JP2010526142A - Process for preparing (R) -2-methylpyrrolidine and (S) -2-methylpyrrolidine and its tartrate salt - Google Patents

Abstract

The present invention provides a short, safe, and inexpensive process that does not require isolation of synthetic intermediates to prepare (R)-or (S) -2-methylpyrrolidine from 2-methylpyrroline. , And provide a commercially expandable method.
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Description

  This application claims the benefit of US Provisional Application No. 60 / 927,356, filed May 3, 2007, which is incorporated herein by reference in its entirety.

(R)-and (S) -2-methylpyrrolidine are useful starting materials in the synthesis of various pharmaceuticals. For example, by using (R)-2-methylpyrrolidine, it can be prepared a number of H ₃ receptor ligands. For this reason, there is great interest in developing cost-effective routes for preparing (R)-and (S) -2-methylpyrrolidine. However, the procedures that have been developed so far use expensive starting materials or require many tedious synthesis steps.

  Pu et al. (Org. Process Res. & Dev., 2005, 9, 45-50) is (R) -2-methylpyrrolidine L-tartaric acid by fractional crystallization of racemic 2-methylpyrrolidine in the presence of L-tartaric acid. The preparation of the salt is disclosed. Racemic 2-methylpyrrolidine costs about $ 20 / gram.

  Van de Kuil et al. (Recl. Trav. Chim. Pays-Bas, 1994, 113, 267-277) is (R) -2-methylpyrrolidine L-tartrate from 2-methylpyrroline (about $ 5 / gram) and (S) A 4-step synthesis of 2-methylpyrrolidine D-tartrate is disclosed. However, this method has disadvantages for several reasons. First, this method requires the preparation of three intermediates, two of which must be isolated. Furthermore, this method requires isolation of the intermediate HCl salt by removing glacial acetic acid and excess 37% aqueous hydrochloric acid in vacuo, which is time consuming, expensive and corrosive. It is. Moreover, the synthesis requires isolation of the intermediate by performing two successive flash distillations from potassium hydroxide.

  Ku et al. (Tetrahedron, 2006, 62, 4584-4589) discloses a four-step synthesis of (R) -2-methylpyrrolidine hydrochloride from N-Boc-L-prolinol. This method has disadvantages for several reasons. First, this method requires the preparation and isolation of three different synthetic intermediates. Second, the process uses the environmentally harmful solvent dichloromethane and the corrosive gases hydrochloric and phosphoric acid. Third, this method uses expensive lithium iodide (about $ 13 / gram). Furthermore, the resulting hydrochloride is very hygroscopic.

  Zhao et al. (J. Org. Chem., 2006, 71, 4336-4338) discloses a four-step synthesis of (R) -2-methylpyrrolidine benzene sulfonate from N-Boc-L-proline. This method has disadvantages for several reasons. First, this method requires the preparation and isolation of three separate synthetic intermediates. Secondly, the method uses corrosive reagents such as phosphoric acid, boron trifluoride etherate, sodium hydroxide, sodium borohydride and Super-Hydride®.

  A method for preparing (R)-and (S) -2-methylpyrrolidine that is short, safe, inexpensive, and commercially scalable and can be performed without the need to isolate multiple synthetic intermediates. is needed.

The inventors surprisingly found that (R) -2-methylpyrrolidine L-tartrate and (S) -2-methylpyrrolidine D-tartrate do not need to isolate any synthetic intermediates, It has been found that it can be prepared in two steps from inexpensive 2-methylpyrroline using corrosive reagents. In one embodiment, the present invention provides a method for preparing (R) -2-methylpyrrolidine L-tartrate, which method comprises the following steps:
(A) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;
(B) optionally removing the hydrogenation catalyst from the mixture;
(C) forming a solution by dissolving L-tartaric acid in the mixture;
(D) crystallizing (R) -2-methylpyrrolidine L-tartrate from the solution; and (e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate. To do.
Preferably, the hydrogenation catalyst is a platinum catalyst. Preferably, the platinum catalyst is platinum (IV) oxide. More preferably, the platinum catalyst is 5% Pt—C.

  Preferably, the alcohol solvent is a mixture of ethanol and methanol. More preferably, the alcohol solvent is a mixture of ethanol and methanol in a ratio of about 2: 1 to about 3: 1 (v / v).

  Preferably step (a) is carried out at ambient temperature.

  Preferably, the platinum catalyst is removed by filtration in step (b).

Preferably, the isolated (R) -2-methylpyrrolidine L-tartrate has an optical purity of at least 50% ee. Optionally, the method further comprises the following steps:
(F) recrystallizing the isolated (R) -2-methylpyrrolidine L-tartrate;
(G) isolating the recrystallized (R) -2-methylpyrrolidine L-tartrate; and (h) optionally repeating steps (f) and (g).

  Optionally, the method further comprises the step of obtaining (R) -2-methylpyrrolidine by reacting the isolated and recrystallized (R) -2-methylpyrrolidine L-tartrate with a base. Include.

Preferably, the method was prepared (R)-2-methylpyrrolidine L- tartrate pharmaceutical composition, preferably _{H 3} receptor ligands, preferably 2- (6- {2 - [( 2R) - 2-Methyl-1-pyrrolidin-1-yl] ethyl} -2-naphthalen-2-yl) -2H-pyridazin-3-one:

It further includes the step of converting into

In one embodiment, the present invention provides 6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one:

Provides a method for preparing the method comprising the following steps:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate; and (2) (R) -2-methylpyrrolidine L-tartrate by reacting with a base (R ) -2-methylpyrrolidine free base; and (3) (R) -2-methylpyrrolidine with 6- [4- (3-halo-propoxy) -phenyl] -2H-pyridazin-3-one. , (R) -6- {4- [3- (2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one for a period of time sufficient to form Reacting under conditions sufficient to form.

Preferably, 6- [4- (3-halo-propoxy) -phenyl] -2H-pyridazin-3-one comprises the following steps:
(A) for a time sufficient to form 1- (4-hydroxy-phenyl) -ethanone with 1,3-dihalopropane to form 1- [4- (3-halo-propoxy) -phenyl] -ethanone And contacting under conditions sufficient to form it; and (b) 1- [4- (3-halo-propoxy) -phenyl] -ethanone with glyoxalic acid and 6- [4- (3 -Halo-propoxy) -phenyl] -2H-pyridazin-3-one prepared by contacting for a time sufficient to produce and under conditions sufficient to produce it.

The present invention also provides a method for preparing (S) -2-methylpyrrolidine D-tartrate, which method comprises the following steps:
(A) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;
(B) optionally removing the hydrogenation catalyst from the mixture;
(C) forming a solution by dissolving D-tartaric acid in the mixture;
(D) crystallizing (S) -2-methylpyrrolidine D-tartrate from the solution; and (e) isolating the crystalline (S) -2-methylpyrrolidine D-tartrate. To do.

Preferably, the hydrogenation catalyst is a platinum catalyst. Preferably, the platinum catalyst is platinum (IV) oxide. More preferably, the platinum catalyst is 5% Pt—C.
Preferably, the alcohol solvent is a mixture of ethanol and methanol. More preferably, the alcohol solvent is a mixture of ethanol and methanol in a ratio of about 2: 1 to about 3: 1 (v / v).

  Preferably step (a) is carried out at ambient temperature.

  Preferably, the platinum catalyst is removed by filtration in step (b).

  Preferably, the isolated (S) -2-methylpyrrolidine D-tartrate has an optical purity of at least 50% ee.

Optionally, the method comprises the following steps:
(F) recrystallizing the isolated (S) -2-methylpyrrolidine D-tartrate;
(G) isolating the recrystallized (S) -2-methylpyrrolidine D-tartrate; and (h) optionally further comprising repeating steps (f) and (g).

  Optionally, the method further comprises the step of obtaining (S) -2-methylpyrrolidine by reacting the isolated and recrystallized (S) -2-methylpyrrolidine D-tartrate with a base. Include.

Optionally, the above method comprises preparing the (S) -2-methylpyrrolidine D-tartrate salt as 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:

It further includes the step of converting into

Definitions “About” refers to a range of values ± 10% of a specified value; for example, the phrase “about 50” includes 50 ± 10%, ie, 45-55.

“Alcohol solvent” refers to a C ₁ -C ₆ alkyl alcohol or a mixture of C ₁ -C ₆ alkyl alcohols.

  “Commercial scale” refers to a single batch of at least about 500 grams.

  “Crystallize” refers to forming a crystal.

“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 forming 2-methylpyrrolidine by catalyzing the reaction of 2-methylpyrroline with hydrogen.

  “Isolating” refers to separating a component (eg, a reagent or product) from a mixture.

“Optical purity” refers to the ratio of one enantiomer in a mixture of enantiomers, expressed as enantiomeric excess (% ee), which is (| R−S | / (R + S)) ^* 100% Where R and S are the respective proportions of enantiomers such that R + S = 1.

  “Pharmaceutical” 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 containing platinum.

  “Purify” refers to increasing the purity of a compound.

  “Purity” refers to the weight percentage of one component in a mixture.

  “Solution” refers to a solvent that includes at least partially dissolved material; and may include undissolved (eg, solid) material.

  All publications referenced herein are incorporated by reference in their entirety for all purposes.

DESCRIPTION The present invention provides a method for preparing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate, which method comprises the following steps:
(A) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;
(B) optionally removing the hydrogenation catalyst from the mixture;
(C) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(D) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution; and (e) the crystalline (R) -2- Isolating methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate.

Step (a)
In step (a), 2-methylpyrroline is hydrogenated in a mixture containing an alkyl alcohol solvent and a hydrogenation catalyst. The 2-methylpyrroline used in this hydrogenation reaction may be purchased from commercial sources (eg, Sigma-Aldrich Corp .; St. Louis, MO). An important advantage of this method is that 2-methylpyrroline is less expensive than other starting materials used to produce (R)-and (S) -2-methylpyrrolidine.

  The hydrogenation catalyst used in this reaction may be purchased from commercial sources (eg, 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 are disclosed in chlorotris (triphenylphosphine) rhodium (Wilkinson catalyst) and U.S. Pat. Nos. 4,581,417, 4,631,315 and 5,670,437. But are not limited to these. Preferably, the hydrogenation catalyst is platinum (IV) oxide. More preferably, the hydrogenation catalyst is 5% Pt—C.

Alcohol solvents used in this reaction _is a C 1 -C ₆ alkyl alcohol or _C 1 -C ₆ mixture of alkyl alcohol. Examples of C ₁ -C ₆ alkyl alcohols include, but are not limited to, methanol, ethanol, isopropanol, and n-butanol. Preferably, the alcohol solvent comprises ethanol. Preferably, the alcohol solvent includes 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 in a ratio of about 0.5: 1 to about 10: 1 (v / v). More preferably, the alcohol solvent is a mixture of ethanol and methanol in a ratio of about 1: 1 to about 5: 1 (v / v). More preferably, the alcohol solvent is a mixture of ethanol and methanol in a ratio of about 2: 1 to about 3: 1 (v / v). More preferably, the alcohol solvent is a mixture of ethanol and methanol in a ratio of about 2.4: 1 (v / v).
The alcohol solvent can be present in any suitable amount in the reaction mixture of step (a). Preferably, 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. In particular, C ₁ -C ₆ alkyl alcohols are removed from the reaction mixture more easily than acetic acid. Furthermore, C ₁ -C ₆ alkyl alcohols are non-corrosive.

Hydrogen (H ₂ ) used in the hydrogenation reaction may be added as a gas to the reaction mixture, such as by performing the reaction in a hydrogen atmosphere, or treat H ₂ PtCl ₆ or RhCl ₃ with NaBH ₄ . May be generated in situ (see, for example, Brown and Sivasankaran, J. Am. Chem. Soc. 1962, 84, 2828). In certain embodiments, the hydrogenation reaction is performed by adding gaseous hydrogen to the reaction mixture. In a preferred embodiment, this hydrogenation is carried out above atmospheric pressure. In certain embodiments, the reaction is performed by generating hydrogen in situ.

The hydrogenation reaction can be performed at any suitable temperature. Preferably this reaction is carried out at ambient temperature.
The advantage of this method is that the hydrogenation reaction is carried out in a non-corrosive alkyl alcohol solvent. Another advantage of this method is that the product of the hydrogenation reaction (ie, 2-methylpyrrolidine) is obtained directly without the need for preparation or isolation of intermediates such as intermediate salts.

Step (b)
Step (b) is an optional step. In step (b), the hydrogenation catalyst is removed from the hydrogenation reaction mixture. Preferably, the hydrogenation catalyst is removed from the hydrogenation reaction mixture after step (a). Preferably, step (b) is performed before step (d), particularly when the hydrogenation catalyst is a heterogeneous catalyst. Suitable methods for removing the hydrogenation catalyst include, but are not limited to, filtration, decanting and centrifugation. In certain embodiments, the hydrogenation catalyst is removed by filtration. Hydrogenation catalysts are generally based on noble metals, but the advantage of this method is that the hydrogenation catalyst can be removed from the mixture, recycled, and reused in subsequent hydrogenation reactions (eg, U.S. Pat. No. 5,554,353 (Schneider et al.); EP1739104A1 (Kobayashi et al.); Setty-Fichman, et al., J. Mol. Cat. A: Chem., 1999, 144 (1), 159-163. checking ...

Step (c)
In 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 (R) -2-methylpyrrolidine, L-tartaric acid is used. If the desired product is (S) -2-methylpyrrolidine, D-tartaric acid is used. L-tartaric acid or D-tartaric acid used in the present method may be purchased from commercial sources (eg, Sigma-Aldrich Corp .; St. Louis, MO).

  Preferably, the solution formed in step (e) is uniform. If the solution is not uniform (eg, contains undissolved particles), the solution is preferably heated to facilitate dissolution.

  The advantage of this method is that 2-methylpyrrolidine prepared in the hydrogenation reaction does not need to be isolated from the reaction mixture before adding tartaric acid. This makes the method simpler, faster, less expensive and less wasteful than prior art methods.

Step (d)
In step (d), (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate is crystallized from the solution prepared in step (c). When L-tartaric acid is added in step (c), (R) -2-methylpyrrolidine L-tartrate is crystallized from the solution in step (d). When D-tartaric acid is added in step (c), (S) -2-methylpyrrolidine D-tartrate is crystallized from the solution in step (d). By using any suitable method, (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate can be crystallized from the solution. In certain embodiments, crystallization is induced by heating the solution to promote dissolution and then cooling.

Step (e)
In step (e), crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate is isolated. When L-tartaric acid is added in step (c), (R) -2-methylpyrrolidine L-tartrate is crystallized from the solution in step (d) and isolated in step (e). When D-tartaric acid is added in step (c), (S) -2-methylpyrrolidine D-tartrate is crystallized from the solution in step (d) and isolated in step (e). Suitable methods for the isolation of crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate include filtration, decanting and centrifuging. It is not limited. The advantage of this method is that the product can be isolated by simple filtration. Preferably, (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate is isolated by filtration. Isolated (R) -2-methylpyrrolidine L-tartrate may contain some (S) -2-methylpyrrolidine L-tartrate and isolated (S) -2-methyl It is understood that pyrrolidine D-tartrate may contain some (R) -2-methylpyrrolidine D-tartrate (which reduces the optical purity of the isolated product). Preferably, the isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate has an optical purity of at least 40% ee. More preferably, the isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate has an optical purity of at least 50% ee. More preferably, the isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate has an optical purity of at least 55% ee.

Optional Additional Steps The present process for preparing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate utilizes inexpensive and non-corrosive reagents and solvents. Can be conveniently and inexpensively carried out at temperatures between 0 ° C. and 25 ° C., requires only the preparation of one intermediate compound, does not require the isolation of synthetic intermediates, and allows catalyst recycling And is advantageous in that it results in a product that can be isolated by simple filtration and then used in subsequent methods.

  The isolated product is the tartaric acid addition salt of (R)-or (S) -2-methylpyrrolidine free base. If desired, the salt may be converted to (R)-or (S) -2-methylpyrrolidine free base. The resulting free base can be isolated using techniques known in the art. Preferably, the free base is generated in situ and can be used in the next synthetic step without isolation. The methods described herein are applicable to both isolated 2-methylpyrrolidine free base and 2-methylpyrrolidine free base generated in situ in the reaction mixture.

  Thus, in certain embodiments, the method comprises the following steps: reacting isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate with a base. To further obtain (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine. Suitable bases for use in this reaction include ammonium hydroxide, alkali metal hydroxides (eg, sodium hydroxide, potassium hydroxide), alkylamines (eg, triethylamine, diisopropylethylamine) and mixtures thereof. However, it is not limited to these. Suitable solvents for use in this reaction include, but are not limited to, diethyl ether and dichloromethane. Furthermore, 2-methylpyrrolidine free base can be generated from the corresponding tartrate salt using an ion exchange resin using procedures known to those skilled in the art.

Preferably, the prepared (R) -2-methylpyrrolidine L-tartrate, (S) -2-methylpyrrolidine D-tartrate, (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine is And an optical purity of at least 50% ee. This means that the major enantiomer makes up 75% of the mixture and the minor enantiomer makes up 25% of the mixture (50% ee = ((0.75-0.25) / (0.75 + 0.25) ^* 100%) This level of purity is often sufficient for products used as reagents in subsequent synthetic methods, for example having an optical purity of 50% ee (R When) -2-methylpyrrolidine L-tartrate is used to prepare a compound having an additional stereocenter, the above reaction results in a mixture of diastereomers, from (S) -2-methylpyrrolidine The non-major diastereomer formed will be removed in the normal purification of the major diastereomer formed from (R) -2-methylpyrrolidine. .

If a higher level of optical purity is desired, the resulting (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate may be recrystallized. Thus, in certain embodiments, the method comprises the following steps:
(F) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(G) isolating the recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (h) optionally, step (f ) And (g) may be further included.

Step (f)
In step (f), (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate isolated in step (e) is recrystallized. Suitable methods for recrystallization of isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate include using the isolated tartrate as a suitable solvent. A method of promoting crystallization by dissolving in a solution and then cooling the solution is not limited thereto. Suitable recrystallization solvents include, but are not limited to, alcohol solvents. Preferably, the recrystallization solvent is an alcohol solvent comprising at least about 70% (v / v) ethanol and methanol. More preferably, the recrystallization solvent is an alcohol solvent comprising at least about 70% (v / v) ethanol and methanol in a ratio of about 1: 1 to about 5: 1 (v / v). More preferably, the recrystallization solvent is an alcoholic solvent comprising at least about 70% (v / v) ethanol and methanol in 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) ethanol and methanol. More preferably, the recrystallization solvent is an alcohol solvent comprising at least about 90% (v / v) ethanol and methanol in 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) ethanol and methanol in a ratio of about 2: 1 to about 3: 1 (v / v).

Step (g)
In step (g), recrystallized (R) -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, filtration, decanting and centrifugation. Preferably, the recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate is isolated by filtration.

By subjecting the tartrate salt isolated in step (e) to a single recrystallization process according to steps (f) and (g), preferably having an optical purity of at least 80% ee (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate is provided. More preferably, the (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate isolated in step (g) has an optical purity of at least 85% ee. An optical purity of 85% ee means that the major enantiomer comprises more than 92% of the mixture and the minor enantiomer comprises less than 8% of the mixture (84% ee = ((0.925− 0.075) / (0.925 + 0.075) ^* 100%), this optical purity is often sufficient for use in subsequent synthetic methods.

Step (h)
If higher optical purity is desired, (R) -2-methylpyrrolidine L-tartrate or (S) can be obtained by repeating the progress of recrystallization (ie, steps (f) and (g)) one or more times. The optical purity of -2-methylpyrrolidine D-tartrate may be increased. After two recrystallizations, (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate preferably has an optical purity of at least 90% ee. More preferably, the isolated and recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate has an optical purity of at least 93% ee. After three recrystallizations, (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate preferably has an optical purity of at least 95% ee. More preferably, the isolated and recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate has an optical purity of at least 97% ee. After four recrystallizations, (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate preferably has an optical purity of at least 98% ee.

Selectively free base , the method involves reacting isolated and recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate with a base. , (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine can be further included. Suitable bases for use in this reaction include ammonium hydroxide, alkali metal hydroxides (eg, sodium hydroxide, potassium hydroxide), alkylamines (eg, triethylamine, diisopropylethylamine) and mixtures thereof. However, it is not limited to these. Suitable solvents for use in this reaction include, but are not limited to, diethyl ether and dichloromethane. In addition, 2-methylpyrrolidine free base can be produced from the corresponding tartrate salt using ion exchange resins using procedures known to those skilled in the art.

  The resulting free base can be isolated using techniques known in the art. Preferably, the free base is generated in situ and can be used in the next synthetic step without isolation. The methods described herein are applicable to both isolated 2-methylpyrrolidine free base and 2-methylpyrrolidine free base generated in situ in the reaction mixture.

Additional Compounds In addition to providing a convenient method for preparing (R)-and (S) -2-methylpyrrolidines and their respective tartrate salts, the present invention provides 2-methylpyrrolidines as other compounds, In particular, methods for incorporation into pharmaceutically useful compounds are also provided. (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate obtained after step (e), (g) or (h) can be used. In certain embodiments, the first step in the conversion comprises converting the salt form of (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate with a base or ion exchange resin. It can be converted to the corresponding free base form (ie (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine, respectively) by reacting. The (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine is then isolated from several pharmaceutical compounds known in the art, whether isolated or prepared in situ, For example, it can be used to prepare histamine-3 receptor ligands.

For example, (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine prepared by the method described above is an H ₃ receptor antagonist and / or inverse agonist of formula (I):

またはそれらの薬学的に許容可能な塩に変換され得、ここで、
Ｒ^１は、

Or may be converted to their pharmaceutically acceptable salts, where
R ¹ is

であり；そして
Ｒ^２は、

And R ² is

である。

It is.

