• the salt of Formula Ila comprises a combination of the compound of Formula II as described herein with (-)-dibenzoyl-Z. -tartaric acid in a ratio of 2:1. Additionally or alternatively, the compound of Formula II as described herein may be combined with (-)- dibenzoyl-Z. -tartaric acid in a ratio of 1 :1 thereby providing a compound of Formula Ila ' :
• the salt of Formula Ila may be used as an intermediate in the manufacturing of the compound of Formula II. Additionally or alternatively, the salt of Formula Ila may also be used as an intermediate in the manufacturing of a pharmaceutically acceptable salt of the compound of Formula II such as in the manufacturing of a salt of Formula lib. For instance, the salt of Formula Ila may also be used as an intermediate in the
• the salt of Formula Ila has superior properties for the resolution process described herein which provides a high chemical yield of the salt of Formula Ila with an unexpectedly high stereochemical purity already after one crystallization. Further, crystals of the salt of Formula Ila ' can be used for determining the absolute configuration of the two enantiomers of the compound of Formula II. Additionally or alternatively, the salt of Formula Ila or Formula Ila ' may be used as a medicament such as a medicament for the treatment of the diseases and/or disorders described herein.
• composition comprising:
• a disease, disorder and/or condition which is at least one of the following: dementia, age-related cognitive impairment, Autism spectrum disorder, ADHD, Cerebral Palsy, Huntington's disease, Gilles de la Tourette's syndrome, depression, bipolar disorder, schizophrenia, schizophreniform disorder, generalized anxiety disorder (GAD), specific phobia, panic disorder, sleep disorder, bipolar disorder, drug induced psychotic disorder, iatrogenic psychosis, iatrogenic hallucinosis, non- iatrogenic psychosis, non-iatrogenic hallucinose, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, emotional disturbances related to ageing, Alzheimer's disease, Parkinson ' s disease dementia, behavioural and psychological symptoms of dementia, substance abuse, disorders characterized by misuse of food, sexual disorders, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, movement disorder, Parkinson's disease, Parkinsonism, parkinsonian syndromes, dyskines
• neurodevelopmental disorder neurodegenerative disorder, tics, tremor, restless legs, narcolepsy, behavioural disorder.
• a disease, disorder and/or condition which is Parkinson ' s disease dementia, behavioural and/or psychological symptoms of dementia.
• a disease, disorder and/or condition which is at least one of the following: dementia, age- related cognitive impairment, Autism spectrum disorder, ADHD, Cerebral Palsy,
• a disease, disorder and/or condition which is Parkinson ' s disease dementia, behavioural and/or psychological symptoms of dementia.
• a disease, disorder and/or condition which is at least one of the following: dementia, age-related cognitive impairment, Autism spectrum disorder, ADHD, Cerebral Palsy, Huntington's disease, Gilles de la Tourette's syndrome, depression, bipolar disorder, schizophrenia,
• schizophreniform disorder generalized anxiety disorder (GAD), specific phobia, panic disorder, sleep disorder, bipolar disorder, drug induced psychotic disorder, iatrogenic psychosis, Iatrogenic hallucinosis, non- iatrogenic psychosis, non-iatrogenic hailucinose, mood disorder, anxiety disorder, depression, obsessive-compulsive disease, emotional disturbances related to ageing, Alzheimer's disease, Parkinson ' s disease dementia, behavioural and psychological symptoms of dementia, brain injury, substance abuse, disorders characterized by misuse of food, sexual disorders, eating disorder, obesity, headache, pains in conditions characterized by increased muscular tone, movement disorder, Parkinson's disease, Parkinsonism, parkinsonian syndromes, dyskinesia, L- DOPA induced dyskinesia, dystonia, neurodevelopmental disorder, neurodegenerative disorder, tics, tremor, restless legs, narcolepsy, behavioural disorder;
• GAD generalized anxiety disorder
• specific phobia panic disorder
• sleep disorder sleep disorder
• a compound of Formula II or a pharmaceutically acceptable salt thereof, obtainable by the process described herein.
• a method for treatment and/or prevention of a disease, disorder and/or condition which is Parkinson ' s disease dementia, behavioural and/or psychological symptoms of dementia,
• the diseases, disorders and/or conditions described herein are associated at least partly with the sigma-1 -receptor (i.e. ⁇ -1 -receptor), said receptor being expressed in many tissue types and being particularly concentrated in certain regions of the central nervous system. Therefore, it is believed that a compound or salt thereof as described herein that exhibits interaction with the sigma-1 -receptor is useful in the treatment and/or prevention of a disease, disorder and/or condition as described herein.
• the compounds and salts thereof as described herein are considered useful in the treatment and/or prevention of the diseases, disorders and/or conditions described herein when they interact with the sigma-1 -receptor in a radioligand binding assay as described in this document to displace at least about 50%, at least about 60% or at least about 70% of haloperidol.
