KR20100017565A - Processes for preparing (r)-2-methylpyrrolidine and (s)-2-methylpyrrolidine and tartrate salts thereof - Google Patents

Abstract

The present invention provides a short, safe, inexpensive, commercially scalable process for preparing (R)-or (S)-2-methylpyrrolidine from 2-methylpyrroline, which does not require the isolation of synthetic intermediates.

Description

PROCESSES FOR PREPARING (R) -2-METHYLPYRROLIDINE AND (S) -2-METHYLPYRROLIDINE AND TARTRATE SALTS THEREOF}

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

(R)-and (S) -2-methylpyrrolidine are useful starting materials for the synthesis of various pharmaceutical products. For example, (R) -2-methylpyrrolidine can be used to prepare many H ₃ receptor ligands. For this reason, there is a great interest in developing cost effective routes for preparing (R)-and (S) -2-methylpyrrolidine. However, previously developed processes either use expensive starting materials or require many lengthy synthesis steps.

Pu et al., Org. Process Res. & Dev., 2005, 9, 45-50 discloses the preparation of (R) -2-methylpyrrolidine L-tartrate by fractional crystallization of racemate 2-methylpyrrolidine in the presence of L-tartaric acid. Is disclosed. The cost of racemate 2-methylpyrrolidine is approximately $ 20 / g.

Van de Kuil et al., Recl. Trav. Chim. Pays-Bas, 1994, 113, 267-277 (R) -2-methylpyrrolidine L-tartrate and (S) -2-methylpyrroli from 2-methylpyrroline (approximately $ 5 / g) A four step synthesis of din D-tartrate is disclosed. However, this method is disadvantageous for some reasons. First, the process requires the preparation of three intermediates, two of which must be isolated. In addition, the process requires the isolation of intermediate HCl salts by in vitro removal of glacial acetic acid and excess aqueous 37% hydrochloric acid solution, which is time consuming, expensive and corrosive. In addition, the synthesis requires the isolation of the intermediate by two sequential flash distillations from potassium hydroxide.

Ku et al., Tetrahedron, 2006, 62, 4584-4589, disclose a four step synthesis of (R) -2-methylpyrrolidine hydrochloride from N-Boc-L-prolinol. The method is disadvantageous for several reasons. First, the method requires the preparation and isolation of three separate synthetic intermediates. Secondly, the process uses corrosive gaseous hydrochloric acid and phosphoric acid as well as environmentally harmful solvent dichloromethane. Third, the method uses expensive lithium iodide (approximately $ 13 / g). In addition, the resulting hydrochloride salt is very hygroscopic.

Zhao et al., J. Org. Chem., 2006, 71, 4336-4338 discloses a four step synthesis of (R) -2-methylpyrrolidine benzenesulfonate from N-Boc-L-proline. The method is disadvantageous for several reasons. First, the 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®.

There is a need for a process for the preparation of (R)-and (S) -2-methylpyrrolidine that is short, safe, inexpensive, commercial scale and can be performed without the need to isolate multiple synthetic intermediates.

Summary of the Invention

The inventors have surprisingly found that (R) -2-methylpyrrolidine L-tartrate and (S) -2-methylpyrrolidine D-tartrate do not require the isolation of any synthetic intermediates without the use of non-corrosive reagents. It has been found that it can be prepared in two steps from inexpensive 2-methylpyrroline. In one embodiment, the present invention

(a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(b) optionally removing a hydrogenation catalyst from said mixture;

(c) dissolving L-tartaric acid in the mixture to form a solution;

(d) crystallizing (R) -2-methylpyrrolidine L-tartrate from the solution; And

(e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate

It provides a method for producing (R) -2-methylpyrrolidine L- tartrate comprising a.

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 in step (b) by filtration.

Preferably, the optical purity of the isolated (R) -2-methylpyrrolidine L-tartrate is at least 50% ee.

Optionally, the method

(f) recrystallizing the isolated (R) -2-methylpyrrolidine L-tartrate;

(g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate; And

(h) optionally repeating steps (f) and (g)

It further includes.

Optionally, the method further comprises reacting the isolated recrystallized (R) -2-methylpyrrolidine L-tartrate with a base to provide (R) -2-methylpyrrolidine.

Preferably, the process comprises the preparation of (R) -2-methylpyrrolidine L-tartrate in a pharmaceutical composition, preferably H ₃ receptor ligand, preferably the following 2- (6- {2-[(2R) ) -2-methyl-1-pyrrolidin-1-yl] ethyl} -2-naphthalen-2-yl) -2H-pyridazin-3-one.

In one embodiment, the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate; And

(2) reacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base; And

(3) sufficient time to form (R) -6- {4- [3- (2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one Reacting (R) -2-methylpyrrolidin with 6- [4- (3-halo-propoxy) -phenyl] -2H-pyridazin-3-one during and under conditions

6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one comprising a to provide.

Preferably, 6- [4- (3-halo-propoxy) -phenyl] -2H-pyridazin-3-one is

(a) 1,3- (4-hydroxy-phenyl) -ethanone for a time and under conditions sufficient to form 1- [4- (3-halo-propoxy) -phenyl] -ethanone; Contacting with dihalopropane; And

(b) 1- [4- (3-halo-propoxy) for a time and under conditions sufficient to produce 6- [4- (3-halo-propoxy) -phenyl] -2H-pyridazin-3-one. Contacting) -phenyl] -ethanone with glyoxalic acid

Is prepared by.

The invention also

(a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(b) optionally removing a hydrogenation catalyst from said mixture;

(c) dissolving D-tartaric acid in the mixture to form a solution;

(d) crystallizing (S) -2-methylpyrrolidine D-tartrate from the solution; And

(e) isolating crystalline (S) -2-methylpyrrolidine D-tartrate

It provides a method for producing (S) -2-methylpyrrolidine D-tartrate comprising a.

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 optical purity of the isolated (S) -2-methylpyrrolidine D-tartrate is at least 50% ee.

Optionally, the method

(f) recrystallizing the isolated (S) -2-methylpyrrolidine D-tartrate;

(g) isolating recrystallized (S) -2-methylpyrrolidine D-tartrate; And

(h) optionally repeating steps (f) and (g)

It further includes.

Optionally, the method further comprises reacting the isolated recrystallized (S) -2-methylpyrrolidine D-tartrate with a base to provide (S) -2-methylpyrrolidine.

Optionally, the process comprises the preparation of (S) -2-methylpyrrolidine D-tartrate with an H ₃ receptor ligand, preferably 2- (6- {2-[(2S) -2-methyl-1-pi Converting to rollidin-1-yl] ethyl} -2-naphthalen-2-yl) -2H-pyridazin-3-one.

Justice

"About" refers to a range of ± 10% of a specific value; For example, the phrase “about 50” includes 50 ± 10%, or 45-55.

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

"Industrial scale" refers to a single batch of at least about 500 g.

"Crystalization" refers to causing a crystal to form.

"H ₃ receptor ligand" refers to a compound that interacts with histamine H ₃ receptor as an antagonist, agonist or partial agonist.

"Heterogeneous catalyst" refers to a hydrogenation catalyst that is not soluble in alcohol solvents.

"Homogeneous catalyst" refers to a hydrogenation catalyst that is soluble in alcohol solvent.

"Hydrogenation catalyst" refers to a composition suitable for catalyzing the reaction of 2-methylpyrroline with hydrogen to form 2-methylpyrrolidine.

"Isolation" refers to the separation of a component (eg, reagent or product) from a mixture.

"Optical purity" refers to the ratio of enantiomers of one of the mixture of enantiomers and is declared as enantiomeric excess (% ee), which is defined as (| R-S | / (R + S)) * 100% Wherein R and S are fractions of each enantiomer such that R + S = 1.

"Pharmaceutical product" refers to a compound or composition that can be used to treat a disease, condition or disorder in a human.

"Platinum catalyst" refers to a hydrogenation catalyst containing platinum.

"Tablet" refers to increasing compound purity.

"Purity" refers to the weight percentage of one component of the mixture.

"Solution" refers to a solvent that contains at least partially dissolved material (s) and may contain undissolved (eg, solid) material (s).

All documents mentioned herein are incorporated by reference in their entirety for all purposes.

Explanation

The present invention

(a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(b) optionally removing a hydrogenation catalyst from said mixture;

(c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution; And

(e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate

Provided is a method for producing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate.

Step (a)

In step (a), 2-methylpyrroline is hydrogenated in a mixture comprising an alkyl alcohol solvent and a hydrogenation catalyst. 2-methylpyrroline used in the hydrogenation reaction can be purchased from commercial sources (eg, Sigma-Aldrich Corp., St. Louis, MO). An important advantage of the process of the invention is that 2-methylpyrroline is less expensive than other starting materials used for the production of (R)-and (S) -2-methylpyrrolidine.

Hydrogenation catalysts used in the reaction can be purchased from commercial sources (eg, Sigma-Aldrich Corp., St. Louis, MO). The hydrogenation catalyst may be a homogeneous catalyst or a heterogeneous catalyst. Examples of hydrogenation catalysts include, but are not limited to, platinum catalysts. Examples of platinum catalysts include, but are not limited to, platinum on carbon (Pt / C), platinum (IV) oxide, and mixtures thereof. Examples of homogeneous catalysts include, but are not limited to, chlorotris (triphenylphosphine) rhodium (Wilkinson catalyst), and catalysts disclosed in US Pat. Nos. 4,581,417, 4,631,315, and 5,670,437. . Preferably, the hydrogenation catalyst is platinum (IV) oxide. More preferably, the hydrogenation catalyst is 5% Pt-C.

The alcohol solvent used in the reaction is a C ₁ -C ₆ alkyl alcohol, or a mixture of C ₁ -C ₆ alkyl alcohols. 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 comprises methanol. More preferably, the alcohol solvent is a mixture of ethanol and methanol. More preferably, the alcohol solvent is a mixture of ethanol and methanol 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 about 2.4: 1 (v / v) ratio of ethanol and methanol.

The alcohol solvent may be present in any suitable amount of step (a) reaction mixture. Preferably, the alcohol solvent comprises at least about 50% (w / w) reaction mixture. More preferably, the alcohol solvent comprises at least about 70% (w / w) reaction mixture. More preferably, the alcohol solvent comprises at least about 90% (w / w) reaction mixture. More preferably, the alcohol solvent comprises at least about 95% (w / w) reaction mixture. Notably, C ₁ -C ₆ alkyl alcohols are more easily removed from the reaction mixture compared to acetic acid. In addition, C ₁ -C ₆ alkyl alcohols are non-corrosive.

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

The hydrogenation reaction can be carried out at any suitable temperature. Preferably, the reaction is carried out at ambient temperature.

An advantage of the process of the invention is that the hydrogenation reaction is carried out in a non-corrosive alkyl alcohol solvent. Another advantage of the process of the invention is that the product of the hydrogenation reaction (ie 2-methylpyrrolidine) is obtained directly without the need to prepare or isolate 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, especially if the hydrogenation catalyst is a heterogeneous catalyst, step (d) is performed after step (b). Suitable methods for removing the hydrogenation catalyst include, but are not limited to, filtration, decantation and centrifugation. In certain embodiments, the hydrogenation catalyst is removed by filtration. Although hydrogenation catalysts are generally precious metal-based, the advantage of the process of the present invention is that the hydrogenation catalyst can be removed from the mixture, recycled and reused in subsequent hydrogenation reactions (eg, US 5,554,353 (Schneider et al.) EP 1 739 104 A1 (Kobayashi et al.); See Setty-Fichman, et al., J. Mol. Cat.A: Chem., 1999, 144 (1), 159-163).