  A suitable method for preparing compounds of formula (I) from 2-methylpyrrolidine is described in WO2007 / 009741 and is prepared according to the method described above (R) -2-methylpyrrolidine or (S)- It can be adapted for the use of 2-methylpyrrolidine. For example, a solution of 1,1 dimethylethyl 4- {4-[(3-chloropropyl) oxy] phenyl} -3-oxo-1-piperazinecarboxylate dissolved in 2 butanone can be provided. Potassium carbonate, potassium iodide and (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine free base are added and the mixture can be heated at 80 ° C. for 24 hours. The reaction can then be cooled to room temperature and partitioned between EtOAc and water. The organic phase is dried and concentrated, the residue is purified by flash chromatography, the appropriate fractions are combined and concentrated to give a BOC protected amine of formula (II):

が得られ得、ここで、Ｒ^２は、

Where R ² is

である（すなわち、化合物１，１−ジメチルエチル４−（４−｛［３−（２Ｒ−メチル−１−ピロリジニル）プロピル］オキシ｝フェニル）−３−オキソ−１−ピペラジンカルボキシレートまたは１，１−ジメチルエチル４−（４−｛［３−（２Ｓ−メチル−１−ピロリジニル）プロピル］オキシ｝フェニル）−３−オキソ−１−ピペラジンカルボキシレート）。次いで、式（ＩＩ）の化合物におけるＢＯＣ保護基が、除去される（例えば、トリフルオロ酢酸との反応によって）ことにより、式（ＩＩＩ）のアミン：

(Ie, the compound 1,1-dimethylethyl 4- (4-{[3- (2R-methyl-1-pyrrolidinyl) propyl] oxy} phenyl) -3-oxo-1-piperazinecarboxylate or 1,1 -Dimethylethyl 4- (4-{[3- (2S-methyl-1-pyrrolidinyl) propyl] oxy} phenyl) -3-oxo-1-piperazinecarboxylate). The BOC protecting group in the compound of formula (II) is then removed (eg, by reaction with trifluoroacetic acid) to give an amine of formula (III):

が形成され得、ここで、Ｒ^２は、

Where R ² is

である。次いで、式（ＩＩＩ）のアミンは、４−シアノ安息香酸、４−（１−アゼチジニルカルボニル）安息香酸、２，４−ジフルオロ安息香酸、３，５−ジフルオロ安息香酸、４−フルオロ安息香酸、１−メチル−１Ｈ−１，２，３−トリアゾール−４−カルボン酸、１，５−ジメチル−１Ｈ−ピラゾール−３−カルボン酸、１−メチル−５−オキソ−３−ピロリジンカルボン酸、３，５−ジメチル−４−イソキサゾールカルボン酸、１，３−ジメチル−１Ｈ−ピラゾール−５−カルボン酸、２，３−ジフルオロ安息香酸、２，５−ジフルオロ安息香酸、２，６−ジフルオロ安息香酸および３，４−ジフルオロ安息香酸から選択されるカルボン酸と反応させることにより、式（Ｉ）の化合物が形成されうる。

It is. Then, the amine of formula (III) is 4-cyanobenzoic acid, 4- (1-azetidinylcarbonyl) benzoic acid, 2,4-difluorobenzoic acid, 3,5-difluorobenzoic acid, 4-fluorobenzoic acid. 1-methyl-1H-1,2,3-triazole-4-carboxylic acid, 1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 1-methyl-5-oxo-3-pyrrolidinecarboxylic acid, 3 , 5-dimethyl-4-isoxazolecarboxylic acid, 1,3-dimethyl-1H-pyrazole-5-carboxylic acid, 2,3-difluorobenzoic acid, 2,5-difluorobenzoic acid, 2,6-difluorobenzoic acid By reaction with a carboxylic acid selected from acids and 3,4-difluorobenzoic acid, compounds of formula (I) may be formed.

1,1-dimethylethyl-4- {4-[(3-chloropropyl) oxy] phenyl} -3-oxo-1-piperazinecarboxylate used in the preparation of the BOC protected amine of formula (II) is , 4 - [(phenylmethyl) oxy] aniline was reacted with chloroacetyl chloride, then 2-aminoethanol may be prepared by reaction with ^N 2 - ^{(2-hydroxyethyl)} -N 1 - {4 - [( 1,1-dimethylethyl- (2-hydroxyethyl) [2-oxo-2-({4-[(phenylmethyl) oxy] phenyl} amino which can be prepared by BOC protection of phenylmethyl) oxy] phenyl} glycinamide 1,1-dimethylethyl which can be prepared by reacting a) ethyl] carbamate with methanesulfonyl chloride 1,1-Dimethylethyl-4- (4-hydroxyphenyl) which can be prepared by catalytic hydrogenolysis of 3-oxo-4- {4-[(phenylmethyl) oxy] phenyl} -1-piperazinecarboxylate It can be prepared by reacting -3-oxo-1-piperazinecarboxylate with 1-bromo-3-chloropropane.

  As an alternative to BOC, other 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.M. Protective Groups in Organic Synthesis, 2d ed. John Wiley and Sons: New York, 1991;

  Accordingly, one embodiment of the present invention is a compound of formula (I):

を調製するための方法に関し、ここで、Ｒ^１およびＲ^２は、上に示されたとおり定義され、その方法は、以下の工程：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を単離する工程；および
（２ａ）単離された（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を式Ｉの化合物に変換する工程
を包含する。

Wherein R ¹ and R ² are defined as indicated above and the method comprises the following steps:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate; and (2a) converting the isolated (R) -2-methylpyrrolidine L-tartrate to a compound of formula I Including the step of converting.

This method optionally comprises the following steps:
(1f) recrystallizing the isolated (R) -2-methylpyrrolidine L-tartrate;
(1g) isolating the recrystallized (R) -2-methylpyrrolidine L-tartrate; and (1h) optionally further comprising repeating steps (f) and (g) .

  In another embodiment, the present invention provides a compound of formula (I):

を調製するための方法に関し、ここで、Ｒ^１およびＲ^２は、上に示されたとおり定義され、その方法は、以下の工程：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を単離する工程；
（１ｆ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と反応させることにより、（Ｒ）−２−メチルピロリジンを得る工程；
（２）その（Ｒ）−２−メチルピロリジンを式（Ｉａ）の保護されたアミン

Wherein R ¹ and R ² are defined as indicated above and the method comprises the following steps:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate;
(1f) A step of obtaining (R) -2-methylpyrrolidine by reacting the (R) -2-methylpyrrolidine L-tartrate with a base;
(2) The (R) -2-methylpyrrolidine is a protected amine of formula (Ia)

（ここで、ＰＧは、保護基である）と反応させることにより、式（ＩＩ）の保護されたアミン

(Wherein PG is a protecting group) by reaction with a protected amine of formula (II)

Forming a step;
(3) An amine of formula (III) by removing the protecting group from the protected amine of formula (III)

を形成する工程；および
（４）４−シアノ安息香酸、４−（１−アゼチジニルカルボニル）安息香酸、２，４−ジフルオロ安息香酸、３，５−ジフルオロ安息香酸、４−フルオロ安息香酸、１−メチル−１Ｈ−１，２，３−トリアゾール−４−カルボン酸、１，５−ジメチル−１Ｈ−ピラゾール−３−カルボン酸、１−メチル−５−オキソ−３−ピロリジンカルボン酸、３，５−ジメチル−４−イソキサゾールカルボン酸、１，３−ジメチル−１Ｈ−ピラゾール−５−カルボン酸、２，３−ジフルオロ安息香酸、２，５−ジフルオロ安息香酸、２，６−ジフルオロ安息香酸および３，４−ジフルオロ安息香酸から選択されるカルボン酸を式（ＩＩＩ）のアミンと反応させることにより、式（Ｉ）の化合物を形成する工程を包含する。

And (4) 4-cyanobenzoic acid, 4- (1-azetidinylcarbonyl) benzoic acid, 2,4-difluorobenzoic acid, 3,5-difluorobenzoic acid, 4-fluorobenzoic acid, 1-methyl-1H-1,2,3-triazole-4-carboxylic acid, 1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 1-methyl-5-oxo-3-pyrrolidinecarboxylic acid, 3, 5-dimethyl-4-isoxazolecarboxylic acid, 1,3-dimethyl-1H-pyrazole-5-carboxylic acid, 2,3-difluorobenzoic acid, 2,5-difluorobenzoic acid, 2,6-difluorobenzoic acid And reacting a carboxylic acid selected from 3,4-difluorobenzoic acid with an amine of formula (III) to form a compound of formula (I).

This method optionally comprises the following steps:
(1f) recrystallizing the isolated (R) -2-methylpyrrolidine L-tartrate;
(1g) isolating the recrystallized (R) -2-methylpyrrolidine L-tartrate; and (1h) optionally further comprising repeating steps (f) and (g) .

  Preferably the protecting group is BOC.

  Another compound exhibiting histamine-3 receptor ligand activity is 2- (6- {2-[(2R) -2-methyl-1-pyrrolidin-1-yl] -ethyl} -2-naphthalen-2-yl ) -2H-pyridazin-3-one. One method for preparing this compound is described in US 2005/0256127.

  Treatment of 6-bromo-naphthalen-2-ol with any suitable trifluoromethanesulfonic acid reagent in the presence of an organic base provides trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester. be able to. Examples of suitable trifluoromethanesulfonic acid reagents include, for example, trifluoromethanesulfonyl anhydride, trifluoromethanesulfonyl chloride, N-phenyltrifluoromethanesulfonimide, trifluoromethanesulfonyl-1--H-imidazole, trifluoromethanesulfonyl acid anilide, Trifluoromethanesulfonyl acid-2-nitrophenyl ester and trifluoromethanesulfonyl acid-4-nitrophenyl ester. Examples of organic bases are, for example, triethylamine, diisopropylamine, diisopropylethylamine, 2,6-lutidine, pyridine and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).

This reaction can be accomplished in any suitable organic solvent. Examples of suitable solvents are CH ₂ Cl ₂ , dimethyl ether (DME) and toluene. This reaction can also be carried out in a biphasic reaction in which an inorganic base is used. For example, suitable inorganic bases are K ₃ PO ₄ , NaHCO ₃ , Na ₂ CO ₃ , NaOH, and the like. A preferred solvent is toluene. Typically, this reaction is accomplished in a biphasic reaction at low temperature, for example, in the use of toluene and 30% potassium phosphate. The preferred temperature range for this reaction is from about -5 ° C to about 0 ° C.

Trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester is converted to 2-bromo-6-vinyl-naphthalene via reaction with a vinyl trifluoroborate reagent. Suitable vinyl trifluoroborate reagents are, for example, potassium vinyl trifluoroborate, 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, dibutyl vinyl boronate. The reagent is used in an amount of about 1.0 molar equivalent to about 1.5 molar equivalents relative to trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester. Typically, this reaction is performed in polar organic solvents such as alcohol and basic solutions such as metal carbonate solutions. A preferred solvent is ethanol. Examples of other solvents that can be used for this reaction are n-propanol, iso-propanol, methanol and other suitable alcohols. The metal carbonate is preferably cesium carbonate. Alternatively, other salts such as Na ₂ CO ₃ and K ₃ PO ₄ can be used. The amount of metal carbonate for this reaction is from about 2 molar equivalents to about 4 molar equivalents relative to trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester. This reaction is accomplished in the presence of a palladium catalyst and an organic amino base (eg, triethylamine, diisopropylamine, etc.). Examples of palladium catalysts for this reaction include tetrakis (triphenylphosphine) palladium, PdCl ₂ (dppf) ₂ , PdCl ₂ (Ph ₃ P) ₂ and PdCl ₂ (CH ₃ CN) ₂ It is not limited to. A preferred palladium catalyst is tetrakis (triphenylphosphine) palladium.

Treatment of 2-bromo-6-vinyl-naphthalene with (R) -2-methylpyrrolidine anion generated with n-butyllithium yields 1- [2- (6-bromo-naphthalene-2- Yl) -ethyl]-(R) -2-methyl-pyrrolidine may be obtained. The method described in US 2005/0256127 can be improved by preparing (R)-and / or (S) -2-methylpyrrolidine according to the method described above. The 2-bromo-6-vinyl-naphthalene is then reacted with (R) -2-methylpyrrolidine anion generated with n-butyllithium or any other suitable base to give 1- [2 -(6-Bromo-naphthalen-2-yl) -ethyl] -2R-methyl-pyrrolidine may be obtained. Treatment of 2-bromo-6-vinyl-naphthalene with (R) -2-methylpyrrolidine anion generated with n-butyllithium yields 1- [2- (6-bromo-naphthalene-2- Yl) -ethyl]-(R) -2-methyl-pyrrolidine may be obtained. Preferably, about 1.2 to about 2.5 molar equivalents of (R) -2-methylpyrrolidine are used for this reaction. This reaction is typically an organic solvent, e.g., THF, methyl -t- butyl ether (MTBE), is achieved in Et ₂ O and DME. A preferred solvent is tetrahydrofuran (THF). n-Butyllithium is added to the (R) -2-methylpyrrolidine in THF in a controlled manner, typically dropwise. To this solution is added a THF solution of 2-bromo-6-vinyl-naphthalene. Alternatively, it is also appropriate to add a THF solution of 2-bromo-6-vinyl-naphthalene to a solution of (R) -2-methylpyrrolidine and n-butyllithium. This reaction is accomplished at temperatures below room temperature, typically in the range of about 0 ° C to about -20 ° C. About 0.3 to about 0.7 molar equivalents of n-butyl lithium are used for the 2-bromo-6-vinylnaphthalene compound. The resulting compound is 1- [2- (6-Bromo-naphthalen-2-yl) -ethyl]-(R) -2-methyl-pyrrolidine.

  The 1- [2- (6-bromo-naphthalen-2-yl) -ethyl]-(R) -2-methyl-pyrrolidine is then reacted with 2H-pyridazin-3-one to give the desired 2- A {6- [2-((R) 2-methyl-pyrrolidin-1-yl) -ethyl] -naphthalen-2-yl} -2H-pyridazin-3-one compound may be obtained and further processed. Thus, a suitable salt can be prepared. This reaction is accomplished using 2H-pyridazin-3-one, 8-hydroxyquinoline, copper catalyst in the presence of a base. About 1.0 to about 1.5 molar equivalents of (2H) -pyridazin-3-one is equivalent to 1- [2- (6-bromo-naphthalen-2-yl) -ethyl]-(R) -2-methyl. -Used for pyrrolidine. The copper catalyst can be any suitable copper catalyst, such as a copper (I) catalyst. Examples of suitable catalysts for this reaction include copper (0) powder, copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) oxide, copper (I) acetate, chloride Examples include, but are not limited to, copper (II), copper (II) bromide, copper (II) iodide, copper (II) oxide, or copper (II) acetate. A preferred copper catalyst is copper (I) chloride. About 0.02 to about 1.0 molar equivalents of copper catalyst is used for 1- [2- (6-bromo-naphthalen-2-yl) -ethyl]-(R) -2-methyl-pyrrolidine. . Examples of suitable ligands for this reaction include p-dimethylaminopyridine, pyridine, 3-picoline, 4-picoline, 8-hydroxyquinoline, 7-methyl-8-hydroxyquinoline, 7-n-propyl-8-hydroxy. Examples include, but are not limited to, quinoline, 1,10-phenanthroline and 2,2′-dipyridyl. A preferred ligand is 8-hydroxyquinoline, which is about 0.02 relative to 1- [2- (6-bromo-naphthalen-2-yl) -ethyl]-(R) -2-methyl-pyrrolidine. Used in amounts of up to about 2.0 molar equivalents. Preferably, the base is a metal carbonate or metal alkoxide, such as cesium carbonate, potassium carbonate, sodium carbonate and sodium tert-butoxide. A preferred base is potassium carbonate, which is about 1.0 to about 1 to 1- [2- (6-bromo-naphthalen-2-yl) -ethyl]-(R) -2-methyl-pyrrolidine. Used in an amount of 2.0 molar equivalents. This reaction is accomplished in polar organic solvents at elevated temperatures. Examples of suitable solvents include, but are not limited to, N, N'-dimethylformamide, N-methylpyrrolidinone, N, N'-dimethylacetamide, pyridine, 3-picoline, 4-picoline and the like. A preferred solvent is dimethylformamide (DMF). Typically, this reaction is accomplished under a nitrogen atmosphere and the reaction mixture is heated to a temperature of about 100 ° C to about 160 ° C. This reaction can typically be accomplished in about 10 to about 48 hours. When the reaction is complete and cooled to 25 ° C., a non-water miscible solvent, such as ethyl acetate, is added. The organic solution is washed several times with an aqueous brine solution, such as 25% NaCl solution or other suitable salt solution. The product is obtained by drying the organic solution and concentrating to dryness.

Alternatively, the 2- (6- {2-[(2R) -2-methyl-1-pyrrolidin-1-yl] -ethyl} -2-naphthalen-2-yl) -2H-pyridazin-3-one active agent is US Pat. No. 7,153,889, filed Oct. 22, 2003, at least, for example, the general procedure and the procedure described in Example 31, or any other suitable for providing a stable active agent It can be prepared according to the procedure. Briefly, reduction of 6-bromo-2-naphthoate using, for example, BH ₃ -THF provides the corresponding alcohol. 6-Bromo-naphthalen-2-yl-methanol was treated with 3 (2H) -pyridazinone, copper powder and base to give 2- [6- (2-hydroxy-ethyl) -naphthalen-2-yl-]- 2H-pyridazin-3-one is obtained, which is activated with a sulfonate such as tosylate. In order to obtain (R) -2-methylpyrrolidine with or without optional steps (f) to (h) and (R) -2-methylpyrrolidine according to steps (a) to (e) above. There is provided (R) 2-methylpyrrolidine prepared by reacting tartrate with a base, and reacting the sulfonate with (R) -2-methylpyrrolidine to give 2- (6-{(2R) 2 -Methyl-1-pyrrolidin-1-yl] -ethyl} -2-naphthalen-2-yl) -2H-pyridazin-3-one is obtained.

Accordingly, one embodiment of the present invention prepares 2- {6- [2- (2-methyl-pyrrolidin-1-yl) -ethyl] -naphthalen-2-yl} -2H-pyridazin-3-one. The method comprises the following steps:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) converting trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester to 2-bromo-6-vinyl-naphthalene;
(3b) By reacting 2-bromo-6-vinyl-naphthalene with (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine in the presence of n-butyllithium, 1- [2- ( Obtaining 6-bromo-naphthalen-2-yl) -ethyl] -2R-methyl-pyrrolidine or 1- [2- (6-bromo-naphthalen-2-yl) -ethyl] -2S-methyl-pyrrolidine; and (3c) 1- [2- (6-Bromo-naphthalen-2-yl) -ethyl] -2-methyl-pyrrolidine is reacted with 2H-pyridazin-3-one to give 2- {6- [2- Including obtaining (2-methyl-pyrrolidin-1-yl) -ethyl] -naphthalen-2-yl} -2H-pyridazin-3-one.

This method optionally comprises the following steps:
(1f) recrystallizing the isolated (R) -2-methylpyrrolidine L-tartrate;
(1g) isolating the recrystallized (R) -2-methylpyrrolidine L-tartrate; and (1h) optionally further comprising repeating steps (f) and (g) .

Further, trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester provides: 6-bromo-naphthalen-2-ol; and 6-bromo-naphthalen-2-ol is converted to a suitable trifluoromethanesulfone. It may be obtained by reacting with an acid reagent.
Exemplary compounds that can be produced using the methods of the present invention include:

Is mentioned.

  WO 2005/117865 also describes the following 2-methyl-pyrrolidinyl moiety of the general formula III:

を含むヒスタミン−３−受容体リガンドが記載されており、ここで、Ａは：

Histamine-3-receptor ligands have been described, wherein A is:

から選択され、ここで：
ｍは、０、１または２であり；
ｎは、０、１または２であり；
Ｒ^３は、水素または低級アルキルであり；
ｔは、１または２であり；
Ｒ^４は、水素または低級アルキルであり
Ｘは、Ｏ、ＳまたはＮ−Ｒ^８であり、ここで、Ｒ^８は、水素または低級アルキルであり；
ｐは、０、１または２であり；
Ｒ^６は、低級アルキルであり；
ｓは、０、１または２であり；および
Ｒ^７は、低級アルキルである。

Where is selected from:
m is 0, 1 or 2;
n is 0, 1 or 2;
R ³ is hydrogen or lower alkyl;
t is 1 or 2;
R ⁴ is hydrogen or lower alkyl and 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.

  Compounds of formula III can be prepared according to Scheme 1.

  The coupling of carboxylic acids and amines is widely described in the literature, and procedures are known to those skilled in the art (for example, see Comprehensive Organic for reaction conditions leading to such reactions as described in the literature). Transformations: See A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY, 1999). (R) by reacting (R) -2-methylpyrrolidine L-tartrate with a base according to steps (a) to (e) described above (with or without optional steps (f) to (h)). Can be conveniently converted to the respective amides by coupling 6-hydroxy-2-naphthoic acid with (R)-or (S) -2-methylpyrrolidine prepared by obtaining 2-methylpyrrolidine . Any suitable coupling agent can be used to effect this conversion. For example, 1,1′-carbonyldiimidazole (CDI), N, N′-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1- [bis ( Dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium-3-oxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), Coupling reagents such as O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium tetrafluoroborate (TBTU) and the like are equally well suited to effect such conversion. Can be used.

  There is no particular restriction on the nature of the solvent used, provided that the solvent used does not have a detrimental effect on the reaction or the reagent involved and can dissolve the reagent at least to some extent. Examples for suitable solvents include: DMF, dichloromethane (DCM), dioxane, THF, and the like. Typically, a base is used with a coupling agent. There is no particular restriction on the nature of the base used at this stage, and any base commonly used in this type of reaction may be used herein as well. Examples of such bases include triethylamine and diisopropylethylamine. This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the reaction with heating from ambient temperature to reflux. Depending on many factors, especially the reaction temperature and the nature of the reagents, the time required for the reaction can also vary greatly. However, usually a period of 0.5 hours to several days is sufficient to obtain the amide derivative.

One exemplary procedure for preparing (6-hydroxy-naphthalen-2-yl)-(2-methyl-pyrrolidin-1-yl) -methanone is as follows. 6-hydroxy-2-naphthoic acid, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate, 2.3 mL of N-ethyldiisopropylamine, A mixture with (R) or (S) -2-methyl-pyrrolidine prepared according to the above procedure is prepared in 10 mL DMF and stirred at room temperature for 16 hours. The mixture was then concentrated to dryness, 50 mL ethyl acetate, 30 mL water and 20 mL NaHCO ₃ aq. (10%) is added. The aqueous phase can then be extracted with 50 mL of ethyl acetate and the combined organic layers can be purified by column chromatography on silica. The product fraction can be concentrated to dryness, triturated twice with 20 mL diethyl ether / heptane 1/1 and the residue can be dried under vacuum at 50 ° C. By carrying out this method with (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine prepared according to the method described herein, (6-hydroxy-naphthalene-2- Yl)-(2R-methyl-pyrrolidin-1-yl) -methanone or (6-hydroxy-naphthalen-2-yl)-(2S-methyl-pyrrolidin-1-yl) -methanone is then used Thus, histamine-3-receptor ligands can be generated.

  To make a histamine-3-receptor ligand, the aforementioned (R) or (S) intermediate is reacted with an alcohol of formula HO-A, where A is defined as above. To form an ether. The synthesis of ethers has been extensively described in the literature, and procedures are known to those skilled in the art (for example, the reaction conditions leading to such reactions described in the literature are: Comprehensive Organic Transformations: A Guide. to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY, 1999). This transformation is known to those skilled in the art and is commonly used in the so-called “Mitsunobu reaction” (Hughes, David L. The Mitsunobu reaction. Organic Reactions (New York) (1992), 42, 335-656). Can be effected by using the reaction conditions to be used. Trialkylphosphines (eg, tributylphosphine, triphenylphosphine, etc.) and diethyl-azodicarboxylate (DEAD) in solvents commonly used in such transformations, such as tetrahydrofuran (THF), toluene, dichloromethane, and the like. ), Diisopropyl azodicarboxylate (DIAD) (optionally polymer-bound), conditions using diazo compounds such as tetramethylazodicarboxamide. There is no particular restriction on the nature of the solvent used, provided that the solvent used does not have a detrimental effect on the reaction or the reagent involved and can dissolve the reagent at least to some extent. This reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. From ambient temperature to reflux is generally appropriate. Depending on many factors, especially the reaction temperature and the nature of the reagents, the time required for the reaction can also vary greatly. However, usually a period of 0.5 hours to several days is sufficient to obtain the desired compound.

  Alternatively, the following synthetic approach may be used.

  As shown in Scheme 2, the starting alcohol HO-A (where A is as described above) is reacted with the methyl ester under Mitsunobu reaction conditions and then the ester is cleaved. The acid formed in the middle is then subjected to (R) -2-methylpyrrolidine L-tartrate according to steps (a) to (e) described above (with or without optional steps (f) to (h)). (R) -2-methylpyrrolidine is obtained by reacting with a base, or (S) -2-methylpyrrolidine is obtained by reacting (S) -2-methylpyrrolidine D-tartrate with a base. To achieve the desired compound by coupling with the prepared (R)-or (S) -2-methylpyrrolidine. Suitable coupling agents and suitable coupling conditions are described above.