• the present disclosure also provides a method for preparing a compound of Formula I, said method comprising the steps of:
• M represents an alkali metal or an alkaline earth metal halide
• PG represents a protecting group such as ie f-butoxycarbonyl
• the compound of Formula IV when the compound of Formula IV is a Grignard reagent it may be prepared as known in the art. In particular, it may be prepared using a Grignard reagent as described in EP 1 582 524 A1 , which is incorporated herein by reference.
• M of the compound of Formula IV may be (MgX) n LiY wherein X and Y may be CI, Br or I.
• the method steps above substantially prevent the formation of impurities such as formation of a compound of Formula VIII described herein thereby avoiding or minimizing the need for additional purification steps.
• the method may provide the compound of Formula I in a chemical purity of about 98% or more as measured by, for instance, HPLC or NMR.
• the conversion of the compound of Formula VI into the compound of Formula VII may be performed using standard procedures such as using methyl iodide in the presence of a base such as potassium ie f-butoxide.
• the removal of the protecting group may be performed using standard procedures such as using acid conditions such as in the presence of strong acidic conditions. Salts
• the chemical structure of the salts comprising a combination of the compound of Formula II and an acid have been drawn as a complex wherein the acidic proton(s) of the acid is attached to the acid.
• the acidic proton(s) of the acid may be attached to the nitrogen atom of the compound of Formula II and/or shared between the nitrogen atom of the compound of Formula II and the acid, and this is also intended to be encompassed by the complexes described herein.
• the salt of Formula lib may also be represented as:
• the salt of Formula Ila may be represented as:
• the compounds or salts of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds or salts.
• a salt which is a combination of a compound as described herein with an acid as described herein
• the compound of said combination may contain one or more atomic isotopes, i.e. the compound may be labelled with an isotope.
• the compound may be labelled with an isotope.
• compounds may be labelled with one or more isotopes, such as for example tritium ( 3 H), deuterium ( 2 H), iodine-125 ( 125 l) or carbon-14 ( 14 C).
• the compound is labelled with one or more deuterium atoms. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.
• the present disclosure provides a compound as described herein, such as a compound of Formula I, a compound of Formula II, a compound of Formula IV, a compound of Formula V, a compound of Formula VI and/or a compound of Formula VII, which is labelled with one or more isotopes such as deuterium.
• the compounds labelled with an isotope as described herein may be combined with an acid as described herein thereby providing a salt as described herein.
• the compound of Formula II may be labelled with an isotope such as deuterium.
• an isotope such as deuterium.
• One or more hydrogen atoms of phenyl ring, the pyrrolidine ring and/or the methoxy group of the compound of Formula II may then be replaced with an isotope such as deuterium.
• X-ray crystallography was performed using a Bruker D8 Venture diffractometer equipped with a photon 100 CMOS detector. The crystal was mounted in a Kapton loop using silicone grease. Temperature: 123 K (open-flow nitrogen cooling device). Data were collected using Mo K-alpha radiation. The Apex suite of programs by Bruker were used for data-reduction.
• Hygroscopicity tests of the salts were performed by keeping exact weight samples of the different salts at varied humidity at 30°C. After one week, the samples were weighed again and based on the original weight the percentage weight difference was calculated.
• the unit of the solubility may be g/L or mg/mL. Flask method water solubility test
• a further water solubility test (Flask method water solubility test) was performed as follows. An excess of salt was added to water. The mixture was equilibrated (shaking) for at least 24 hours thereby providing a saturated salt solution. Then the saturated solution was clear-filtered and transferred into a clean pre-weighed flask (mv). The mass of flask + saturated solution (mvs) was recorded. The solvent was evaporated under reduced pressure until constant mass. Flask containing dried residue was weighed (mvdr). The solubility expressed as "grams of solute/kg of solvent", i.e. "grams of salt/ kg of solvent”, was calculated according to the equation:
• (mvdr-mv) is the weight difference in kg between (i) the mass of the flask containing dried residue after evaporation of the solvent and (ii) the mass of the flask, and
• (mvs-mvdr) is the weight difference in kg between (i) the mass of the flask including the saturated salt solution and (ii) the mass of the flask containing the dried residue. Since the solubility was measured in water, and water has a density of 1 g/mL the unit of the solubility may be g/L or mg/mL.
• the combined aqueous phases were cooled to 0 °C and 50% NaOH aqueous solution was added until a pH of 12.9 was obtained (approximately 50 mL).
• the cooling bath was removed and the basic aqueous phase was extracted twice with MTBE (120 mL and 60 mL).
• the combined organic layers were washed with water (60 mL) and then concentrated under reduced pressure until approximately 100 mL were left.
• Ethanol (100 mL) was added and distillation continued until approximately 100 mL were left.
• the addition and evaporation procedure with ethanol was repeated twice by adding 100 mL of fresh ethanol each time. Final distillation continued until the remaining volume approximately was 22 mL.
• the absolute configuration was determined for a combination of the compound of Formula II and (-)-dibenzoyl-L-tartaric acid in a 1 :1 ratio (i.e. the salt of Formula Ila ' ), which was synthesized in a similar manner as in Example 5, from single X-ray diffraction.