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 preferred product is (R) -2-methylpyrrolidine, L-tartaric acid is used. If the preferred product is (S) -2-methylpyrrolidine, D-tartaric acid is used. L-tartaric acid or D-tartaric acid for use in the process of the present invention can 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 homogeneous (eg contains undissolved particles), then the solution is preferably heated to promote dissolution.

An advantage of the process of the present invention is that it does not require 2-methylpyrrolidine to be produced in the hydrogenation reaction, which must be isolated from the reaction mixture before adding tartaric acid. This makes the method simpler, faster, less expensive and less wasteful compared to the 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). If L-tartaric acid is added in step (c), (R) -2-methylpyrrolidine L-tartrate is crystallized from the solution in step (d). If D-tartaric acid is added in step (c), (S) -2-methylpyrrolidine D-tartrate is crystallized from the solution in step (d). Any suitable method can be used to crystallize (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from solution. In certain embodiments, the solution is heated to facilitate dissolution and then cooled to induce crystallization.

Step (e)

In step (e), crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate is isolated. If 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). If 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 isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate include, but are not limited to, filtration, decanting And centrifugation. An advantage of the process of the invention 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-methylpyrrolidine It is understood that D-tartrate may contain some (R) -2-methylpyrrolidine D-tartrate, which reduces the optical purity of the isolated product. Preferably, the optical purity of the isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate is at least 40% ee. More preferably, the optical purity of the isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate is at least 50% ee. More preferably, the optical purity of the isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate is at least 55% ee.

Any additional steps

The process of the present invention for preparing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate provides reagents and solvents that are inexpensive and non-corrosive. It is advantageous in terms of use, can be conveniently and inexpensively carried out at temperatures from 0 ° C. to 25 ° C., requires the preparation of only one intermediate compound, does not require the isolation of synthetic intermediates, permits catalyst recycling and It provides a product which can be isolated by simple filtration, which is then used in a later method.

The isolated product is a tartrate 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 produced in situ and can be used in the next synthesis step without isolation. The method described herein is applicable to both isolated 2-methylpyrrolidine free base and 2-methylpyrrolidine free base, which are produced in situ in the reaction mixture.

Thus, in certain embodiments, the method comprises reacting isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate with a base to (R)- It further comprises the step of providing 2-methylpyrrolidine or (S) -2-methylpyrrolidine. Suitable bases used in the reaction include, but are not limited to, ammonium hydroxide, alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide), alkylamines (eg triethylamine, diisopropylethylamine ), And mixtures thereof. Suitable solvents used in the reaction include, but are not limited to, diethyl ether and dichloromethane. In addition, 2-methylpyrrolidine free base can be generated from the corresponding tartrate salt using ion-exchange resins using procedures known to those skilled in the art.

Preferably, (R) -2-methylpyrrolidine L-tartrate prepared, (S) -2-methylpyrrolidine D-tartrate, (R) -2-methylpyrrolidine or (S) The optical purity of -2-methylpyrrolidine is at least 50% ee. This means that the main enantiomers make up 75% of the mixture and the minor enantiomers make up 25% (50% ee = ((0.75-0.25) / (0.75 + 0.25) * 100%). Purity is often sufficient for products that must be used as reagents in subsequent synthetic methods, for example, (R) -2-methylpyrrolidine L-tartrate having an optical purity of 50% ee may be added to the stereogenic center (s). When used to prepare a compound having R, the reaction will result in a mixture of diastereomers and the minor diastereomer (s) formed from (S) -2-methylpyrrolidine is (R) -2- It can be removed during conventional purification of the main diastereomer (s) formed from methylpyrrolidine.

If higher levels of optical purity are required, the resulting (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate can be recrystallized. Thus, in certain embodiments, the method

(f) recrystallizing the isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate;

(g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(h) optionally repeating steps (f) and (g)

It may further include.

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 recrystallizing isolated (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate are, but are not limited to, isolated tarts Dissolving the late salt in a suitable solvent and then cooling the solution to promote crystallization. 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 alcohol 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 recrystallized tartrate salts 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.

Applying the tartrate salt isolated in step (e) for the sequence of single recrystallization according to steps (f) and (g) is preferably isolated (R) -2-methyl having an optical purity of at least 80% ee. Pyrrolidin L-tartrate or (S) -2-methylpyrrolidine D-tartrate. More preferably, the optical purity of (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate isolated in step (g) is at least 85% ee. . Optical purity 85% ee means that the main enantiomers make up more than 92% of the mixture, and the minor enantiomers make up less than 8% and (84% ee = ((0.925-0.075) / (0.925 + 0.075) * 100%), which is often of sufficient purity for use in subsequent synthetic methods.

Step (h)

If higher optical purity is required, the recrystallization sequence (ie steps (f) and (g)) is repeated one or more times to (R) -2-methylpyrrolidine L-tartrate or (S) -2- It is possible to increase the optical purity of methylpyrrolidine D-tartrate. After two recrystallizations, (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate is preferably at least 90% ee in optical purity. More preferably, the isolated 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 is preferably at least 95% ee in optical purity. More preferably, the optical purity of the isolated recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate is at least 97% ee. After four recrystallizations, (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate is preferably at least 98% ee in optical purity.

Free base

Optionally, the method comprises reacting the isolated recrystallized (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate with a base (R) -2- It may further comprise providing methylpyrrolidine or (S) -2-methylpyrrolidine. Suitable bases for use in such reactions include, but are not limited to, ammonium hydroxide, alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide), alkylamines (eg triethylamine, diisopropylethyl Amines), and mixtures thereof. Suitable solvents for use in such reactions include, but are not limited to, diethyl ether and dichloromethane. In addition, 2-methylpyrrolidine free base can be generated 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 produced 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, which are produced in situ in the reaction mixture.

Additional compounds

In addition to providing conventional methods for preparing (R)-and (S) -2-methylpyrrolidine and their respective tartaric acid salts, the present invention also provides 2-methylpyrrolidine to other compounds, particularly pharmaceuticals. Methods of incorporation into phase useful compounds are 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 initial step in the conversion is (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate by reaction with a base or ion exchange resin. The salt form can be modified into the corresponding free base form (ie, (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine, respectively). Such (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine, which is isolated or prepared in situ, can be prepared by a number of pharmaceutical compounds known in the art, for example histamine-3 receptor ligands. Can be used to make.

For example, (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine prepared by the above process may be a H ₃ receptor antagonist and / or inverse agonist of formula (I), or a pharmaceutical thereof Can be converted into a phase-acceptable salt:

In the above formula,

R ¹ is

이고;

ego;

R ² is

이다.

to be.

Suitable methods for the preparation of the compounds of formula (I) from 2-methylpyrrolidine are described in WO 2007/009741 and are prepared according to the above process (R) -2-methylpyrrolidine or (S) -2- It is applicable to the use of methylpyrrolidine. For example, a solution of 1,1-dimethylethyl 4- {4-[(3-chloropropyl) oxy] phenyl} -3-oxo-1-piperazinecarboxylate dissolved in 2-butanone may be provided. Can be. Potassium carbonate, potassium iodide, and (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine free base can be added and the mixture is heated at 80 ° C. for 24 hours. The reaction is then cooled to room temperature and partitioned between EtOAc and water. The organic phase can be dried and concentrated, the residue is purified by flash chromatography, the appropriate fractions combined and concentrated to give the BOC-protected amine of formula II:

Wherein R ² is — (ie, 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-piperazinecarboxyl Rating). The BOC protecting group in the compound of formula II can then be removed to form an amine of formula III, for example by reaction with trifluoroacetic acid:

이다. 이어서, 화학식 III의 아민을, 4-시아노벤조산, 4-(1-아제티디닐카르보닐)벤조산, 2,4-디플루오로벤조산, 3,5-디플루오로벤조산, 4-플루오로벤조산, 1-메틸-1H-1,2,3-트리아졸-4-카르복실산, 1,5-디메틸-1H-피라졸-3-카르복실산, 1-메틸-5-옥소-3-피롤리딘카르복실산, 3,5-디메틸-4-이속사졸카르복실산, 1,3-디메틸-1H-피라졸-5-카르복실산, 2,3-디플루오로벤조산, 2,5-디플루오로벤조산, 2,6-디플루오로벤조산 및 3,4-디플루오로벤조산으로부터 선택된 카르복실산과 반응시켜 화학식 I의 화합물을 형성할 수 있다. In the formula, R ²

to be. Subsequently, the amine of the formula (III) is prepared by 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-py Lolidinecarboxylic acid, 3,5-dimethyl-4-isoxazolecarboxylic acid, 1,3-dimethyl-1H-pyrazole-5-carboxylic acid, 2,3-difluorobenzoic acid, 2,5- The compound of formula (I) may be formed by reaction with a carboxylic acid selected from difluorobenzoic acid, 2,6-difluorobenzoic acid and 3,4-difluorobenzoic acid.

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 1 -Bromo-3-chloropropane can be prepared by reacting with 1,1-dimethylethyl-4- (4-hydroxyphenyl) -3-oxo-1-piperazinecarboxylate, which is 1,1- Can be prepared by catalytic hydrogenolysis of dimethylethyl-3-oxo-4- {4-[(phenylmethyl) oxy] phenyl} -1-piperazinecarboxylate, which yields methanesulfonyl chloride with 1, Can be prepared by reacting with 1-dimethylethyl- (2-hydroxyethyl) [2-oxo-2-({4-[(phenylmethyl) oxy] phenyl} amino) ethyl] carbamate, which is N ² Can be prepared by BOC protection of-(2-hydroxyethyl) -N ^1- {4-[(phenylmethyl) oxy] phenyl} glycinamide, which converts 4-[(phenylmethyl) oxy] aniline to chloroacetyl Chloride and then reacted with 2-aminoethanol It can be prepared by.

As a workaround for BOC, other nitrogen protecting groups known in the art can be used. Examples of suitable nitrogen protecting groups are described in Green, T.W .; Wutz, P.G.M. Protective Groups in Organic Synthesis, 2d ed .; John Wiley and Sons: New York, 1991.

Thus, one embodiment of the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate; And

(2a) converting the isolated (R) -2-methylpyrrolidine L-tartrate into a compound of formula (I)

It relates to a process for the preparation of a compound of formula (I) comprising:

<Formula I>

Wherein R ¹ and R ² are as defined above.

The method is

(1f) recrystallization of isolated (R) -2-methylpyrrolidine L-tartrate;

(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate; And

(1h) optionally repeating steps (f) and (g)

It may optionally further include.

