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
  • C07D207/06—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 radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• (R)- and (5)-2-methylpyrrolidine are starting materials useful in the synthesis of various pharmaceutical products.
• (i?)-2-methylpyrrolidine can be used to prepare many H 3 receptor ligands.
• the procedures previously developed either employ costly starting materials or require many tedious synthetic steps.
• Pu et al. (Org. Process Res. & Dev., 2005, 9, 45-50) discloses the preparation of (7?)-2-methylpyrrolidine L-tartrate by fractional crystallization of racemic 2- methylpyrrolidine in the presence of L-tartaric acid. Racemic 2-methylpyrrolidine costs approximately $20/gram.
• Van de Kuil et al. discloses a four (4) step synthesis of (7?)-2-methylpyrrolidine L-tartrate and (iS)-2-methylpyrrolidine D-tartrate from 2-methylpyrroline (approximately $5/gram).
• the process is disadvantageous for several reasons. First, the process requires the preparation of three intermediates, two of which must be isolated. Additionally, the process requires isolation of the intermediate HCl salt by in vacuo removal of glacial acetic acid and excess 37% aqueous hydrochloric acid, which is time consuming, expensive, and corrosive. Moreover, the synthesis requires isolation of an intermediate by two sequential flash distillations from potassium hydroxide.
• Ku et al. discloses a four (4) step synthesis of (7?)-2-methylpyrrolidine hydrochloride from TV-Boc-L-prolinol.
• the process is disadvantageous for several reasons. First, the process requires the preparation and isolation of three different synthetic intermediates. Second, the process employs the environmentally deleterious solvent dichloromethane, as well as corrosive gaseous hydrochloric acid and phosphoric acid. Third, the process employs expensive lithium iodide (approximately $13/gram). In addition, the resulting hydrochloride salt is very hygroscopic. Zhao et al. (J. Org.
• Chem., 2006, 71, 4336-4338) discloses a four (4) step synthesis of ( ⁇ )-2-methylpyrrolidine benzenesulfonate from N-Boc-L-proline.
• the process is disadvantageous for several reasons. First, the process requires the preparation and isolation of three (3) separate synthetic intermediates. Second, the process employs corrosive reagents such as phosphoric acid, boron trifluoride etherate, sodium hydroxide, sodium borohydride, and Super-Hydride®.
• (i?)-2-methylpyrrolidine L-tartrate and (5)-2- methylpyrrolidine D-tartrate can be prepared in two steps from inexpensive 2- methylpyrroline using non-corrosive reagents without the necessity of isolating any synthetic intermediates.
• the present invention provides processes for preparing (i?)-2-methylpyrrolidine L-tartrate, comprising the steps of:
• the hydrogenation catalyst is a platinum catalyst.
• the platinum catalyst is platinum (IV) oxide. More preferably, the platinum catalyst is 5% Pt- C.
• the alcohol solvent is a mixture of ethanol and methanol. More preferably, the alcohol solvent is a mixture of ethanol and methanol at a ratio of about 2:1 to about 3:1 (v/v).
• step (a) is performed at ambient temperature.
• the platinum catalyst is removed in step (b) by filtration.
• the isolated (i?)-2-methylpyrrolidine L-tartrate has an optical purity of at least 50% ee.
• the process further comprises the steps of:
• the process further comprises the step of reacting the isolated recrystallized (i?)-2-methylpyrrolidine L-tartrate with a base to provide (R)-2- methylpyrrolidine.
• the process further comprises the step of converting the prepared (R)-2- methylpyrrolidine L-tartrate into a pharmaceutical composition, preferably an H 3 receptor ligand, preferably 2-(6- ⁇ 2-[(2i?)-2-methyl-l-pyrrolidin-l-yl]ethyl ⁇ -2-naphthalen-2-yl)-2H- pyridazin-3-one:
• the present invention provides a process for preparing 6- ⁇ 4-[3- ((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl ⁇ -2H-pyridazin-3-one :
• the present invention also provides processes for preparing (S)-2- methylpyrrolidine D-tartrate, comprising the steps of: (a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;
• the hydrogenation catalyst is a platinum catalyst.
• the platinum catalyst is platinum (IV) oxide. More preferably, the platinum catalyst is 5% Pt- C.
• the alcohol solvent is a mixture of ethanol and methanol. More preferably, the alcohol solvent is a mixture of ethanol and methanol at a ratio of about 2:1 to about 3:1 (v/v).
• step (a) is performed at ambient temperature.
• the platinum catalyst is removed in step (b) by filtration.
• the isolated (5)-2-methylpyrrolidine D-tartrate has an optical purity of at least 50% ee.
• the process further comprises the steps of:
• the process further comprises the step of reacting the isolated recrystallized (5)-2-methylpyrrolidine D-tartrate with a base to provide (5)-2- methylpyrrolidine.
• the process further comprises the step of converting the prepared (5)-2- methylpyrrolidine D-tartrate into an H 3 receptor ligand, preferably 2-(6- ⁇ 2-[(2S)-2- methyl- 1 -pyrrolidin- 1 -yl] ethyl ⁇ -2-naphthalen-2-yl)-2H-pyridazin-3 -one :
• “about 50” includes ⁇ 10% of 50, or from 45 to 55.
• Alcohol solvent refers to a C ! -C 6 alkyl alcohol or a mixture of C ! -C 6 alkyl alcohols.
• Common scale refers to a single batch of at least about 500 grams.
• Crystalizing refers to causing crystals to form.
• H 3 receptor ligand refers to a compound that interacts with the histamine H 3 receptor as an antagonist, agonist, or partial agonist.
• Heterogeneous catalyst refers to a hydrogenation catalyst that is not soluble in an alcohol solvent.
• Homogeneous catalyst refers to a hydrogenation catalyst that is soluble in an alcohol solvent.
• Hydrogenation catalyst refers to a composition suitable for catalyzing the reaction of 2- methylpyrroline with hydrogen to form 2-methylpyrrolidine.
• Isolating refers to separating a component (e.g., a reagent or product) from a mixture.
• Optical purity refers to the proportion of one enantiomer in a mixture of enantiomers, and is expressed as enantiomeric excess (% ee), which is defined as (
• “Pharmaceutical product” refers to a compound or composition that can be used to treat a disease, condition, or disorder in a human.
• Platinum catalyst refers to a hydrogenation catalyst that contains platinum. “Purifying” refers to increasing the purity of a compound. “Purity” refers to the percentage by weight of one component in a mixture.
• Solution refers to a solvent containing a substance(s) that is at least partially dissolved; and which may contain an undissolved (e.g., solid) substance(s).
• the present invention provides processes for preparing (i?)-2-methylpyrrolidine L- tartrate or (iS)-2-methylpyrrolidine D-tartrate, comprising the steps of:
• step (a) 2-methylpyrroline is hydrogenated in a mixture comprising an alkyl alcohol solvent and a hydrogenation catalyst.
• the 2-methylpyrroline used in the hydrogenation reaction may be purchased from commercial sources (e.g., Sigma-Aldrich Corp.; St. Louis, MO).
• An important benefit of the present process is that 2- methylpyrroline is less expensive than other starting materials used for the production of (R)- and (S)-2-methylpyrrolidine.
• the hydrogenation catalyst used in the reaction may be purchased from commercial sources (e.g., Sigma-Aldrich Corp.; St. Louis, MO).
• the hydrogenation catalyst can be a homogeneous catalyst or a heterogeneous catalyst.
• Examples of hydrogenation catalysts include, but are not limited to, platinum catalysts.
• Examples of platinum catalysts include, but are not limited to, platinum on carbon (Pt/C), platinum (IV) oxide, and mixtures thereof.
• Examples of homogeneous catalysts include, but are not limited to, chlorotris(triphenylphosphine)rhodium (Wilkinson's catalysts) and catalysts disclosed in U.S. Patent Nos. 4,581,417, 4,631,315, and 5,670,437.
• the hydrogenation catalyst is platinum (IV) oxide. More preferably, the hydrogenation catalyst is 5% Pt-C.
• the alcohol solvent used in the reaction is a Cj-C ⁇ alkyl alcohol or a mixture Of C 1 - Qalkyl alcohols. Examples of d-C 6 alkyl alcohols include, but are not limited to, methanol, ethanol, isopropanol, and n-butanol.
• the alcohol solvent comprises ethanol.
• the alcohol solvent comprises methanol. More preferably, the alcohol solvent is a mixture of ethanol and methanol. More preferably, the alcohol solvent is a mixture of ethanol and methanol at a ratio of about 0.5:1 to about 10:1 (v/v).
• the alcohol solvent is a mixture of ethanol and methanol at a ratio of about 1 :1 to about 5:1 (v/v). More preferably, the alcohol solvent is a mixture of ethanol and methanol at a ratio of about 2:1 to about 3:1 (v/v). More preferably, the alcohol solvent is a mixture of ethanol and methanol at a ratio of about 2.4: 1 (v/v).
• the alcohol solvent may be present in any suitable amount in the step (a) reaction mixture.