• the absolute configuration of the crystallographic model was correct and that Compound of Formula II is an S form.
• Formula lib Fumaric acid (1.77 g, 15.2 mmol) was dissolved in ethanol (99%, contains 1 % of methyl ethyl ketone) (54 mL) at room temperature.
• the solution of Compound (II) from Example 6 (3.25 g, 15.2 mmol) in ethanol (6 mL) was added to the acid solution.
• the flask was rinsed with ethanol (2.8 mL) and added to the reaction mixture.
• the reaction mixture was stirred at room temperature overnight and then at 0 to 5 °C for 2 hours.
• the precipitate was filtered and the filter cake was washed with ethanol (2 x 15 mL).
• X-ray powder diffraction analysis was performed on a sample of the crystals of the fumarate salt of (+)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine as prepared above according to standard methods using the instrument, equipment and the conditions described in the general description.
• the analysis provided the diffractogram depicted in Figure 1.
• the main characteristic peaks, with positions and relative intensities, have been extracted from the diffractogram in Figure 1 and is given below in Table 1 . It will be understood that the relative intensities of peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used so that the intensities in the XRD traces included herein are illustrative and not intended to be used for absolute comparison.
• Table 1 Positions and intensities of the major peaks in the XRP-diffractogram of the salt of Formula lib.
• the title salt was prepared according to the general procedure above, and precipitated when MTBE was added to an ethanol solution of the acid and the base.
• the salt was crystalline but the crystallization did not seem to have a purification effect.
• the title salt was prepared according to the general procedure above, and precipitated from an ethanol solution.
• the salt was crystalline.
• the title salt was prepared according to the general procedure above, and precipitated when ethyl acetate was added to an isopropanol solution of the acid and the base.
• the salt was crystalline.
• Solubility in water 159 mg/mL.
• the title salt was prepared according to the general procedure above, and precipitated from an ethanol solution.
• the salt was crystalline.
• Solubility in water 34 mg/mL.
• the value for water solubility of the fumaric acid salt was found to be 74.1 mg/mL when measured by the Flask method water solubility test.
• the title salt was prepared according to the general procedure above, and precipitated from an ethyl acetate solution of the acid and the base.
• the salt was crystalline.
• the title salt was prepared according to the general procedure above, and precipitated from an isopropanol solution of the acid and the base.
• the salt was crystalline.
• Solubility in water 132 mg/mL.
• the title salt was prepared according to the general procedure above, and precipitated from a diluted isopropanol solution of the acid and the base.
• the title salt was prepared according to the general procedure above, and precipitated when MTBE was added to an acetonitrile solution of the acid and the base.
• the salt was crystalline.
• Solubility in water 167 mg/mL.
• the title salt was prepared according to the general procedure above, and precipitated when methanol was added to an MTBE solution of the acid and the base.
• the salt was crystalline.
• Example 9 Example 1 1 and Example 13.
• the fumaric acid salt of (+)-3-(2,3-difluorophenyl)-3- 5 methoxypyrrolidine according to Example 1 1 does not adsorb or desorb water at any humidity.
• the salt has a very low hygroscopicity, i.e. a weight change of ⁇ 0.2 % or less, even when it is exposed to a very high relative humidity such as 73%, 83% or 97% for a week at 30°C.
• Nonspecific binding was determined in the presence of 10 ⁇ haloperidol. Following incubation, the samples were filtered under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCI using a 96-sample cell harvester (Unifilter, Packard). The filters were dried then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation 5 cocktail (Microscint 0, Packard).
• GF/B glass fiber filters
• the standard reference compound was haloperidol, which was tested in each experiment at several concentrations to obtain a competition curve from which its IC50 value was 10 calculated.
• test compound was tested in a single concentration at 1.0 E-5 M and in duplicate.
• the reported value in Table 3 is a mean value.
• Reference Example 19 (Reference compound disclosed in WO 2010/058018)
• Oxalic acid (6.9 g, 54.7 mmol) was added to a solution of (+)-3-(2,3-difluorophenyl)-3- methoxypyrrolidine (12.0g, 56.3 mmol) in methanol (200 mL). The mixture was heated to
• the fumaric acid salt of (+)-3-(2,3-difluorophenyl)-3- methoxypyrrolidine according to Example 1 1 has a solubility in water (74.1 mg/mL) that is about two-and-a-half fold higher than the aqueous solubility of the corresponding oxalic acid salt according to Reference Example 19 (28 mg/mL). Since drug dissolution is the rate-limiting step to absorption from the gastro-intestinal tract, the salt of Formula lib possesses significantly enhanced pharmaceutical properties as compared to the
• the fumaric acid salt of (+)-3-(2,3-difluorophenyl)-3- methoxypyrrolidine according to Example 1 1 has both satisfactory water solubility and hygroscopicity. Additionally, it has a melting point of 164.1 °C making it suitable for manufacturing of a pharmaceutical composition such as a tablet.

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