  Accordingly, one embodiment of the present invention is a compound of formula (III):

を調製するための方法に関し、ここで、変数は上で示したとおりであり、その方法は：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸またはＤ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を単離する工程；および
（２ａ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と接触させることにより（Ｒ）−２−メチルピロリジン遊離塩基を形成する工程、またはその（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と接触させることにより（Ｓ）−２−メチルピロリジンを形成する工程；
（３ａ）以下の式のカルボン酸：

Where the variables are as indicated above and the method is:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) Carboxylic acids of the following formula:

を（Ｒ）−または（Ｓ）−２−メチルピロリジンのいずれかと、対応するアミドフェノールを形成するのに十分な時間にわたり、それを形成するのに十分な条件下で接触させる工程；および
（３ｂ）上記アミドフェノールを式ＨＯ−Ａ（ここで、Ａは、上に記載されたとおりである）のアルコールと、対応するアミドエーテルを得るのに十分な時間にわたり、それを得るのに十分な条件下で接触させる工程
を包含する。

Contacting with either (R)-or (S) -2-methylpyrrolidine for a time sufficient to form the corresponding amidophenol under conditions sufficient to form it; and (3b) ) The amidophenol for a time sufficient to obtain an alcohol of formula HO-A, where A is as described above, and the corresponding amide ether, sufficient conditions to obtain it. A step of contacting under.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1 h) optionally, step (f ) And (g) may be further included.
Compound of formula (III):

を調製するための方法に関する他の実施形態、ここで、変数は上で示したとおりであり、その方法は：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸またはＤ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を単離する工程；および
（２ａ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と接触させることにより（Ｒ）−２−メチルピロリジン遊離塩基を形成する工程、またはその（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と接触させることにより（Ｓ）−２−メチルピロリジンを形成する工程；
（３ａ）以下の式のエステルフェノール：

Other embodiments relating to a method for preparing wherein the variables are as indicated above and the method is:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) Esterphenol of the following formula:

を式ＨＯ−Ａ（ここでＡは、上に記載されたとおりである）のアルコールと、対応するエステルエーテルを形成するのに十分な時間にわたり、それを形成するのに十分な条件下で接触させる工程；および
（３ｂ）上記エステルエーテルを（Ｒ）−または（Ｓ）−２−メチルピロリジンのいずれかと、対応するアミドエーテルを得るのに十分な時間にわたり、それを得るのに十分な条件下で接触させる工程
を包含する。

Is contacted with an alcohol of formula HO-A (where A is as described above) for a time sufficient to form the corresponding ester ether under conditions sufficient to form it. And (3b) the ester ether under conditions sufficient to obtain either (R)-or (S) -2-methylpyrrolidine and sufficient time to obtain the corresponding amide ether. The process of making it contact in is included.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1h) optionally, step (f ) And (g) may be further included.

Particularly preferred compounds that can be prepared using the method of the present invention include:
(2-methyl-pyrrolidin-1-yl)-{6- [2- (1-methyl-pyrrolidin-2-yl) -ethoxy] -naphthalen-2-yl} -methanone;
[6- (1-Isopropyl-pyrrolidin-3-yloxy) -naphthalen-2-yl]-(2-methyl-pyrrolidin-1-yl) -methanone;
[6- (1-Isopropyl-piperidin-4-yloxy-) naphthalen-2-yl]-(2-methyl-pyrrolidin-1-yl) -methanone; and [6- (1-isobutyl-piperidin-4-yloxy) ) -Naphthalen-2-yl]-(2-methyl-pyrrolidin-1-yl) -methanone.

  Another group of compounds that can be prepared from (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine produced according to the methods described herein is disclosed in US2008 / 0027041A1. Specifically, the application discloses compounds of the general formula IV

およびその薬学的な塩であり；
ここで：
Ｒ^１は、

And pharmaceutical salts thereof;
here:
R ¹ is

であり、
ＸおよびＸ^ａは、各々独立して、ＣＨまたはＮであり；
Ｙは、Ｓ（Ｏ）_ｑ、ＯまたはＮＲ^１５であり；
Ｒ^２は、

And
X and ^Xa are each independently CH or N;
Y is S (O) _q , O or NR ¹⁵ ;
R ² is

And here:
When X and X ^a are both CH, R ² is meta or para to the Y— (CHR ⁴ ) _m —R ¹ group; and either X or X ^a is N When R ² is para to the Y— (CHR ⁴ ) _m —R ¹ group;
Each R ³ is:
Independently, H, F, Cl, Br, I, OR ²¹ , NR ²³ R ²⁴ , NO ₂ , CN, CF ₃ , C ₁ -C ₆ alkyl, C (═O) R ²¹ , CO ₂ R ²¹ or C (= ^O) or a ^NR 23 ^{R 24;} or ^{R 3,} is ortho to ^{R 2, R 2} is, (i), (ii) , (iv), (vi) or (ix) R ³ and R ¹⁴ together form — (CH ₂ ) _s —, —CH ₂ Z—, —ZCH ₂ —, —ZCH ₂ CH ₂ — or CH ₂ CH ₂ Z—. obtained; where, Z is, O, S _{(O) y} or ^{NR 27} in either; is or ^{R 3,} is ortho to ^{R 2, R 2} is, (iv), (v) or (viii ), R ³ and R ¹³ are taken together to form — (CH ₂ ) _s —, —CH ₂ Z—, —ZC. _{H 2 -, - ZCH 2 CH} 2 - or _CH 2 _CH 2 Z- or can form; or ^{R 3} is ortho to ^{R 2,} when ^{R 2} is (viii), ^{R 3} and R ^13b may be taken together to form — (CH ₂ ) _s —, —CH ₂ Z—, —ZCH ₂ —, —ZCH ₂ CH ₂ — or CH ₂ CH ₂ Z—; or R ³ is is ortho to X ^{a, R 2} is, when ortho to ^{R 3,} and with respect to ^{X a} is meta, ^{R 2} and ^{R 3} are taken together:

を形成し得；
各Ｒ^４は、独立して、Ｈ、Ｃ_１−Ｃ_６アルキルまたはＯＲ^２１であり、ここでそのアルキル基は、選択的に、１〜３個のＲ^２０基で置換され；
Ｒ^１２は、Ｈ、Ｃ_１−Ｃ_６アルキル、シクロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロシクロアルキル、Ｃ（＝Ｏ）Ｒ^２７またはＣＯ_２Ｒ^２７であり、ここで、そのアルキル、シクロアルキル、アリール、アリールアルキル、ヘテロアリールまたはヘテロシクロアルキル基は、選択的に、１〜３個のＲ^２０基で置換され；
Ｒ^１３およびＲ^１４は、各々独立して、Ｈ、Ｃ_１−Ｃ_６アルキル、アリール、アリールアルキルＣ_１−Ｃ_６アルコキシル、Ｓ（＝Ｏ）_ｙ−Ｃ_１−Ｃ_６アルキル、シクロアルキル、ヘテロシクロアルキルまたはヘテロアリールであり；
Ｒ^１３ａ、Ｒ^１３ｂ、Ｒ^１３ｃおよびＲ^１４ａは、各々独立して、Ｈ、Ｃ_１−Ｃ_６アルキルであるか；またはＲ^１３およびＲ^１４は、それらが接続している炭素原子と一緒になって、縮合フェニル、チエニル、ピロリル、オキサゾリル、ピリジニルまたはＣ_３−Ｃ_６シクロアルキル環を形成するか；またはＲ^１３ｂおよびＲ^１４、もしくはＲ^１３および^１４ａ、もしくはＲ^１３ｂおよび^１４ａ、もしくはＲ^１３ｃおよびＲ^１４ａは、それらが接続している炭素原子と一緒になって、縮合Ｃ_３−Ｃ_６シクロアルキル環を形成するか；またはＲ^１３およびＲ^１３ａ、もしくはＲ^１４およびＲ^１４ａは、それらが結合している炭素原子と一緒になって、Ｃ_３−Ｃ_８シクロアルキル環を形成するが；ただし、Ｒ^１３とＲ^１４、Ｒ^１３ｂとＲ^１４、Ｒ^１３とＲ^１４ａ、Ｒ^１３ｂとＲ^１４ａ、Ｒ^１３ｃとＲ^１４ａ、Ｒ^１３とＲ^１３ａ、およびＲ^１４とＲ^１４ａとの１対だけが、それらが接続しているか、またはそれらが結合している炭素原子と一緒になって、環を形成し；そして、その縮合フェニル、チエニル、ピロリル、オキサゾリル、ピリジニルまたはシクロアルキル環は、選択的に、１〜３個のＲ^２０基で置換され；
Ｒ^１５は、Ｈ、Ｃ_１−Ｃ_６アルキル、Ｃ（＝Ｏ）Ｒ^２５、ＣＯ_２Ｒ^２５であり；
各存在におけるＲ^２０は、独立して、Ｈ、Ｆ、Ｃｌ、Ｂｒ、Ｉ、ＯＲ^２１、ＯＲ^２２、ＮＲ^２３Ｒ^２４、ＮＨＯＨ、ＮＯ_２、ＣＮ、ＣＦ_３、選択的にＯＲ^２６で置換されたＣ_１−Ｃ_６アルキル、Ｃ_２−Ｃ_６アルケニル、Ｃ_２−Ｃ_６アルキニル、Ｃ_３−Ｃ_７シクロアルキルＣ_０−Ｃ_４アルキル、３〜７員のヘテロシクロアルキルＣ_０−Ｃ_４アルキル、フェニル、５もしくは６員のヘテロアリールＣ_０−Ｃ_４アルキル、アリールアルキル、（＝Ｏ）、Ｃ（＝Ｏ）Ｒ^２１、ＣＯ_２Ｒ^２１、ＯＣ（＝Ｏ）Ｒ^２１、Ｃ（＝Ｏ）ＮＲ^２３Ｒ^２４、ＮＲ^２７Ｃ（＝Ｏ）Ｒ^２１、ＮＲ^２７Ｃ（＝Ｏ）ＯＲ^２１、ＯＣ（＝Ｏ）ＮＲ^２３Ｒ^２４、ＮＲ^２７Ｃ（＝Ｓ）Ｒ^２１またはＳ（Ｏ）_ｑＲ^２１であり；
各Ｒ^２１は、独立して、Ｈ、Ｃ_１−Ｃ_６アルキル、アリールまたはアリールアルキルであり；
各Ｒ^２２は、独立して、カルボキシル基のヒドロキシル基が除去された後のアミノ酸の残基であり；
Ｒ^２３およびＲ^２４の各々は、独立して、Ｈ、Ｃ_１−Ｃ_６アルキルおよびアリールから選択されるか、またはＲ^２３およびＲ^２４は、それらが結合している窒素原子と一緒になって、選択的に＝Ｏで置換される３〜７員の複素環式環を形成し；
Ｒ^２５は、Ｃ_１−Ｃ_６アルキル、アリールまたはアルキルアリールであり；
Ｒ^２６は、Ｈ、Ｃ_１−Ｃ_６アルキル、アリールまたはアルキルアリールであり；
Ｒ^２７ は、ＨまたはＣ_１−Ｃ_６アルキルであり；
Ｒ^１が窒素原子を介して結合するとき、ｍは、１、２、３、４または５であり、そしてＲ^１が炭素原子を介して結合するとき、ｍは、０、１、２、３、４または５であり；
ｎは、１、２または３であり；
ｑは、０、１または２であり；
ｓは、１，２または３であり；および
ｙは、０、１または２である。

Can form;
Each R ⁴ is independently H, C ₁ -C ₆ alkyl or OR ²¹ , wherein the alkyl group is optionally substituted with 1 to 3 R ²⁰ groups;
R ¹² is H, C ₁ -C ₆ alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocycloalkyl, C (═O) R ²⁷ or CO ₂ R ²⁷ , wherein the alkyl, cyclo An alkyl, aryl, arylalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with 1 to 3 R ²⁰ groups;
R ¹³ and R ¹⁴ are each independently H, C ₁ -C ₆ alkyl, aryl, arylalkyl C ₁ -C ₆ alkoxyl, S (═O) _y -C ₁ -C ₆ alkyl, cycloalkyl, hetero Is cycloalkyl or heteroaryl;
R ^13a , R ^13b , R ^13c and R ^14a are each independently H, C ₁ -C ₆ alkyl; or R ¹³ and R ¹⁴ together with the carbon atom to which they are attached. Forming a fused phenyl, thienyl, pyrrolyl, oxazolyl, pyridinyl or C ₃ -C ₆ cycloalkyl ring; or R ^13b and R ¹⁴ , or R ¹³ and ^14a , or R ^13b and ^14a , or R ^13c and R ^14a, together with the carbon atoms to which they are connected, or form a fused _C 3 -C ₆ cycloalkyl ring; or ^{R 13} and ^{R 13a} or ^{R 14} and ^{R 14a,} is to which they are attached and together with the carbon _atom, forms a C 3 -C ₈ cycloalkyl ring; ^{provided, R 13} and ^{R 14} , R ^13b and R ¹⁴ , R ¹³ and R ^14a , R ^13b and R ^14a , R ^13c and R ^14a , R ¹³ and R ^13a , and R ¹⁴ and R ^14a are connected only by one pair Or, together with the carbon atom to which they are attached, form a ring; and the fused phenyl, thienyl, pyrrolyl, oxazolyl, pyridinyl or cycloalkyl ring is optionally selected from 1 to 3 R Substituted with ²⁰ groups;
R ¹⁵ is H, C ₁ -C ₆ alkyl, C (═O) R ²⁵ , CO ₂ R ²⁵ ;
R ²⁰ in each occurrence is independently substituted with H, F, Cl, Br, I, OR ²¹ , OR ²² , NR ²³ R ²⁴ , NHOH, NO ₂ , CN, CF ₃ , optionally OR ^26. C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₇ cycloalkyl C ₀ -C ₄ alkyl, 3-7 membered heterocycloalkyl C ₀ -C ₄ alkyl , Phenyl, 5 or 6 membered heteroaryl C ₀ -C ₄ alkyl, arylalkyl, (═O), C (═O) R ²¹ , CO ₂ R ²¹ , OC (═O) R ²¹ , C (═O ^{) NR 23 R 24, NR 27} C (= O) R 21, NR 27 C (= O) oR 21, OC (= O) NR 23 R 24, NR 27 C (= S) R 21 or S (O) _q R ²¹ ;
Each R ²¹ is independently H, C ₁ -C ₆ alkyl, aryl or arylalkyl;
Each R ²² is independently the residue of an amino acid after removal of the hydroxyl group of the carboxyl group;
Each of R ²³ and R ²⁴ is independently selected from H, C ₁ -C ₆ alkyl and aryl, or R ²³ and R ²⁴ are taken together with the nitrogen atom to which they are attached. Forming a 3-7 membered heterocyclic ring optionally substituted with = O;
R ²⁵ is C ₁ -C ₆ alkyl, aryl or alkylaryl;
R ²⁶ is H, C ₁ -C ₆ alkyl, aryl or alkylaryl;
R ²⁷ is H or C ₁ -C ₆ alkyl;
When R ¹ is bonded through a nitrogen atom, m is 1, 2, 3, 4 or 5 and when R ¹ is bonded through a carbon atom, m is 0, 1, 2, 3 4 or 5;
n is 1, 2 or 3;
q is 0, 1 or 2;
s is 1, 2 or 3; and y is 0, 1 or 2.

Specific examples of compounds as described above that can be prepared using the process for preparing 2-methylpyrrolidine of the present invention include:
2-methyl-6- {4-[(R) -2-methyl-3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
6- {3,5-difluoro-4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2-methyl-2H-pyridazin-3-one;
6- {3-chloro-4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2-methyl-2H-pyridazin-3-one;
2,6-dimethyl-5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
6-methyl-5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
2-methyl-5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2-pyridin-2-yl-2H-pyridazin-3-one;
2- (6-Methyl-pyridin-2-yl) -5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazine-3- on;
2- (3-Methyl-pyridin-2-yl) -5- {4- [3-((R) -2-methylpyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one ;
6-methyl-5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2-pyridin-2-yl-2H-pyridazin-3-one;
6-Methyl-2- (3-methyl-pyridin-2-yl) -5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H- Pyridazin-3-one;
6-methyl-5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2-thiophen-3-yl-2H-pyridazin-3-one;
5- {4- [3-((S) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2-pyridin-2-yl-2H-pyridazin-3-one;
6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -5-pyridin-2-yl-4,5-dihydro-2H-pyridazine-3- on;
6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -5-pyridin-2-yl-2H-pyridazin-3-one;
2- (2-Fluoro-ethyl) -6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
6- {3-fluoro-4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
4-methyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3-one;
4-methyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
2-Methyl-4- {3- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2,5,6,7-tetrahydro-cyclopenta [d] pyridazine- 1-one;
2-isopropyl-5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
2- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -5- (6-oxo-1,6-dihydro-pyridazin-3-yl) -benzonitrile;
2- (2-hydroxyethyl) -6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
6- {4-[(S) -2-methyl-3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
6- {3-methoxy-4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2-pyrimidin-2-yl-2H-pyridazin-3-one;
6- {6- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -pyridin-3-yl} -2H-pyridazin-3-one;
6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2- (2,2,2-trifluoro-ethyl) -4,5-dihydro -2H-pyridazin-3-one;
6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2- (2,2,2-trifluoro-ethyl) -2H-pyridazine-3 -ON;
5- {4- [3-((R) -2-Methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -3,4-diaza-bicyclo [4.2.0] oct-4-ene- 2-on;
4- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2,4a, 5,6,7,7a-hexahydro-cyclopenta [d] pyridazine- 1-one;
6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3-one;
4,4-dimethyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3-one;
6- {3-Fluoro-4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3-one;
5,5-dimethyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3-one;
6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2-pyridin-2-yl-4,5-dihydro-2H-pyridazine-3- on;
6- {3,5-difluoro-4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
6- {3,5-dibromo-4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
6- {3,5-difluoro-4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3-one;
5-methyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3-one racemate;
5-Methyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3-one diastereomer ;
5-Methyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3-one diastereomer ;
6-{(R) -2-methyl-4- [3- (2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3-one;
2- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -6-phenyl-2H-pyridazin-3-one;
6-methyl-2- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
2- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-phthalazin-1-one;
2- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -6-pyridin-3-yl-2H-pyridazin-3-one;
3-methyl-4- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -6H-isoxazolo [3,4-d] pyridazin-7-one;
8- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -5,6-dihydro-2H-benzo [h] cinnoline-3-one;
5-methyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
5-ethyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
8- [3- (2-Methyl-pyrrolidin-1-yl) -propoxy] -4,4a, 5,6-tetrahydro-2H-benzo [h] cinnoline-3-one;
6- {2-methoxy-4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
6- {2-Fluoro-4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2-pyridin-2-yl-2H-pyridazin-3-one;
6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4-pyridin-2-yl-4,5-dihydro-2H-pyridazine-3- on;
6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4-pyridin-2-yl-2H-pyridazin-3-one;
8- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -5,6-dihydro-3H-benzo [f] cinnolin-2-one;
5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
2-methoxymethyl-5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
5- {4-[(S) -2-methyl-3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
5- {4-[(R) -2-methyl-3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
5- {3,5-dibromo-4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
2-methoxymethyl-5- {2-methyl-4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
5- {2-methyl-4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
4-methoxy-2-methoxymethyl-5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
5-methoxy-2-methoxymethyl-4- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
5-methoxy-4- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
6- {4- [3-((S) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -3,4-diaza-bicyclo [4.1.0] hept-4-ene- 2-on;
5- {4-[(S) -2-Methyl-3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -3,4-diaza-bicyclo [4.1. 0] hept-4-en-2-one;
5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -3,4-diaza-bicyclo [4.1.0] hept-4-ene- 2-one single isomer;
5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -3,4-diaza-bicyclo [4.1.0] hept-4-ene- 2-one single isomer;
6- {4- [2-hydroxy-3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
6- {4-[(S) -2-hydroxy-3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
6- {4-[(R) -2-hydroxy-3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
And 6-cyclopropyl-2- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
Or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

Of these, the following are preferred:
5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2-pyridin-2-yl-2H-pyridazin-3-one;
6- {4-[(S) -2-methyl-3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
4,4-dimethyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3-one;
5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -3,4-diaza-bicyclo [4.1.0] hept-4-ene- 2-on;
5- {4-[(S) -2-Methyl-3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -3,4-diaza-bicyclo [4.1. 0] hept-4-en-2-one;
5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -3,4-diaza-bicyclo [4.1.0] hept-4-ene- 2-on;
5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -3,4-diaza-bicyclo [4.1.0] hept-4-ene- 2-on;
One of 5-methyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3-one Diastereomers;
One of 5-methyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3-one Diastereomers;
5-methyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazin-3-one; and 6 -{4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one;
Or a compound selected from the group consisting of a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

  Particularly preferred among the foregoing are the compounds 6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one or its steric form. An isomer, a mixture of stereoisomers or a pharmaceutically acceptable salt. This compound can be prepared from (R) -2-methylpyrrolidine prepared according to the method described above. Scheme 3 illustrates an exemplary method for preparing 6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one. Is shown.

According to Scheme 3, Step _1, heated overnight mixture of CH 3 COCH ₃ of l- (4-hydroxyphenyl) ethanone and 3-bromo-1-chloropropane in 65 ° C.. The mixture is filtered, washed with acetone and concentrated to dryness. The crude product is dissolved in CH ₂ Cl ₂ , washed with saturated NaHCO ₃ , NaCl solution and dried over Na ₂ SO ₄ . The product is obtained by concentrating to dryness under vacuum.

The mixture of product from Step 1 and glyoxalic acid monohydrate is stirred in 15 mL acetic acid at 100 ° C. for 2 hours. Evaporate the solvent, add water to the residue and cool to 0 ° C. with concentrated aqueous NH ₄ OH until pH 8 is reached. To this mixture, hydrated hydrazine is added and heated to 100 ° C. for 1 hour. The resulting solid may be filtered and washed with water. The crude material may be dissolved in CH ₂ Cl ₂ / MeOH and purified by column chromatography using 10% MeOH in CH ₂ Cl ₂ to CH ₂ Cl ₂ .

A mixture of the product from Step 2, K ₂ CO ₃ , 100 mg NaI and R-2-methylpyrrolidine hydrochloride in acetonitrile is heated to 80 ° 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 over Na ₂ SO ₄ and concentrated. The residue was subjected to ISCO gradient chromatography using 100% CH ₂ Cl ₂ to 95% CH ₂ Cl ₂ in 5% MeOH: 2-aminopropane and then 90% CH ₂ Cl ₂ in 10% MeOH: 2-aminopropane. The product may be obtained by purification with The free base of the product was dissolved in MeOH, after adding 0.5 N HCl in EtOH, the solvent was evaporated, MeOH: Crystallization from Et ₂ O, may be converted to the HCl salt .