• the alcohol solvent comprises at least about 50% (w/w) of the reaction mixture. More preferably, the alcohol solvent comprises at least about 70% (w/w) of the reaction mixture. More preferably, the alcohol solvent comprises at least about 90% (w/w) of the reaction mixture. More preferably, the alcohol solvent comprises at least about 95% (w/w) of the reaction mixture.
• C ! -C 6 alkyl alcohols are more readily removed from the reaction mixture as compared to acetic acid.
• Ci- C 6 alkyl alcohols are non-corrosive.
• the hydrogen (H 2 ) used in the hydrogenation reaction may be added to the reaction mixture as a gas, such as by performing the reaction in a hydrogen atmosphere, or generated in situ, such as by treatment OfH 2 PtCl 6 or RhCl 3 with NaBH 4 (see Brown and Sivasankaran, J. Am. Chem. Soc. 1962, 84, 2828).
• the hydrogenation reaction is performed by adding gaseous hydrogen to the reaction mixture.
• the hydrogenation is performed above atmospheric pressure.
• the reaction is performed by generating hydrogen in situ.
• the hydrogenation reaction may be performed at any suitable temperature. Preferably, the reaction is performed at ambient temperature.
• An advantage of the present process is that the hydrogenation reaction is performed in a non-corrosive alkyl alcohol solvent.
• Another advantage of the present process is that the product of the hydrogenation reaction (i.e., 2-methylpyrrolidine) is obtained directly without the need to prepare or isolate intermediates, such as intermediate salts.
• Step ( ⁇ ) Step (b) is an optional step.
• the hydrogenation catalyst is removed from the hydrogenation reaction mixture.
• the hydrogenation catalyst is removed from the hydrogenation reaction mixture after step (a).
• step (b) is performed prior to step (d), particularly when the hydrogenation catalyst is a heterogeneous catalyst.
• Suitable methods for removing the hydrogenation catalyst include, but are not limited to, filtering, decanting, and centrifuging.
• the hydrogenation catalyst is removed by filtration.
• hydrogenation catalysts are generally precious metal-based
• an advantage of the present process is that the hydrogenation catalyst may be removed from the mixture, recycled and reused in subsequent hydrogenation reactions ⁇ see, e.g., US 5,554,353 (Schneider et al.); EP 1 739 104 Al (Kobayashi et al.); Setty-Fichman, et al., J MoI. Cat. A: Chem., 1999, 144(1), 159-163.
• Step (c) L-tartaric acid or D-tartaric acid is dissolved in the hydrogenation reaction mixture to form a solution. If the desired product is (i?)-2-methylpyrrolidine, then L-tartaric acid is used. If the desired product is (S)-2-methylpyrrolidine, then D-tartaric acid is used.
• the L-tartaric acid or D-tartaric acid used in the present process may be purchased from commercial sources (e.g., Sigma-Aldrich Corp.; St. Louis, MO).
• the solution formed in step (e) is homogeneous. If the solution is not homogeneous (e.g., contains undissolved particles), the solution is preferably heated to promote dissolution.
• An advantage of the present process is that it does not require the 2- methylpyrrolidine prepared in the hydrogenation reaction to be isolated from the reaction mixture before the addition of tartaric acid. This makes the process simpler, faster, less expensive, and less wasteful as compared to prior art processes.
• step (d) ( ⁇ )-2-methylpyrrolidine L-tartrate or (5)-2-methylpyrrolidine D-tartrate is crystallized from the solution prepared in step (c). If L-tartaric acid is added in step (c), then (Z?)-2-methylpyrrolidine L-tartrate is crystallized from the solution in step (d). IfD- tartaric acid is added in step (c), then (5)-2-methylpyrrolidine D-tartrate is crystallized from the solution in step (d). Any suitable method may be used to crystallize (R)-2- methylpyrrolidine L-tartrate or (5)-2-methylpyrrolidine D-tartrate from the solution. In certain embodiments, the solution is heated to promote dissolution, and then cooled to induce crystallization.
• Step Ce In step (e), the crystalline (i?)-2-methylpyrrolidine L-tartrate or (S)-2- methylpyrrolidine D-tartrate is isolated. If L-tartaric acid is added in step (c), then (R)-2- methylpyrrolidine L-tartrate is crystallized from the solution in step (d) and isolated in step (e). If D-tartaric acid is added in step (c), then (5)-2-methylpyrrolidine D-tartrate is crystallized from the solution in step (d) and isolated in step (e).
• Suitable methods for isolating the crystalline (i?)-2-methylpyrrolidine L-tartrate or (5)-2-methylpyrrolidine D- tartrate include, but are not limited to, filtering, decanting, and centrifuging.
• An advantage of the present process is that the product can be isolated by simple filtration.
• the (i?)-2-methylpyrrolidine L-tartrate or (5)-2-methylpyrrolidine D-tartrate is isolated by filtration.
• the isolated (i?)-2-methylpyrrolidine L-tartrate is likely to contain some (5)-2-methylpyrrolidine L-tartrate
• the isolated (S)-2-methylpyrrolidine D-tartrate is likely to contain some (i?)-2-methylpyrrolidine D-tartrate, which will reduce the optical purity of the isolated product.
• the isolated (i?)-2-methylpyrrolidine L-tartrate or (5)-2-methylpyrrolidine D-tartrate has an optical purity of at least 40% ee. More preferably, the isolated (i?)-2-methylpyrrolidine L-tartrate or (5)-2- methylpyrrolidine D-tartrate has an optical purity of at least 50% ee. More preferably, the isolated (7?)-2-methylpyrrolidine L-tartrate or (5)-2-methylpyrrolidine D-tartrate has an optical purity of at least 55% ee.
• the present process for preparing (i?)-2-methylpyrrolidine L-tartrate or (S)-2- methylpyrrolidine D-tartrate is advantageous in that it utilizes inexpensive and non- corrosive reagents and solvents, can be conveniently and inexpensively conducted at temperatures between 0 0 C and 25 °C, requires the preparation of only one intermediate compound, does not require the isolation of synthetic intermediates, permits catalyst recycling, and provides a product that can be isolated by simple filtration and then used in subsequent processes.
• the isolated product is a tartrate acid addition salt of (R)- or (S)-2- methylpyrrolidine free base.
• the salt may be converted to (R)- or (S)-2- methylpyrrolidine free base.
• the resulting free base may be isolated using techniques known in the art.
• the free base may be generated in situ and used in the next synthetic step without isolation. The methods described herein are applicable to both the isolated 2-methylpyrrolidine free base and the 2-methylpyrrolidine free base generated in situ in a reaction mixture.
• the process further comprises the step of: reacting the isolated (i?)-2 -methylpyrrolidine L-tartrate or (5)-2-methylpyrrolidine D-tartrate with a base to provide (i?)-2-methylpyrrolidine or (5)-2-methylpyrrolidine.
• bases for use in this reaction include, but are not limited to, ammonium hydroxide, alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkylamines (e.g., triethylamine, diisopropylethylamine), and mixtures thereof.
• Suitable solvents for use in this reaction include, but are not limited to, diethyl ether and dichloromethane.
• the 2-methylpyrrolidine free base can be generated from the corresponding tartrate salt using ion-exchange resin using procedures known to those in the art.
• the process may further comprise the steps of:
• Step ffl the (7?)-2-methylpyrrolidine L-tartrate or (5)-2-methylpyrrolidine D- tartrate isolated in step (e) is recrystallized.
• Suitable methods for recrystallizing the isolated (i?)-2-methylpyrrolidine L-tartrate or (5)-2-methylpyrrolidine D-tartrate include, but are not limited to, dissolving the isolated tartrate salt in a suitable solvent and then cooling the solution to promote crystallization.
• Suitable recrystallization solvents include, but are not limited to, alcohol solvents.
• the recrystallization solvent is an alcohol solvent comprising at least about 70% (v/v) of ethanol and methanol.
• the recrystallization solvent is an alcohol solvent comprising at least about 70% (v/v) of ethanol and methanol at a ratio of about 1:1 to about 5:1 (v/v). More preferably, the recrystallization solvent is an alcohol solvent comprising at least about 70% (v/v) of ethanol and methanol at a ratio of about 2:1 to about 3:1 (v/v). More preferably, the recrystallization solvent is an alcohol solvent comprising at least about 90% (v/v) of ethanol and methanol. More preferably, the recrystallization solvent is an alcohol solvent comprising at least about 90% (v/v) of ethanol and methanol at a ratio of about 1 :1 to about 5:1 (v/v). More preferably, the recrystallization solvent is an alcohol solvent comprising at least about 90% (v/v) of ethanol and methanol at a ratio of about 2:1 to about 3:1 (v/v).
• Step (g) the recrystallized (i?)-2-methylpyrrolidine L-tartrate or (S)-2- methylpyrrolidine D-tartrate is isolated.
• Suitable methods for isolating the recrystallized tartrate salt include, but are not limited to, filtering, decanting, and centrifuging.
• the recrystallized (/?)-2-methylpyrrolidine L-tartrate or (5)-2-methylpyrrolidine D-tartrate is isolated by filtration.