In another embodiment, the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate;

(1f) reacting (R) -2-methylpyrrolidine L-tartrate with a base to provide (R) -2-methylpyrrolidin;

(2) reacting (R) -2-methylpyrrolidine with a protected amine of formula (Ia) to form a protected amine of formula (II)

<Formula Ia>

<Formula II>

(Wherein, PG is a protecting group)

(3) removing the protecting group from the protected amine of formula III to form an amine of formula III; And

<Formula III>

(4) 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-py Lolidinecarboxylic acid, 3,5-dimethyl-4-isoxazolecarboxylic acid, 1,3-dimethyl-1H-pyrazole-5-carboxylic acid, 2,3-difluorobenzoic acid, 2,5- Reacting with a carboxylic acid selected from difluorobenzoic acid, 2,6-difluorobenzoic acid and 3,4-difluorobenzoic acid to form a compound of formula (I)

It relates to a process for the preparation of a compound of formula (I) comprising:

<Formula I>

Wherein R ¹ and R ² are as defined above.

The method is

(1f) recrystallization of isolated (R) -2-methylpyrrolidine L-tartrate;

(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate; And

(1h) optionally repeating steps (f) and (g)

It may optionally further include.

Preferably, the protecting group is BOC.

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

6-Bromo-naphthalen-2-ol can be treated with any suitable trifluoromethanesulfonic acid reagent in the presence of an organic base to give trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester. Examples of suitable trifluoromethanesulfonic acid reagents include, for example, trifluoromethanesulfonyl acid anhydride, trifluoromethanesulfonyl chloride, N-phenyltrifluoromethanesulfonimide, trifluoromethanesulfonyl- 1-H-imidazole, trifluoromethanesulfonyl acid anilide, trifluoromethanesulfonic acid-2-nitrophenyl ester, trifluoromethanesulfonyl acid-4-nitrophenyl ester. Examples of the organic base include, for example, triethylamine, diisopropylamine, diisopropylethylamine, 2,6-lutidine, pyridine and 1,8-diazabicyclo [5.4.0] undec- There is a 7-yen (DBU).

The reaction can be accomplished in any suitable organic solvent. Examples of suitable solvents are CH ₂ Cl ₂ , dimethyl ether (DME) and toluene. The reaction can also be carried out under biphasic conditions when an inorganic base is used. For example, suitable inorganic bases include K ₃ PO ₄ , NaHCO ₃ , Na ₂ CO ₃ , NaOH, and the like. Preferred solvent is toluene. Typically, the reaction is carried out at low temperature, for example under biphasic conditions using toluene and 30% potassium phosphate. The preferred temperature range for the reaction is 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 vinyltrifluoroborate reagent. Suitable vinyltrifluoroborate reagents include, for example, potassium vinyltrifluoroborate, 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, dibutyl vinylborate There is a ronate. The reagent is used in an amount of about 1.0 molar equivalents to about 1.5 molar equivalents relative to trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester. Typically, the reaction is carried out in polar organic solvents such as alcohols and basic solutions such as metal carbonate solutions. Preferred solvent is ethanol. Examples of other solvents that can be used for the reaction include n-propanol, iso-propanol, methanol, and other suitable alcohols. The metal carbonate is preferably cesium carbonate. Alternatively, other salts may also be used, such as Na ₂ CO ₃ and K ₃ PO ₄ . The amount of metal carbonate for the reaction is from about 2 molar equivalents to about 4 molar equivalents relative to trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester. The reaction is carried out in the presence of a palladium catalyst and an organic amino base such as triethylamine, diisopropylamine and the like. Examples of palladium catalysts for the reaction include, but are not limited to, tetrakis (triphenylphosphine) palladium, PdCl ₂ (dppf) ₂ , PdCl ₂ (Ph ₃ P) ₂ and PdCl ₂ (CH ₃ CN) ₂ Included. Preferred palladium catalyst is tetrakis (triphenylphosphine) palladium.

2-bromo-6-vinyl-naphthalene was treated with (R) -2-methylpyrrolidin anion produced using n-butyllithium to yield 1- [2- (6-bromo-naphthalen-2-yl ) -Ethyl]-(R) -2-methyl-pyrrolidine can be obtained. The method described in US2005 / 0256127 can be improved by producing (R)-and / or (S) -2-methylpyrrolidine according to the above method. 2-bromo-6-vinyl-naphthalene is then reacted with (R) -2-methylpyrrolidine anion produced using n-butyllithium or any other suitable base to give 1- [2- (6- Bromo-naphthalen-2-yl) -ethyl] -2R-methyl-pyrrolidine can be obtained. 2-Bromo-6-vinyl-naphthalene was treated with (R) -2-methylpyrrolidine anion produced using n-butyllithium to produce 1- [2- (6-bromo-naphthalene-2- Yl) -ethyl]-(R) -2-methyl-pyrrolidine. Preferably, about 1.2 to about 2.5 molar equivalents of (R) -2-methylpyrrolidine are used for this reaction. The reaction is typically carried out in organic solvents such as THF, methyl-t-butyl ether (MTBE), Et ₂ O and DME. Preferred solvent is tetrahydrofuran (THF). n-butyllithium is added to the THF solution of (R) -2-methylpyrrolidine in a controlled manner, typically in a dropwise manner. To this solution is added a THF solution of 2-bromo-6-vinyl-naphthalene. Alternatively, it is also suitable for adding a THF solution of 2-bromo-6-vinyl-naphthalene to a solution of (R) -2-methylpyrrolidine and n-butyllithium. The reaction is carried out at temperatures below room temperature, typically from about 0 ° C to about -20 ° C. About 0.3 to about 0.7 molar equivalents of n-butyllithium are used relative to the 2-bromo-6-vinylnaphthalene compound. The resulting compound is 1- [2- (6-bromo-naphthalen-2-yl) -ethyl]-(R) -2-methyl-pyrrolidine.

Subsequently, 1- [2- (6-bromo-naphthalen-2-yl) -ethyl]-(R) -2-methyl-pyrrolidine is reacted with 2H-pyridazin-3-one to give a preferred 2- { Obtain 6- [2-((R) 2-Methyl-pyrrolidin-1-yl) -ethyl] -naphthalen-2-yl} -2H-pyridazin-3-one compound, which is further processed to Suitable salts can be prepared. The reaction is carried out using 2H-pyridazin-3-one, 8-hydroxyquinoline, a copper catalyst in the presence of a base. From about 1.0 to about 1.5 molar equivalents of (2H) -pyridazine-3 relative to 1- [2- (6-bromo-naphthalen-2-yl) -ethyl]-(R) -2-methyl-pyrrolidine Use -on. The copper catalyst can be any suitable copper catalyst, for example a copper (I) catalyst. Examples of suitable catalysts for the reaction include, but are not limited to, copper (0) powder, copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) oxide, copper ( I) acetate, copper (II) chloride, copper (II) bromide, copper (II) iodide, copper (II) oxide or copper (II) acetate. Preferred copper catalyst is copper (I) chloride. About 0.02 to about 1.0 molar equivalents of copper catalyst are used for 1- [2- (6-bromo-naphthalen-2-yl) -ethyl]-(R) -2-methyl-pyrrolidine. Examples of suitable ligands for the reaction include, but are not limited to, p-dimethylaminopyridine, pyridine, 3-picoline, 4-picoline, 8-hydroxyquinoline, 7-methyl-8-hydroxyquinoline, 7 -n-propyl-8-hydroxyquinoline, 1,10-phenanthroline and 2,2'-dipyridyl. Preferred ligand is 8-hydroxyquinoline, which is from about 0.02 to about 2.0 for 1- [2- (6-bromo-naphthalen-2-yl) -ethyl]-(R) -2-methyl-pyrrolidine Used in molar equivalents. Preferably, the base is a metal carbonate or metal alkoxide, for example cesium carbonate, potassium carbonate, sodium carbonate and sodium tert-butoxide. Preferred base is potassium carbonate, which is about 1.0 to about 2.0 molar equivalents relative to 1- [2- (6-bromo-naphthalen-2-yl) -ethyl]-(R) -2-methyl-pyrrolidine Used in quantity. The reaction is carried out in a polar organic solvent at elevated temperature. 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. This includes. Preferred solvent is dimethylformamide (DMF). Typically, the reaction is carried out under a nitrogen atmosphere and the reaction mixture is heated to a temperature of about 100 ° C to about 160 ° C. The reaction can typically be carried out 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 for several hours with aqueous saline solution, for example 25% NaCl solution or other suitable salt solution. The organic solution is dried and concentrated to dryness to afford the product.

Alternatively, 2- (6- {2-[(2R) -2-methyl-1-pyrrolidin-1-yl] -ethyl} -2-naphthalen-2-yl) -2H-pyridazine-3- Warm active agents according to the procedures described in US 7,153,889 (filed Oct. 22, 2003), at least, for example, in general procedures and in Example 31, or any other suitable procedure for providing a stable active agent. Can be prepared. Briefly, for example, 6-bromo-2-naphthoate is reduced with BH ₃ -THF to provide 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 and activated with a sulfonate such as tosylate. (R) -2-methylpyrrolidine is prepared according to steps (a) to (e) with or without any of steps (f) to (h), and (R) -2-methyl It is obtained by reacting pyrrolidine L-tartrate with a base to obtain (R) -2-methylpyrrolidine, and sulfonate is reacted 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.

Thus, one embodiment of the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or (S) -2-methylpyrrolidine D Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

(3a) converting trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester to 2-bromo-6-vinyl-naphthalene;

(3b) 2-bromo-6-vinyl-naphthalene is reacted with (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine in the presence of n-butyllithium to give 1- [2- (6-Bromo-naphthalen-2-yl) -ethyl] -2R-methyl-pyrrolidine or 1- [2- (6-bromo-naphthalen-2-yl) -ethyl] -2S-methyl-py Providing lollidine; And

(3c) 2- {6- [2 by reacting 1- [2- (6-bromo-naphthalen-2-yl) -ethyl] -2-methyl-pyrrolidine with 2H-pyridazin-3-one Providing-(2-methyl-pyrrolidin-1-yl) -ethyl] -naphthalen-2-yl} -2H-pyridazin-3-one

It relates to a method for producing 2- {6- [2- (2-methyl-pyrrolidin-1-yl) -ethyl] -naphthalen-2-yl} -2H-pyridazin-3-one, including

The method is

(1f) recrystallization of isolated (R) -2-methylpyrrolidine L-tartrate;

(1 g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate; And

(1h) optionally repeating steps (f) and (g)

It may optionally further include.

Further, the trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester can be prepared by providing 6-bromo-naphthalen-2-ol; And reacting 6-bromo-naphthalen-2-ol with a suitable trifluoromethanesulfonic acid reagent.

Exemplary compounds that can be prepared using the methods of the invention include:

This includes.

WO 2005/117865 also describes histamine-3-receptor ligands comprising a 2-methyl-pyrrolidinyl residue of formula III:

<Formula III>

In the formula, A

Is selected from,

here,

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;

X is O, S or NR ^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;

R ⁷ is lower alkyl.