  Accordingly, one embodiment of the invention is a compound of formula (IV):

特に（Ｒ）−または（Ｓ）−６−｛４−［３−（２−メチル−ピロリジン−１−イル）−プロポキシ］−フェニル｝−２Ｈ−ピリダジン−３−オン、を調製するための方法に関し、
ここで、変数は上で示したとおりであり、その方法は：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸またはＤ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を単離する工程；および
（２ａ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と接触させることにより（Ｒ）−２−メチルピロリジン遊離塩基を形成する工程、またはその（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と接触させることにより（Ｓ）−２−メチルピロリジンを形成する工程；
（３ａ）１−（４−ヒドロキシ−フェニル）−エタノンを１，３−ジハロプロパンと、１−［４−（３−ハロ−プロポキシ）−フェニル］−エタノンを形成するのに十分な時間にわたり、それを形成するのに十分な条件下で接触させる工程；
（３ｂ）その１−［４−（３−ハロ−プロポキシ）−フェニル］−エタノンをグリオキサル酸と、６−［４−（３−ハロ−プロポキシ）−フェニル］−２Ｈ−ピリダジン−３−オンを生成するのに十分な時間にわたり、それを生成するのに十分な条件下で接触させる工程；および
（３ｃ）その６−［４−（３−ハロ−プロポキシ）−フェニル］−２Ｈ−ピリダジン−３−オンを（Ｒ）−または（Ｓ）−２−メチルピロリジンのいずれかと、対応する（Ｒ）−または（Ｓ）−６−｛４−［３−（２−メチル−ピロリジン−１−イル）−プロポキシ］−フェニル｝−２Ｈ−ピリダジン−３−オンを形成するのに十分な時間にわたり、それを形成するのに十分な条件下で接触させる工程
を包含する。

Process for preparing in particular (R)-or (S) -6- {4- [3- (2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one Regarding
Where the variables are as shown above and the method is:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) for a time sufficient to form 1- (4-hydroxy-phenyl) -ethanone with 1,3-dihalopropane to form 1- [4- (3-halo-propoxy) -phenyl] -ethanone Contacting under conditions sufficient to form it;
(3b) The 1- [4- (3-halo-propoxy) -phenyl] -ethanone with glyoxalic acid and 6- [4- (3-halo-propoxy) -phenyl] -2H-pyridazin-3-one Contacting for a time sufficient to produce under conditions sufficient to produce it; and (3c) 6- [4- (3-halo-propoxy) -phenyl] -2H-pyridazine-3 -One with either (R)-or (S) -2-methylpyrrolidine and the corresponding (R)-or (S) -6- {4- [3- (2-methyl-pyrrolidin-1-yl) -Propoxy] -phenyl} -2H-pyridazin-3-one comprising contacting for a time sufficient to form it under conditions sufficient to form it.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1h) optionally, step (f ) And (g) may be further included.

  More generally, the compound of formula V:

に、前述の方法に従って調製される（Ｒ）または（Ｓ）２−メチルピロリジン塩酸塩、Ｋ_２ＣＯ_３およびＣＨ_３ＣＮ中のＮａＩを提供し、そして生成物を回収することによって、前述の方法を、ＵＳ２００８／００２７０４１Ａ１に記載されている化合物の調製に適用してもよい。

By providing NaI in (R) or (S) 2-methylpyrrolidine hydrochloride, K ₂ CO ₃ and CH ₃ CN prepared according to the method described above and recovering the product May be applied to the preparation of the compounds described in US2008 / 0027041A1.

  A further embodiment of the present invention provides a compound of formula (IV):

を調製するための方法に関し、ここで、変数は上で示したとおりであり、その方法は：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸またはＤ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を単離する工程；および
（２ａ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と接触させることにより（Ｒ）−２−メチルピロリジン遊離塩基を形成する工程、またはその（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と接触させることにより（Ｓ）−２−メチルピロリジンを形成する工程；
（３ａ）その（Ｒ）−２−メチルピロリジンまたは（Ｓ）−２−メチルピロリジンを式ＩＶの化合物に変換する工程
を包含する。

Where the variables are as indicated above and the method is:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) converting the (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine into a compound of formula IV.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1h) optionally, step (f ) And (g) may be further included.

  Exemplary compounds that can be produced according to these methods include (R)-or (S) -6- {4- [3- (2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H. -Pyridazin-3-one:

が挙げられる。好ましくは、その化合物は、６−｛４−［３−（（Ｒ）−２−メチル−ピロリジン−１−イル）−プロポキシ］−フェニル｝−２Ｈ−ピリダジン−３−オンである。

Is mentioned. Preferably, the compound is 6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one.

  A further group of histamine-3-receptor ligands that can be prepared using (R) or (S) 2-methylpyrrolidine prepared according to the methods described herein is described in WO 2006/059778. . These compounds are compounds of general formula VI:

およびその薬学的な塩を包含し；
ここで、Ｙは、（Ｒ）または（Ｓ）２−メチルピロリジンであり；
各Ｒ^１は、独立して、水素原子、ヒドロキシル基、ハロゲン原子、低級アルキル基、ハロ−低級アルキル基、低級アルコキシ基、ハロ−低級アルコキシ基、低級アルコキシ−低級アルキル基もしくはハロ−低級アルコキシ−低級アルキル基を表しており；
ｐは、０〜４の整数を示し；
Ｒ^２は、ヒドロキシル基、ハロゲン原子、低級アルキル基、ハロ−低級アルキル基、低級アルコキシ基、ハロ−低級アルコキシ基、低級アルコキシ−低級アルキル基もしくはハロ−低級アルコキシ−低級アルキル基を表しているか、または
Ｒ^２は、以下の式の基、

And pharmaceutical salts thereof;
Where Y is (R) or (S) 2-methylpyrrolidine;
Each R ¹ is independently a hydrogen atom, hydroxyl group, halogen atom, lower alkyl group, halo-lower alkyl group, lower alkoxy group, halo-lower alkoxy group, lower alkoxy-lower alkyl group or halo-lower alkoxy- Represents a lower alkyl group;
p represents an integer of 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 is a group of the following formula:

を表しており、ここで、Ａは、式（ＩＩＩ−１）または式（ＩＩＩ−２）の化合物

Wherein A is a compound of formula (III-1) or formula (III-2)

を表しており、ここで、Ｒ３は、水素原子、または選択的に低級アルキル基、ハロ−低級アルキル基、シクロアルキル基、ハロゲン原子もしくはヒドロキシル基で置換されるシクロアルキル基を表しており、そしてＲ４は、水素原子、ヒドロキシル基、ハロゲン原子、低級アルキル基、ハロ−低級アルキル基、低級アルコキシ基、ハロ−低級アルコキシ基、低級アルコキシ−低級アルキル基またはハロ−低級アルコキシ−低級アルキル基を表しており；
ｍは、０または１を示し；ｎは、０、１または２を示し；そして
Ｘ^１〜Ｘ^４は、各々独立して、選択的に低級アルキル基、低級アルコキシ基、ハロ−低級アルコキシ基またはハロゲン原子で置換される炭素原子を表している。

In which 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. There;
m represents 0 or 1; n represents 0, 1 or 2; and X ^{1 to} X ⁴ each independently represent a lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group or Represents a carbon atom substituted with a halogen atom.

Specifically disclosed compounds within this group that can be prepared according to the methods described herein include:
1-methyl-4- {4- [3-((2S) -2-methyl-1-pyrrolidinyl) propoxy] phenyl} -2 (1H) -pyridone; and 1-methyl-4- {4- [3- ((2R) -2-methyl-1-pyrrolidinyl) propoxy] phenyl} -2 (1H) -pyridone.

Such compounds provide intermediate compounds of formula (VI), where Y is Cl, and are prepared according to the methods previously described (R) or (S) 2-methyl It can be prepared by reacting with Nal in pyrrolidine, K ₂ CO ₃ and CH ₃ CN and recovering the product as described above for the compound of US2008 / 0027041A1.

  Accordingly, another embodiment of the present invention provides a compound of formula (VI):

を調製するための方法に関し、ここで、変数は上で示したとおりであり、その方法は：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸またはＤ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を単離する工程；および
（２ａ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と接触させることにより（Ｒ）−２−メチルピロリジン遊離塩基を形成する工程、またはその（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と接触させることにより（Ｓ）−２−メチルピロリジンを形成する工程；
（３ａ）式ＶＩの化合物（ここで、Ｙは、Ｃｌである）を（Ｒ）−または（Ｓ）−２−メチルピロリジンのいずれかと、対応するアミドを形成するのに十分な時間にわたり、それを形成するのに十分な条件下で接触させる工程
を包含する。

Where the variables are as indicated above and the method is:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) a compound of formula VI (where Y is Cl) with either (R)-or (S) -2-methylpyrrolidine for a time sufficient to form the corresponding amide Contacting under conditions sufficient to form.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1h) optionally, step (f ) And (g) may be further included.

  Yet another application describing a histamine-3-receptor ligand containing a 2-methylpyrrolidine moiety is WO2007 / 105053. This application describes a compound of formula VII:

の調製を記載しており、ここで、
Ａは、（Ｒ）または（Ｓ）２−メチルピロリジンであり；
Ｚ、Ｙ、Ｑ、Ｘは、独立して、窒素または炭素であり；
Ｒ^３は、水素、（Ｃ_１−Ｃ_８）アルキル、（Ｃ_１−Ｃ_８）アルコキシ、ハロ、５〜６員のアリール、５〜６員のヘテロアリール、ヒドロキシル、メチレンヒドロキシル、−（Ｃ＝Ｏ）ＮＲ^４Ｒ^５およびＳ（Ｏ）_ｐ（Ｃ_１−Ｃ_４）アルキルであり、ここで、ｐは、１または２であり；
Ｒ^４およびＲ^５は、独立して：
水素；１〜４個のハロゲンで選択的に置換される（Ｃ_１−Ｃ_８）アルキル；ＯＨ、１〜４個の（Ｃ_１−Ｃ_４）アルキル、（Ｃ_３−Ｃ_７）シクロアルキル、（Ｃ_１−Ｃ_４）ジアルキルアミノ、ハロゲンで選択的に置換され、かつ１〜２個のハロゲンで選択的に置換される（Ｃ_６−Ｃ_１０）アリールオキシで選択的に置換される（Ｃ_６−Ｃ_１０）アリール、および（Ｃ_６−Ｃ_１０）アリール基で選択的に置換され、かつ１〜３個の（Ｃ_１−Ｃ_４）アルキル基で選択的に置換される５〜１０員のヘテロアリール；（Ｃ_３−Ｃ_７）シクロアルキル；（Ｃ_６−Ｃ_１４）アリール；（Ｃ_１−Ｃ_３）アルキルで選択的に置換される−（Ｃ_２−Ｃ_３）アルキル−Ｏ−（Ｃ_１−Ｃ_３）アルキル；−（Ｃ_１−Ｃ_３）アルキル−Ｃ（＝Ｏ）Ｏ−（Ｃ_１−Ｃ_３）アルキル；１つ以上の（Ｃ_１−Ｃ_４）アルキルカルボニル基で選択的に置換される３〜８員のヘテロシクロアルキル；１つ以上の（Ｃ_１−Ｃ_２）アルキルで選択的に置換される（Ｃ_６−Ｃ_１４）アリールスルホニル；５〜１０員のヘテロアリール；および（Ｃ_６−Ｃ_１４）アリール−（Ｃ_０−Ｃ_４）アルキレン−Ｏ−（Ｃ_０−Ｃ_４）アルキル（ここで、各（Ｃ_０−Ｃ_４）アルキルおよび各（Ｃ_０−Ｃ_４）アルキレンは、１〜４個の（Ｃ_１−Ｃ_４）アルキルで選択的に置換される）からなる群から選択される置換基で選択的に置換される（Ｃ_１−Ｃ_８）アルキル基からなる群から選択されるか；または選択的に、Ｒ^４およびＲ^５は、それらが結合している窒素と一緒になって、４〜６員の複素環式環を形成し、ここで、前記複素環式環中の前記窒素から少なくとも２つの原子によって隔てられている前記複素環式環の炭素のうちの１つは、選択的に、ＯまたはＮＲ^６で置換され、ここで、Ｒ^６は、水素、（Ｃ_１−Ｃ_３）アルキルまたは−Ｃ（＝Ｏ）（Ｃ_１−Ｃ_３）アルキルであり；そして、前記複素環式環は、ハロ、（Ｃ_１−Ｃ_３）アルキルまたはヒドロキシルで選択的に置換され；
Ｒ^７は、水素であるか；
または選択的に、Ｒ^３およびＲ^７は、それらが結合するＺ、Ｙ、ＱおよびＸを含む環における２つの隣接原子と一緒になって、５または６員の複素環式環を形成し；ここで、前記複素環式環中の前記窒素から少なくとも２つの原子によって隔てられている前記複素環式環の炭素のうちの１つは、選択的に、ＯまたはＮＲ^８によって置換され；ここで、Ｒ^８は、水素または（Ｃ_１−Ｃ_３）アルキルである。

Which describes the preparation of:
A is (R) or (S) 2-methylpyrrolidine;
Z, Y, Q, X are independently nitrogen or carbon;
R ³ is hydrogen, (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) alkoxy, halo, 5-6 membered aryl, 5-6 membered heteroaryl, hydroxyl, methylene hydroxyl, — (C═ O) NR ⁴ R ⁵ and S (O) _p (C ₁ -C ₄ ) alkyl, where p is 1 or 2;
R ⁴ and R ⁵ are independently:
Hydrogen; (C ₁ -C ₈ ) alkyl selectively substituted with 1 to 4 halogens; OH, 1 to 4 (C ₁ -C ₄ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₄ ) dialkylamino, optionally substituted with halogen, and optionally substituted with 1 to 2 halogens (C ₆ -C ₁₀ ) optionally substituted with aryloxy (C ₆ -C ₁₀₎ aryl, and _(C 6 _{-C 10)} an optionally substituted aryl group, and one to three _(C 1 -C _{4) 5~10-membered} which is optionally substituted by an alkyl group _{heteroaryl; (C} 3 -C _{7) cycloalkyl;} (C 6 _{-C 14) aryl; (C} 1 -C ₃₎ which is optionally substituted with alkyl - _(C 2 -C ₃₎ alkyl -O- _(C 1 -C ₃₎ alkyl _;-( C 1 -C ₃₎ alkyl _{-C (= O) O- (C} 1 -C 3) alkyl; more than one; one or more _(C 1 -C ₄₎ selectively 3-8 membered heterocycloalkyl substituted with alkyl group of _(C 1 -C ₂₎ is optionally substituted with alkyl _(C 6 _{-C 14)} aryl sulfonyl; 5-10 membered heteroaryl; and _(C 6 _{-C 14)} aryl - _(C 0 -C ₄ ) Alkylene-O- (C ₀ -C ₄ ) alkyl where each (C ₀ -C ₄ ) alkyl and each (C ₀ -C ₄ ) alkylene is 1-4 (C ₁ -C ₄ ) Selected from the group consisting of (C ₁ -C ₈ ) alkyl groups optionally substituted with a substituent selected from the group consisting of (optionally substituted with alkyl); or, optionally, R ⁴ and R ^5, together with the nitrogen to which they are attached One of the carbons of the heterocyclic ring forming a 4-6 membered heterocyclic ring, wherein the carbon of the heterocyclic ring separated from the nitrogen in the heterocyclic ring by at least two atoms is selected Optionally substituted with O or NR ⁶ , wherein R ⁶ is hydrogen, (C ₁ -C ₃ ) alkyl or —C (═O) (C ₁ -C ₃ ) alkyl; and The cyclic ring is optionally substituted with halo, (C ₁ -C ₃ ) alkyl or hydroxyl;
Is R ⁷ hydrogen;
Or alternatively, 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 heterocyclic ring carbons separated by at least two atoms from the nitrogen in the heterocyclic ring is optionally substituted by O or NR ⁸ ; , R ⁸ is hydrogen or (C ₁ -C ₃ ) alkyl.

Scheme 4 illustrates a method for preparing compounds having the basic structure of Formula VII, where A, R ³ , Y, Q, Z and X are defined as above. Referring to Scheme 4 below, compound (III) can be synthesized in a solvent such as CH ₂ Cl ₂ or DCE at a temperature in the range of −5 ° C. to room temperature, preferably about room temperature, bromo- The tetralone compound is prepared by treatment with a suitable reducing agent such as (R) or (S) 2-methylpyrrolidine, and NaHB (OAc) ₃ prepared according to the method described above, thereby providing the desired A compound of formula (III) can be obtained. Other reducing agents suitable for this reaction include NaCNBH ₃ or NaBH _{4 in} a solvent such as MeOH or EtOH. Other conditions suitable for this transformation include the corresponding tetralone of formula (I) according to the procedure of the present invention at room temperature in CH ₂ Cl ₂ or DCE in the presence of 4Å molecular sieves and a base such as TEA. Treatment with (R)-or (S) -2-methylpyrrolidine prepared, followed by treatment with NaBH ₄ or NaHB (OAc).

  Then, 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 a solvent such as dimethoxyethane, from room temperature to about Treatment of compound III with an appropriately substituted boronic acid of formula (IV) at a temperature in the range of 100 ° C., preferably about 90 ° C., can give the desired compound of formula (V). Other conditions suitable for this transformation include a compound of formula (III) and a suitable compound of formula (IV) in an ethanol / water mixture at a temperature in the range of 30 ° C. to 110 ° C., preferably at about reflux temperature. Treatment of the substituted boronic acid with tetrakis (triphenylphosphine) palladium (0) and sodium carbonate provides the corresponding compound of formula (V).

  Accordingly, one embodiment of the present invention is a compound of formula (VII):

を調製するための方法に関し、ここで、変数は上で示したとおりであり、その方法は：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸またはＤ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を単離する工程；および
（２ａ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と接触させることにより（Ｒ）−２−メチルピロリジン遊離塩基を形成する工程、またはその（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と接触させることにより（Ｓ）−２−メチルピロリジンを形成する工程；
（３ａ）６−ハロ−３，４−ジヒドロ−１Ｈ−ナフタレン−２−オンを（Ｒ）−または（Ｓ）−２−メチルピロリジンのいずれかと、対応するアミンを形成するのに十分な時間にわたり、それを形成するのに十分な条件下で接触させる工程；および
（３ｂ）上記アミドを以下の式のボロン酸

Where the variables are as indicated above and the method is:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) 6-halo-3,4-dihydro-1H-naphthalen-2-one with either (R)-or (S) -2-methylpyrrolidine for a time sufficient to form the corresponding amine Contacting under conditions sufficient to form it; and (3b) a boronic acid of the formula

（ここで、変数は、上に記載したとおりである）と、式ＶＩＩの化合物を得るのに十分な時間にわたり、それを得るのに十分な条件下で接触させる工程
を包含する。

(Where the variables are as described above) includes contacting for a time sufficient to obtain a compound of formula VII under conditions sufficient to obtain it.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1h) optionally, step (f ) And (g) may be further included.

Scheme 5 illustrates an alternative method for preparing compounds having the basic structure of Formula VII, where R ³ is CONR ⁴ R ⁵ and Y, Z, Q, and X are as described above. It is defined as follows. Referring to Scheme 5, conjugation of bromide (III) with an appropriate boronic acid reagent of formula (VI) is performed as described above in Scheme 4 to produce the desired compound of formula (VIII). Can do. Treatment of the corresponding t-butyl ester derivative of formula (VIII) with trifluoroacetic acid in methylene chloride at room temperature gives the corresponding carboxylic acid (not shown). Treatment of the carboxylic acid with an amine of formula NHR ⁴ R ⁵ in the presence of a suitable coupling reagent such as HOBT and EDCI, and a tertiary amine such as triethylamine provides the desired compound of formula (IX). Can be generated.

  Alternatively, the compound of formula (IX) can be treated by treating the carboxylic acid and a suitable amine with a suitable base such as 2-chloro-1,3-dimethylimidazolinium chloride and diisopropylethylamine in a solvent such as methylene chloride. Can also be prepared.

  Another embodiment is a compound of formula (VII):

を調製するための方法であり、ここで、変数は上で示したとおりであり、その方法は：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸またはＤ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を単離する工程；および
（２ａ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と接触させることにより（Ｒ）−２−メチルピロリジン遊離塩基を形成する工程、またはその（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と接触させることにより（Ｓ）−２−メチルピロリジンを形成する工程；
（３ａ）１−（６−ハロ−１，２，３，４−テトラヒドロ−ナフタレン−２−イル）−（Ｒ）−２−メチル−ピロリジンまたは１−（６−ハロ−１，２，３，４−テトラヒドロ−ナフタレン−２−イル）−（Ｓ）−２−メチル−ピロリジンを、以下の式のボロン酸

Where the variables are as indicated above and the method is:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) 1- (6-halo-1,2,3,4-tetrahydro-naphthalen-2-yl)-(R) -2-methyl-pyrrolidine or 1- (6-halo-1,2,3 4-tetrahydro-naphthalen-2-yl)-(S) -2-methyl-pyrrolidine is converted to a boronic acid of the formula

（ここで、変数は、上に記載したとおりである）と、以下の式の化合物：

(Where the variables are as described above) and a compound of the following formula:

を得るのに十分な時間にわたり、それを得るのに十分な条件下で接触させる工程；および
以下の式の化合物

Contacting for a time sufficient to obtain a compound under conditions sufficient to obtain the compound; and a compound of the formula:

をアミンと、式ＶＩＩの化合物を形成するのに十分な時間にわたり、それを形成するのに十分な条件下で接触させる工程
を包含する。

Contacting with an amine for a time sufficient to form a compound of formula VII under conditions sufficient to form it.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1h) optionally, step (f ) And (g) may be further included.

Specific examples of compounds that can be prepared according to these methods include: (S, R) -3- [6- (2-methyl-pyrrolidin-1-yl) -5,6,7,8-tetrahydro-naphthalene- 2-yl] -pyridine;
(R, R) -3- [6- (2-Methyl-pyrrolidin-1-yl) -5,6,7,8-tetrahydro-naphthalen-2-yl] -pyridine;
(R, R) -3 [6- (2-Methyl-pyrrolidin-1-yl) -5,6,7,8-tetrahydro-naphthalen-2-yl] -benzamide; and (S, R) 3- [ 6- (2-Methyl-pyrrolidin-1-yl) -5,6,7,8-tetrahydro-naphthalen-2-yl] -benzamide.