• step (e) Subjecting the tartrate salt isolated in step (e) to a single recrystallization sequence according to steps (f) and (g) preferably provides isolated (/?)-2-methylpyrrolidine L- tartrate or (5)-2-methylpyrrolidine D-tartrate having an optical purity of at least 80% ee. More preferably, the (i?)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D- tartrate isolated in step (g) has an optical purity of at least 85% ee.
• the recrystallization sequence (i.e., steps (f) and (g)) may be repeated one or more times to increase the optical purity of the (R)-2- methylpyrrolidine L-tartrate or (5)-2-methylpyrrolidine D-tartrate.
• the (i?)-2-methylpyrrolidine L-tartrate or (5)-2-methylpyrrolidine D- tartrate preferably has an optical purity of at least 90% ee.
• the isolated recrystallized (i?)-2-methylpyrrolidine L-tartrate or (iS)-2-methylpyrrolidine D-tartrate has an optical purity of at least 93% ee.
• the (R)-2- methylpyrrolidine L-tartrate or (5)-2-methylpyrrolidine D-tartrate preferably has an optical purity of at least 95% ee. More preferably, the isolated recrystallized (i?)-2- methylpyrrolidine L-tartrate or (5 r )-2-methylpyrrolidine D-tartrate has an optical purity of at least 97% ee. After four (4) recrystallizations, the (R)-2 -methylpyrrolidine L-tartrate or (iS)-2-methylpyrrolidine D-tartrate preferably has an optical purity of at least 98% ee.
• the process may further comprise the step of reacting the isolated recrystallized (R)-2 -methylpyrrolidine L-tartrate or (5)-2-methylpyrrolidine D-tartrate with a base to provide (R)-2 -methylpyrrolidine or (5)-2-methylpyrrolidine.
• Suitable bases for use in this reaction include, but are not limited to, ammonium hydroxide, alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkylamines (e.g., triethylamine, diisopropylethylamine), and mixtures thereof.
• Suitable solvents for use in this reaction include, but are not limited to, diethyl ether and dichloromethane.
• the 2-methylpyrrolidine free base can be generated from the corresponding tartrate salt using ion-exchange resin using procedures known to those in the art.
• the resulting free base may be isolated using techniques known in the art.
• the free base may be generated in situ and used in the next synthetic step without isolation. The methods described herein are applicable to both the isolated 2- methylpyrrolidine free base and the 2-methylpyrrolidine free base generated in situ in a reaction mixture.
• the present invention also provides methods for incorporating 2-methylpyrrolidine into other compounds, in particular, pharmaceutically useful compounds.
• the (R)-2 -methylpyrrolidine L-tartrate or (5)-2-methylpyrrolidine D-tartrate obtained after steps (e), (g) or (h) may be used.
• an initial step in the conversion may be to transform the (R)-2- methylpyrrolidine L-tartrate or (iS)-2-methylpyrrolidine D-tartrate salt form into the corresponding free base form (i.e., (i?)-2-methylpyrrolidine or (5)-2-methylpyrrolidine, respectively) by reaction with a base or an ion exchange resin.
• This (R)-2- methylpyrrolidine or ( 1 S)-2-methylpyrrolidine, whether isolated or prepared in situ may then be used to prepare a number of pharmaceutical compounds, for example, histamine-3 receptor ligands, known in the art.
• the (/?)-2-methylpyrrolidine or (5)-2-methylpyrrolidine prepared by the foregoing processes may be converted into an H 3 receptor antagonist and/or inverse agonist of formula (I):
• R 2 is or a pharmaceutically acceptable salt thereof.
• Suitable methods for preparing a compound of formula (I) from 2- methylpyrrolidine are described in WO 2007/009741, and may be adapted for use with the (i?)-2-methylpyrrolidine or (iS)-2-methylpyrrolidine prepared in accordance with foregoing processes. For example, a solution of 1,1 dimethylethyl 4- ⁇ 4-[(3- chloropropyl)oxy]phenyl ⁇ -3-oxo-l-piperazinecarboxylate dissolved in 2 butanone may be provided.
• R z is (/. e. , the compound 1 , 1 -dimethylethyl 4-(4- ⁇ [3-
• the amine of formula (III) can then be reacted with a carboxylic acid chosen from 4-cyanobenzoic acid, 4-(l-azetidinylcarbonyl)benzoic acid, 2,4-difluorobenzoic acid, 3,5-difluorobenzoic acid, 4-fluorobenzoic acid, 1-methyl- lH-l,2,3-triazole-4-carboxylic acid, l,5-dimethyl-l//-pyrazole-3-carboxylic acid, 1- methyl-5-oxo-3-pyrrolidinecarboxylic acid, 3,5-dimethyl-4-isoxazolecarboxylic acid, 1,3- dimethyl- lH-pyrazole-5-carboxylic acid, 2,3-difluorobenzoic acid, 2,5-difluorobenzoic acid, 2,6-difluorobenzoic acid, and 3,4-difluorobenzoic acid to form a compound of formula (I).
• a carboxylic acid chosen
• the l,l-dimethylethyl-4- ⁇ 4-[(3-chloropropyl)oxy]phenyl ⁇ -3-oxo-l- piperazinecarboxylate used in the preparation of the BOC-protected amine of formula (II) can be prepared by reacting l-bromo-3-chloropropane with l,l-dimethylethyl-4-(4- hydroxyphenyl)-3-oxo-l -piperazinecarboxylate, which can be prepared by catalytic hydrogenolysis of l,l-dimethylethyl-3-oxo-4- ⁇ 4-[(phenylmethyl)oxy]phenyl ⁇ -l- piperazinecarboxylate, which can be prepared by reacting methanesulfonyl chloride with 1,1 -dimethylethyl-(2-hydroxyethyl)[2-oxo-2-( ⁇ 4-
• [(phenylmethyl)oxy]phenyl ⁇ amino)ethyl] carbamate which can be prepared by BOC protection of N 2 -(2-hydroxyethyl)-N 1 - ⁇ 4-[(phenylmethyl)oxy]phenyl ⁇ glycinamide, which can be prepared by reacting 4- [(phenylmethyl)oxy] aniline with chloroacetyl chloride and then 2-aminoethanol.
• nitrogen protecting groups known in the art may be used. Examples of suitable nitrogen protecting groups are described in Green, T. W.; Wutz, P.G.M. Protective Groups in Organic Synthesis, 2d ed.; John Wiley and Sons: New York, 1991.
• one embodiment of the invention relates to a process for preparing a compound of formula (I):
• R 1 and R 2 are defined as set forth above comprising the steps of:
• This process may optionally further include the steps of: (If) recrystallizing the isolated (i?)-2-methylpyrrolidine L-tartrate; (Ig) isolating the recrystallized (i?)-2-methylpyrrolidine L-tartrate; and
• the invention relates to a process for preparing a compound of formula (I):
• R and R are defined as set forth above comprising the steps of:
• This process may optionally further include the steps of: (If) recrystallizing the isolated (i?)-2-methylpyrrolidine L-tartrate;
• the protecting group is BOC.
• Another compound which demonstrates histamine-3 receptor ligand activity is 2- (6- ⁇ 2-[(2i?)-2-methyl-l-pyrrolidin-l-yl]-ethyl ⁇ -2-naphthalen-2-yl)-2 ⁇ -pyridazin-3-one.
• One process for the preparation of this compound is described in US 2005/0256127.
• 6-Bromo-naphthalen-2-ol can be treated with any suitable trifluoromethanesulfonic reagent in the presence of an organic base to provide a trifluoro-methanesulfonic acid 6- bromo-naphthalen-2-yl ester.
• trifluoromethanesulfonic reagents are, for example, trifiuoromethanesulfonyl acid anhydride, trifluoromethanesulfonyl chloride, N-phenyltrifluoromethanesulfonimide, trifluoromethanesulfonyl- 1 - -H-imidazole, trifluoromethanesulfonyl acid anilide, trifluoromethanesulfony acid-2-nitrophenyl ester, trifluoromethanesulfony- 1 acid-4-nitrophenyl ester.
• organic base examples include triethylamine, diisopropylamine, diisopropylethylamine, 2,6-lutidine, pyridine, and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
• DBU l,8-diazabicyclo[5.4.0]undec-7-ene
• the reaction can be accomplished in any suitable organic solvent.
• suitable solvents are CH 2 Cl 2 , dimethyl ether (DME), and toluene.
• the reaction also can be carried out in a biphasic condition where an inorganic base is used.
• suitable inorganic bases are K 3 PO 4 , NaHCO 3 , Na 2 CO 3 , NaOH, and the like.
• the preferred solvent is toluene.
• the reaction is accomplished in biphasic conditions, for example use of toluene and 30% potassium phosphate, at low temperatures. The preferred temperature range for the reaction is from about -5 °C to about 0 °C.
• Suitable vinyltrifluoroborate reagents are, for example, potassium vinyltriflurorborate, 2-vinyl- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane, dibutyl vinylboronate.
• the reagent is used in an ,amount of from about 1.0 molar equivalent to about 1.5 molar equivalents relative to the trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester.
• the reaction is carried out in a polar organic solvent, for example an alcohol, and a basic solution, for example a metal carbonate solution.
• a preferred solvent is ethanol.