Compounds of formula III can be prepared according to the following scheme 1:

Coupling of carboxylic acids with amines is extensively described in the literature, and such procedures are known to those skilled in the art (for reaction conditions described in the literature affecting the reaction, for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock.John Wiley & Sons, New York, NY.1999). 6-hydroxy-2-naphthoic acid is conveniently prepared according to steps (a) to (e) (with or without any of steps (f) to (h)) or Coupling with (S) -2-methylpyrrolidine and reacting (R) -2-methylpyrrolidine L-tartrate with base to give (R) -2-methylpyrrolidine, respectively. It can be modified with amide of. Any suitable coupling agent can be used to achieve the modification. 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-oxidehexafluorophosphate (HATU), 1- Couples such as hydroxy-1,2,3-benzotriazole (HOBT), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU) and the like Ring reagents can be used equally to achieve this modification.

There is no particular limitation on the nature of the solvent used, provided that such solvent has no adverse effect on the reaction or reagents involved and can dissolve the reagents in at least some ranges. Examples of suitable solvents include DMF, dichloromethane (DCM), dioxane, THF and the like. Typically, bases are used with coupling agents. There is no specific limitation on the nature of the base used in this step, and any base commonly used in this type of reaction may equally be used herein. Examples of such bases include triethylamine, diisopropylethylamine, and the like. The reaction can be carried out over a wide range of temperatures and the exact reaction temperature is not critical for the present invention. It is convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction can also vary widely depending on many factors, notably the reaction temperature and the nature of the reagent. However, a period of usually 0.5 hours to several days will be sufficient to obtain an 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, N-ethyldiisopropylamine 2.3 mL, and a mixture of (R) or (S) -2-methyl-pyrrolidine prepared according to the above procedure, are prepared in 10 mL of DMF and stirred at room temperature for 16 hours. The mixture is then concentrated to dryness and 50 mL ethyl acetate, 30 mL water and 20 mL of NaHCO ₃ aqueous (10%) are added. The aqueous phase can then be extracted with 50 mL of ethyl acetate and the combined organic layers are purified by column chromatography on silica. The product fractions can be concentrated to dryness, triturated twice with diethyl ether / heptane 1/1 20 mL and the residue can be dried in vacuo at 50 ° C. The execution of this method using (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine prepared according to the methods described herein is carried out by (6-hydroxy-naphthalen-2-yl)-( Will produce 2R-methyl-pyrrolidin-1-yl) -methanone or (6-hydroxy-naphthalen-2-yl)-(2S-methyl-pyrrolidin-1-yl) -methanone, This can then be used to generate histamine-3-receptor ligands.

To prepare a histamine-3-receptor ligand, the (R) or (S) intermediate is reacted with an alcohol of formula HO-A, wherein A is as defined above to form an ether. The synthesis of ethers is extensively described in the literature and the procedure is known to those skilled in the art. (For reaction conditions described in the literature affecting this reaction, see, for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999]. Such modifications can be achieved by using reaction conditions commonly used in so-called "Mitsunobu reactions" known to those skilled in the art and widely described (Hughes, David L. The Mitsunobu Reaction. Organic Reaction (New York) (1992), 42, 335-656). Conditions include trialkylphosphines such as tributylphosphine, triphenylphosphine and the like, and diazo-compounds such as diethyl-azodicarboxylate (DEAD), diisopropylazodicarboxylate (DIAD) ( Optionally polymer bonded), tetramethyl azodicarboxamide and the like are used in the solvents commonly used for such modifications, such as tetrahydrofuran (THF), toluene, dichloromethane and the like. There is no particular limitation on the nature of the solvent used, provided that such solvent has no adverse effect on the reaction or reagents involved and can dissolve the reagents in at least some ranges. The reaction can be carried out over a wide range of temperatures, and the exact reaction temperature is not critical for the present invention. Ambient temperatures to reflux are generally suitable. The time required for the reaction may also vary widely depending on many factors, notably the reaction temperature and the nature of the reagent. However, a period of usually 0.5 hours to several days will be sufficient to obtain an amide derivative.

Alternatively, the following synthetic approach can 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 intermediate formed acid is then (R)-or (S) -2- prepared according to steps (a) to (e) above (with or without any of steps (f) to (h)). Coupling with methylpyrrolidine and reacting (R) -2-methylpyrrolidine L-tartrate with base to obtain (R) -2-methylpyrrolidine, or (S) -2-methyl Pyrrolidine D-tartrate is reacted with a base to give (S) -2-methylpyrrolidine to give the desired compound. Suitable coupling agents and conditions are described above.

Thus, one embodiment of the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or (S) -2-methylpyrrolidine D Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

의 카르복실산을 (R)- 또는 (S)-2-메틸피롤리딘과 접촉시키는 단계; 및(3a) Formula for a time and under conditions suitable to obtain the corresponding amide phenol

Contacting a carboxylic acid of with (R)-or (S) -2-methylpyrrolidine; And

(3b) contacting the amide phenol with an alcohol of formula HO-A, wherein A is as defined above, for a time and under conditions sufficient to obtain the corresponding amide ether.

It relates to a process for the preparation of a compound of formula III, comprising:

<Formula III>

Wherein the variables are as defined above.

The method is

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

Another embodiment is

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or (S) -2-methylpyrrolidine D Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

의 에스테르 페놀을 화학식 HO-A의 알코올 (여기서, A는 상기 정의된 바와 같음)과 접촉시키는 단계; 및(3a) a formula for a time and under conditions sufficient to form the corresponding ester ether

Contacting an ester phenol of with an alcohol of formula HO-A, wherein A is as defined above; And

(3b) contacting the ester ether with (R)-or (S) -2-methylpyrrolidine for a time and under conditions sufficient to form the corresponding amide ether.

It relates to a process for the preparation of a compound of formula III, comprising:

<Formula III>

Wherein the variables are as defined above.

The method is

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

Particularly preferred compounds which can be prepared using the process of the invention include:

(2-methyl-pyrrolidin-1-yl)-{6- [2- (l-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

This includes.

Another group of compounds that can be prepared from (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine prepared according to the methods described herein are disclosed in US 2008 / 0027041A1. In particular, the present application discloses compounds of Formula IV and pharmaceutical salts thereof.

In the above formula,

이고, R ¹ is

ego,

X and X ^a are each independently CH or N;

Y is S (O) _q , O or NR ¹⁵ ;

R ² is

이고,

ego,

here,

When both X and X ^a are CH, R ² is meta or para to the Y— (CHR ⁴ ) _m —R ¹ group;

When X or X ^a is N, 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 (= 0) R ²¹ , CO ₂ R ²¹ or C (═O) NR ²³ R ²⁴ ; or

When R ³ is ortho to R ² and R ² is (i), (ii), (iv), (vi) or (ix), then R ³ and R ¹⁴ together are-(CH ₂ ) _s- , May form —CH ₂ Z—, ZCH ₂ —, —ZCH ₂ CH ₂ — or CH ₂ CH ₂ Z—, wherein Z is O, S (O) _y or NR ²⁷ ; or

When R ³ is ortho to R ² and R ² is (iv), (v) or (viii), R ³ and R ¹³ together are — (CH ₂ ) _s —, —CH ₂ Z—, ZCH ₂ -, -ZCH ₂ CH ₂ -or CH ₂ CH ₂ Z- can be formed; or

When R ³ is ortho to R ² and R ² is (viii), R ³ and R ^13b together are (CH ₂ ) _s- , -CH ₂ Z-, ZCH _2- , -ZCH ₂ CH ₂ -or May form CH ₂ CH ₂ Z-; or

을 형성할 수 있고;If R ³ is ortho to X ^a , R ² is ortho to R ³ and meta to X ^a , then R ² and R ³ together

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 said alkyl, cycloalkyl, aryl, Arylalkyl, heteroaryl, or heterocycloalkyl groups are 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 alkoxy, S (═O) _y , C ₁ -C ₆ alkyl, cycloalkyl, heterocycloalkyl 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 linked form a phenyl, thienyl, pyrrolyl, oxazolyl, pyridinyl or C ₃ -C ₆ cycloalkyl ring; Or R ^13b and R ¹⁴ , or R ¹³ and R ^14a , or R ^13b and R ^14a , or R ^13c and R ^14a , together with the carbon atom to which they are linked, form a fused C ₃ -C ₆ cycloalkyl ring; Or R ¹³ and R ^13a , or R ¹⁴ and R ^14a , together with the carbon atom to which they are attached, form a C ₃ -C ₈ cycloalkyl ring; Provided that no more than one pair of 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 Together with the linked carbon atoms or with the carbon atoms to which they are attached form a ring; Wherein the fused phenyl, thienyl, pyrrolyl, oxazolyl, pyridinyl or cycloalkyl ring is optionally substituted with 1 to 3 R ²⁰ groups;

R ¹⁵ is H, C ₁ -C ₆ alkyl, C (═O) R ²⁵ , CO ₂ R ²⁵ ;

R ²⁰ is, at each occurrence, independently C ₁ − optionally substituted with H, F, Cl, Br, I, OR ²¹ , OR ²² , NR ²³ R ²⁴ , NHOH, NO ₂ , CN, CF ₃ , OR ²⁶ . C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₇ cycloalkylC ₀ -C ₄ alkyl, 3- to 7 membered heterocycloalkylC ₀ -C ₄ alkyl, phenyl , 5 or 6 membered heteroarylC ₀ -C ₄ alkyl, arylalkyl, (= O), C (= 0) R ²¹ , CO ₂ R ²¹ , OC (= 0) R ²¹ , C (= 0) NR ²³ R ²⁴ , NR ²⁷ C (= 0) R ²¹ , NR ²⁷ C (= 0) OR ²¹ , OC (= 0) NR ²³ R ²⁴ , NR ²⁷ C (= S) R ²¹ or S (O) _q R ²¹ ego;

Each R ²¹ is independently H, C ₁ -C ₆ alkyl, aryl or arylalkyl;

Each R ²² is independently a residue of an amino acid after removal of the hydroxyl group of the carboxyl group;

Each R ²³ and R ²⁴ is independently selected from H, C ₁ -C ₆ alkyl and aryl, or R ²³ and R ²⁴ together with the nitrogen atom to which they are attached are 3- to 7 optionally substituted with ═O To form a heterocyclic ring;

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;

M is 1, 2, 3, 4 or 5 when R ¹ is attached via a nitrogen atom, and m is 0, 1, 2, 3, 4 or 5 when R ¹ is attached via a carbon atom;

n is 1, 2 or 3;

q is 0, 1 or 2;

s is 1, 2 or 3;

y is 0, 1 or 2.