  The compounds described in WO2006 / 066197 can also be more easily prepared by using the synthesis of (R)-and (S) 2-methylpyrrolidines of the present invention. WO 2006/066197 describes the following compounds of formula VIII and IX:

ならびにそれらの薬学的な塩、ならびにそれらのエナンチオマー、ジアステレオマー、水和物、溶媒和化合物および薬学的に許容可能な塩、エステルおよびアミドを記載しており；
ここで、
Ｌは、−Ｏ−であり、ｎは、１または２であるか；またはＬは、−Ｃ≡Ｃ−または−ＣＨ_２ＣＨ_２−であり、ｎは、０または１であり；
Ｒ^１は、−Ｈであるか、またはＣ_１−６アルキルＣ_３−７シクロアルキル、−ＣＯＯＣ_１−６アルキルもしくは−ＣＯＯベンジルであり、各々選択的に、Ｒａで一置換、二置換または三置換され；
ここで、Ｒａは、−ＯＨ、−ＯＣ_１−６アルキル、−ＯＣ_１−４アルキルまたはハロで選択的に置換されるフェニル、−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_２Ｃ_１−６アルキル、−Ｃ（Ｏ）Ｃ_１−６アルキル、−Ｓ（Ｏ）_０−２−Ｃ_１−６アルキル、−ＳＯ_２Ｎ（Ｒ^ｂ）^Ｒｃ、−ＳＣＦ_３、ハロ、−ＣＦ_３、−ＯＣＦ_３、−ＣＯＯＨおよび−ＣＯＯＣ_１−６アルキルから選択され；ここで、Ｒ^ｂおよびＲ^ｃは、各々独立して、−Ｈまたは−Ｃ_１−６アルキルであり；
Ｒ^４は、−ＯＨ、−ＯＣ_１−６アルキル、−ＣＦ_３、−Ｃ_１−６アルキルまたはハロであり；２つのＲ^４置換基は、一緒になって、メチレンまたはエチレンを形成し得；
Ｍは、０、１または２であり；
Ｒ^５は、−Ｃ_１−６アルキル、−ＯＨ、−ＯＣ_１−６アルキル、−ＳＣ_１−６アルキルおよびハロからなる群から選択され；
Ａｒ^１は：
ａ）Ｒ^ｊで選択的に一置換、二置換または三置換され、かつ、フルオロ、−（ＣＨ_２）_２−３ＮＨ−、−（ＣＨ_２）_１−２ＮＨ（ＣＨ_２）−、−（ＣＨ_２）_２−３Ｎ（Ｃ_１−４アルキル）−または−（ＣＨ_２）_１−２Ｎ（Ｃ_１−４アルキル）（ＣＨ_２）−で選択的に一置換または二置換される−ＯＣ_１−４アルキレンＯ−で、隣接炭素上において選択的に二置換される、フェニル；
（ここで、Ｒ^ｊは、
１）−ＯＨ、−Ｃ_１−６アルキル、ハロで選択的に一置換、二置換または三置換される−ＯＣ_１−６アルキル、−Ｃ_２−６アルケニル、−ＯＣ_３−６アルケニル、トリメチルシリルで選択的に置換される−Ｃ_２−６アルキニル、−ＯＣ_３−６アルキニル、−Ｃ_３−６シクロアルキル、−ＯＣ_３−６シクロアルキル、−ＣＮ、−ＮＯ_２、−Ｎ（Ｒ^ｋ）Ｒ^ｌ、−Ｎ（Ｒ^ｋ）Ｃ（Ｏ）Ｒ^ｌ、−Ｎ（Ｒ^ｋ）ＳＯ_２Ｃ_１−６アルキル、−Ｃ（Ｏ）Ｃ_１−６アルキル、−Ｓ（Ｏ）_０−２−Ｃ_１−６アルキル、−Ｃ（Ｏ）Ｎ（Ｒ^ｍ）Ｒ^ｎ、ＳＯ_２Ｎ（Ｒ^ｍ）Ｒ^ｎ、−ＳＣＦ_３、ハロ、−ＣＦ_３、−ＣＯＯＨ、−ＣＯＯＣ_１−６アルキルおよび−ＣＯＯＣ_３−７シクロアルキル；
（ここで、Ｒ^ｋおよびＲ^ｌは、各々独立して、−Ｈまたは−Ｃ_１−６アルキルであり；
Ｒ^ｍおよびＲ^ｎは、各々独立して、−Ｈもしくは−Ｃ_１−６アルキルであるか、またはＲ^ｍおよびＲ^ｎは、それらが結合している窒素と一緒になって、>Ｏ、>Ｓ（Ｏ）_０−２、>ＮＨおよび>ＮＣ_１−６アルキルから選択される１または２個のヘテロ原子メンバーを有し、０または１個の二重結合を有し、０または１個のカルボニルメンバーを有する、４〜８員の複素環式環を形成する）；
２）−Ｇ−Ａｒ^２（ここで、Ｇは、結合、−Ｏ−または−Ｓ−であり、Ａｒ^２は、フェニルであるか、または５もしくは６個の環原子を有し、>Ｏ、>Ｓ、>ＮＨまたは>Ｎ（Ｃ１．４アルキル）で置換される１つの炭素原子を有し、−Ｎ＝で選択的に置換される最大１個のさらなる炭素原子を有する、単環式の芳香族炭化水素基である（各々、選択的に、Ｒ^ｐで一置換、二置換または三置換され；ここで、Ｒ^ｐは：−ＯＨ、−Ｃ_１−６アルキル、−ＯＣ_１−６アルキル、フェニル、−ＣＮ、−ＮＯ_２、−Ｎ（Ｒ^ｑ）Ｒ^ｒ−、−Ｃ（Ｏ）Ｎ（Ｒ^ｑ）Ｒ^ｒ、−Ｎ（Ｒ^ｑ）Ｃ（Ｏ）Ｒ^ｒ、−Ｎ（Ｒ^ｑ）ＳＯ_２Ｃ_１−６アルキル、−Ｃ（Ｏ）Ｃ_１−６アルキル、−Ｓ（Ｏ）_０−２−Ｃ_１−６アルキル、−ＳＯ_２Ｎ（Ｒ^ｑ）Ｒ^ｒ、−ＳＣＦ_３、ハロ、−ＣＦ_３、−ＯＣＦ_３、−ＯＣＨＦ_２、−ＣＯＯＨおよび−ＣＯＯＣ_１−６アルキルからなる群から独立して選択される置換基であり；
Ｒ^ｑおよびＲ^ｒは、各々独立して、−Ｈ、−Ｃ_１−６アルキルおよび−Ｃ_２−６アルケニルから選択される））；および
３）>Ｏ、>Ｓ（Ｏ）_０−２、>ＮＨおよび>ＮＣ_１−６アルキルから選択される１または２個のヘテロ原子メンバーを有し、０または１個のカルボニルメンバーを有する、４〜８員の飽和または部分飽和の複素環式環（前記環は、選択的に、Ｒ^ｐで一置換、二置換または三置換される）；
からなる群から選択される）、
ｂ）２つの隣接炭素環メンバーにおいて３員の炭化水素部分（この部分は、>Ｏ、>Ｓ、>ＮＨまたは>Ｎ（Ｃ_１−４アルキル）で置換される１つの炭素原子を有し、−Ｎ＝で選択的に置換される最大１個のさらなる炭素原子を有する）と縮合されることにより、縮合５員芳香族環を形成する、フェニルまたはピリジル（その縮合環は、選択的に、Ｒ^ｔで一置換、二置換または三置換され；ここで、Ｒ^ｔは：−ＯＨ、−Ｃ_１−６アルキル、−ＯＣ_１−６アルキル、フェニル、−ＣＮ、−ＮＯ_２、−Ｎ（Ｒ^ｕ）Ｒ^ｖ、−Ｃ（Ｏ）Ｎ（Ｒ^ｕ）Ｒ^ｖ、−Ｎ（Ｒ^ｕ）Ｃ（Ｏ）Ｒ^ｖ、−Ｎ（Ｒ^ｕ）ＳＯ_２Ｃ_１−６アルキル、−Ｃ（Ｏ）Ｃ_１−６アルキル．−Ｓ（Ｏ）_０−２−Ｃ_１−６アルキル、−ＳＯ_２Ｎ（Ｒ^ｕ）Ｒ^ｖ、−ＳＣＦ_３、ハロ、−ＣＦ_３、−ＯＣＦ_３、−ＯＣＨＦ_２、−ＣＯＯＨおよび−ＣＯＯＣ_１−６アルキルからなる群から独立して選択される置換基であり；
Ｒ^ｕおよびＲ^ｖは、各々独立して、−Ｈまたは−Ｃ_１−６アルキルである）；
ｃ）２つの隣接環メンバーにおいて、４員の炭化水素部分（この部分は、−Ｎ＝で置換される１または２個の炭素原子を有する）と縮合されることにより、縮合６員芳香族環を形成する、フェニル（その縮合環は、選択的に、Ｒ^ｔで一置換、二置換または三置換される）；
ｄ）選択的にＲ^ｔで一置換、二置換または三置換される、ナフチル；
ｅ）５個の環原子を有し、結合点である炭素原子を有し、>Ｏ、>Ｓ、>ＮＨまたは>Ｎ（Ｃ_１−４アルキル）で置換される１つの炭素原子を有し、−Ｎ＝で選択的に置換され、Ｒ^ｊで選択的に一置換または二置換され、そして２つの隣接炭素原子において選択的にベンゾ縮合される（ｂｅｎｚｏｆｕｓｅｄ）かまたはピリド縮合される（ｐｙｒｉｄｏｆｕｓｅｄ）、最大１個のさらなる炭素原子を有する、単環式芳香族炭化水素基（ここで、ベンゾ縮合またはピリド縮合される部分は、選択的に、Ｒ^ｔで一置換、二置換または三置換される）；および
ｆ）６個の環原子を有し、結合点である炭素原子を有し、−Ｎ＝で置換され、Ｒ^ｊで選択的に一置換または二置換され、そして２つの隣接炭素原子において選択的にベンゾ縮合されるかまたはピリド縮合される、１または２個の炭素原子を有する、単環式芳香族炭化水素基（ここで、ベンゾ縮合またはピリド縮合される部分は、選択的に、Ｒ^ｊで一置換または二置換される）；
からなる群から選択される、アリール環またはヘテロアリール環である。

And their pharmaceutical salts, and their enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides;
here,
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 C _1-6 alkyl C _3-7 cycloalkyl, —COOC _1-6 alkyl or —COO benzyl, each optionally mono-, di- or tri-substituted with Ra. Replaced;
Here, Ra represents phenyl, —CN, —NO ₂ , —N (R ^b ) R ^c , —, optionally substituted with —OH, —OC _1-6 alkyl, —OC _1-4 alkyl or halo. C (O) N (R ^b ) R ^c , —N (R ^b ) C (O) R ^b , —N (R ^b ) SO ₂ C _1-6 alkyl, —C (O) C _1-6 alkyl, Selected from —S (O) _0-2 —C _1-6 alkyl, —SO ₂ N (R ^b ) ^Rc , —SCF ₃ , halo, —CF ₃ , —OCF ₃ , —COOH and —COOC _1-6 alkyl. Wherein R ^b and R ^c are each independently —H or —C _1-6 alkyl;
R ⁴ is —OH, —OC _1-6 alkyl, —CF ₃ , —C _1-6 alkyl or halo; the two R ⁴ substituents can be taken together to form methylene or ethylene;
M is 0, 1 or 2;
R ⁵ is selected from the group consisting of —C _1-6 alkyl, —OH, —OC _1-6 alkyl, —SC _1-6 alkyl, and halo;
Ar ¹ is:
a) mono-, di- or tri-substituted selectively with R ^j , and fluoro, — (CH ₂ ) _2-3 NH—, — (CH ₂ ) _1-2 NH (CH ₂ ) —, — ( CH ₂ ) _2-3 N (C _1-4 alkyl) _-or — (CH ₂ ) _1-2 —OC selectively mono- or di-substituted with N (C _1-4 alkyl) (CH ₂ ) — Phenyl optionally substituted with _1-4 alkylene O- and adjacent carbons;
(Where R ^j is
1) —OH, —C _1-6 alkyl, selectively —OC _1-6 alkyl, —C _2-6 alkenyl, —OC _3-6 alkenyl, trimethylsilyl selectively mono-, di- or tri-substituted with halo Optionally substituted —C _2-6 alkynyl, —OC _3-6 alkynyl, —C _3-6 cycloalkyl, —OC _3-6 cycloalkyl, —CN, —NO ₂ , —N (R ^k ) R ^{l, -N (R k) C} (O) R l, -N (R k) SO 2 C 1-6 alkyl, -C _{(O) C 1-6} alkyl, _{-S (O)} 0-2 -C _{^{6alkyl, -C (O) n (R}} m) R n, SO 2 n (R m) R n, -SCF 3, _halo, -CF _{3, -COOH, -COOC 1-6} alkyl and -COOC _3-7 cycloalkyl;
(Wherein R ^k and R ¹ are each independently —H or —C _1-6 alkyl;
R ^m and R ⁿ are each independently —H or —C _1-6 alkyl, or R ^m and R ⁿ together with the nitrogen to which they are attached,>O,> Having 1 or 2 heteroatom members selected from S (O) _0-2 ,> NH and> NC _1-6 alkyl, having 0 or 1 double bond, 0 or 1 Forming a 4-8 membered heterocyclic ring having a carbonyl member);
2) -G-Ar ² (wherein G is a bond, -O- or -S-, Ar ² is phenyl or has 5 or 6 ring atoms,> O, Monocyclic having one carbon atom substituted with>S,> NH or> N (C1.4 alkyl) and having at most one additional carbon atom selectively substituted with -N = an aromatic hydrocarbon group (each optionally monosubstituted with ^{R p,} disubstituted or tri-substituted; wherein, ^{R p} is: _{-OH, -C 1-6 alkyl, -OC 1-6} alkyl , Phenyl, —CN, —NO ₂ , —N (R ^q ) R ^r —, —C (O) N (R ^q ) R ^r , —N (R ^q ) C (O) R ^r , —N (R ^q) _SO 2 _{C 1-6} alkyl, -C _{(O) C 1-6 alkyl, -S (O)} 0-2 _{-C 1-6 ^{alkyl, -SO 2 N (R q)}} R r, A substituent independently selected from the group consisting of -SCF ₃ , halo, -CF ₃ , -OCF ₃ , -OCHF ₂ , -COOH and -COOC _1-6 alkyl;
R ^q and R ^r are each independently selected from —H, —C _1-6 alkyl and —C _2-6 alkenyl))); and 3)>O,> S (O) _0-2 , A 4-8 membered saturated or partially saturated heterocyclic ring having 1 or 2 heteroatom members selected from> NH and> NC _1-6 alkyl and having 0 or 1 carbonyl member ( The ring is optionally mono-, di- or tri-substituted with R ^p );
Selected from the group consisting of:
b) a three-membered hydrocarbon moiety in two adjacent carbocyclic members (this moiety having one carbon atom substituted with>O,>S,> NH or> N (C _1-4 alkyl); Phenyl or pyridyl, the condensed ring being optionally fused to form a fused 5-membered aromatic ring by condensing with -N = selectively having at least one additional carbon atom R ^t is mono-, di- or tri-substituted; where R ^t is: —OH, —C _1-6 alkyl, —OC _1-6 alkyl, phenyl, —CN, —NO ₂ , —N (R ^{u) R v, -C (O} ) N (R u) R v, -N (R u) C (O) R v, -N (R u) SO 2 C 1-6 alkyl, -C (O) C _1-6 alkyl.—S (O) _0-2 —C _1-6 alkyl, —SO ₂ N (R ^u ) R ^v , —SCF ₃ A substituent independently selected from the group consisting of, halo, —CF ₃ , —OCF ₃ , —OCHF ₂ , —COOH and —COOC _1-6 alkyl;
R ^u and R ^v are each independently —H or —C _1-6 alkyl);
c) a fused 6-membered aromatic ring by condensation with a 4-membered hydrocarbon moiety (which has 1 or 2 carbon atoms substituted with -N =) in two adjacent ring members Phenyl (the fused ring is optionally mono-, di- or tri-substituted with R ^t );
d) naphthyl optionally mono-, di- or tri-substituted with R ^t ;
e) having 5 ring atoms, having the carbon atom that is the point of attachment, and having one carbon atom substituted with>O,>S,> NH or> N (C _1-4 alkyl) is optionally substituted with -N =, selectively mono- or di-substituted with ^{R j,} and is engaged selectively be benzofused (benzofused) or pyrido condensed at two adjacent carbon atoms (pyridofused) A monocyclic aromatic hydrocarbon group having a maximum of one additional carbon atom, wherein the moiety to be benzo-fused or pyrido-fused is optionally mono-, di- or tri-substituted with R ^t F) having 6 ring atoms, having a carbon atom that is the point of attachment, substituted with ^—N═ , optionally mono- or disubstituted with R ^j , and two adjacent carbon atoms Selectively benzofused in or Lido condensed, 1 or having two carbon atoms, a monocyclic aromatic hydrocarbon group (wherein, the portion engaged benzofused or pyrido condensation is optionally mono- or di-substituted with R ^j ;);
An aryl or heteroaryl ring selected from the group consisting of

  These compounds can be prepared, for example, according to Scheme 6.

Referring to Scheme 6, the reagents of formulas A1, A2 and A5 are commercially available or are prepared according to known methods. Using a suitable base (eg, K ₂ CO ₃ , Na ₂ CO ₃ or NaH) in a solvent such as acetonitrile, and with or without catalytic KI or NaI, 3-5 hydroxybenzaldehyde derivative A1 is converted to alcohol A2 and Williamson. Ether A3 is formed by reacting according to the ether synthesis protocol. Alternatively, if A2 contains a protected hydroxyl instead of a bromide substituent, an ether of formula A3 may be prepared under Mitsunobu conditions. Reductive amination of the aldehyde functionality of compound A3 results in a compound of formula A4. The aldehyde is added with or without an activator such as a protonic acid or Lewis acid and with a suitable reducing agent (eg NaBH ₄ , NaCNBH ₃ or NaHB (OAc) ₃ ) Treat with ^1- containing amine. Preferred conditions include NaBH ₄ in methanol. Alkylation of amine A4 with alpha-haloketone A5 to form ketone 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. Is done. Cyclization to produce tetrahydroisoquinoline A7 can be accomplished with or without a suitable proton acid or Lewis acid (eg, methanesulfonic acid (MSA), trifluoroacetic acid (TFA), AlCl ₃ , TiCl, with or without a solvent such as DCM. ₄ or BF ₃ ^* OEt ₂ ) to effect cyclization of the tetrahydroisoquinolinium salt. Preferred conditions are neat MSA or MSA in DCM. The intermediate salt may be reduced with a standard reducing agent such as NaCNBH ₃ in an acidic methanol medium. Alternatively, ketone A6 may be first reduced to the corresponding alcohol by a known method involving NaBH4. Treatment of the intermediate alcohol with MSA in DCM yields cyclic species A7. Finally, after activation of the attached primary alcohol group in compound A7 to form the appropriate leaving group (eg, mesylate or bromide), the leaving group was prepared according to the present invention (R)- Alternatively, it may be converted to the corresponding amine A9 by substitution with (S) -2-methylpyrrolidine. The substitution can be performed with a suitable base such as Na ₂ CO ₃ in a polar solvent such as n-BuOH, with or without catalytic KI or NaI. Alternatively, amine A9 may be prepared via oxidation of the alcohol and reductive amination of the resulting aldehyde.

  Accordingly, one embodiment of the present invention is a compound of formula (VIII) and (IX):

を調製するための方法に関し、ここで、変数は上で示したとおりであり、その方法は：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸またはＤ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を単離する工程；および
（２ａ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と接触させることにより（Ｒ）−２−メチルピロリジン遊離塩基を形成する工程、またはその（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と接触させることにより（Ｓ）−２−メチルピロリジンを形成する工程；
（３ａ）以下の式の化合物

Where the variables are as indicated above and the method is:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) Compounds of the following formula

（ここで、変数は、上に記載したとおりである）を（Ｒ）−または（Ｓ）−２−メチルピロリジンのいずれかと、式ＶＩＩＩまたはＩＸの化合物を形成するのに十分な時間にわたり、それを形成するのに十分な条件下で接触させる工程
を包含する。

(Where the variables are as described above) over a period of time sufficient to form a compound of formula VIII or IX with either (R)-or (S) -2-methylpyrrolidine. Contacting under conditions sufficient to form.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1h) optionally, step (f ) And (g) may be further included.
Alternatively, 2-methylpyrrolidine-containing compounds may be prepared according to Scheme 7.

  Referring to Scheme 7, first an ether of formula A3 was selectively protected as described in Scheme A using (R)-or (S) -2-methylpyrrolidine prepared according to the present invention. Can be converted to the corresponding amine B1. Benzaldehyde B1 can then be converted to diamine B2 (where Q is (R)-or (S) -2-methylpyrrolidinyl) using a reductive amination protocol as in Scheme A. . Alkylation to form ketone B3 and cyclization to obtain a compound of formula A12 are performed as shown for Scheme 6.

Another embodiment of the invention relates to a method for preparing compounds of formula (VIII) and (IX), which method comprises:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) Compounds of the following formula

（ここで、変数は、上に記載したとおりである）を（Ｒ）−または（Ｓ）−２−メチルピロリジンのいずれかと、対応するアミンを形成するのに十分な時間にわたり、それを形成するのに十分な条件下で接触させる工程；
（３ｂ）そのアミンを式ＶＩＩＩまたはＩＸの化合物に変換する工程
を包含する。

(Where the variables are as described above) form either (R)-or (S) -2-methylpyrrolidine with sufficient time to form the corresponding amine. Contacting under conditions sufficient for
(3b) converting the amine to a compound of formula VIII or IX.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1h) optionally, step (f ) And (g) may be further included.
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-1-yl) -propoxy]- 1,2,3,4-tetrahydro-isoquinoline.

  The method of the present invention is a compound of the following formulas X and XI as described in WO06 / 077875:

およびそれらの薬学的に許容可能な塩の調製においても有用であり、ここで：
ｎは、２、３、４または５であり、
Ｒは、Ｒ^３−アリール、Ｒ^３−ヘテロアリール、Ｒ^３−シクロアルキル、Ｒ^３−ヘテロシクロアルキル、アルキル、ハロアルキル、−ＯＲ^４、−ＳＲ^４または−Ｓ（Ｏ）_１−２Ｒ^５であり；
Ｒ^１は、Ｈであり、Ｒ^２は、Ｒ^６−フェニルもしくは

And also in the preparation of their pharmaceutically acceptable salts, where:
n is 2, 3, 4 or 5;
R is, ^{R 3} - aryl, ^{R 3} - heteroaryl, ^{R 3} - cycloalkyl, ^{R 3} - heterocycloalkyl, alkyl, ^haloalkyl, -OR 4, at -SR ⁴ or _{-S (O)} 1-2 ^{R 5} Yes;
R ¹ is H and R ² is R ⁶ -phenyl or

であるか；またはＲ^１は、Ｒ^６−フェニルもしくは

Or R ¹ is R ⁶ -phenyl or

であり、Ｒ^２は、Ｈであるか；またはＲ^１およびＲ^２は、独立して、Ｒ^６−フェニルおよびからなる群から選択され；そしてＸは、−Ｏ−または−Ｓ−であるか；
またはＲ^１およびＲ^２は、それらが結合している炭素原子と一緒になって、

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 atom to which they are attached,

を形成し；そしてＸは、−Ｏ−、−Ｓ−または−ＮＲ^７であり；
Ｒ^３は、Ｈ、アルキル、ハロ、ＯＨ、アルコキシおよび−ＮＲ^１１Ｒ^１２からなる群から独立して選択される１〜３個の置換基であり、
Ｒ^４は、アルキル、アリールアルキルまたはシクロアルキルであり；
Ｒ^５は、アルキル、−ＮＲ^１１Ｒ^１２、Ｒ^３−アリールまたはＲ^３−アリールアルキルであり；
Ｒ^６は、Ｈ、アルキル、−ＣＦ_３、ハロ、−ＮＯ_２、−ＣＮ、−Ｃ（Ｏ）ＯＲ^１３、−Ｃ（Ｏ）ＮＲ^１１Ｒ^１２、−ＮＲ^１４Ｒ^１５、−ＯＲ^１３およびハロアルキルからなる群から独立して選択される１〜３個の置換基であり；
Ｒ^７は、Ｈ、アルキル、−ｃ（Ｏ）ＯＲ^１３、−Ｃ（Ｏ）ＮＲ^１１Ｒ^１２または−Ｃ（Ｏ）Ｒ^１３であり；
Ｒ^１１およびＲ^１２は、独立して、Ｈ、アルキル、シクロアルキル、アリールおよびアリールアルキルからなる群から選択され；
Ｒ^１３は、Ｈ、アルキル、シクロアルキルまたはアリールアルキルであり；
Ｒ^１４は、Ｈ、アルキル、シクロアルキルまたはアリールアルキルであり；そして
Ｒ^１５は、Ｈ、アルキル、シクロアルキル、−Ｃ（Ｏ）ＯＲ^１３、−Ｃ（Ｏ）ＮＲ^１１Ｒ^１２または−ＣＯ）Ｒ^１３である；
式ＸおよびＸＩの化合物は、以下のスキーム８に従って調製されうる。

And X is —O—, —S— or —NR ⁷ ;
R ³ is 1 to 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 H, alkyl, —CF ₃ , halo, —NO ₂ , —CN, —C (O) OR ¹³ , —C (O) NR ¹¹ R ¹² , —NR ¹⁴ R ¹⁵ , —OR ¹³ and haloalkyl. 1 to 3 substituents independently selected from the group consisting of;
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; and R ¹⁵ is H, alkyl, cycloalkyl, —C (O) OR ¹³ , —C (O) NR ¹¹ R ¹² or —CO) R. ¹³ ;
Compounds of formula X and XI can be prepared according to Scheme 8 below.