• examples of other solvents that can be used for the reaction are n-propanol, iso-propanol, methanol, and other suitable alcohols.
• the metal carbonate preferably is cesium carbonate. Alternatively, other salts, for example Na 2 CO 3 , and K 3 PO 4 also can be used.
• the amount of metal carbonate for the reaction is from about 2 molar equivalents to about 4 molar equivalents relative to the trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester.
• the reaction is accomplished in the presence of a palladium catalyst and an organic amino base, for example, such as triethylamine, diisopropylamine, and the like.
• palladium catalysts for the reaction include, but are not limited to, tetrakis(triphenylphosphine)palladium, PdCl 2 (dppf) 2 , PdCl 2 (Ph 3 P) 2 , and PdCl 2 (CH 3 CN) 2 .
• the preferred palladium catalyst is tetrakis(triphenylphosphine)palladium.
• 2-Bromo-6-vinyl-naphthalene may treated with an ( ⁇ ?)-2-methylpyrrolidine anion generated with n-butyllithium to provide l-[2-(6-bromo-naphthalen-2-yl)-ethyl]-(i?)-2- methyl-pyrrolidine.
• the method described in US2005/0256127 may be improved by preparing (R)- and/or (S)-2-methylpyrrolidine in accordance with foregoing processes.
• 2- bromo-6-vinyl-naphthalene may then be reacted with an (i?)-2-methylpyrrolidine anion generated with n-butyllithium, or any other suitable base, to provide l-[2-(6-bromo- naphthalen-2-yl)-ethyl]-2i?-methyl-pyrrolidine.
• 2-Bromo-6-vinyl-naphthalene may treated with an (/?)-2-methylpyrrolidine anion generated with n-butyllithium to provide l-[2-(6- bromo-naphthalen-2-yl)-ethyl]-(/?)-2-methyl-pyrrolidine.
• ⁇ 1.2 to about 2.5 molar equivalents of (i?)-2-methylpyrrolidine are used for the reaction.
• the reaction typically is accomplished in an organic solvent, for example, THF, methyl-t-butyl ether (MTBE), Et 2 O, and DME.
• the preferred solvent is tetrahydrofuran (THF).
• THF tetrahydrofuran
• the n- butyllithium is added to a THF solution of (i?)-2-methylpyrrolidine in a controlled fashion, typically in a dropwise manner. To this solution is added a THF solution of 2-bromo-6- vinyl-naphthalene.
• the THF solution of 2-bromo-6- vinyl-naphthalene to the solution of (i?)-2-methylpyrrolidine and n-butyllithium.
• the reaction is accomplished at below room temperature, typically in a temperature range from about 0 °C to about -20 °C. From about 0.3 to about 0.7 molar equivalents of n- butyllithium are used relative to the 2-bromo-6-vinylnaphthalene compound.
• the resulting compound is l-[2-(6-bromo-naphthalen-2-yl)-ethyl]-(i? y )-2-methyl-pyrrolidine.
• the l-[2-(6-bromo-naphthalen-2-yl)-ethyl]-(/?j-2-methyl-pyrrolidine may then be reacted with 2H-pyridazin-3-one to provide the desired 2- ⁇ 6-[2-((i?j2-methyl-pyrrolidin-l- yl)-ethyl]-naphthalen-2-yl ⁇ -2H-pyridazin-3-one compound, which can be further processed to prepare a suitable salt.
• the reaction is accomplished using 2H-pyridazin-3- one, 8-hydroxyquinoline, a copper catalyst in the presence of base.
• the copper catalyst can be any suitable copper catalyst, for example copper (I) catalysts.
• suitable catalysts for the reaction include but are not limited to copper (0) powder, copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) oxide, copper (I) acetate, copper (II) chloride, copper (II) bromide, copper (II) iodide, copper (II) oxide, or copper (II) acetate.
• the preferred copper catalyst is copper (I) chloride.
• About 0.02 to about 1.0 molar equivalents of copper catalyst are used relative to the l-[2-(6-bromo-naphthalen-2-yl)- ethyl]-(i?J-2-methyl-pyrrolidine.
• Suitable ligands for the reaction include, but are not limited to p-dimethylaminopyridine, pyridine, 3-picoline, 4-picoline, 8- hydroxyquinoline, 7-methyl-8-hydroxyquinoline, 7-n-propyl-8-hydroxyquinoline, 1,10- phenanthroline, and 2,2'-dipyridyl.
• the preferred ligand is 8-hydroxyquinoline, which is used in an amount of from about 0.02 to about 2.0 molar equivalents relative to the l-[2- (6-bromo-naphthalen-2-yl)-ethyl]-(/? > )-2-methyl-pyrrolidine.
• the base is a metal carbonate or a metal alkoxide, for example cesium carbonate, potassium carbonate, sodium carbonate, and sodium tert-butoxide.
• the preferred base is potassium carbonate, which is used in an amount of from about 1.0 to about 2.0 molar equivalents relative to the l-[2-(6-bromo-naphthalen-2-yl)-ethyl]-(/?j-2-memyl-pyrrolidine. The reaction is accomplished at elevated temperatures in a polar organic solvent.
• suitable solvents include but are not limited to N,N'-dimethylformamide, N-methylpyrrolidinone, N,N'-dimethylacetamide, pyridine, 3-picoline, 4-picoline, and the like.
• the preferred solvent is dimethylformamide (DMF).
• DMF dimethylformamide
• the reaction is accomplished under a nitrogen atmosphere, and the reaction mixture is heated to temperatures of from about 100 °C. to about 160 ° C. The reaction typically can be accomplished in about 10 to about 48 hours.
• a non-water miscible solvent for example ethyl acetate
• the organic solution is washed with a brine aqueous solution, for example 25% NaCl solution or other suitable salt solution several times.
• the organic solution is dried, and concentrated to dryness to give the product.
• a 2-(6- ⁇ 2- [(2/?)-2-methyl- 1 -pyrrolidin- 1 -yl] -ethyl ⁇ -2-naphthalen-2- yl)-2H-pyridazin-3-one active agent can be prepared according to procedures described in US 7,153,889, filed on Oct. 22, 2003, at least in, for example, the general procedures and Example 31 , or any other suitable procedure for providing a stable active agent. Briefly, for example, a 6-bromo-2-naphthoate is reduced using BH 3 -THF to provide the corresponding alcohol.
• 6-Bromo-naphthalen-2-yl-methanol is treated with 3(2H)- pyridazinone, copper powder, and base to provide 2-[6-(2-hydroxy-ethyl)-naphthalen-2-yl- ]-2H-pyridazin-3-one, which is activated with a sulfonate, such as tosylate.
• one embodiment of the invention relates to a method of preparing a 2- ⁇ 6- [2- (2-methyl-pyrrolidin-l-yl)-ethyl]-naphthalen-2-yl ⁇ -2H-pyridazin-3-one, comprising the steps of:
• This method may optionally further include the steps of:
• the trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester may be obtained by: providing 6-bromo-naphthalen-2-ol; and reacting 6-bromo- naphthalen-2-ol with a suitable trifluoromethanesulfonic reagent.
• Exemplary compounds that can be produced using the methods of the present invention include:
• WO 2005/117865 also describes histamine-3 -receptor ligands that include a 2- methyl-pyrrolidinyl moiety of the following general formula III:
• A is selected from:
• R 4 is hydrogen or lower alkyl X is O, S. or N-R 8 , wherein R 8 is hydrogen or lower alkyl; p is 0, 1 or 2;
• R 6 is lower alkyl; s is 0, 1 or 2; and
• R 7 is lower alkyl.
• 6-Hydroxy-2-naphthoic acid can conveniently be transformed to the respective amide through coupling with (R)- or (S)-2-methylpyrrolidine that has been prepared in accordance with the foregoing steps (a) to (e) (with or without optional steps (f) to (h)) and reacting the (i?)-2-methylpyrrolidine L-tartrate with a base to provide (i?)-2-methylpyrrolidine.
• any suitable coupling agent can be employed to effect the transformation.
• coupling reagents like l,l '-carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1 - [bis(dimethylamino)methylene] - lH-l,2,3-triazolo[4,5- b]pyridinium-3-oxidhexafluorophosphate (HATU), 1-hydroxy- 1 ,2,3-benzotriazole (HOBT), O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and the like can equally well be employed to affect such transformation.
• CDI l,l '-carbonyldiimidazole
• DCC N,N
• solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent.
• suitable solvents include: DMF, dichloromethane (DCM), dioxane, THF, and the like.
• a base is used with the coupling agent.
• any base commonly used in this type of reaction may equally be employed here. Examples of such bases include triethylamine and diisopropylethylamine, and the like.
• the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
• One exemplary procedure for the preparation of (6-hydroxy-naphthalen-2-yl)-(2- methyl-pyrrolidin-l-yl)-methanone is as follows. A mixture of 6-hydroxy-2-naphthoic acid, 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate, 2.3 mL N- ethyldiisopropylamine, and (R) or (S)-2-methyl-pyrrolidine that has been prepared in accordance with the foregoing procedures, is prepared in 10 mL DMF is stirred for 16 hours at room temperature.