Specific examples of such compounds that may be prepared using the 2-methylpyrrolidine preparation method of the present invention include:

2-Methyl-6- {4-[(R) -2-methyl-3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazine- 3-one;

6- {3,5-Difluoro-4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2-methyl-2H-pyridazine- 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-pyri Dajin-3-one;

2- (3-methyl-pyridin-2-yl) -5- {4- [3-((R) -2-methylpyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazine 3-one;

6-Methyl-5- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2-pyridin-2-yl-2H-pyridazine- 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-pyridazine 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- Pyridazin-3-ones;

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-pyridazine-3 -On;

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-pyridazine-3 -On;

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] pyridazin-1-ones;

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) -benzo Nitrile;

2- (2-hydroxyethyl) -6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazine-3- On;

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 -Pyridazin-3-one;

5- {4- [3-((R) -2-Methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -3,4-diaza-bicyclo [4.2.0] oct-4 -En-2-one;

4- {4- [3-((R) -2-Methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2,4a, 5,6,7,7a-hexahydro-cyclopenta [d] pyridazin-1-ones;

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-pyridazine 3-one;

6- {3-Fluoro-4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazine- 3-one;

5,5-dimethyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazine 3-one;

6- {4- [3-((R) -2-Methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2-pyridin-2-yl-4,5-dihydro-2H- Pyridazin-3-ones;

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-ones;

5-Methyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazine-3 -On racemates;

5-Methyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazine-3 -On diastereomers;

5-Methyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazine-3 -On diastereomers;

6-{(R) -2-methyl-4- [3- (2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazine-3 -On;

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] pyridine Chopped-7-one;

8- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -5,6-dihydro-2H-benzo [h] cinnolin-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] cinnolin-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- Pyridazin-3-ones;

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] cinnoline-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-pyridazine-3- On;

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-pyridazine-3 -On;

5-methoxy-2-methoxymethyl-4- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazine-3 -On;

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 -En-2-one;

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 -En-2-one single isomer;

5- {4- [3-((R) -2-Methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -3,4-diaza-bicyclo [4.1.0] hept-4 -En-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 stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salts thereof.

Especially 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-pyridazine 3-one;

5- {4- [3-((R) -2-Methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -3,4-diaza-bicyclo [4.1.0] hept-4 -En-2-one;

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 -En-2-one;

5- {4- [3-((R) -2-Methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -3,4-diaza-bicyclo [4.1.0] hept-4 -En-2-one;

5-Methyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazine-3 One diastereomer of one;

5-Methyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazine-3 One diastereomer of one;

5-Methyl-6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -4,5-dihydro-2H-pyridazine-3 -On; And

6- {4- [3-((R) -2-Methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one

Compounds selected from the group consisting of, or stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salts thereof.

Especially preferred of these compounds are 6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one, or a Stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salts. This compound can be prepared from (R) -2-methylpyrrolidine prepared according to the method described above. Scheme 3 provides an exemplary method for preparing 6- {4- [3- ((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one. Illustrated.

According to Scheme 3, in step 1, the mixture of 1- (4-hydroxyphenyl) ethanone and 3-bromo-1-chloropropane in CH ₃ COCH ₃ is heated to 65 ° C. overnight. 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 . Concentrate to dryness in vacuo to afford the product.

The mixture of product from step 1 and glyoxalic acid monohydrate is stirred in 15 mL of acetic acid at 100 ° C. for 2 hours. The solvent is evaporated and water is added to the residue and concentrated aqueous NH ₄ OH is added to pH 8 while cooling to 0 ° C. To this mixture, hydrazine hydrate is added and heated to 100 ° C. for 1 hour. The resulting solid can be filtered and washed with water. The crude material can 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 .

The mixture of product from step 2 in acetonitrile, K ₂ CO ₃ , 100 mg NaI and R-2-methylpyrrolidine hydrochloride 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 , 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 5% MeOH: 95% CH ₂ Cl _{2 in} 2-aminopropane followed by 10% MeOH: 90% CH ₂ Cl ₂ in 2-aminopropane. Purification can yield the product. The free base of the product can be converted to the HCl salt by dissolving in MeOH, adding 0.5 N HCl in EtOH, then evaporating the solvent and crystallizing from MeOH: Et ₂ O.

Thus, one embodiment of the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or (S) -2-methylpyrrolidine D Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

(3a) 1,3- (4-hydroxy-phenyl) -ethanone for a time and under conditions sufficient to form 1- [4- (3-halo-propoxy) -phenyl] -ethanone; Contacting with dihalopropane;

(3b) 1- [4- (3-halo-propoxy) for a time and under conditions sufficient to produce 6- [4- (3-halo-propoxy) -phenyl] -2H-pyridazin-3-one Contacting) -phenyl] -ethanone with glyoxalic acid; And

(3c) corresponding (R)-or (S) -6- {4- [3- (2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazine-3- 6- [4- (3-hal-propoxy) -phenyl] -2H-pyridazin-3-one for (R)-or (S) -2-methylpi for a time and under conditions sufficient to form an on; Contact with lollidine

A compound of formula IV, in particular (R)-or (S) -6- {4- [3- (2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H, comprising To a process for preparing pyridazin-3-one:

<Formula IV>

Wherein the variables are as indicated above.

The method is

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

More generally, the process provides a compound of formula V with (R) or (S) 2-methylpyrrolidine hydrochloride (prepared according to the method), K ₂ CO ₃ and NaI in CH ₃ CN and It can be applied to prepare the compounds described in US 2008 / 0027041A1 by recovering the product.

Further embodiments of the invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or (S) -2-methylpyrrolidine D Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

(3a) converting (R) -2-methylpyrrolidine or (S) -2-methylpyrrolidine to a compound of formula IV

It relates to a process for the preparation of a compound of formula (IV) comprising:

<Formula IV>

Wherein the variables are as indicated above.

This way

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

Exemplary compounds that may be prepared according to this method are: (R)-or (S) -6- {4- [3- (2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-ones include:

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

Additional groups of histamine-3-receptor ligands which can be prepared using (R) or (S) 2-methylpyrrolidine prepared according to the methods described herein are described in WO 2006/059778. These compounds include compounds of formula VI and pharmaceutical salts thereof:

In the above formula,

Y is (R) or (S) 2-methylpyrrolidine;

Each R ¹ is independently a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a lower alkoxy-lower alkyl group or a halo-lower alkoxy-lower alkyl Group;

p 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

의 기를 나타내고, 여기서 A는 하기 화학식 III1 또는 화학식 III2의 화합물을 나타내고, R ² is a chemical formula

Wherein A represents a compound of formula III1 or formula III2,

Wherein R ³ 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 R ⁴ represents a hydrogen atom, a hydroxyl group, a halogen atom, a lower group An alkyl group, halo-lower alkyl group, lower alkoxy group, halo-lower alkoxy group, lower alkoxy-lower alkyl group or halo-lower alkoxy-lower alkyl group;

m represents 0 or 1; n represents 0, 1 or 2;

X ¹ to X ⁴ each independently represent a carbon atom optionally substituted with a lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group or a halogen atom.

Compounds specifically disclosed in this group which may 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

This includes.

This compound provides an intermediate compound of Formula VI wherein Y is Cl, and the compound is selected from (R) or (S) 2-methylpyrrolidine (prepared according to the above method), K in CH ₃ CN. _By reacting with ₂ CO ₃ and NaI and recovering the product, as described above for compounds of US 2008 / 0027041A1.

Thus, another embodiment of the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or (S) -2-methylpyrrolidine D Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

(3a) contacting a compound of Formula VI, wherein Y is Cl, with (R)-or (S) -2-methylpyrrolidine for a time and under conditions sufficient to form the corresponding amide;

It relates to a process for the preparation of a compound of formula (VI) comprising:

<Formula VI>

Wherein the variables are as indicated above.

The method is

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

Another application describing histamine-3-receptor ligands containing a 2-methylpyrrolidine residue is WO 2007/105053. This application describes the preparation of compounds of Formula (VII):

In the above formula,

A is (R) or (S) 2-methyl pyrrolidine;

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 or 6 membered aryl, 5 or 6 membered heteroaryl, hydroxyl, methylene hydroxyl,-(C═O ) NR ⁴ R ⁵ and S (O) _p (C ₁ -C ₄ ) alkyl, wherein p is 1 or 2;

Wherein R ⁴ and R ⁵ are independently hydrogen; (C ₁ -C ₈ ) alkyl optionally 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, (C ₆ -C optionally substituted with 1 or 2 halogens ₁₀ ) (C ₆ -C ₁₀ ) aryl optionally substituted with aryloxy and optionally substituted with halogen, and optionally substituted with 1 to 3 (C ₁ -C ₄ ) alkyl groups, optionally substituted with (C ₆ -C ₁₀ ) aryl groups A (C ₁ -C ₈ ) alkyl group optionally substituted with a substituent selected from the group consisting of 5 to 10 membered heteroaryl; (C ₃ -C ₇ ) cycloalkyl; (C ₆ -C ₁₄ ) aryl; (C ₁ -C ₃₎ alkyl optionally substituted by - (C ₂ -C ₃₎ alkyl, -O- (C ₁ -C ₃₎ alkyl; - (C ₁ -C ₃₎ alkyl, -C (= O) O- (C 1 -C 3) alkyl; 3-8 membered heterocycloalkyl optionally substituted with one or more (C ₁ -C ₄ ) alkylcarbonyl groups; (C ₆ -C ₁₄ ) arylsulfonyl optionally substituted with one or more (C ₁ -C ₂ ) alkyl; 5 to 10 membered heteroaryl; And (C ₆ -C ₁₄ ) aryl- (C ₀ -C ₄ ) alkylene-O- (C ₀ -C ₄ ) alkyl, wherein each (C ₀ -C ₄ ) alkyl and each (C _0- C ₄ ) alkylene is optionally substituted with 1 to 4 (C ₁ -C ₄ ) alkyl; or

Optionally R ⁴ and R ⁵ together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein said heterocycle is separated by up to 2 atoms from said nitrogen in said heterocyclic ring; Carbon of one of the click rings is optionally replaced by O or NR ⁶ , wherein R ⁶ is hydrogen, (C ₁ -C ₃ ) alkyl or -C (═O) (C ₁ -C ₃ ) alkyl; Wherein said heterocyclic ring is optionally substituted with halo, (C ₁ -C ₃ ) alkyl or hydroxyl;

R ⁷ is hydrogen;

Or optionally R ³ and R ⁷ together with two adjacent atoms in the ring comprising Z, Y, Q and X to which they are attached form a five or six membered heterocyclic ring; Wherein the carbon of one of the heterocyclic rings separated by up to two atoms from the nitrogen in the heterocyclic ring is optionally replaced with O or NR ⁸ ; Then R ⁸ is hydrogen or (C ₁ -C ₃ ) alkyl.

Scheme 4 describes a process for the preparation of compounds having a basic structure of formula VII, wherein A, R ³ , Y, Q, Z and X are as defined above. In connection with Scheme 4, compound III is prepared according to the process described above for the bromo-tethalone compound of formula I in a solvent such as CH ₂ Cl ₂ or DCE at −5 ° C. Can be prepared by treatment with R) or (S) 2-methyl pyrrolidine and a suitable reducing agent such as NaHB (OAc) ₃ to give the desired compound of formula III. Other suitable reducing agents for this reaction include NaCNBH ₃ or NaBH ₄ in a solvent such as MeOH or EtOH. Other suitable conditions for this modification include the corresponding tetralin of formula (I) prepared according to the procedure of the invention at room temperature in the presence of 4 ′ molecular sieve and a base such as TEA in CH ₂ Cl ₂ or DCE (R)- Or (S) -2-methylpyrrolidine followed by NaBH ₄ or NaHB (OAc).

Compound III is then subjected to room temperature to about Preferred compounds of formula V can be prepared by treatment with appropriately substituted boronic acids of formula IV at a temperature of 100 ° C., preferably about 90 ° C. Other suitable conditions for this modification include the addition of tetrakis (triphenylphosphine) palladium of compounds of formula III and suitably substituted boronic acids of formula IV at 30 ° C. to 110 ° C., preferably at about reflux temperature, in an ethanol / water mixture. And (0) and treatment with sodium carbonate to produce the corresponding compound of formula (V).