Referring to Scheme 8, compound 1 is reacted with aniline derivative 2 in a suitable solvent such as THF or dioxane, preferably in dioxane, at a temperature sufficient to effect this reaction, preferably 50-150 ° C. To obtain compound 3. The nitro group of compound 3 can be converted to a suitable catalyst (eg Pd / C, PtO ₂ , Raney nickel), preferably in the presence of Raney nickel, in a suitable solvent (eg methanol, ethanol or isopropanol), preferably methanol. Alternatively, it is reduced to amine 4 using hydrogen gas in ethanol. Other reduction methods well known to those skilled in the art are also suitable.

The primary amine of compound 4 is reacted with carboxylic acid in the presence of a coupling agent such as DEC and HOBT in a suitable solvent (eg ether, THF or CH ₂ Cl ₂ ), preferably in CH ₂ Cl _2. Acylation by reaction with an acid gives compound 5. Alternatively, the amine can be acylated with an acid chloride in the presence of a base. Compound 5 in acetic acid is heated for a time sufficient for cyclization to occur. In step 5, if a protecting group is present on the X group, it is removed at this point. Suitable protecting groups for X = O, N or S and methods for their removal can be found in Green's Protecting Groups in Organic Synthesis. Compound 6 is present in a suitable solvent (eg, acetone, THF, ether, etc.), preferably in acetone, preferably in the presence of a base (eg, Na ₂ CO ₃ or K ₂ CO ₃ ), preferably K ₂ CO ₃ . A compound 7 is obtained by reacting with α, ω-dihaloalkane at a temperature of 0 to 65 ° C. below (wherein Y is halo).

A solution of compound 7 in a suitable solvent (eg, CH ₃ CN, THF, ether, etc.), preferably in CH ₃ CN, is converted to a tertiary amine base (eg, Et ₃ N, DIPEA, etc.), preferably After treatment with DIPEA, treatment with (R)-or (S) -2-methylpyrrolidine prepared according to the present invention. The reaction is then heated at a temperature of 0-100 ° C. to give compound 8.

  Alternatively, scheme 9 below can continue.

Referring to Scheme 9, compound 9 known in the literature is combined with α, ω-dihaloalkane and a suitable solvent (eg, acetone, THF, ether, etc.), preferably in acetone, preferably with a base (eg, Na ₂ CO ₃ or K ₂ CO ₃ ), preferably in the presence of K ₂ CO ₃ at a temperature of 0 to 65 ° C. to give compound 10. A solution of compound 10 in a suitable solvent (eg, CH ₃ CN, THF, ether, etc.), preferably in CH ₃ CN, is a tertiary amine base (eg, Et ₃ N, DIPEA, etc.), preferably DIPEA Followed by treatment with (R)-or (S) -2-methylpyrrolidine prepared according to the invention. The reaction is then heated at a temperature of 0-100 ° C. to give compound 11.

  Alternatively, the compound can be made according to Scheme 10 below.

Referring to Scheme 10, compound 12 is treated with α, ω-dihaloalkane and a base (eg, Na ₂ CO ₃ or K ₂ ) in an appropriate solvent (eg, acetone, THF, ether, etc.), preferably in acetone. CO ₃ ), preferably in the presence of K ₂ CO ₃ , is reacted at a temperature of 0 to 65 ° C. to give compound 13 (where Y is halo). A solution of compound 13 in a suitable solvent (eg, CH ₃ CN, THF, ether, etc.), preferably in CH ₃ CN, is converted to a tertiary amine base (eg, Et ₃ N, DIPEA, etc.), preferably After treatment with DIPEA, treatment with (R)-or (S) -2-methylpyrrolidine prepared according to the present invention. The reaction is then heated at a temperature of 0-100 ° C. to give compound 14. The nitro group of compound 14 is converted to a suitable catalyst (eg Pd / C, PtO ₂ or Raney nickel), preferably in the presence of Raney nickel, in a suitable solvent (eg methanol, ethanol or isopropanol), preferably methanol or Reduction to amine 15 using H ₂ gas in ethanol. Other reduction methods well known to those skilled in the art are also suitable.

  Still referring to Scheme 10, compound 15 is combined with 16 in a suitable solvent (eg, THF or dioxane), preferably in dioxane, at a temperature sufficient to effect this reaction, preferably 50-150 ° C. To give compound 17. The nitro group of compound 17 is reduced to an amine followed by reduction to compound 18. The amine 18 in a suitable solvent (eg, THF, ether, etc.) can be converted to Treatment with any of the imidazoles (Q = O) provides compound 19.

Suitable solvents (e.g., DMSO, DMF, etc.) 19 solution in, 0 to 100 ° C., preferably at a temperature of 25 to 75 ° _C., a base and an alkylating agent such as K 2 CO ₃ ^R 4 L (here L is Cl, Br or I, or is mesylate or sulfonate) to give 20.

  Accordingly, one embodiment of the present invention is a compound of formula (X) and (XI):

を調製するための方法に関し、ここで、変数は上で示したとおりであり、その方法は：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸またはＤ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を単離する工程；および
（２ａ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と接触させることにより（Ｒ）−２−メチルピロリジン遊離塩基を形成する工程、またはその（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と接触させることにより（Ｓ）−２−メチルピロリジンを形成する工程；
（３ａ）その（Ｒ）−または（Ｓ）−２−メチルピロリジンを式ＶＩＩＩまたはＩＸの化合物に変換する工程
を包含する。

Where the variables are as indicated above and the method is:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) converting the (R)-or (S) -2-methylpyrrolidine to a compound of formula VIII or IX.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1h) optionally, step (f ) And (g) may be further included.

  Compounds of the following formulas XII and XIII described in WO2007 / 099423:

またはそれらの薬学的に許容可能な塩もまた、本発明の方法に受け入れられ、ここで、
Ｒ^３は、最大３個のフッ素原子で選択的に置換される、（Ｃ_１−６）−アルキル、アリールまたはヘテロアリールであり；
Ｒ^４は、水素、ハロゲン、（Ｃ_１−６）−アルキルまたは（Ｃ_３−７）−シクロアルキル、（Ｃ_１−６）−アルコキシルまたは（Ｃ_３−７）−シクロアルコキシル（選択的に、最大３個のフッ素原子で置換される）、アリール、ヘテロアリールであり；
Ｒ^５は、（ＣＲ^６Ｒ^９）_ｍ−（ＣＲ^１０Ｒ^１１）_ｐ−Ｂであり、ここで、Ｒ^６、Ｒ^９、Ｒ^１０およびＲ^１１は、それらが結合している炭素と一緒になって、３〜１０員の単環式または二環式の環系を形成し；
Ｂは、Ｎ、Ｏ、Ｓから選択される最大３個のヘテロ原子を含む４〜７員のヘテロシクロアルキル（例えば、アゼチジン、ピロリジン、ピペリジン、アゼピン、モルホリン、チオモルホリン、ピペラジンまたは１−４ジアゼピン）またはＮＲ^１２Ｒ^１３であり；
Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３は、独立して、水素、Ｃ_１−６アルキル、（Ｃ_１−６アルキル）−アリール、（Ｃ_１−６アルキル）−ヘテロアリールから選択されるか；または
Ｒ^１２およびＲ^１３は、それらが結合している窒素と一緒になって、３〜１０員の単環式または二環式の環系（例えば、アゼピン、ピペリジン、ピロリジンまたはモルホリン）を形成するが、ただし、ＮＲ^１２Ｒ^ｌ３は、ＮＨ_２ではなく；
ｍは、０、１、２、３または４であり；
ｎは、０、１、２または３であり；そして
ｐは、０〜３である。

Or a pharmaceutically acceptable salt thereof is also accepted in the method of the invention, wherein
R ³ is (C _1-6 ) -alkyl, aryl or heteroaryl, optionally substituted with up to 3 fluorine atoms;
R ⁴ is hydrogen, halogen, (C _1-6 ) -alkyl or (C _3-7 ) -cycloalkyl, (C _1-6 ) -alkoxyl or (C _3-7 ) -cycloalkoxyl (optionally, Substituted with up to 3 fluorine atoms), aryl, heteroaryl;
R ⁵ is (CR ⁶ R ⁹ ) _m- (CR ¹⁰ R ¹¹ ) _p -B, where R ⁶ , R ⁹ , R ¹⁰ and R ¹¹ together with the carbon to which they are attached. Forming a 3-10 membered monocyclic or bicyclic ring system;
B is a 4-7 membered heterocycloalkyl containing up to 3 heteroatoms selected from N, O, S (eg, azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazine or 1-4 diazepine) ) Or NR ¹² R ¹³ ;
R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently hydrogen, C _1-6 alkyl, (C _1-6 alkyl) -aryl, (C _1-6 alkyl) -hetero Or R ¹² and R ¹³ together with the nitrogen to which they are attached are 3 to 10 membered monocyclic or bicyclic ring systems (eg, azepine, piperidine, Pyrrolidine or morpholine) provided that NR ¹² R ¹³ is not NH ₂ ;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2 or 3; and p is 0-3.

  These compounds can be prepared by the general procedure shown in Scheme 11 below.

Referring to Scheme 11, a ketone of general formula II where the hydroxyl (—OH) group is not protected) can be combined with (R)-or (S) -2-methylpyrrolidine prepared in the present invention. By reacting, an amino-phenol of the general formula III is produced. This conversion can be accomplished using one or more of the methods and procedures available to those skilled in the art. For example, a ketone of formula II and 2-methylpyrrolidine in an inert aprotic solvent such as chloroform or dichloromethane in the presence of a Lewis acid reagent such as titanium tetrachloride (TiCl ₄ ) or titanium isopropoxide. Can generate an intermediate imine through the removal of water. Alternatively, reflux a solution of II and 2-methylpyrrolidine in a solvent such as toluene in the presence of a catalytic amount of para-toluenesulfonic acid (provided that water is used by using Dean-Stark trap or activated molecular sieves). Can also be used to efficiently produce the intermediate imine. This imine can then be converted to the amino-phenol intermediate III in situ or in a separate step after its isolation. This can be accomplished in a reaction inert solvent such as dichloromethane, methanol, THF or dioxane, such as sodium borohydride (NaBH ₄ ), sodium cyanoborohydride (NaBH ₃ CN), sodium triacetoxyborohydride and the like. This can be achieved by reduction of the C═N double bond using a simple boron reagent. Alternatively, the imine may be used using a suitable metal catalyst or similar catalyst such as hydrogen gas (H ₂ ) and Raney nickel (RaNi), palladium on carbon (Pd / C) using catalytic hydrogenation conditions. In a reaction inert solvent such as methanol or ethanol, at temperatures ranging from about 20 ° C. to the boiling point of the solvent used, and pressures ranging from about 1 to 5 atmospheres of hydrogen gas. Other relevant examples for this transformation can be found in the literature.

Still referring to Scheme 11, the phenolic OH group present in the intermediate of formula III can be converted to a reagent of general formula R ⁵ -A (in the presence of a base as shown in route b) and in a reaction inert solvent ( Where R ⁵ is as defined above and A is halogen (eg Cl, Br, I), mesylate (ie —OSO ₂ CH ₃ or —OMs) or tosylate (ie —OSO _2). Can be converted to ether products of general formula I by alkylation of III with a leaving group comprising C ₆ H ₅ or —OTs). Suitable bases include sodium carbonate, potassium carbonate or cesium carbonate, sodium bicarbonate or potassium bicarbonate, sodium tert-butoxide or potassium tert-butoxide, sodium hydride or potassium hydride, with cesium carbonate being preferred. . Suitable solvents include DMF, DMSO, DMA, THF and the like, with DMSO being preferred.

  Accordingly, one embodiment of the present invention is a compound of formula (XII) and (XIII):

を調製するための方法に関し、ここで、変数は上で示したとおりであり、その方法は：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸またはＤ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を単離する工程；および
（２ａ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と接触させることにより（Ｒ）−２−メチルピロリジン遊離塩基を形成する工程、またはその（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と接触させることにより（Ｓ）−２−メチルピロリジンを形成する工程；
（３ａ）以下の式の化合物

Where the variables are as indicated above and the method is:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) Compounds of the following formula

を（Ｒ）−または（Ｓ）−２−メチルピロリジンのいずれかと、対応するアミンフェノールを形成するのに十分な時間にわたり、それを形成するのに十分な条件下で接触させる工程；および
（３ｂ）そのアミンフェノールをアルコールと、式ＸＩＩまたはＸＩＩＩの化合物を得るのに十分な時間にわたり、それを得るのに十分な条件下で接触させる工程
を包含する。

Contacting with either (R)-or (S) -2-methylpyrrolidine for a time sufficient to form the corresponding amine phenol under conditions sufficient to form it; and (3b) ) Contacting the amine phenol with an alcohol for a time sufficient to obtain a compound of formula XII or XIII under conditions sufficient to obtain it.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1h) optionally, step (f ) And (g) may be further included.

  Compounds of general formulas XII and XIII can also be prepared via the route shown in Scheme 12 below.

Referring to Scheme 12, phenolic ketones of general formula II can be converted to ethers by methods generally known to those skilled in the art (route c.). For example, phenol II can be reacted with a reagent of general formula R ⁵ -A in the presence of a base, as described for scheme 1, pathway b, to produce a ketone of general formula IV. Alternatively, a ketone of general formula VII (wherein L ₁ is a suitable leaving group (ie, F, —OMs, etc.)) in the presence of a suitable base in an inert solvent, general formula R ⁵ An intermediate of general formula IV may be formed by reacting with a reagent of -OH (route e.). The ketone IV so obtained can then be converted to the desired product of general formula I using reductive amination conditions as previously described in Scheme 11 (route d.). In some situations, the intermediate ketone IV is first converted to the corresponding benzylic alcohol of general formula V by using a reducing agent such as NaBH _{4 in} a solvent such as methanol (path f.), Benzylic alcohol V is then activated (path g.) To produce an intermediate of formula VI where L ² is a leaving group (eg, OMs, OTs, Cl); And finally, the leaving group w is prepared according to the above-mentioned steps (a) to (e) (with or without optional steps (f) to (h)) (R)-or (S)- Substitution with 2-methylpyrrolidine and reaction of (R) -2-methylpyrrolidine L-tartrate with a base gives (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine D- Tartrate base By reacting, it can be also useful (S) -2- methylpyrrolidine obtain (path h.) It.

  Accordingly, another embodiment of the present invention provides compounds of formula (XII) and (XIII):

を調製するための方法に関し、ここで、変数は上で示したとおりであり、その方法は：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸またはＤ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を単離する工程；および
（２ａ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と接触させることにより（Ｒ）−２−メチルピロリジン遊離塩基を形成する工程、またはその（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と接触させることにより（Ｓ）−２−メチルピロリジンを形成する工程；
（３ａ）以下の式の化合物

Where the variables are as indicated above and the method is:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) Compounds of the following formula

を式Ｒ^５−ＬＧの化合物（ここで、ＬＧは、脱離基である）と、以下の式の化合物

A compound of the formula R ⁵ -LG (where LG is a leaving group) and a compound of the formula

を形成するのに十分な時間にわたり、それを形成するのに十分な条件下で接触させる工程；および
（３ｂ）以下の式の化合物

Contacting for a time sufficient to form a compound under conditions sufficient to form it; and (3b) a compound of the formula

を（Ｒ）−または（Ｓ）−２−メチルピロリジンのいずれかと、式ＸＩＩまたはＸＩＩＩの化合物を形成するのに十分な時間にわたり、それを形成するのに十分な条件下で接触させる工程
を包含する。

Contacting with either (R)-or (S) -2-methylpyrrolidine for a time sufficient to form a compound of formula XII or XIII under conditions sufficient to form it. To do.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1h) optionally, step (f ) And (g) may be further included.
An exemplary compound that can be prepared using the methods of the present invention is 1- {3- [1- (2-methyl-pyrrolidin-1-yl) -indan-5-yloxy] -propyl} azepane.

  The method of the present invention is a compound such as the compounds described in WO2007 / 094962, for example compounds of the formulas XIV and XV

ならびにそれらの薬学的に許容可能な塩を調製するためにも適しており、ここで、
Ｘは、ＯまたはＮＲ_７であり；
ｙは、０、１または２であり；
Ｒ_３は、ハロゲン、（Ｃ_１−８）アルキル、（Ｃ_１−８）アルコキシル、（Ｃ_３−７）シクロアルキル、（Ｃ_３−７）シクロアルキル−（Ｃ_１−６）アルキル、Ｏ、Ｓから選択される１〜３個のヘテロ原子を含むヘテロシクロアルキルおよび（Ｃ_１−５）アルキル−Ｏ−（Ｃ_１−５）アルキルから選択される群の０〜２個であり；
Ｒ_４およびＲ_６は、独立して、（Ｃ_１−８）アルキル、（Ｃ_１−８）アルコキシ、（Ｃ_３−７）シクロアルキル、（Ｃ_３−７）シクロアルキル−（Ｃ_１−６）アルキル、Ｏ、Ｓ、Ｎから選択される１〜３個のヘテロ原子を含むヘテロシクロアルキル、（Ｃ_１−５）アルキル−Ｏ−（Ｃ_１−５）アルキル、アミド、（Ｃ_１−５）アルキル−アリールおよびＣＦ_３から選択され；
Ｒ_５は、水素、（Ｃ_１−８）アルキル、アリール、（Ｃ_１−５）アルキル−Ｏ−（Ｃ_１−５）アルキルおよび（Ｃ_１−５）アルキル−アリールからなる群から選択されるか、
または
Ｒ_５およびＲ_４およびそれらが結合している原子は、５〜６員の縮合飽和炭素環または１０員の縮合二環式環系、例えば、

As well as for preparing their pharmaceutically acceptable salts, where
X is O or NR ₇ ;
y is 0, 1 or 2;
R ₃ is halogen, (C _1-8 ) alkyl, (C _1-8 ) alkoxyl, (C _3-7 ) cycloalkyl, (C _3-7 ) cycloalkyl- (C _1-6 ) alkyl, O, From 0 to 2 of the group selected from heterocycloalkyl containing 1 to 3 heteroatoms selected from S and (C _1-5 ) alkyl-O— (C _1-5 ) alkyl;
R ₄ and R ₆ are independently (C _1-8 ) alkyl, (C _1-8 ) alkoxy, (C _3-7 ) cycloalkyl, (C _3-7 ) cycloalkyl- (C _1-6 ) Heterocycloalkyl containing 1-3 heteroatoms selected from alkyl, O, S, N, (C _1-5 ) alkyl-O— (C _1-5 ) alkyl, amide, (C _1-5 ) Selected from alkyl-aryl and CF ₃ ;
R ₅ is selected from the group consisting of hydrogen, (C _1-8 ) alkyl, aryl, (C _1-5 ) alkyl-O— (C _1-5 ) alkyl and (C _1-5 ) alkyl-aryl. Or
Or R ₅ and R ₄ and the atom to which they are attached can be a 5-6 membered saturated saturated carbocycle or a 10 membered fused bicyclic ring system, such as

を形成するか、
または
Ｒ_５およびＲ_６およびそれらが結合している原子は、５〜６員の縮合飽和炭素環または１０員の縮合二環式環系、例えば、

Form or
Or R ₅ and R ₆ and the atom to which they are attached can be a 5-6 membered fused saturated carbocyclic or 10 membered fused bicyclic ring system, for example

を形成するか、
または
Ｒ_５およびＲ_４およびそれらが結合している原子は、６員の芳香族環が縮合している５〜６員の縮合飽和炭素環、例えば、

Form or
Or atom which R ₅ and R ₄ and they are attached, a 5-6 membered fused saturated carbocyclic ring aromatic rings 6 membered are fused, for example,

を形成するか、
または
Ｒ_５およびＲ_６およびそれらが結合している原子は、６員の芳香族環が縮合している５〜６員の縮合飽和炭素環、例えば、

Form or
Or atom which R ₅ and R ₆ and they are attached, a 5-6 membered fused saturated carbocyclic ring aromatic rings 6 membered are fused, for example,

を形成するか、
または
Ｒ_５およびＲ_６およびそれらが結合している原子は、縮合ベンゾチオフェン環系または縮合ベンゾフラン環系、例えば、

Form or
Or R ₅ and R ₆ and the atom to which they are attached can be a fused benzothiophene ring system or a fused benzofuran ring system, for example

を形成し、ここで、Ｘは、ＮＲ_７であり、Ｒ_７およびＲ_２は、一緒になって、−（ＣＨ_２ＣＨ_２）−であり、２つの窒素を含有する環を形成する（ここで、ｙは、０である（ピペラジン）か、またはｙは、１であり（ホモピペラジン）、Ｒ_１は、先に定義したとおりである）。

Where X is NR ₇ and R ₇ and R ₂ are taken together as — (CH ₂ CH ₂ ) — to form a ring containing two nitrogens (here Where y is 0 (piperazine) or y is 1 (homopiperazine) and R ₁ is as defined above).

  The above compounds having a 2-methylpyrrolidine group can be prepared according to the following scheme. (R)-or (S) by reacting (R)-or (S) -2-methylpyrrolidine prepared according to the present invention with 1,3-dichloropropane under conditions known in the art. -1- (3-Chloro-propyl) -2-methyl-pyrrolidine can be produced and can be used as in the following scheme.

を調製するための方法に関し、ここで、変数は上で示したとおりであり、その方法は：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸またはＤ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を単離する工程；および
（２ａ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と接触させることにより（Ｒ）−２−メチルピロリジン遊離塩基を形成する工程、またはその（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と接触させることにより（Ｓ）−２−メチルピロリジンを形成する工程；
（３ａ）（Ｒ）−または（Ｓ）−２−メチルピロリジンを１−（３−ハロ−プロピル）−（Ｒ）−２−メチル−ピロリジンまたは１−（３−ハロ−プロピル）−（Ｓ）−２−メチル−ピロリジンに変換する工程；および
（３ｂ）１−（３−ハロ−プロピル）−（Ｒ）−２−メチル−ピロリジンまたは１−（３−ハロ−プロピル）−（Ｓ）−２−メチル−ピロリジンを式ＸＩＩまたはＸＩＩＩの化合物に変換する工程
を包含する。 Accordingly, another embodiment of the present invention provides compounds of formula (XIV) and (XV):

Where the variables are as indicated above and the method is:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) (R)-or (S) -2-methylpyrrolidine as 1- (3-halo-propyl)-(R) -2-methyl-pyrrolidine or 1- (3-halo-propyl)-(S) Converting to 2-methyl-pyrrolidine; and (3b) 1- (3-halo-propyl)-(R) -2-methyl-pyrrolidine or 1- (3-halo-propyl)-(S) -2 Converting methyl-pyrrolidine to a compound of formula XII or XIII.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1h) optionally, step (f ) And (g) may be further included.

Exemplary compounds that can be prepared according to the method of the present invention include:
3-methyl-1- {4- [3- (2R-methylpyrrolidin-1-yl) propoxy] phenyl} -4,5-dihydro-1H-benzo [g] indazole;
5-methyl-2- {4- [3- (2R-methylpyrrolidin-1-yl) propoxy] phenyl} -2H-pyrazole-3-carboxylic acid cyclohexylamide;
1- {4- [3- (2- (R) -methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -5-phenyl-3-trifluoromethyl-1H-pyrazole;
3-methyl-1- {4- [3- (2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl)}-1H-benzo [4,5] thieno [3,2-c] pyrazole; and 3- {4- [3- (2-Methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -1-trifluoromethyl-3H-8-oxa-2,3-diaza-cyclopenta [a] indene Can be mentioned.