• the mixture is then concentrated to dryness and 50 mL ethyl acetate, 30 mL water and 20 mL NaHCO 3 aq. (10%) is added.
• the aqueous phase may then be extracted with 50 mL ethyl acetate and the combined organic layers purified with column chromatography on silica.
• the product fractions may be concentrated to dryness and triturated twice with 20 mL diethyl ether/heptane 1/1, and the residue dried under vacuum at 50 °C.
• reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. Ambient temperature to reflux is generally appropriate.
• the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the desired compounds.
• one embodiment of the invention relates to processes for preparing a compound of formula III :
• variables are as set forth above, comprising: (Ia) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (Ib) optionally removing the hydrogenation catalyst from the mixture;
• This method may optionally further include the steps of: (If) recrystallizing the isolated (i?)-2-methylpyrrolidine L-tartrate or (S)-2- methylpyrrolidine D-tartrate;
• variables comprises: (Ia) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;
• This method may optionally further include the steps of:
• Particularly preferred compounds that can be prepared using the methods of the present invention include:
• X and X a are each independently CH or N; YisS(O) q ,O,orNR 15 ;
• each R 4 is independently H, Ci-C 6 alkyl, or OR 21 , wherein the alkyl group is optionally substituted with 1 to 3 R 2 groups;
• R 13a , R 13b , R 13c , and R 14a are each independently H, d-C 6 alkyl; or R 13 and R 14 , taken together with the carbon atoms through which they are connected form a fused phenyl, thi
• R 20 at each occurrence is independently, H, F, Cl, Br, I, OR 21 , OR 22 , NR 23 R 24 , NHOH, NO 2 , CN, CF 3 , C 1 -C 6 alkyl optionally substituted with OR 26 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
• R 25 is CrQalkyl, aryl, or alkylaryl
• R 26 is H, Ci-C 6 alkyl, aryl, or alkylaryl
• R 27 is H or Ci-C 6 alkyl; m is 1, 2, 3, 4, or 5 when R 1 is attached via a nitrogen atom, and m is 0, 1, 2, 3, 4, or 5 when R 1 is attached via a carbon atom; n is 1, 2, or 3; q is O, I, or 2; s is 1, 2, or 3; and y is O, I, or 2.
• Specific examples of such compounds that can be prepared using the 2- methylpyrrolidine preparation methods of the present invention include:
• Preferred among these are compounds selected from the group consisting of: 5- ⁇ 4-[3-((R)-2-methyl-pyrrolidin-l-yl)-propoxy]-phenyl ⁇ -2-pyridin-2-yl-2H-pyridazin-3- one;
• the compound is 6- ⁇ 4-[3-((R)-2-methyl- pyrrolidin-l-yl)-propoxy]-phenyl ⁇ -2H-pyridazin-3-one, or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof.
• This compound may be prepared from (i?)-2-methylpyrrolidine prepared in accordance with the methods described above.
• Scheme 3 sets forth an exemplary process for the preparation of 6- ⁇ 4-[3- ((R)-2-methyl-pyrrolidin-l-yl)-propoxy]-phenyl ⁇ -2H-pyridazin-3-one.
• step 1 a mixture of l-(4-hydroxyphenyl)ethanone and 3-bromo-l-chloropropane in CH 3 COCH 3 is heated to 65 0 C overnight. The mixture is filtered, washed with acetone, and concentrated to dryness. The crude product is dissolved in CH 2 Cl 2 , and washed with saturated NaHCO 3 , NaCl solution and dried over Na 2 SO 4 . Concentration to dryness under vacuum affords product.
• a mixture of the product from step 1 and glyoxalic acid monohydrate is stirred in 15 mL of acetic acid at 100 0 C for 2 h.
• the solvent is evaporated, water is added to the residue and cooled to 0 0 C while cone, aqueous NH 4 OH is added to pH 8.
• hydrazine hydrate is added and heated to 100 0 C for 1 h.
• the resulting solid may be filtered and washed with water.
• the crude material may be dissolved in CH 2 Cl 2 /Me0H and purified by column chromatography with CH 2 Cl 2 to 10 % MeOH in CH 2 Cl 2 .
• a mixture of the product from step 2, K 2 CO 3 , 100 mg of NaI, and R-2- methylpyrrolidine hydrochloride in acetonitrile is heated to 80 0 C for 2 days.
• the reaction mixture is then filtered, washed with CH 2 Cl 2 , and concentrated.
• the residue is dissolved in CH 2 Cl 2 , and washed with saturated NaHCO 3 , saturated NaCl, dried with Na 2 SO 4 and concentrated.
• the residue may be purified by ISCO gradient chromatography with 100% CH 2 Cl 2 to 5%MeOH: 95% CH 2 Cl 2 in 2-aminopropane and then to 10%MeOH: 90% CH 2 Cl 2 in 2-aminopropane to give the product.
• the free base of the product may be converted to the HCl salt by dissolving in MeOH and adding 0.5 N HCl in EtOH, followed by evaporation of the solvent and crystallization from MeOH: Et 2 O.
• one embodiment of the invention relates to processes for preparing a compound of formula IV: IV> in particular (R)- or (S)-6- ⁇ 4-[3-(2-Methyl- pyrrolidin- 1 -yl)-propoxy] -phenyl ⁇ -2H-pyridazin-3 -one, wherein the variables are as set forth above, comprising: (Ia) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;
• variables are as set forth above, comprising: (Ia) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;
• This method may optionally further include the steps of: (If) recrystallizing the isolated (i?)-2-methylpyrrolidine L-tartrate or (S)-2- methylpyrrolidine D-tartrate;
• Exemplary compounds that can be produced according to these methods include
• the compound is 6- ⁇ 4-[3-((R)-2-methyl-pyrrolidin-l-yl)-propoxy]-phenyl ⁇ - 2H-pyridazin-3-one
• histamine-3 -receptor ligands that may be prepared using (R) or (S) 2-methylpyrrolidine prepared in accordance with the methods described herein is described in WO 2006/059778. These compounds include compounds of the general formula VI:
• R 1 each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a lower alkoxy-lower alkyl group, or a halo-lower alkoxy-lower alkyl group; p indicates an integer from 0 to 4; R 2 represents a hydroxyl group, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a lower alkoxy-lower alkyl group, or a halo-lower alkoxy-lower alkyl group, or
• R 2 represents a group of the formula, X 3 -X 4 wherein A represents a compound of formula (HI-I) or of formula (III-2) wherein R3 represents a hydrogen atom, or a cycloalkyl group optionally substituted with a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a halogen atom or a hydroxyl group and R4 represents a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a lower alkoxy-lower alkyl group, or a halo-lower alkoxy-lower alkyl group; m indicates 0 or 1 ; n indicates 0, 1 or 2; and
• X 1 to X 4 each independently represent a carbon atom optionally substituted with a lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group or a halogen atom.
• Specifically disclosed compounds within this group that can be prepared according to the methods described herein include: l-methyl-4- ⁇ 4-[3-((2S)-2-methyl-l-pyrrolidinyl)propoxy]phenyl ⁇ -2(lH)-pyridone; and 1 -methyl-4- ⁇ 4- [3 -((2R)-2-methyl- 1 -pyrrolidinyl)propoxy] phenyl ⁇ -2( 1 H)-pyridone.
• Such compounds may be prepared by providing an intermediate compound of Formula (VI) wherein Y is Cl, and reacting the compound with (R) or (S) 2- methylpyrrolidine, prepared according to the foregoing methodology, K 2 CO 3 and NaI in CH 3 CN and recovering the product, much as described above for the compounds of US 2008/0027041 Al.
• Another embodiment of the invention relates to processes for preparing a compound of formula VI:
• This method may optionally further include the steps of:
• A is (R) or (S) 2-methyl pyrrolidine;
• Z, Y, Q, X are independently nitrogen or carbon;
• R 4 and R 5 are independently selected from the group consisting of: hydrogen; (C 1 -Cg) alkyl optionally substituted with 1 to 4 halogens; (Ci-Cg) alkyl group optionally substituted with a substituent selected from the group consisting of OH, 1 to 4 (Ci-C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )dialkylamino, (C 6 -Ci 0 )aryl optionally substituted with a halogen and optionally substituted with (C 6 -C 10 )aryloxy optionally substituted with 1 to 2 halogens, and 5 to 10-membered heteroaryl optionally substituted with a (C 6 - C 10 )aryl group and optionally substituted with 1 to 3 (C !
• R 7 is hydrogen; or optionally R 3 and R 7 together with two adjacent atoms in the ring comprising Z , Y, Q and X to which they are attached, form a 5- or 6-membered heterocyclic ring; wherein one of the carbons of said heterocyclic ring that is separated by at least two atoms from said nitrogen in said heterocyclic ring is optionally replaced by O or NR 8 ; wherein R 8 is hydrogen or (Ci-C 3 )alkyl.
• Scheme 4 illustrates a method for the preparation of compounds having the basic structure of formula VII, where A, R 3 , Y, Q, Z and X are defined as above.