Thus, one embodiment of the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or (S) -2-methylpyrrolidine D Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

(3a) 6-halo-3,4-dihydro-1H-naphthalen-2-one is substituted for (R)-or (S) -2-methylpyrrolidine for a time and under conditions sufficient to form the corresponding amine. Contacting with; And

의 보론산 (여기서, 변수는 상기 기재된 바와 같음)을 접촉시키는 단계(3b) formulating the amide for a time and under conditions sufficient to provide a compound of formula VII;

Contacting boronic acid, wherein the variables are as described above

It relates to a process for the preparation of a compound of formula (VII) comprising:

<Formula VII>

Wherein the variables are as indicated above.

This way

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

Scheme 5 illustrates an alternative process for the preparation of compounds having a basic structure of formula VII, wherein R ³ is CONR ⁴ R ⁵ and Y, Z, Q and X are as defined above. In connection with Scheme 5, coupling of bromide III with a suitable boronic acid reagent of Formula VI may be carried out as described above in Scheme 4 to yield the desired compound of Formula VIII. The corresponding t-butyl ester derivative of formula VIII is treated with trifluoroacetic acid in methylene chloride at room temperature to produce the corresponding carboxylic acid (not shown). Treatment of the carboxylic acid with an amine of formula NHR ⁴ R ⁵ in the presence of suitable coupling reagents such as HOBT and EDCI, and tertiary amines such as triethyl amine can give the preferred compounds of formula IX.

Alternatively, the compound of formula IX is also prepared by treating the carboxylic acid and a suitable amine with 2-chloro-1,3-dimethyl imidazolinium chloride and a suitable base such as diisopropylethyl amine in a solvent such as methylene chloride. Can be.

Another embodiment is

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or (S) -2-methylpyrrolidine D Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

의 화합물 (여기서, 변수는 상기 기재된 바와 같음)을 제공하기에 충분한 시간 동안 및 조건하에 1-(6-할로-1,2,3,4-테트라히드로-나프탈렌-2-일)-(R)-2-메틸-피롤리딘 또는 1-(6-할로-1,2,3,4-테트라히드로-나프탈렌-2-일)-(S)-2-메틸-피롤리딘을 화학식

의 보론산 (여기서, 변수는 상기 기재된 바와 같음)과 접촉시키는 단계; 및(3a) chemical formula

1- (6-halo-1,2,3,4-tetrahydro-naphthalen-2-yl)-(R) for a time and under conditions sufficient to provide a compound of wherein the variables are as described above 2-methyl-pyrrolidine or 1- (6-halo-1,2,3,4-tetrahydro-naphthalen-2-yl)-(S) -2-methyl-pyrrolidine

Contacting with boronic acid, wherein the variables are as described above; And

의 화합물을 아민과 접촉시키는 단계For a time and under conditions sufficient to form a compound of Formula VII

Contacting a compound of with an amine

A process for the preparation of compounds of Formula (VII) comprising:

<Formula VII>

Wherein the variables are as indicated above.

The method is

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

Specific examples of compounds that may be prepared according to this method include:

(S, 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] -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

Included.

The compounds described in WO 2006/066197 can also be readily prepared using the (R)-and (S) 2-methylpyrrolidine synthesis of the present invention. WO 2006/066197 describes compounds of the formulas VIII and IX and pharmaceutical salts thereof, and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof:

In the above formula,

L is -O- and n is 1 or 2; Or L is -C≡C- or -CH ₂ CH _2- , n is 0 or 1;

R ¹ is -H, or is C _{1 - 6} alkyl, C _{3 - 7} cycloalkyl, -COOC _{1 - 6} alkyl or -COO-benzyl, each optionally with one Ra -, or tri-substituted, and;

Wherein Ra is -OH, -OC _{1 - 6} alkyl, -OC _{1 - 4} optionally substituted by alkyl or _{halo-phenyl, -CN, -NO 2, -N (} R b) R c, -C (O) N ( ^{R b) R c, -N (} R b) C (O) R b, -N (R b) SO 2 C 1- 6 alkyl, -C (O) C _{1- 6} alkyl, -S (O) _{0 -2} -C _{1-6 ^{alkyl, -SO 2 N (R b)}} R c, -SCF 3, halo, -CF _3, -OCF _3, -COOH and -COOC _{1 - 6} is selected from alkyl; Wherein, R ^b and R ^c are each independently -H or -C _{1 - 6} alkyl, and;

R ⁴ is -OH, -OC _{1 - 6} alkyl, -CF _3, -C _{1 - 6} alkyl or halo; Two R ⁴ substituents may together form methylene or ethylene;

M is 0, 1 or 2;

R ⁵ is -C _{1 - 6} is selected from the group consisting of alkyl and _{halo-6-alkyl,} -OH, -OC _{1 - - 6} alkyl, -SC _1;

Ar ¹ is

a) optionally mono-, di- or trisubstituted with R ^j , 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 N (} C 1 - 4 alkyl) (CH ₂₎ - in the alkylene-O- _4-yl optionally mono-or di -OC ₁ to Phenyl optionally disubstituted on adjacent carbons by

{Where R ^j is

₁₎ -OH, -C 1 _- to ₆ alkenyl, _{trimethylsilyl-6-alkyl,} optionally substituted with one halo-, di-, or tri-substituted -OC _{1 - 6} alkyl, -C _{2 - 6} alkenyl, -OC ₃ 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 1 ^{, -N (R k) C (} O) R 1, -N (R k) SO 2 C 1- 6 alkyl, -C (O) C _{1- 6} alkyl, -S (O) _0-2 -C _{1 - 6} alkyl, -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

(here,

R ^k and R ^l are each independently -H or -C _{1 - 6} alkyl, and;

R ^m and R ⁿ are each independently -H or -C _{1 - 6} alkyl or, or R ^m and R ⁿ is, together with their attached nitrogen,>O,> S (O ) 0-2,> NH , and > NC _{1 -} to form a _six members with one or two heteroatoms selected from alkyl, zero or one double bond, and 0 or 1 carbonyl of 4 to 8-membered heterocyclic ring having the members);

2) -G-Ar ² , wherein G is a bond, -O- or -S-, and Ar ² is phenyl or 5 or 6 ring atoms,>O,>S,> NH or> N (C _{1 - 4} alkyl) 1 carbon atoms, and a monocyclic aromatic hydrocarbon group having more carbon atoms of more than one substituted with -N =, each optionally substituted with one R ^p -, 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, -SCF 3, _{halo, -CF 3, -OCF 3, -OCHF} 2, -COOH , and -COOC _{1 - 6} alkyl group consisting of Substituents independently selected from;

Wherein, R ^q and R ^r are each independently selected from -H, -C _{1 - 6,} selected from alkenyl) _{- 6} alkyl, and -C _2; And

3)>O,> S ( O) 0-2,> NH , and> NC _{1 - 1} or 2 heteroatoms selected from 0 or 4 to ₆ members, and the alkyl, saturated or part of a circle having the 8 1 carbonyl members Saturated heterocyclic rings, wherein said ring is optionally mono-, di-, or trisubstituted by R ^p ;

Selected from the group consisting of;

b) phenyl or pyridyl fused to a three-membered hydrocarbon residue in two adjacent carbon ring members to form a fused five-membered aromatic ring, wherein the residue is>O,>S,> NH or> N ( C _{1 -} to have a one carbon atom replaced by a _4-alkyl), wherein the moiety has more than one carbon atom of the substituted with -N =, the fused ring is optionally substituted with one R ^t -, two -, or tri substituted; wherein 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, _{halo, -CF 3, -OCF 3, -OCHF} 2, -COOH , and -COOC _{1 - 6} alkyl group consisting of independently represent a substituent selected from; where, R ^u and R ^v are each independently -H or -C _{1 - 6} an alkyl);

c) phenyl fused to a four-membered hydrocarbon residue in two adjacent ring members to form a fused six-membered aromatic ring, wherein the residue has one or two carbon atoms replaced with -N =, The ring is optionally mono-, di-, or trisubstituted with R ^t );

d) naphthyl optionally mono-, di-, or trisubstituted with R ^t ;

e) 5 ring atoms, the attachment point is a carbon atom,>O,>S,> NH or> N (C _{1 - 4} alkyl) one carbon atom, of less than 1 substituted with -N = replaced with Monocyclic aromatic hydrocarbon groups having additional carbon atoms, optionally mono- or di-substituted with R ^j , optionally benzofused or pyrifused at two adjacent carbon atoms, wherein the benzofused or pyridofused Residue is optionally mono-, di-, or trisubstituted with R ^t ); And

f) having 6 ring atoms, carbon atoms at the point of attachment, 1 or 2 carbon atoms replaced with -N =, optionally mono- or di-substituted with R ^j , optionally benzofused at two adjacent carbon atoms Or pyridofused monocyclic aromatic hydrocarbon groups, wherein said benzofused or pyridofused residues are optionally mono- or di-substituted with R ^j ;

It is an aryl or heteroaryl ring selected from the group consisting of.

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

Regarding Scheme 6, reagents of Formulas A1, A2 and A5 are commercially available or prepared according to known methods. 3-5 hydroxybenzaldehyde derivative A1 is reacted with alcohol A2 according to the Williamson ether synthesis protocol to react in a solvent such as acetonitrile with or without a suitable base such as K ₂ CO ₃ , Na ₂ CO ₃ or NaH is used to form ether A3. Alternatively, ethers of formula A3 may be prepared under Mitsunobu conditions, where A2 contains protected hydroxyl instead of bromide substituents. Reductive amination of the aldehyde functional group of compound A3 will provide a compound of formula A4. The aldehyde can be treated with a suitable R ¹ -containing amine with or without the addition of an activator such as an amphoteric or Lewis acid, and with an appropriate reducing agent such as NaBH ₄ , NaCNBH ₃ or NaHB (OAc) ₃ . Preferred conditions include NaBH ₄ in methanol. Alkylation of amine A4 with alpha-haloketone A5 to form ketone A6 is accomplished in a suitable solvent such as THF or DCM in the presence of a tertiary amine base such as TEA or DIPEA. Cyclization to produce tetrahydroisoquinoline A7 can be carried out with a suitable protic or Lewis acid such as methanesulfonic acid (MSA), trifluoroacetic acid (TFA), AlCl ₃ , TiCl _{4 with} or without solvents such as DCM. Or achieving cyclization to the tetrahydroisoquinolinium salt by exposure to BF ₃ * OEt ₂ . Preferred conditions are pure MSA or MSA in DCM. Intermediate salts can be reduced using standard reducing agents such as NaCNBH ₃ in acidic methanol medium. Alternatively, ketones A6 may first be reduced to their corresponding alcohols by known methods, including NaBH ₄ . Treatment of the intermediate alcohol with MSA in DCM gives cyclic species A7. Finally, the suspended primary alcohol group in compound A7 is converted to the corresponding amine A9 by activation to form the appropriate leaving group (such as mesylate or bromide), and then the leaving group is prepared according to the invention (R)-or ( S) -2-methylpyrrolidine. The replacement can be carried out using a suitable base such as Na ₂ CO ₃ , in a polar solvent such as n-BuOH, with or without the catalyst KI or NaI. Alternatively, amine A9 can be prepared through oxidation of the alcohol and reductive amination of the resulting aldehyde.