  Additional compounds that may benefit from the method of preparing 2-methylpyrrolidine as set forth herein include compounds of formulas XVI and XVII as described in WO2007 / 048595:

ならびにそれらの薬学的に許容可能な塩が挙げられ；
ここで、Ａ^１は、ＣＨ、Ｃ−ハロゲンまたはであり；
Ａ^２は、酸素または硫黄であり；
Ｒ^２ａは、水素、アリール、Ｃ_１−６アルコキシ、アミノ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、ヘテロアリール、Ｃ_３−８シクロアルキル、３〜８員のヘテロシクロアルキル、アシル、Ｃ_１−６−アルキルアリール、Ｃ_１−６−アルキル、ヘテロアリール、Ｃ_１−６−アルキルシクロアルキル、Ｃ_１−６−アルキルヘテロシクロアルキル、カルボキシ、アルコキシカルボニル、アミノカルボニル、Ｃ_１−６−アルキルカルボキシ、Ｃ_１−６−アルキルアシル、Ｃ_１−６−アルキルアルコキシ、Ｃ_１−６−アルキルアルコキシカルボニル、Ｃ_１−６−アルキルアミノカルボニル、Ｃ_１−６−アルキルアシルアミノ、アシルアミノ、Ｃ_１−６−アルキルウレイド、Ｃ_１−６−アルキルカルバメート、Ｃ_１−６−アルキルアミノ、Ｃ_３−８−シクロアルキルアミノ、ヒドロキシ、Ｃ_１−６アルキルヒドロキシ、ハロゲンまたはシアノであり；
Ｒ^２ｂは、水素、ハロゲン、Ｃ_１−８−アルキルまたはＣ_３−８シクロアルキルであるか；
またはＲ^２ａおよびＲ^２ｂは、一緒に連結して、Ｃ_３−８シクロアルキル、３〜８員のヘテロシクロアルキルまたはオキソ基を形成し；
Ｒ^３は、水素、ハロゲン、Ｃ_１−４アルキルまたはＣ_１−４アルコキシであり；
Ｒ^４は、水素、ハロゲン、Ｃ_１−４アルキルまたはＣ_１−４アルコキシであり；
Ｌ^１は、−（Ｏ）_ｖ−（ＣＲ^９ａＲ^９ｂ）_ｍ−（ＣＨ_２）_ｚであり；
Ｒ^９ａは、水素または非置換Ｃ_１−８アルキルであり；
Ｒ^９ｂは、Ｃ_１−６−アルキルアリールまたは非置換Ｃ_１−８アルキルであり；
ｎは、０、１または２に等しい整数であり；
ｔは、２、３または４に等しい整数であり；
ｗは、２、３または４に等しい整数であり；
ｖは、０または１に等しい整数であり；
ｍは、０または１に等しい整数であり；および
ｚは、０、１、２または３に等しい整数である。

As well as their pharmaceutically acceptable salts;
Where A ¹ is CH, C-halogen or;
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, C _1-6 - alkyl _{aryl, C 1-6} - alkyl, _{heteroaryl, C 1-6} - alkyl _{cycloalkyl, C 1-6} - alkyl heterocycloalkyl, carboxy, alkoxycarbonyl, _{aminocarbonyl, C 1-6} - alkyl _{carboxy, C 1-6} - alkyl _{acyl, C 1-6} - alkyl _{alkoxy, C 1-6} - alkyl _{alkoxycarbonyl, C 1-6} - _{alkylaminocarbonyl, C 1-6} - alkyl acylamino, _{acylamino, C 1- 6} - _{alkylureido, C 1-6} - alkyl _{carbamate, C 1-6} - alkyl Ruamino, C _3-8 -cycloalkylamino, hydroxy, C _1-6 alkylhydroxy, halogen or cyano;
R ^2b is hydrogen, halogen, C _1-8 -alkyl or C _3-8 cycloalkyl;
Or R ^2a and R ^2b are joined together to form a C _3-8 cycloalkyl, 3-8 membered heterocycloalkyl or oxo group;
R ³ is hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy;
R ⁴ is hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy;
L ¹ is — (O) _v — (CR ^9a R ^9b ) _m — (CH ₂ ) _z ;
R ^9a is hydrogen or unsubstituted C _1-8 alkyl;
R ^9b is C _1-6 -alkylaryl 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.

  Similar compounds, such as those described in WO 2006/103045 (incorporated herein in its entirety for all purposes) can also be prepared according to the methods of the invention.

  The compounds described above can be prepared according to Scheme 20.

ここで、Ｒ^３は、Ｈ、ＦまたはＣｌであり、Ｙ^１は、ＩまたはＢｒである。

Here, R ³ is H, F or Cl, and Y ¹ is I or Br.

  These reactions are carried out in a solvent (eg dioxane, tetrahydrofuran, dimethylformamide or toluene) in the presence of a base (eg potassium phosphate or sodium tert-butyrate) at a temperature ranging from 25 ° C. to 120 ° C., inert. Under an atmosphere (argon or nitrogen), a ligand such as 1,2-diamine (eg, trans-1,2-diaminocyclohexane), phosphine (eg, 1,1′-bis (diphenylphosphino) ferrocene or 2- ( Dicyclohexylphosphino) -2 ′-(N, N-dimethylamino) -biphenyl) or an amino acid (eg, glycine) and a related catalyst (eg, copper iodide or palladium acetate). Alternatively, this reaction can be performed using Klapars A. et al. et al. J. et al. Am. Chem. Soc. 2002, 124, 7421.

  Compounds of formulas Ia and Ib shown in Scheme 20 can be prepared according to Scheme 21 using (R) or (S) -2-methylpyrrolidine prepared according to the methods of the present invention.

  These reactions can be performed in acetonitrile or acetone as a solvent in the presence of a base such as triethylamine or potassium carbonate, or can be performed according to any conventional method known to those skilled in the art.

  Accordingly, one embodiment of the present invention is a compound of formula (XVI) and (XVII):

を調製するための方法に関し、ここで、変数は上で示したとおりであり、その方法は：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸またはＤ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を単離する工程；および
（２ａ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と接触させることにより（Ｒ）−２−メチルピロリジン遊離塩基を形成する工程、またはその（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と接触させることにより（Ｓ）−２−メチルピロリジンを形成する工程；
（３ａ）以下の式の化合物

Where the variables are as indicated above and the method is:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) Compounds of the following formula

（ここで、Ｙ１は、

(Where Y1 is

である）を（Ｒ）−または（Ｓ）−２−メチルピロリジンのいずれかと、式ＸＶＩの化合物を形成するのに十分な時間にわたり、それを形成するのに十分な条件下で接触させる工程
を包含する。

Contacting with either (R)-or (S) -2-methylpyrrolidine for a time sufficient to form a compound of formula XVI under conditions sufficient to form it. Include.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1h) optionally, step (f ) And (g) may be further included.

  Alternatively, the following Scheme 22 can be performed, wherein 2-methylpyrrolidine alkoxy is prepared according to steps (a)-(e) above (with or without optional steps (f)-(h)). (R) -2- or (S) -2-methylpyrrolidine and (R) -2-methylpyrrolidine L-tartrate is reacted with a base to give (R) -2-methylpyrrolidine. Alternatively, (S) -2-methylpyrrolidine D-tartrate is reacted with a base to give (S) -2-methylpyrrolidine, which is then reacted with a reagent such as halo-alkoxy.

  The reaction shown in Scheme 22 is described in Penning et al. J. et al. Med. Chem. Of palladium or copper based catalysts in a solvent such as dimethylformamide or tetrahydrofuran in the presence of a base (eg potassium tert-butyrate, cesium carbonate or sodium hydride) according to the method described in 2000,43,721. It can be done in the presence.

  Accordingly, another embodiment of the present invention is a compound of formula (XVI) and (XVII):

を調製するための方法を包含し、ここで、変数は上で示したとおりであり、その方法は：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸またはＤ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を単離する工程；および
（２ａ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と接触させることにより（Ｒ）−２−メチルピロリジン遊離塩基を形成する工程、またはその（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と接触させることにより（Ｓ）−２−メチルピロリジンを形成する工程；
（３ａ）（Ｒ）−または（Ｓ）−２−メチルピロリジンを対応する２−メチルピロリジニルアルキル−ＯＨに変換する工程；
（３ａ）以下の式の化合物：

Include the process wherein the variables are as indicated above and the process is:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) converting (R)-or (S) -2-methylpyrrolidine to the corresponding 2-methylpyrrolidinylalkyl-OH;
(3a) Compounds of the following formula:

（ここで、Ｙ１は、

(Where Y1 is

である）を（Ｒ）−または（Ｓ）−２−メチルピロリジニルアルキル−ＯＨのいずれかと、式ＸＶＩの化合物を形成するのに十分な時間にわたり、それを形成するのに十分な条件下で接触させる工程
を包含する。

For a time sufficient to form a compound of formula XVI with either (R)-or (S) -2-methylpyrrolidinylalkyl-OH under conditions sufficient to form it The process of making it contact in is included.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1h) optionally, step (f ) And (g) may be further included.

Exemplary compounds that can be prepared according to the method of the present invention include:
1- [3- (4- {4-[(2-methylpyrrolidin-1-yl) methyl] -1,3-oxazol-2-yl} phenoxy) propylpiperidine;
2-[(2- {4- [3- (2-methylpyrrolidin-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] -2-azaspiro [5.5] undecane;
4-[(2-methylpyrrolidin-1-yl) methyl] -2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazole;
1-isopropyl-4- [3- (4- {4-[(2-methylpiperidin-1-yl) methyl] -1,3-oxazol-2-yl} phenoxy) propyl] piperazine;
4-methyl-1- [3- (4- {4-[(2-methylpyrrolidin-1-yl) methyl] -1,3-oxazol-2-yl} phenoxy) propyl] piperidine;
2-methyl-1- [3- (4- {4-[(2-methylpyrrolidin-1-yl) methyl] -1,3-oxazol-2-yl} phenoxy) propylipiperidine;
4-[(2-Methylpyrrolidin-1-yl) methyl] -2- (4- {3- [2- (pyrrolidin-1-yl) ethyl) pyrrolidin-1-yl] propoxy} phenyl) -1,3 -Oxazole;
1-cyclopentyl-4- [3- (4- {4-[(2-methylpyrrolidin-1-yl) methyl] -1,3oxazol-2-yl} phenoxy) propylipiperazine;
N, N-dimethyl-1- [4- (4- {4-[(2-methylpyrrolidin-1-yl) methyl] -1,3-oxazol-2-yl} phenoxy) butyl] pyrrolidin-3-amine ;
1- [2- (4- {4-[(2-methylpyrrolidin-1-yl) methyl] -1,3-oxazol-2-yl} phenoxy) ethyl] -4- (2-pyrrolidin-1-ylethyl ) Piperazine;
2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy]-[3-4- (2-oxo-2-pyrrolidin-1-ylethyl) -1,3-oxazole;
1-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl] -1,3-oxazol-4-yl) methyl] pyrrolidin-2-one;
N-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] -N-phenylamine;
2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy]-[3-4- (2-pyrrolidin-1-ylethyl) -1,3-oxazole;
4-[(2-methyl-1H-imidazol-1-yl) methyl] -2- {4- [3- (2-methylpyrrolidin-yl) propoxy] phenyl} -1,3-oxazole;
1-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] -1H-1,2,4-triazole;
1-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl-1,3-oxazol-4-yl) methyl] piperidine;
1- [3- (4- [4-[(2-methylpyrrolidin-1-yl) methyl] -1,3-oxazol-2-yl) phenoxy) propyl) azepane;
1- (3- {4- [4-methyl-5- (piperidin-1-yl) methyl) -1,3-oxazol-2-yl] phenoxy} propyl) piperidine;
(2R) -4-methyl-2-{[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] amino} Pentan-1-ol;
N-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] cyclopentanamine;
1- [4- (4- {4-[(2-methylpyrrolidin-1-yl) methyl] -1,3-oxazol-2-yl} phenoxy) butyl] azepane;
1- [2- (4- {4-[(2-methylpyrrolidin-1-yl) methyl} -1,3-oxazol-2-yl} phenoxy) ethyl] azepane;
N- (1,3-dimethylbutyl) -N-[(2- {4- [3- (2-methylpyroarin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl ] Amine;
N- (cyclopropylmethyl) -N-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] -N- Propylamine;
1-[(2- {4- [2- (2-methylpyrrolidin-1-yl) ethoxy] phenyl} -1,3-oxazol-4-yl) methyl] piperidine;
2-methyl-1- [4- (4- {4-[(2-methylpyrrolidin-1-yl) methyl] -1,3-oxazol-2-yl} phenoxy) butyl] piperidine;
7,8-dimethyl-1-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-thiazol-4-yl) methyl] -1-azaspiro [ 4.4] Nonane;
N- (2-furylmethyl) -N-methyl-N-[(2- {4- [3- (2-methylpyrazin-1-yl) propoxy] phenyl} -1,3-thiazol-4-yl) methyl ] Amine; N- (sec-butyl) -N-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-thiazol-4-yl) methyl] -N-propylamine;
1-[(2- [4- (3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-thiazol-4-yl) methyl] piperidine;
1-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-ylacetyl] piperidine;
1- [2- (2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) ethyl] piperidine;
2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-thiazole;
4-Benzyl-1-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] piperidine;
1-cyclopentyl-4-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methylpiperazine;
4-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) carbonyl] morpholine;
1-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) carbonyl] piperidine;
1-cyclopentyl-4-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) carbonyl] piperazine;
4-[(2-methylpyrrolidin-1-yl) methyl] -2- (4- {3-[(2S) -2- (pyrrolidin-1-ylmethyl) pyrrolidin-1-yl] propoxy} phenyl) -1, 3-oxazole;
1-[(2- {3-fluoro-4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] piperidine;
1-[(4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl-1,3-oxazol-5-yl) carbonyl] piperidine;
N- (cyclopropylmethyl) -4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy]-[3-N-propyl-1,3-oxazole-5-carboxamide;
N-cyclopentyl-4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazole-5-carboxamide;
4-[(benzylamino) methyl] -2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazole-5-carboxylate;
4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-thiazole-5-carboxylate;
2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy]-[3-4- (piperidin-1-ylmethyl) -1,3-oxazole-5-carboxylic acid;
N- (cyclopropylmethyl) -2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] -phenyl} -N-propyl-1,3-oxazole-4-carboxamide;
N-cyclopentyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazole-4-carboxamide;
N- (4-fluorobenzyl) -2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazole-4-carboxamide;
N-benzyl-4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazole-5-carboxamide;
1-cyclopentyl-4- [4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl) -1,3-oxazol-5-yl) carbonyl] piperazine;
2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy]-[3-4- (pyrrolidin-1-ylcarbonyl) -1,3-oxazole;
4-{(4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-5-yl) carbonyl} morpholine;
4-{[4-methyl-2- (4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} phenyl) -1,3-oxazol-5-yl] carbonyl} morpholine;
4-{[4-methyl-2- (4- {3-[(2S) -2-methylpyrrolidin-1-yl] propoxy} phenyl) -1,3-oxazol-5-yl] carbonyl} morpholine;
1-cyclopentyl-4-[(4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl) -1,3-oxazol-5-yl) methyl] piperazine;
N- (cyclopropylmethyl) -N-[(4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-5-yl) methyl ] -N-propylamine;
N-benzyl-N-[(4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxyphenyl-1,3-oxazol-5-yl) methyl] amine;
1-[(2- {3-methoxy-4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl-1,3-oxazol-4-yl) methyl] piperidine;
N- (4-chlorobenzyl) -N-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] amine;
N-{(4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-5-yl) methyl] cyclopentanamine;
1-[(5-bromo-2-14- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] piperidine;
1-{[2- (4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} phenyl) -1,3-oxazol-4-yl-methyl} piperidine;
1-{[2- (4- {3-[(2S) -2-methylpyrrolidin-1-yl] propoxy} phenyl) -1,3-oxazol-4-yl] -methyl] piperidine;
4-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] morpholine;
1- [2- (2- {4- [2- (2-methylpyrrolidin-1-yl) ethoxy] phenyl} -1,3-oxazol-4-yl) ethyl] piperidine;
1-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] piperidin-2-one;
(5S) -1-[(2- {4- [3- (2-Methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] -5- (pyrrolidine-1 -Ylmethyl) pyrrolidin-2-one;
1-[(2- {3-chloro-4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] piperidine;
2- {3-bromo-4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl-4-methyl-1,3-thiazole-5-carboxylate;
N- (4-fluorophenyl) -2- (2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) acetamide; (4aR, 8aS) -2-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] decahydroisoquinoline;
2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -4-{[(2S) -2- (pyrrolidin-1-ylmethyl) pyrrolidin-1-yl] carbonyl} -1 , 3-oxazole;
4-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) acetyl] morpholine;
N-cyclopentyl-2- (2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) acetamide;
N- (cyclopropylmethyl) -2- (2- (4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) -N-propylacetamide;
1-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) -acetyl] azepane;
(5S) -1-[(2- {4- [3- (2-Methylpyrrolidin-1-yl) propoxy] phenyl) -1,3-oxazol-4-yl) methyl] -5- (morpholine-4 -Ylmethyl) pyrrolidin-2-one;
2-Methyl-N-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] -2H-tetrazole-5 Amines;
N- (3-methoxyphenyl) -N-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] amine;
N- (4-fluorophenyl) -N-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] amine;
N-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methylpyridin-3-amine;
4-[(4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-5-yl) methyl] morpholine;
4-({(2S) -1-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] pyrrolidine-2 -Yl} methyl) morpholine;
1-[(2- {2-fluoro-4- {3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] piperidine;
4,4-difluoro-1-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] piperidine;
4-[(4-methyl-2- {6- [3- (2-methylpyrrolidin-1-yl) propoxy] pyridin-3-yl} -1,3-thiazol-5-yl) carbonyl} morpholine;
1- (2- {3,5-difluoro-4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl-1,3-oxazol-4-yl) methyl] piperidine;
4,4-Difluoro-1-{(4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-thiazol-5-yl) carbonyl] piperidine ;
4,4-Difluoro-1-{{4-methyl-2- (4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} phenyl) -1,3-thiazol-5-yl Carbonyl] piperidine;
4,4-Difluoro-1-{[4-methyl-2- (4- {3-[(2S) -2-methylpyrrolidin-1-yl] propoxy] phenyl) -1,3-thiazol-5-yl } Carbonyl) piperidine;
4-[(4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-thiazol-5-yl) carbonyl] morpholine;
4-{[4-methyl-2- (4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} phenyl) -1,3-thiazol-5-yl] carbonyl} morpholine;
4-{[methyl-2- (4- {3-[(2S) -2-methylpyrrolidin-1-yl] propoxy} phenyl) -1,3-thiazol-5-yl] carbonyl} morpholine;
1-[(2- {2-methyl-4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] piperidine; and 1-[( 4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-thiazol-5-yl) methyl] pyrrolidin-2-one.

  Compounds of formula XVIII and XIX as described in WO2008 / 005338:

およびそれらの薬学的に許容可能な塩もまた、本発明の方法を用いて一層容易に調製され得；
ここで、
Ｒ^１およびＲ^２は、各々独立して、Ｈ、Ｃ_１−６アシル、Ｃ_１−８アルキル、Ｃ_２−８アルケニル、Ｃ_２−８アルキニル、Ｃ_３−７シクロアルキル、アリール、ヘテロシクリル、ヘテロアリール、アリール−Ｃ_１−４−アルキレニル、アリールオキシ−Ｃ_１−４−アルキレニル、ヘテロアリール−Ｃ_１−４−アルキレニルおよびヘテロアリールオキシ−Ｃ_１−４−アルキレニルからなる群から選択され、Ｒ^１およびＲ^２の各々は、Ｃ_１−６アシル、Ｃ_１−６アシルオキシ、Ｃ_２−８アルケニル、Ｃ_１−６アルコキシ、Ｃ_１−８アルキル、Ｃ_１−８アルキルカルボキサミド、Ｃ_２−８アルキニル、Ｃ_１−８アルキルスルホンアミド、Ｃ_１−８アルキルスルフィニル、Ｃ_１−８アルキルスルホニル、Ｃ_１−８アルキルチオ、Ｃ_１−８アルキルウレイル、アミノ、アリール、Ｃ_１−８アルキルアミノ、Ｃ_２−８ジアルキルアミノ、カルボ−Ｃ_１−６−アルコキシ、カルボキサミド、カルボキシ、シアノ、Ｃ_３−７シクロアルキル、Ｃ_２−８ジアルキルカルボキサミド、Ｃ_２−８ジアルキルスルホンアミド、ハロゲン、Ｃ_１−６ハロアルコキシ、Ｃ_１−６ハロアルキル、Ｃ_１−６ハロアルキルスルフィニル、Ｃ_１−６ハロアルキルスルホニル、Ｃ_１−６ハロアルキルチオ、ヘテロシクリル、ヒドロキシル、チオール、ニトロおよびスルホンアミドからなる群から独立して選択される、１、２、３、４または５個の置換基で選択的に置換され；ここで、各Ｃ_１−８アルキルは、ヒドロキシルでさらに置換され得；ヒドロキシでさらに置換され得；
Ｊは、−ＣＨ_２ＣＨ_２−または１，２−Ｃ_３−７−シクロアルキレニル基であり、その各々が、選択的に、Ｃ_１−３アルキル、Ｃ_１−４アルコキシ、カルボキシ、シアノ、Ｃ_１−３ハロアルキル、ハロゲン、ヒドロキシルおよびオキソからなる群から独立して選択される１、２、３または４個の置換基で置換され；
Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^１０、Ｒ^１１およびＲ^１２は、各々独立して、Ｈ、Ｃ_１−６アシル、Ｃ_１−６アシルオキシ、Ｃ_２−８アルケニル、Ｃ_１−６アルコキシ、Ｃ_１−８アルキル、Ｃ_１−８アルキルカルボキサミド、Ｃ_２−８アルキニル、Ｃ_１−８アルキルスルホンアミド、Ｃ_１−８アルキルスルフィニル、Ｃ_１−８アルキルスルホニル、Ｃ_１８アルキルチオ、Ｃ_１−８アルキルウレイル、アミノ、Ｃ_１−８アルキルアミノ、Ｃ_２−８ジアルキルアミノ、カルボ−Ｃ_１−６−アルコキシ、カルボキサミド、カルボキシ、シアノ、Ｃ_３−７シクロアルキル、Ｃ２−８ジアルキルカルボキサミド、Ｃ_２−８ジアルキルスルホンアミド、ハロゲン、Ｃ_１−６ハロアルコキシ、Ｃ_１−６ハロアルキル、Ｃ_１−６ハロアルキルスルフィニル、Ｃ_１−６ハロアルキルスルホニル、Ｃ_１−６ハロアルキルチオ、ヒドロキシル、チオール、ニトロおよびスルホンアミドからなる群から選択され；
そして
Ｒ^８およびＲ^９は、各々独立して、Ｈ、Ｃ_１−８アルキル、Ｃ_２−８アルケニル、Ｃ_２−８アルキニル、Ｃ_３−７シクロアルキル、アリール、ヘテロシクリル、ヘテロアリール、アリール−Ｃ_１−４−アルキレニル、アリールオキシ−Ｃ_１−４アルキレニル、ヘテロアリール−Ｃ_１−４−アルキレニルおよびヘテロアリールオキシ−Ｃ_１−４−アルキレニルからなる群から選択され、Ｒ^８およびＲ^９の各々は、選択的に、Ｃ_１−６アシル、Ｃ_１−６アシルオキシ、Ｃ_２−８アルケニル、Ｃ_１−６アルコキシ、Ｃ_１−８アルキル、Ｃ_１−８アルキルカルボキサミド、Ｃ_２−８アルキニル、Ｃ_１−８アルキルスルホンアミド、Ｃ_１−８アルキルスルフィニル、Ｃ_１−８アルキルスルホニル、Ｃ_１−８アルキルチオ、Ｃ_１−８アルキルウレイル、アミノ、Ｃ_１−８アルキルアミノ、Ｃ_２−８ジアルキルアミノ、カルボ−Ｃ_１−６−アルコキシ、カルボキサミド、カルボキシ、シアノ、Ｃ_３−７シクロアルキル、Ｃ_２−８ジアルキルカルボキサミド、Ｃ_２−８ジアルキルスルホンアミド、ハロゲン、Ｃ_１−６ハロアルコキシ、Ｃ_１−６ハロアルキル、Ｃ_１−６ハロアルキルスルフィニル、Ｃ_１−６ハロアルキルスルホニル、Ｃ_１−６ハロアルキルチオ、ヒドロキシル、チオール、ニトロおよびスルホンアミドからなる群から独立して選択される１、２、３，４または５個の置換基で置換される；
（Ｒ）および（Ｓ）２−メチルピロリジンを調製する本発明の方法を用いることにより、上で述べた化合物を一層容易に調製することができる。（Ｒ）−または（Ｓ）−２−メチルピロリジンは、本発明に従い、（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と反応させることにより（Ｒ）−２−メチルピロリジンを得るか、または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と反応させることにより（Ｓ）−２−メチルピロリジンを得ることにより、調製され得る。以下のスキームは、そのように調製された２−メチルピロリジンの使用を示している。