• a compound (III) can be prepared by treatment of a bromo-tetralone compound of formula (I) with (R) or (S) 2-methyl pyrrolidine prepared in accordance with the methods described above and a suitable reducing agent such as NaHB(OAc) 3 in a solvent such as CH 2 Cl 2 or DCE, at temperatures ranging from -5 °C to room temperature, preferably at about room temperature, to produce the desired compound of formula (III).
• suitable reducing agents for this reaction include NaCNBH 3 or NaBH 4 , in solvents such as MeOH or EtOH.
• Compound III can then be treated with an appropriately substituted boronic acid of formula (IV), in the presence of a suitable palladium catalyst such as 1,1- bis(diphenylphosphino)ferrocene palladium (II) chloride and a suitable aqueous solution of an alkali base such as sodium carbonate and in solvents such as dimethoxy ethane, at temperatures ranging from room temperature to about 100 0 C, preferably at about 90 °C, to produce the desired compound of formula (V).
• a suitable palladium catalyst such as 1,1- bis(diphenylphosphino)ferrocene palladium (II) chloride
• a suitable aqueous solution of an alkali base such as sodium carbonate and in solvents such as dimethoxy ethane
• one embodiment of the invention relates to processes for preparing a compound of formula VII:
• This method may optionally further include the steps of:
• Scheme 5 illustrates an alternative method for the preparation of compounds having the basic structure of formula VII, where R 3 is CONR 4 R 5 and Y, Z, Q and X are defined as above.
• R 3 is CONR 4 R 5 and Y, Z, Q and X are defined as above.
• coupling of the bromide (III) and a suitable boronic acid reagent of formula (VI) can be carried out as described above in scheme 4 to produce the desired compound of formula (VIII).
• Treatment of the corresponding t-butyl ester derivative of formula (VIII) with trifluoroacetic acid in methylene chloride at room temperature produces the corresponding carboxylic acid (not depicted).
• compounds of formula (IX) can also be prepared by treatment of the carboxylic acid and suitable amine with 2-chloro- 1,3 -dimethyl imidazolinium chloride and a suitable base such as diisopropylethyl amine, in solvents such as methylene chloride.
• This method may optionally further include the steps of: (If) recrystallizing the isolated (i?)-2-methylpyrrolidine L-tartrate or (S)-2- methylpyrrolidine D-tartrate;
• WO 2006/066197 describes the following compounds of formulas VIII and IX: ⁇
• L is -O- and n is 1 or 2; or L is -C ⁇ C- or -CH 2 CH 2 - and n is 0 or 1;
• R 1 is -H or is C 1-6 alkylC 3-7 cycloaklyl, -COOCi -6 alkyl, or -COObenzyl, each optionally mono-, di-, or tri-substituted with Ra; where Ra is selected from -OH, -OC 1-6 alkyl, phenyl optionally substituted with -OC 1-4 alkyl or halo, -CN, -NO 2 , -N(R b )R c , -C(O)N(R b )R c , -N(R b )C(O) R b , -N(R b )SO 2 Ci- ealkyl, -C(O)C 1-6 alkyl, -S(O) 0-2 -C I-6 alkyl, -SO 2 N(R b ) Rc , -SCF 3 , halo, -CF 3 , -OCF 3 ,
• R 4 is -OH, -OC 1-6 alkyl,-CF 3 , -Ci -6 alkyl, or halo; two R 4 substituents may be taken together to form methylene or ethylene;
• M is O, I, or 2;
• R 5 is selected from the group consisting of-C 1-6 alkyl, -OH, -OCi -6 alkyl, -SCi- 6 alkyl, and halo;
• Ar 1 is an aryl or heteroaryl ring selected from the group consisting of: a) phenyl, optionally mono-, di-, or tri-substituted with R J and optionally di- substituted on adjacent carbons with -OC M alkyleneO-optionally mono or di-substituted with fluoro,
• R j is selected from the group consisting of 1) -OH, -C
• reagents of formulae Al, A2, and A5 are commercially available or are prepared according to known methods.
• 3-5 Hydroxybenzaldehyde derivatives Al are reacted with alcohols A2 according to a Williamson ether synthesis protocol to form ethers A3, using a suitable base such as K 2 CO 3 , Na 2 CO 3 , or NaH, in a solvent such as acetonitrile, with or without catalytic KI or NaI.
• ethers of formula A3 may be prepared under Mitsunobu conditions where A2 contains a protected hydroxyl in place of the bromide substituent. Reductive animation of the aldehyde functionality of compounds A3 will provide compounds of formula A4.
• the aldehyde can be treated with a suitable R'-containing amine, with or without the addition of an activating agent such as a protic or Lewis acid, and with an appropriate reducing agent such as NaBH 4 , NaCNBH 3 , or NaHB(OAc) 3 .
• Preferred conditions include NaBH 4 in methanol.
• Alkylation of amines A4 with alpha-haloketones A5 to form ketones A6 is accomplished in the presence of a tertiary amine base such as TEA or DIPEA, in a suitable solvent such as THF or DCM.
• Cyclization to generate tetrahydroisoquinolines A7 involves effecting cyclization to a tetrahydroisoquinolinium salt by exposure to a suitable protic or Lewis acid, such as methanesulfonic acid (MSA), trifluoroacetic acid (TFA), AlCl 3 , TiCl 4 , or BF 3 + OEt 2 with or without a solvent such as DCM.
• a suitable protic or Lewis acid such as methanesulfonic acid (MSA), trifluoroacetic acid (TFA), AlCl 3 , TiCl 4 , or BF 3 + OEt 2 with or without a solvent such as DCM.
• MSA methanesulfonic acid
• TFA trifluoroacetic acid
• AlCl 3 AlCl 3
• TiCl 4 BF 3 + OEt 2
• BF 3 + OEt 2 BF 3 + OEt 2
• Preferred conditions are neat MSA or MSA in D
• the pendant primary alcohol group in compounds A7 may be converted to the corresponding amines A9 by activation to form an appropriate leaving group (such as a mesylate or bromide), followed by displacement of the leaving group with (R)- or (S)-2-methylpyrrolidine that has been prepared in accordance with the present invention.
• the displacement may be performed using a suitable base such as Na 2 CO 3 , in a polar solvent such as n-BuOH, with or without catalytic KI or NaI.
• amines A9 may be prepared through oxidation of the alcohol and reductive animation of the resulting aldehyde.
• one embodiment of the invention relates to processes for preparing compounds of formulas VIII and IX:
• This method may optionally further include the steps of:
• 2-methylpyrrolidine-containing compounds may be prepared according to Scheme 7:
• ethers of formula A3 may first be converted as described in Scheme A to the corresponding optionally protected amines Bl using (R)- or (S)-2- methylpyrrolidine that has been prepared in accordance with the present invention.
• Benzaldehydes Bl may then be transformed into diamines B2, wherein Q is (R)- or (S)-2- methylpyrrolidinyl, using reductive animation protocols as in Scheme A.
• Alkylation to form ketones B3, and cyclization to produce compounds of formula A12 are accomplished as shown for Scheme 6.
• Another embodiment of the invention relates to processes for preparing compounds of formulas VIII and IX comprising:
• This method may optionally further include the steps of:
• An exemplary compound that can be made using the methods of the present invention is 4- (4-methoxy-phenyl)-2-methyl-7-[3-(2-methyl-pyrrolidin-l-yl)-propoxy]-l, 2,3,4- tetrahydro-isoqunoline.
• n 2, 3, 4, or 5
• R is R 3 -aryl, R 3 -heteroaryl, R 3 -cycloalkyl, R 3 -heterocycloalkyl, alkyl, haloalkyl,
• R 1 is H and R 2 is R 6 -phenyl or and R 2 is H; or R 1 and R 2 are independently selected from the group consisting of R 6 -phenyl and ; and X is -O- or -S-; or R 1 and R 2 , together with the carbon atoms to which they are attached form
• X is -O-, -S-, or -NR 7 ;
• R 3 is 1-3 substituents independently selected from the group consisting of H, alkyl, halo, OH, alkoxy and -NR 11 R 12 , R 4 is alkyl, arylalkyl or cycloalkyl; R 5 is alkyl, -NR 11 R 12 , R 3 -aryl or R 3 -arylalkyl; R 6 is 1-3 substituents independently selected from the group consisting of H, alkyl, -CF 3 , halo,
• R 7 is H, alkyl, -c(O)OR 13 , -C(O)NR 11 R 12 or -C(O)R 13 ;
• R 11 and R 12 are independently selected from the group consisting of H, alkyl, cycloalkyl, aryl and arylalkyl;
• R 13 is H, alkyl, cycloalkyl or arylalkyl
• R 14 is H , alkyl, cycloalkyl or arylalkyl
• R 15 is H, alkyl, cycloalkyl, -C(O)OR 13 , -C(O)NR 11 R 12 or -CO)R 13 ;
• Compounds of formulas X and XI can be prepared according to the following
• the primary amine of compound 4 is acylated by reaction with a carboxylic acid in the presence of coupling agents such as DEC and HOBT in a suitable solvent such as ether, THF, or CH 2 Cl 2 , preferably CH 2 Cl 2 to give compound 5.