Thus, one embodiment of the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or (S) -2-methylpyrrolidine D Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

의 화합물 (여기서, 변수는 상기 기재된 바와 같음)을 (R)- 또는 (S)-2-메틸피롤리딘과 접촉시키는 단계(3a) for a time and under conditions sufficient to form a compound of formula VIII or IX

Contacting a compound of (wherein the variables are as described above) with (R)-or (S) -2-methylpyrrolidine

It relates to a process for the preparation of compounds of formula (VIII) and (IX) comprising:

<Formula VIII>

<Formula IX>

Wherein the variables are as indicated above.

The method is

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

Alternatively, the 2-methylpyrrolidine-containing compound can be prepared according to Scheme 7:

With respect to Scheme 7, the ether of formula A3 is first reacted with the corresponding optionally protected amine B1 using (R)-or (S) -2-methylpyrrolidine prepared according to the invention as described in Scheme A. Can be switched. Benzaldehyde B1 can then be modified to diamine B2, wherein Q is (R)-or (S) -2-methylpyrrolidinyl) using a reductive amination protocol as in Scheme A. Alkylation to form ketone B3, and cyclization to produce compounds of Formula A12, are achieved as shown in Scheme 6.

Another embodiment of the invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or (S) -2-methylpyrrolidine D Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

의 화합물 (여기서, 변수는 상기 기재된 바와 같음)을 (R)- 또는 (S)-2-메틸피롤리딘과 접촉시키는 단계;(3a) for a time sufficient and under conditions sufficient to form the corresponding amine

Contacting a compound of wherein the variables are as described above with (R)-or (S) -2-methylpyrrolidine;

(3b) converting the amine to a compound of formula VIII or IX

It relates to a process for the preparation of the compounds of the formulas (VIII) and (IX).

The method is

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

Exemplary compounds that can be prepared using the methods of the invention are 4- (4-methoxy-phenyl) -2-methyl-7- [3- (2-methyl-pyrrolidin-1-yl) -pro Foxy] -1,2,3,4-tetrahydro-isoquinoline.

The process of the invention is also useful in the process for the preparation of compounds of formulas X and XI and their pharmaceutically acceptable salts, as described in WO 06/078775:

In the above formula,

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 , -SR ⁴ or -S (O) _1-2 R ⁵ ;

이거나; 또는 R¹은 R⁶-페닐 또는

이고, R²는 H이거나; 또는 R¹ 및 R²는 R⁶-페닐로 이루어진 군으로부터 독립적으로 선택되고; X는 -O- 또는 -S-이거나;R ¹ is H, R ² is R ⁶ -phenyl or

Or; Or R ¹ is R ⁶ -phenyl or

And R ² is H; Or R ¹ and R ² are independently selected from the group consisting of R ⁶ -phenyl; X is -O- or -S-;

를 형성하고;Or R ¹ and R ² together with the carbon atom to which they are attached,

To form;

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;

R ¹⁵ is H, alkyl, cycloalkyl, —C (O) OR ¹³ , —C (O) NR ¹¹ R ¹² or —C (O) R ¹³ .

Compounds of Formulas (X) and (XI) can be prepared according to Scheme 8 below.

With respect to Scheme 8, compound 1 is reacted with aniline derivative 2 at a temperature sufficient to achieve the reaction, preferably 50 to 150 ° C., in a suitable solvent such as THF or dioxane, preferably dioxane. Get The nitro group of compound 3 uses hydrogen gas in a suitable solvent such as methanol, ethanol, or isopropanol, preferably methanol or ethanol, in the presence of a suitable catalyst such as Pd / C, PtO ₂ , Raney nickel, preferably Raney nickel. To amine 4. Other reduction methods known to those skilled in the art are also suitable.

Suitable solvents for the primary amine of compound 4 under a coupling agent, for example, the presence of DEC, and HOBT, such as ether, THF or CH ₂ Cl _2, preferably CH ₂ Cl ₂ was from acylated by a carboxylic acid and of the reaction of Compound 5 Get Alternatively, the amine can be acylated with acid chloride in the presence of a base. Compound 5 in acetic acid is heated for a time sufficient to achieve cyclization. In step 5, if the protecting group is on group X, it is removed at this point. Suitable protecting groups for X = O, N or S and methods of their removal can be found in Green's Protective Groups in Organic Synthesis. Suitable solvent such as acetone, THF, ether, etc., preferably in acetone, a base, such as Na ₂ CO ₃ or K ₂ CO _3, preferably K ₂ in the presence of CO _3, 0 to a temperature of 65 ℃ Compound 6 Is reacted with α, ω-dihaloalkan at to yield compound 7, wherein Y is halo.

A solution of compound 7 in a suitable solvent such as CH ₃ CN, THF, ether and the like, preferably CH ₃ CN, is treated with a tertiary amine base such as Et ₃ N, DIPEA and the like, preferably DIPEA and then Treatment with (R)-or (S) -2-methylpyrrolidine prepared accordingly. The reaction is then heated at a temperature of 0-100 ° C. to yield compound 8.

Alternatively, Scheme 9 can be followed.

With respect to Scheme 9, compound 9 known in the literature can be prepared in a suitable solvent such as acetone, THF, ether, etc., preferably in acetone, with a base such as Na ₂ CO ₃ or K ₂ CO ₃ , preferably K ₂ CO _In the presence of ₃ , compound 10 is obtained by reacting with α, ω-dihaloalkane at a temperature of 0 to 65 ° C. A solution of compound 10 in a suitable solvent such as CH ₃ CN, THF, ether and the like, preferably CH ₃ CN, is treated with a tertiary amine base such as Et ₃ N, DIPEA and the like, preferably DIPEA, and then Treatment with (R)-or (S) -2-methylpyrrolidine prepared accordingly. The reaction is then heated at a temperature of 0-100 ° C. to yield compound 11.

Alternatively, the compound may be prepared according to the following Scheme 10.

Under in conjunction with Scheme 10, a suitable solvent, the compound 12, such as acetone, THF, ether and the like, the presence of preferably in acetone, a base, such as Na ₂ CO ₃ or K ₂ CO _3, preferably K ₂ CO _3, Treatment with α, ω-dihaloalkane at a temperature between 0 and 65 ° C. yields compound 13, wherein Y is halo. A solution of compound 13 in a suitable solvent such as CH ₃ CN, THF, ether and the like, preferably CH ₃ CN, is treated with a tertiary amine base such as Et3N, DIPEA and the like, preferably DIPEA and then prepared according to the invention. Treated with (R)-or (S) -2-methylpyrrolidine. The reaction is then heated at a temperature of 0-100 ° C. to give compound 14. The nitro group of compound 14 is prepared using H ₂ gas in the presence of a suitable catalyst such as Pd / C, PtO ₂ or Raney nickel, preferably Raney nickel in a suitable solvent such as methanol, ethanol or isopropanol, preferably methanol or ethanol. Reduced to amine 15. Other reduction methods known to those skilled in the art are also suitable.

Still with respect to Scheme 10, compound 15 is reacted with compound 16 at a temperature sufficient to achieve the reaction, preferably 50-150 ° C., in a suitable solvent such as THF or dioxane, preferably dioxane. Get The nitro group of compound 17 is reduced to amine followed by reduction to compound 18. Amine 18 in a suitable solvent such as THF, ether and the like is thiocarbonyldiimidazole (Q = S) or 1,1'-carbonyldiimidazole ( Q = O) to give compound 19.

A solution of compound 19 in a suitable solvent, such as DMSO, DMF, etc., is prepared at a temperature of 0-100 ° C., preferably 25-75 ° C., such as a base such as K ₂ CO ₃ , and an alkylating agent R ⁴ L where L is Cl, Br Or I, or mesylate or sulfonate) to afford compound 20.

Thus, one embodiment of the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or (S) -2-methylpyrrolidine D Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

(3a) converting (R)-or (S) -2-methylpyrrolidine to a compound of formula VIII or IX

It relates to a process for the preparation of compounds of formulas (X) and (XI) comprising:

<Formula X>

(XI)

Wherein the variables are as indicated above.

The method is

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

According to the process of the invention, the compound is also a compound of formulas XII and XIII as described in WO 2007/099423, or a pharmaceutically acceptable salt thereof:

In the above formula,

R ³ is optionally substituted with up to three fluorine atoms, (C _{1 -6)} - alkyl, aryl or heteroaryl;

R ⁴ is hydrogen, halogen, (C _{1 -6)} - alkyl or (C _{3 -7)} - cycloalkyl, (C _{1 -6)} - alkoxyl or (C _3-7) - cycloalkyl alkoxyl (no more than three Optionally substituted with a fluorine atom), aryl, heteroaryl;

R ⁵ is (CR ⁶ R ⁹ ) _m- (CR ¹⁰ R ¹¹ ) _p -B, wherein R ⁶ , R ⁹ , R ¹⁰ and R ¹¹ are 3-10 membered mono- or bi-alky together with the carbon to which they are attached; -Form a cyclic ring system;

B is selected from N, O, S (e.g., azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazine or 1-4 diazepines) or NR ¹² R ¹³ 4-7 membered heterocycloalkyl containing up to 3 hetero atoms;

^{R 8, R 9, R 10} , R 11, R 12 and R ¹³ is hydrogen, C _{1 -6} alkyl, (C _{1 -6} alkyl) -aryl, (C _{1 -6} alkyl) - independently selected from heteroaryl Or;

R ¹² and R ¹³ together with the nitrogen to which they are attached form a 3 to 10 membered mono- or bicyclic ring system (e.g., 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;

p is 0-3.

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

In connection with Scheme 11, the ketone of Formula II, wherein the hydroxyl (—OH) group is unprotected) is reacted with (R)-or (S) -2-methylpyrrolidine prepared according to the present invention To produce amino-phenol. Such modifications may be accomplished using one or more methods and procedures that may be useful to those skilled in the art. For example, the ketones of formula II and 2-methylpyrrolidine may be combined 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 Water can be removed to form intermediate imine. Alternatively, compound II and 2-methylpi in a solvent such as toluene in the presence of a catalytic amount of para-toluenesulfonic acid, with preparation for removing water using a Dean-Stark trap or activated molecular sieves. Refluxing the solution of lollidine may also be used to effectively produce intermediate imines. This imine can then be converted to amino-phenol intermediate III in situ or in a separate step after its isolation. It is used in reaction inert solvents such as dichloromethane, methanol, THF or dioxane, for example, boron reagents such as sodium borohydride (NaBH ₄ ), sodium cyanoborohydride (NaBH ₃ CN), sodium triacetoxyboro It can be achieved by reducing C = N double bonds using hydrides and the like. Alternatively, the imine can be reacted with a catalyst inert solvent using, for example, hydrogen gas (H ₂ ) and a suitable metal catalyst such as Raney nickel (RaNi), palladium on carbon (Pd / C) or similar catalyst. Such as in methanol or ethanol and at a temperature of about 20 ° C. to the boiling point of the solvent used and hydrogen gas at a pressure of about 1 to 5 atm. Other related examples of modifications can be found in the literature.