And their pharmaceutically acceptable salts can also be more easily prepared using the methods of the invention;
here,
R ¹ and R ² are each independently H, C _1-6 acyl, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-7 cycloalkyl, aryl, heterocyclyl, hetero R ¹ selected from the group consisting of aryl, aryl-C _1-4 -alkylenyl, aryloxy-C _1-4 -alkylenyl, heteroaryl-C _1-4 -alkylenyl and heteroaryloxy-C _1-4 -alkylenyl; And each of R ² is C _1-6 acyl, C _1-6 acyloxy, C _2-8 alkenyl, C _1-6 alkoxy, C _1-8 alkyl, C _1-8 alkyl carboxamide, C _2-8 alkynyl, C _1-8 alkyl _{sulfonamide, C 1-8 alkylsulfinyl, C 1-8 alkylsulfonyl, C 1-8} alkylthio, C _1-8 alkylureyl, amino, _{aryl, C 1-8 alkylamino, C 2-8} dialkylamino, carbo _{-C 1-6} - alkoxy, carboxamide, carboxy, _{cyano, C 3-7 cycloalkyl, C 2- 8 dialkylcarboxamide, C 2-8} dialkylsulfonamide, _{halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6} haloalkylthio, heterocyclyl, Optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of hydroxyl, thiol, nitro and sulfonamide; wherein each C _1-8 alkyl is May be further substituted with hydroxyl; may be further substituted with hydroxy;
J is —CH ₂ CH ₂ — or a 1,2-C _3-7 -cycloalkylenyl group, each of which is optionally selected from C _1-3 alkyl, C _1-4 alkoxy, carboxy, cyano. Substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C ₁ -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 independently H, C _1-6 acyl, C _1-6 acyloxy, C _2-8 alkenyl, C _{1-6 alkoxy, C 1-8 alkyl, C 1-8 alkylcarboxamide, C 2-8 alkynyl, C 1-8} alkyl _{sulfonamide, C 1-8 alkylsulfinyl, C 1-8 alkylsulfonyl, C 18} alkylthio , _{C 1-8} alkylureyl, _{amino, C 1-8 alkylamino, C 2-8} dialkylamino, carbo _{-C 1-6} - alkoxy, carboxamide, carboxy, _{cyano, C 3-7} cycloalkyl, C2-8 _{dialkylcarboxamide, C 2-8} dialkylsulfonamide, _{halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6} B alkylsulfinyl, C _1-6 haloalkylsulfonyl, C _1-6 haloalkylthio, hydroxyl, thiol, is selected from the group consisting of nitro and sulfonamide;
And R ⁸ and R ⁹ are each independently H, 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 _{-C 1-4} alkylenyl, heteroaryl _{-C 1-4} - alkylenyl and heteroaryloxy _{-C 1-4} - is selected from the group consisting of alkylenyl, each of ^{R 8} and ^{R 9} , Optionally, C _1-6 acyl, C _1-6 acyloxy, C _2-8 alkenyl, C _1-6 alkoxy, C _1-8 alkyl, C _1-8 alkyl carboxamide, C _2-8 alkynyl, C _{1 -8} alkyl _{sulfonamide, C 1-8 alkylsulfinyl, C 1-8 alkylsulfonyl, C 1-8} alkylthio, _{C 1 -8} alkylureyl, _{amino, C 1-8 alkylamino, C 2-8} dialkylamino, carbo _{-C 1-6} - alkoxy, carboxamide, carboxy, _{cyano, C 3-7 cycloalkyl, C 2-8} dialkylcarboxamide , _{C 2-8} dialkylsulfonamide, _{halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6} haloalkylthio, hydroxyl, thiol, nitro And substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of sulfonamides;
By using the method of the present invention for preparing (R) and (S) 2-methylpyrrolidine, the above mentioned compounds can be prepared more easily. (R)-or (S) -2-methylpyrrolidine is obtained according to the invention by reacting (R) -2-methylpyrrolidine L-tartrate with a base to give (R) -2-methylpyrrolidine, Or it can be prepared by obtaining (S) -2-methylpyrrolidine by reacting (S) -2-methylpyrrolidine D-tartrate with a base. The following scheme illustrates the use of 2-methylpyrrolidine so prepared.

Here, LG ¹ , LG ² , X and Y are each independently a leaving group such as halogen, triflate and the like, and R ¹⁵ is C _1-8 alkyl.

Here, LG ¹ , LG ² , X and Y are each independently a leaving group such as halogen, triflate and the like, and R ¹⁵ is C _1-8 alkyl.

  Here, X is a leaving group such as halogen, triflate and the like.

  Here, X is a leaving group such as halogen, triflate and the like.

Here, LG ³ is a leaving group (for example, sulfonate, triflate, halogen, etc.), and Z is halogen.

Here, LG ³ is a leaving group (for example, sulfonate, triflate, halogen, etc.), and Z is halogen.

  Accordingly, another embodiment of the present invention provides compounds of formula (XVIII) and (XIX):

を調製するための方法を包含し、ここで、変数は上で示したとおりであり、その方法は：
（１ａ）アルコール溶媒および水素化触媒を含む混合物中において２−メチルピロリンを水素化する工程；
（１ｂ）選択的に、その混合物から水素化触媒を除去する工程；
（１ｃ）Ｌ−酒石酸またはＤ−酒石酸をその混合物に溶解することにより、溶液を形成する工程；
（１ｄ）その溶液から（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を結晶化させる工程；
（１ｅ）その結晶性（Ｒ）−２−メチルピロリジンＬ−酒石酸塩または（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を単離する工程；および
（２ａ）その（Ｒ）−２−メチルピロリジンＬ−酒石酸塩を塩基と接触させることにより（Ｒ）−２−メチルピロリジン遊離塩基を形成する工程、またはその（Ｓ）−２−メチルピロリジンＤ−酒石酸塩を塩基と接触させることにより（Ｓ）−２−メチルピロリジンを形成する工程；
（３ａ）（Ｒ）−または（Ｓ）−２−メチルピロリジンを式ＸＶＩＩＩまたはＸＩＸの化合物に変換する工程
を包含する。

Include the process wherein the variables are as indicated above and the process is:
(1a) hydrogenating 2-methylpyrroline in a mixture containing an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid or D-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (2a) the (R) -2-methylpyrrolidine Contacting L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or contacting the (S) -2-methylpyrrolidine D-tartrate with a base (S) Forming a 2-methylpyrrolidine;
(3a) converting (R)-or (S) -2-methylpyrrolidine to a compound of formula XVIII or XIX.

This method optionally comprises the following steps:
(1f) recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;
(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; and (1h) optionally, step (f ) And (g) may be further included.

Exemplary compounds that can be produced according to the method of the present invention include:
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (tetrahydropyran-4-yl) -amide;
2- {4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -2,3-dihydro-1H-isoindole;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (pyridin-2-ylmethyl) -amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid 4-methyl-benzylamide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (2-ethoxy-ethyl) -amide;
4- {4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -thiomorpholine 1,1-dioxide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (2-isopropoxy-ethyl) -amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] biphenyl-4-sulfonic acid (2-phenoxy-ethyl) -amide;
4 '-[2- (2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid 4-methoxy-benzylamide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid cyclohexylamide;
2-methyl-1- {2- [4 ′-(pyrrolidin-1-sulfonyl) -biphenyl-4-yl] -ethyl} -pyrrolidine;
2- {4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl) -1,2,3,4-tetrahydro-isoquinoline;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid benzyl-ethyl-amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid 4-trifluoromethyl-benzylamide;
1- {2- [4 ′-(azetidine-1-sulfonyl) -biphenyl-4-yl] -ethyl} -2-methyl-pyrrolidine;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid cyclobutyramide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid tert-butyramide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid propylamide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid isopropylamide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid methylamide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (2-methoxy-ethyl) -amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (4-fluoro-phenyl) -amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid 4-fluoro-benzylamide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid 4-chloro-benzylamide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (2-hydroxy-ethyl) -amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid diethylamide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (1-propyl-butyl) -amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid cyclohexylmethyl-amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid benzylamide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid phenylamide;
4 ′-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid cyclopropylmethyl-amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid cyclopentylamide;
4- {4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -morpholine;
1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidine;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid cyclopropylamide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid ethylamide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl-biphenyl-4-sulfonic acid (2-methoxy-1-methyl-ethyl) -amide;
1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -pyrrolidin-3-ol;
(1- {4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidin-3-yl) -methanol;
1- {2- [4 ′-(aziridin-1-sulfonyl) -biphenyl-4-yl] -ethyl} -2-methyl-pyrrolidine;
2- (methoxymethyl) -1- (4 ′-(2- (2-methylpyrrolidin-1-3,1) ethyl) biphenyl-4-ylsulfonyl) pyrrolidine;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (2-methoxy-ethyl) -methyl-amide;
1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidin-3-ol;
Propionic acid 1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidin-4-yl ester;
4 '-(2-pyrrolidin-1-yl-ethyl) -biphenyl-4-sulfonic acid ethylamide;
(1- {4 ′-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -pyrrolidin-2-yl) -methanol;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid benzyl- (2-hydroxy-ethyl) -amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid 3,5-dichloro-benzylamide;
4 '-{2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid acetyl- (2-hydroxy-ethyl) -amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid 3,4-dichloro-benzylamide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (2-hydroxy-1-methyl-ethyl) -amide;
Propionic acid 2- (1- (4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidin-4-yl) -ethyl ester;
1- {4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidine-4-carboxylic acid benzyl ester;
Acetic acid 2- (acetyl- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -amino) -ethyl ester;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid [2- (4-fluoro-phenyl) -ethyl] -amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (tetrahydro-pyran-4-ylmethyl) -amide;
Propionic acid 1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidin-4-ylmethyl ester;
Propionic acid 2- (methyl- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -amino) -ethyl ester;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (2-methoxyethyl)-(tetrahydro-pyran-4-ylmethyl) -amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid benzhydrylamide;
2-Methyl-7- {4- [2- (2-methyl-pyrrolidin-1-yl) -ethyl) -phenyl} -3,4-dihydro-2Hbenzo [b] [1,4,5] oxathiazepine 1 , 1-dioxide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide;
Propionic acid 1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -pyrrolidin-2-ylmethyl ester;
4 ′-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid isobutyl- (2-methoxy-ethyl) -amide;
7- {4 ′-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] phenyl) -3,4-dihydro-2H-benzo [b] [1,4,5] oxathiazepine 1,1- Dioxide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl] -sulfonic acid (2-hydroxy-ethyl) -methyl-amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid bis- (2-hydroxyethyl) -amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid isopropyl- (2-methoxy-ethyl) -amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (2-hydroxyethyl) -isopropyl-amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (3-phenylpropyl) -amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid [2- (2-oxo-imidazolidin-1-yl) -ethyl] -amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid [3- (2-oxo-pyrrolidin-1-yl) -propyl] -amide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid benzyl- (2-methoxy-ethyl) -amide;
3-methoxymethyl-1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidine;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid phenethylamide;
(1- {4 ′-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidin-4-yl) -methanol;
1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidine-4-carboxylic acid ethyl ester;
4- (2-ethoxy-ethyl) -1- {4 '-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidine;
1- (4- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperazin-1-yl) -propan-1-one;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl) -biphenyl-4-sulfonic acid (pyridin-4-ylmethyl) -amide;
3- {4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonylaminol-propionic acid methyl ester;
4-ethoxymethyl-1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidine;
(1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl-biphenyl-4-sulfonyl) -piperidin-3-yl) -methanol;
3-methoxy-1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidine;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (pyridin-3-ylmethyl) -amide;
2- (1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidin-4-yl) -ethanol;
2- {4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonylamino} -propionic acid methyl ester;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (1-hydroxymethyl-cyclopentyl) -amide;
(1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidin-2-yl) -methanol;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid 4-trifluoromethoxy-benzylamide;
4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid bis- (2-methoxy-ethyl) -amide;
{4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonylamino) -acetic acid methyl ester;
2- {4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonylamino} -propionic acid isopropyl ester;
1- {4 ′-{2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -pyrrolidine-2-carboxylic acid;
6,7-dimethoxy-2- {4 '-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -1,2,3,4-tetrahydro-isoquinoline;
4-methoxy-1-{"2- (2-methyl-pyrrolidin-1-yl) -ethyl-biphenyl-4-sulfonyl} -piperidine;
4- {4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl) -piperazin-2-one;
{4 ′-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl-biphenyl-4-sulfonylamino} -acetic acid isopropyl ester;
1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl-pyrrolidine-2-carboxylic acid methylamide;
3,5-dimethyl-4- {4 '-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl) -morpholine;
Propionic acid 1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl-pyrrolidin-3-yl ester;
1- {4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl) -biphenyl-4-sulfonyl} -piperidin-4-ol;
2-methyl-2- {4 '-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonylamino} -propyl ester of propionic acid;
2- {4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonylamino) -propionic acid tert-butyl ester;
1- {4 ′-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidine-4-carboxylic acid;
{4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonylamino} -acetic acid tert-butyl ester;
4-hydroxy-1- {4 '-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -pyrrolidine-2-carboxylic acid methyl ester;
4- (2-methoxy-ethyl) -1- {4 ′-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidine; and 4-methoxymethyl-1 -{4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidine.

Example Methods and Protocols
Determination of chiral purity of (R) -2-methylpyrrolidine by gas chromatography (GC)

Synthesis of (R) -2-methylpyrrolidine L-tartrate using 5% Pt-C In a mixture of 5% Pt-C (250 mg, catalyst), absolute ethanol (62 mL) and methanol (26 mL), 2-Methylpyrroline (2.50 g, 30.12 mmol) was hydrogenated at 55 psi for 16 hours at ambient temperature. Gas chromatographic analysis showed that 93.7% of the starting material was converted to product. The mixture was filtered through Celite® (4 g) and the filtrate was placed in a 250 mL one-necked round bottom flask with a stir bar along with L-tartaric acid (3.80 g, 25.32 mmol). The mixture was heated to 25 ° C. until a solution was obtained. As seed crystals, authentic (R) -2-methylpyrrolidine L-tartrate (10.0 mg) was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was cooled to 0 ° C. using an ice bath and stirred for an additional 2 hours. The solid was filtered and then air dried for 1 hour to give (R) -2-methylpyrrolidine L-tartrate (3.55 g, 15.09 mmol, 50.1%). Chiral gas chromatographic analysis showed 55% ee, 93% overall purity.

Synthesis of (R) -2-methylpyrrolidine L-tartrate using oxidized Pt (IV) In a mixture of platinum (IV) oxide (250 mg, catalyst), absolute ethanol (62 mL) and methanol (26 mL). 2-Methylpyrroline (2.50 g, 30.12 mmol) was hydrogenated at 55 psi at ambient temperature for 5 hours. Gas chromatographic analysis showed that 98.3% of the starting material was converted to product. The mixture was filtered through Celite® (4 g) and the filtrate was placed in a 250 mL one-necked round bottom flask with a stir bar along with L-tartaric acid (3.80 g, 25.32 mmol). The mixture was heated to 25 ° C. until a solution was obtained. As seed crystals, authentic (R) -2-methylpyrrolidine L-tartrate (100.0 mg) was added and the mixture was stirred at 25 ° C. for 8 hours. The mixture was cooled to ambient temperature and stirred for an additional 16 hours. The mixture was cooled to 0 ° C. using an ice bath and stirred for an additional 2 hours. The solid was filtered, washed with methanol (5 mL) and then air dried for 1 hour to give (R) -2-methylpyrrolidine L-tartrate (2.85 g, 12.12 mmol, 40.3 %). Chiral gas chromatographic analysis showed 49.2% ee, 75% overall purity.

Recrystallization of (R) -2-methylpyrrolidine L-tartrate General recrystallization procedure: A portion of the product obtained in Example 1 (2.71 g) was mixed with absolute ethanol (38 mL) and methanol ( 16 mL) in a 100 mL one-necked round bottom flask with a star bar. The mixture was heated to 60 ° C. to form a solution and then cooled to ambient temperature. As seed crystals, authentic (R) -2-methylpyrrolidine L-tartrate (2.50 mg) was added and the mixture was stirred for 16 hours at ambient temperature and then for a further 2 hours at 0 ° C. (ice bath). did. The solid was filtered and 29 in. (R) -2-methylpyrrolidine L-tartrate was obtained by drying in a vacuum oven at 60 ° C. for 1 hour while flowing Hg nitrogen (1.80 g, 66.4% recovery). Chiral gas chromatographic analysis showed 84.9% ee, a total purity of 93%.

  The resulting solid (1.79 g) was further divided according to the general recrystallization procedure described above with 25 mL absolute ethanol and 11 mL methanol to give (R) -2-methylpyrrolidine L-tartrate. (1.70 g, 95.5% recovery). Chiral gas chromatographic analysis showed 93.4% ee, 97% overall purity.

  The resulting solid (1.69 g) was further subdivided according to the general recrystallization procedure described above with 24 mL absolute ethanol and 10 mL methanol to give (R) -2-methylpyrrolidine L-tartrate. (1.58 g, 93.5% recovery). Chiral gas chromatographic analysis showed 96.7% ee, 98% overall purity.

  The obtained solid (1.57 g) was not seeded and the above crystals were dried using 22.5 mL absolute ethanol and 9.5 mL methanol except that the crystals obtained were dried for 4 hours. (R) -2-methylpyrrolidine L-tartrate was obtained by further resolution according to a typical recrystallization procedure (1.49 g, 94.9% recovery, 6.334 mmol, total from 2-methylpyrroline. 21.0% yield). Chiral gas chromatographic analysis showed 98.4% ee, 99% overall purity.

  As those skilled in the art will appreciate, many modifications and variations of the present invention are possible in light of the above teachings. Therefore, within the scope of the appended claims, the present invention may be practiced otherwise than as specifically described herein, and the scope of the present invention shall cover all such modifications. It is understood that it is intended to include.

Claims (22)

A process for preparing (R) -2-methylpyrrolidine L-tartrate, comprising
(A) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;
(B) optionally removing the hydrogenation catalyst from the mixture;
(C) forming a solution by dissolving L-tartaric acid in the mixture;
(D) crystallizing (R) -2-methylpyrrolidine L-tartrate from the solution;
(E) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate.   The method of claim 1, wherein the hydrogenation catalyst is a platinum catalyst.   3. The method of claim 2, wherein the platinum catalyst is 5% Pt-C.   The method of claim 2, wherein the platinum catalyst is platinum (IV) oxide.   The method according to claim 1, wherein the alcohol solvent is a mixture of ethanol and methanol.   6. The method of claim 5, wherein the alcohol solvent is a mixture of ethanol and methanol in a ratio of about 2: 1 to about 3: 1 (v / v).   The method according to any one of claims 1 to 6, wherein step (a) is performed at ambient temperature.   The method according to claim 2, wherein the platinum catalyst is removed by filtration in the step (b).   9. The method according to any one of claims 1 to 8, wherein the isolated (R) -2-methylpyrrolidine L-tartrate has an optical purity of at least 50% ee. 10. The method according to any of claims 1-9, further comprising:
(F) recrystallizing the isolated (R) -2-methylpyrrolidine L-tartrate;
(G) isolating the recrystallized (R) -2-methylpyrrolidine L-tartrate;
(H) optionally, repeating steps (f) and (g). 11. The method of claim 10, wherein the method further comprises reacting the isolated and recrystallized (R) -2-methylpyrrolidine L-tartrate with a base, whereby (R ) A method that further comprises the step of reacting to provide 2-methylpyrrolidine. 10. The method according to any of claims 1-9, further comprising:
A method comprising the step of converting the prepared (R) -2-methylpyrrolidine L-tartrate into an H ₃ receptor ligand. 12. The method according to claim 10 or 11, further comprising:
A method comprising the step of converting the prepared (R) -2-methylpyrrolidine L-tartrate into an H ₃ receptor ligand. The method according to claim 12 or 13, wherein the _{H 3} receptor ligands, 6- {4- [3 - ( (R) -2- methyl - pyrrolidin-1-yl) - propoxy] - phenyl}-2H -Pyridazin-3-one:

Is that way. 6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one:

A method for preparing
(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;
(1b) optionally removing the hydrogenation catalyst from the mixture;
(1c) forming a solution by dissolving L-tartaric acid in the mixture;
(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate from the solution;
(1e) isolating the crystalline (R) -2-methylpyrrolidine L-tartrate;
(2) reacting the (R) -2-methylpyrrolidine L-tartrate with a base, thereby forming the (R) -2-methylpyrrolidine free base, the reacting step;
(3) (R) -2-methylpyrrolidine and 6- [4- (3-halo-propoxy) -phenyl] -2H-pyridazin-3-one are combined with (R) -6- {4- [3- Reacting for a time sufficient to form (2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one and under conditions sufficient to form it. And a method. 16. The method of claim 15, wherein the 6- [4- (3-halo-propoxy) -phenyl] -2H-pyridazin-3-one is
(A) Time sufficient for 1- (4-hydroxy-phenyl) -ethanone and 1,3-dihalopropane to form 1- [4- (3-halo-propoxy) -phenyl] -ethanone. And contacting under conditions sufficient to form it;
(B) The 1- [4- (3-halo-propoxy) -phenyl] -ethanone and glyoxalic acid are combined with 6- [4- (3-halo-propoxy) -phenyl] -2H-pyridazin-3-one. And contacting for a time sufficient to produce and under conditions sufficient to produce it. The method of claim 15, further comprising:
(F) recrystallizing the isolated (R) -2-methylpyrrolidine L-tartrate;
(G) isolating the recrystallized (R) -2-methylpyrrolidine L-tartrate;
(H) optionally, repeating steps (f) and (g). A process for preparing (S) -2-methylpyrrolidine D-tartrate, comprising
(A) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;
(B) optionally removing the hydrogenation catalyst from the mixture;
(C) forming a solution by dissolving D-tartaric acid in the mixture;
(D) crystallizing (S) -2-methylpyrrolidine D-tartrate from the solution;
(E) isolating the crystalline (S) -2-methylpyrrolidine D-tartrate.   The method of claim 18, wherein the hydrogenation catalyst is a platinum catalyst.   21. The method of claim 19, wherein the platinum catalyst is 5% Pt-C.   21. The method of claim 20, wherein the platinum catalyst is platinum (IV) oxide.   The method according to any one of claims 18 to 21, wherein the alcohol solvent is a mixture of ethanol and methanol.