• the amine can be acylated by an acid chloride in the presence of a base.
• Compound 5 in acetic acid is heated for a sufficient time for cyclization to occur.
• Compound 6 is reacted with an ⁇ , ⁇ -dihaloalkane in a suitable solvent such as acetone, THF, ether or the like, preferably acetone, in the presence of a base such as Na 2 CO 3 or K 2 CO 3 , preferably K 2 CO 3 , at a temperature from O to 65 °C to give compound 7 wherein Y is halo.
• a suitable solvent such as acetone, THF, ether or the like, preferably acetone
• a base such as Na 2 CO 3 or K 2 CO 3 , preferably K 2 CO 3
• a suitable solvent such as CH 3 CN, THF, ether, or the like, preferably CH 3 CN
• a tertiary amine base such as Et 3 N, DIPEA or the like, preferably DIPEA
• a suitable solvent such as CH 3 CN, THF, ether, or the like, preferably CH 3 CN
• a tertiary amine base such as Et 3 N, DIPEA or the like, preferably DIPEA
• (R)- or (S)-2-methylpyrrolidine that has been prepared in accordance with the present invention.
• the reaction is then heated at a temperature from O to 100°C to give compound 11.
• the compounds can be made according to the following Scheme
• compound 12 is reacted with an ⁇ , ⁇ -dihaloalkane in a suitable solvent such as acetone, THF, ether or the like, preferably acetone, in the presence of a base such as Na 2 CO 3 or K 2 CO 3 , preferably K 2 CO 3 , at a temperature from O to 65 °C to give compound 13, wherein Y is halo.
• a suitable solvent such as acetone, THF, ether or the like, preferably acetone
• a base such as Na 2 CO 3 or K 2 CO 3 , preferably K 2 CO 3
• a suitable solvent such as CH 3 CN, THF, ether, or the like, preferably CH 3 CN
• a tertiary amine base such as Et 3 N, DIPEA or the like, preferably DIPEA
• (R)- or (S)-2- methylpyrrolidine that has been prepared in accordance with the present invention.
• the reaction is then heated at a temperature from 0 to 100°C to give compound 14.
• the nitro group of compound 14 is reduced to the amine 15 using H 2 gas in the presence of a suitable catalyst such as Pd/C, PtO 2 , or Raney nickel, preferably Raney Nickel, in a suitable solvent such as methanol, ethanol, or isopropanol, preferably methanol or ethanol.
• a suitable catalyst such as Pd/C, PtO 2 , or Raney nickel, preferably Raney Nickel
• a suitable solvent such as methanol, ethanol, or isopropanol, preferably methanol or ethanol.
• Other reduction methods well known to those versed in the art are also suitable.
• a solution of 19 in a suitable solvent such as DMSO, DMF or the like is treated with a base such as K 2 CO 3 or the like and an alkylating agent R 4 L, in which L is Cl, Br or I, or a mesylate or sulfonate, at a temperature of 0 to 100 °C, preferably from 25 to 75 °C, to give 20.
• a suitable solvent such as DMSO, DMF or the like
• R 4 L in which L is Cl, Br or I, or a mesylate or sulfonate
• one embodiment of the invention relates to processes for preparing compounds of formulas X and XI
• This method may optionally further include the steps of:
• R 3 is (Ci. 6 )-alkyl, aryl or heteroaryl, optionally substituted with up to 3 fluorine atoms;
• R 4 is hydrogen, halogen, (C ⁇ -alkyl or (C 3-7 )-cycloalkyl, (Ci -6 )-alkoxyl or (C 3-7 )- cycloalkoxyl (optionally substituted with up to 3 fluorine atoms), aryl, heteroaryl;
• R 5 is (CR 6 RV(CR 10 R 1 VB, wherein R 6 , R 9 , R 10 and R 1 ' together with the carbon to which they are attached form a 3-10 member mono- or bi-cyclic ring system;
• B is a 4-7 member heterocycloalkyl containing up to 3 heteroatoms selected from N, O, S
• azetidine e.g., azetidine, pyrrolidine, piperdine, azeplne, morpholine, thiomorpholine, piperazine or
• R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from hydrogen, Ci -6 alkyl, (Ci -6 alkyl)-aryl, (Ci -6 alkyl)-heteroaryl; or
• R 12 and R 13 together with the nitrogen to which they are attached form a 3-10 member mono- or bi-cyclic ring system (e.g., azepine, piperidine, pyrrolidine or morpholine), and with the proviso that NR 12 R 13 is not NH 2 ; m is O, 1, 2, 3, or 4; n is 0, 1, 2 or 3; and p is 0 to 3.
• azepine e.g., piperidine, pyrrolidine or morpholine
• a ketone of the general formula II wherein the hydroxyl (-OH) group is unprotected, is reacted with (R)- or (S)-2-methylpyrrolidine that has been prepared in present invention, to generate an amino-phenol of general formula III.
• This transformation can be accomplished using one or more of the methods and procedures available to those skilled in the art.
• a ketone of formula II and 2- methylpyrrolidine can be combined in an inert aprotic solvent, like chloroform or dichloromethane, in the presence of a Lewis acid reagent like titanium tetrachloride (TiCl 4 ) or titanium isopropoxide to produce an intermediate imine through the elimination of water.
• a Lewis acid reagent like titanium tetrachloride (TiCl 4 ) or titanium isopropoxide
• refluxing a solution of II and 2-methylpyrrolidine in a solvent like toluene in the presence of a catalytic amount of para-toluenesulfonic acid, with provision for removal of the water by using a Dean-Stark trap or activated molecular sieves, may also be employed to effectively produce the intermediate imine.
• This imine may then be converted in situ, or in a separate step following its isolation, to the amino-phenol intermediate III.
• This can be accomplished by reduction of the C N double bond using, for example, boron reagents like sodium borohydride (NaBH 4 ), sodium cyanoborohydride (NaBH 3 CN), sodium triacetoxyborohydride and the like, in reaction inert solvents like dichloromethane, methanol, THF or dioxane.
• boron reagents like sodium borohydride (NaBH 4 ), sodium cyanoborohydride (NaBH 3 CN), sodium triacetoxyborohydride and the like, in reaction inert solvents like dichloromethane, methanol, THF or dioxane.
• the imine can be reduced using catalytic hydrogenation conditions, e.g., employing hydrogen gas (H 2 ) and a suitable metal catalyst like Raney nickel (RaNi), palladium on carbon (Pd/C) or similar catalysts in a reaction inert solvent like methanol or ethanol and at temperatures in the range of about 20 °C up to the boiling point of the solvent employed and at pressures in the range of about one to five atmospheres of hydrogen gas.
• a suitable metal catalyst like Raney nickel (RaNi), palladium on carbon (Pd/C) or similar catalysts in a reaction inert solvent like methanol or ethanol and at temperatures in the range of about 20 °C up to the boiling point of the solvent employed and at pressures in the range of about one to five atmospheres of hydrogen gas.
• a suitable metal catalyst like Raney nickel (RaNi), palladium on carbon (Pd/C) or similar catalysts in a reaction inert solvent like methanol or ethanol and at temperatures in the range of
• the phenolic OH group present in the intermediate of formula III can be converted to an ether product of the general formula I by alkylation of III with a reagent of the general formula R 5 -A, wherein R 5 is as defined previously and A is a leaving group including halogen (e.g., Cl, Br, I), mesylate (i.e., -OSO 2 CH 3 , or -OMs) or tosylate (i,e., -OSO 2 C 6 H 5 or -OTs), in the presence of a base and in a reaction inert - solvent, as depicted in pathway b.
• halogen e.g., Cl, Br, I
• mesylate i.e., -OSO 2 CH 3 , or -OMs
• tosylate i,e., -OSO 2 C 6 H 5 or -OTs
• Suitable bases will include sodium, potassium or cesium carbonate(s), sodium or potassium bicarbonate(s), sodium or potassium tert- butoxide(s), sodium or potassium hydride(s) and the like, with cesium carbonate being preferred.
• Suitable solvents will include DMF, DMSO, DMA, THF and the like, with DMSO preferred.
• one embodiment of the invention relates to processes for preparing compounds of formula XII and XIII:
• This method may optionally further include the steps of: (If) recrystallizing the isolated (7?)-2-methylpyrrolidine L-tartrate or (S)-2- methylpyrrolidine D-tartrate;
• a phenolic ketone of the general formula II may be converted to an ether (pathway c.) by methods generally known to one skilled in the art.
• the phenol II can be reacted with a reagent of general formula R 5 -A in the presence of a base, as described for pathway b in Scheme 1 to produce a ketone of general formula IV.
• a ketone of the general formula VII wherein Li is a suitable leaving group (i.e., F, -OMs, etc.), may be reacted with a reagent of general formula R 5 - OH in the presence of a suitable base and in an inert solvent to produce an intermediate of general formula IV (pathway e.).
• the ketone IV so obtained may then be converted, using reductive animation conditions as previously described in Scheme 11 to the desired products of general formula I (pathway d.).
• Another embodiment of the invention relates to processes for preparing compounds of formula XII and XIII: wherein the variables are as set forth above, comprising: (Ia) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;
• This method may optionally further include the steps of:
• An exemplary compound that can be prepared using the methods of the present invention is l- ⁇ 3-[l-(2-methyl-pyrrolidin-l-yl)-indan-5-yloxy]-propyl ⁇ azepane.
• the methods of the present invention are also suitable for preparing compounds such as those described in WO 2007/094962, for example, those of formulas XIV and XV.
• R 3 is 0-2 of groups selected from halogen, (C 1-8 )alkyl, (C 1-8 )alkoxyl, (C 3-7 )cycloalkyl,
• R 4 and R 6 are independently selected from (C 1- s)alkyl, (C 1-8 )alkoxy, (C 3-7 )cycloalkyl,
• R 5 is selected from the group consisting of hydrogen, aryl, (Ci -5 )alkyl-O-(C 1-
• R 5 and R 6 and the atoms to which they are attached form a fused 5-6 member saturated carbocyclic ring or a fused 10 member bi-cyclic ring system, such as
• R 5 and R 4 and the atoms to which they are attached form a fused 5-6 member saturated carbocyclic ring to which a 6 member aromatic ring is fused, such as
• R 5 and R 6 and the atoms to which they are attached form a fused 5-6 member saturated carbocyclic ring to which a 6 member aromatic ring is fused, such as
• R 5 and R 6 and the atoms to which they are attached form a fused benzothiophene or fused benzofuran ring system, such as
• X is NR 7 , R 7 and R 2 taken together are -(CH 2 CH 2 )- to form a two nitrogen containing ring where y is 0 (piperazine) or y is 1 (homopiperazine), and wherein Ri is as defined previously, and the pharmaceutically acceptable salts thereof.
• Another embodiment of the invention relates to processes for preparing compounds of formula XIV and XV:
• This method may optionally further include the steps of: (If) recrystallizing the isolated (7?)-2-methylpyrrolidine L-tartrate or (S)-2- methylpyrrolidine D-tartrate;
• a 2 is oxygen or sulfur
• R 2a is hydrogen, aryl, C 1-6 alkoxy, amino, C 1-6 alkyl, C 2-6 alkenyl, heteroaryl, C 3-8 cycloalkyl, 3-8-membered heterocycloalkyl, acyl, aryl, C 1-6 -alkyl, heteroaryl,
• R 2b is hydrogen, halogen, Ci -8 -alkyl or C 3-8 cycloalkyl; or R 2a and R 2b are linked together to form a C 3-8 cycloalkyl, a 3-8-membered heterocycloalkyl or an oxo group;
• R 3 is hydrogen, halogen, Cj -4 alkyl or C 1-4 alkoxy
• R 4 is hydrogen, halogen, Ci -4 alkyl or Ci -4 alkoxy
• R 9a is hydrogen or unsubstituted Ci -8 alkyl
• R 9b is a Ci -6 -alkyl aryl or unsubstituted C 1-8 alkyl; n is an integer equal to 0, 1 or 2; t is an integer equal to 2, 3 or 4; w is an integer equal to 2, 3 or 4; v is an integer equal to 0 or 1 ; m is an integer equal to 0 or 1 ; and z is an integer equal to 0, 1,2 or 3;
• R 3 is H, F, or Cl, and Y 1 is I or Br.
• reactions may be carried out using a catalyst such as copper iodide or palladium acetate, associated with a ligand such as 1,2-diamine (e.g. trans- 1,2- diaminocyclohexane), a phosphine (e.g.
• one embodiment of the present invention relates to processes for the preparation of compounds of formulas XVI and XVII
• This method may optionally further include the steps of:
• the 2- methylpyrrolidinealkoxy is prepared from (R)- or (S)-2-methylpyrrolidine that has been prepared in accordance with the foregoing steps (a) to (e) (with or without optional steps (f) to (h)) and reacting the (i?)-2-methylpyrrolidine L-tartrate with a base to provide (R)-2- methylpyrrolidine or (5)-2-methylpyrrolidine D-tartrate with a base to provide (5)-2- methylpyrrolidine, which is then reacted with a reagent such as halo-alkoxy.
• a reagent such as halo-alkoxy
• the reactions set forth in Scheme 22 may be performed in the presence of a base, such as potassium tert-butylate, cesium carbonate or sodium hydride, in a solvent, such as dimethylformamide or tetrahydrofuran, in the presence of a palladium- or a copper based catalyst, according to method described by Penning et al. in J. Med. Chem. 2000, 43, 721.
• a base such as potassium tert-butylate, cesium carbonate or sodium hydride
• a solvent such as dimethylformamide or tetrahydrofuran
• Another embodiment of the present invention comprises methods of preparing compounds of formulas XVI and XVII
• This method may optionally further include the steps of:
• Exemplary compounds that can be prepared according to the methods of the invention include: l-[3-(4- ⁇ 4-[(2-methylpyrrolidin-l-yl)methyl]-l,3-oxazol-2-yl ⁇ phenoxy)propyl piperidine;
• R 1 and R 2 are each selected independently from the group consisting of H, C 1-6 acyl, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 cycloalkyl, aryl, heterocyclyl, heteroaryl, aryl-C 1-4 -alkylenyl, aryloxy-Ci- 4 -alkylenyl, heteroaryl-C 1-4 -alkylenyl and heteroaryloxy- C M -alkylenyl, and each R 1 and R 2 is optionally substituted with 1,2,3,4 or 5 substituents selected independently from the group consisting Of C 1-6 acyl, C 1-6 acyloxy, C 2-8 alkenyl, C 1-6 alkoxy, Cj -8 alkyl, C 1-8 alkylcarboxanide, C 2-8 alkynyl, C 1-8 alkylsulfonamide, C 1- 8 alkylsulfinyl, C 1-8 al
• substituents selected independently from the group consisting of C 1-3 alkyl, Ci- 4alkoxy, carboxy, cyano, Ci -3 haloalkyl, halogen, hydroxyl and oxo;
• R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , and R 12 are each selected independently from the group consisting of H, Ci -6 acyl, Cj -6 acyloxy, C 2-8 alkenyl, Ci -6 alkoxy, Cj -8 alkyl, Ci -8 alkylcarboxamide, C 2-8 alkynyl, Ci -8 alkylsulfonamide, Ci -8 alkylsulfinyl, Ci -8 alkylsulfonyl, Ci -8 alkylthio, Ci -8 alkylureyl, amino, Ci -8 alkylamino, C 2- 8dialkylamino, carbo-Ci -6 - alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C2-8 dialkylcarboxamide,C 2-8 dialkylsulfonamide, halogen, Cj -6 haloalkoxy, Ci -6 hal
• R and R are each selected independently from the group consisting of H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 cycloalkyl, aryl, heterocyclyl, heteroaryl, aryl-Ci- 4 - alkylenyl, aryloxy-C 1-4 alkylenyl, heteroaryl-C M -alkylenyl and heteroaryloxy-Ci- 4 - alkylenyl, and each R 8 and R 9 is optionally substituted with 1, 2, 3,4, or 5 substituents selected independently from the group consisting of C 1-6 acyl, Ci -6 acyloxy, C 2-8 alkenyl, Ci -6 alkoxy, Ci -8 alkyl, Ci -8 alkylcarboxamide, C 2-8 alkynyl, Cj -8 alkylsulfonamide, Ci- 8 alkylsulfinyl, Ci -8 alkylsulfonyl, Ci
• the methods of the present invention of preparing (R) and (S) 2-methylpyrrolidine can be used to more readily prepare the above mentioned compounds.
• (R)- or (S)-2- methylpyrrolidine can be prepared in accordance with the present invention and reacting the (i?)-2-methylpyrrolidine L-tartrate with a base to provide (i?)-2-methylpyrrolidine or (5)-2-methylpyrrolidine D-tartrate with a base to provide (5)-2-methylpyrrolidine.
• the following schemes demonstrate the use of the so prepared 2-methylpyrrolidine.
• X, and Y are each independently a leaving group, for example, halogen, triflate and the like and R 15 is Ci -8 alkyl.
• R 15 is C 1-8 alkyl.
• X is a leaving group, for example halogen, triflate and the like.
• X is a leaving group, for example halogen, triflate and the like SCHEME 27
• LG 3 is a leaving group such as sulfonate, triflate, halogen and the like and Z is halogen.
• LG 3 is a leaving group such as sulfonate, triflate, halogen and the like and Z is halogen.
• Another embodiment of the present invention comprises methods of preparing compounds of formulas XVIII and XIX:
• This method may optionally further include the steps of:
• Exemplary compounds that can be prepared according to the methods of the invention include:
• Example 1 (2.71 g) was placed in a 100 mL, single-neck round bottom flask with stir bar along with absolute ethanol (38 mL) and methanol (16 mL). The mixture was heated to 6O 0 C to form a solution and then allowed to cool to ambient temperature.
• 2-methylpyrrolidine L-tartrate (2.50 mg) was added as seed crystals and the mixture was stirred at ambient temperature for 16 hours, and then at O 0 C (ice bath) for 2 more hours.
• Solids were filtered and dried at 60°C in a vacuum oven with a stream of nitrogen at 29 in.

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