In connection with Scheme 11, the phenolic OH group is present in the intermediate of formula III, as shown in path b, the formula III in the presence of a base and a reaction inert solvent in the reagent R ⁵ -A (wherein, R ⁵ is As defined above, A is halogen (eg, Cl, Br, I), mesylate (ie, -OSO ₂ CH ₃ or -OMs) or tosylate (ie, -OSO ₂ C ₆ H ₅ or- OTs), including leaving groups) to convert into ether products of formula (I). Suitable bases will include sodium carbonate, potassium carbonate or cesium carbonate (s), sodium bicarbonate or potassium bicarbonate (s), sodium or potassium tert-butoxide (s), sodium or potassium hydride (s), and the like. desirable. Suitable solvents will include DMF, DMSO, DMA, THF, and the like, with DMSO being preferred.

Thus, one embodiment of the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or (S) -2-methylpyrrolidine D Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

의 화합물을 (R)- 또는 (S)-2-메틸피롤리딘과 접촉시키는 단계; 및(3a) a formula for a time and under conditions sufficient to form the corresponding amine phenol;

Contacting a compound of with (R)-or (S) -2-methylpyrrolidine; And

(3b) contacting the amine phenol with an alcohol for a time and under conditions sufficient to provide a compound of formula XII or XIII

It relates to a process for the preparation of compounds of formula (XII) and (XIII) comprising:

<Formula XII>

<Formula XIII>

Wherein the variables are as indicated above.

The method is

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

Compounds of formulas (XII) and (XIII) of the present invention may also be prepared via the routes shown in Scheme 12 below.

With regard to Scheme 12, the phenolic ketones of formula (II) can be converted to ethers (path c.) By methods generally known to those skilled in the art. For example, phenol II is reacted with a reagent of formula R ⁵ -A in the presence of a base as described for route b in Scheme 1 to produce a ketone of formula IV. Alternatively, the ketone of Formula VII, wherein L ¹ is a suitable leaving group (ie, F, -OMs, etc.) is reacted with a reagent of Formula R ⁵ -OH in the presence of a suitable base and in an inert solvent to Generate intermediates (path e.). The ketone IV thus prepared can then be converted to the desired product of formula (I) using reductive amination conditions as already described in Scheme 11 (route d.). In some circumstances, also a solvent, for example, by using a reducing agent such as NaBH ₄ in methanol to first convert the intermediate ketone IV to the corresponding benzyl alcohols of formula (V) and (path f.), Followed by activation of benzyl alcohol V (path g. ) An intermediate of formula VI, wherein L ² produces a leaving group (eg OMs, OTs, Cl), and finally leaving group w prepared according to steps (a) to (e) above ( R)-or (S) -2-methylpyrrolidine (with or without any of steps (f)-(h)) and (R) -2-methylpyrrolidine L-tart The rate is reacted with base to give (R) -2-methylpyrrolidine, or (S) -2-methylpyrrolidine D-tartrate is reacted with base to give (S) -2-methylpyrrolidine It may be advantageous to provide (path h.).

Thus, another embodiment of the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or (S) -2-methylpyrrolidine D Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

의 화합물을 형성하기에 충분한 시간 동안 및 조건하에 화학식

의 화합물을 화학식 R⁵-LG의 화합물 (여기서, LG는 이탈기임)과 접촉시키는 단계; 및(3a) chemical formula

For a time and under conditions sufficient to form a compound of

Contacting a compound of with a compound of Formula R ⁵ -LG wherein LG is a leaving group; And

의 화합물을 (R)- 또는 (S)-2-메틸피롤리딘과 접촉시키는 단계(3b) for a time and under conditions sufficient to form a compound of formula XII or XIII

Contacting a compound of (R)-or (S) -2-methylpyrrolidine

It relates to a process for the preparation of compounds of formula (XII) and (XIII) comprising:

<Formula XII>

<Formula XIII>

Wherein the variables are as indicated above.

The method is

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

Exemplary compounds that can be prepared using the methods of the invention are 1- {3- [1- (2-methyl-pyrrolidin-1-yl) -indan-5-yloxy] -propyl} azane .

The process of the invention is also suitable for preparing compounds such as the compounds described in WO 2007/094962, for example compounds of the formulas XIV and XV, and pharmaceutically acceptable salts thereof.

In the above formula,

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, containing from 1 to 3 heteroatoms selected from S heterocycloalkyl, and (C _{1 -5)} alkyl, -O- (C _{1 -5)} alkyl selected from 0 to 2 group;

R ₄ and R ₆ is (C _{1 -8)} alkyl, (C _{1 -8)} alkoxy, (C _{3 -7)} cycloalkyl, (C _{3 -7)} cycloalkyl - (C _{1 -6)} alkyl, O, S, a heterocycloalkyl containing 1 to 3 heteroatoms selected from N Al Kiel, (C _{1 -5)} alkyl, -O- (C _{1 -5)} alkyl, an amide, (C _{1 -5)} alkyl-aryl, and CF Independently selected from ₃ ;

R ₅ is hydrogen, (C _{1 -8)} alkyl, aryl, (C _{1 -5)} alkyl, -O- (C _{1 -5)} alkyl and (C _{1 -5)} alkyl, - or selected from the group consisting of aryl,

or

R ₅ and R ₄ and the atoms to which they are attached are fused 5 or 6 membered saturated carbocyclic rings or fused 10 member bi-cyclic ring systems,

를 형성하거나,for example

Form a

R ₅ and R ₆ and the atoms to which they are attached are fused 5 or 6 membered saturated carbocyclic rings or fused 10 member bi-cyclic ring systems,

를 형성하거나,for example

Form a

or

R ₅ and R ₄ and the atoms to which they are attached are fused 5 or 6 membered saturated carbocyclic rings to which 6 membered aromatic rings are fused,

을 형성하거나,for example

Or

or

R ₅ and R ₆ and the atoms to which they are attached are fused 5 or 6 membered saturated carbocyclic rings to which a 6 membered aromatic ring is fused,

를 형성하거나,for example

Form a

or

R ₅ and R ₆ and the atoms to which they are attached are fused benzothiophene or fused benzofuran ring system,

를 형성하며,for example

Form the

Wherein X is NR ₇ and R ₇ and R _{2 together} with — (CH ₂ CH ₂ ) — form a ring containing two nitrogens, where y is 0 (piperazine) or y is 1 (homo Piperazine), wherein R ₁ is as defined above.

The compounds described above having 2-methylpyrrolidine groups can be prepared according to the following schemes. (R)-or (S) -2-methylpyrrolidine prepared according to the invention can be used in the following scheme by reacting with 1,3-dichloropropane under conditions known in the art. To produce (S) -1- (3-chloro-propyl) -2-methyl-pyrrolidine.

Thus, another embodiment of the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or (S) -2-methylpyrrolidine D Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

(3a) (R)-or (S) -2-methylpyrrolidine to 1- (3-halo-propyl)-(R) -2-methyl-pyrrolidine or 1- (3-halo-propyl) Converting to-(S) -2-methyl-pyrrolidine; And

(3b) 1- (3-halo-propyl)-(R) -2-methyl-pyrrolidine or 1- (3-halo-propyl)-(S) -2-methyl-pyrrolidine is represented by Formula XII or Converting to a compound of XIII

It relates to a process for the preparation of compounds of formulas XIV and XV comprising:

<Formula XIV>

<Formula XV>

Wherein the variables are as indicated above

The method is

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

Exemplary compounds that can be prepared according to the methods of the 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-1 H-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-cyclo Penta [a] inden

This includes.

Additional compounds that may benefit from the process for the preparation of 2-methylpyrrolidine as described herein include the compounds of Formulas XVI and XVII and pharmaceutically acceptable salts thereof described in WO 2007/048595:

In the above formula,

A ¹ is CH or C-halogen;

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 of, 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-alkyl-aminocarbonyl,} C _{1 -6-alkyl-acylamino,} acyl amino, C _1-6 - alkyl ureido, C _{1 -6} - alkyl carbamate, C _{1 -6} - alkylamino, C _{3 -8} - cycloalkyl, amino, hydroxy, C _{1 -6} alkyl, hydroxy, halogen Or cyano;

R ^2b is hydrogen, halogen, C _{1 -8} - alkyl or C _{3 -8} cycloalkyl alkyl;

Or is R ^2a and R ^2b are linked together to form C _{3 -8} cycloalkyl, heterocycloalkyl groups, or oxo in the 3 to 8;

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} - alkyl aryl or unsubstituted C _{1 -8} alkyl;

n is an integer of 0, 1 or 2;

t is an integer of 2, 3 or 4;

w is an integer of 2, 3 or 4;

v is an integer of 0 or 1;

m is an integer of 0 or 1;

z is an integer of 0, 1, 2 or 3.

Similar compounds, such as those described in WO 2006/103045, the entirety of which is incorporated herein 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 below:

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

This reaction is carried out in a solvent (such as dioxane, tetrahydrofuran, dimethylformamide or toluene), in the presence of a base (such as potassium phosphate or sodium tert-butylate), at a temperature of 25 ° C. to 120 ° C. and under an inert atmosphere ( Argon or nitrogen) ligands 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 (e.g. glycine), or a catalyst such as copper iodide or palladium acetate have. Alternatively, the reaction is described in Klapars A. et al. in J. Am. Chem. Soc. 2002, 124, 7421].

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

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

Thus, one embodiment of the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidin free base, or (S) -2-methylpyrrolidine D- Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

의 화합물 (여기서, Y1은

임)을 (R)- 또는 (S)-2-메틸피롤리딘과 접촉시키는 단계(3a) a formula for a time and under conditions sufficient to form a compound of formula XVI

Of compounds (where Y1 is

(R)-or (S) -2-methylpyrrolidine

It relates to a process for the preparation of compounds of the formulas XVI and XVII, including.

<Formula XVI>

<Formula XVII>

Wherein the variables are as indicated above.

The method is

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

Alternatively, Scheme 22 can be performed wherein 2-methylpyrrolidinalkoxy is carried out in steps (a) to (e) (with or without any of steps (f) to (h)). Prepared from (R)-or (S) -2-methylpyrrolidine and reacted with (R) -2-methylpyrrolidine L-tartrate with a base to (R) -2-methylpyrroli A Dean is obtained or (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 by Penning et al. in J. Med. Chem. 2000, 43, 721, in the presence of a base such as potassium tert-butylate, cesium carbonate or sodium hydride, in a solvent such as dimethylformamide or tetrahydrofuran, to provide a catalyst based on palladium- or copper May be performed in the presence.

Thus, another embodiment of the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base, or (S) -2-methylpyrrolidine D Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

(3a) converting (R)-or (S) -2-methylpyrrolidine to the corresponding 2-methylpyrrolidinylalkyl-OH;

의 화합물 (여기서, Y¹은

임)을 (R)- 또는 (S)-2-메틸피롤리디닐알킬-OH와 접촉시키는 단계(3a) a formula for a time and under conditions sufficient to form a compound of formula XVI

Of compounds wherein Y ¹ is

Contacting (R)-or (S) -2-methylpyrrolidinylalkyl-OH

Including a process for the preparation of compounds of formulas XVI and XVII, comprising:

<Formula XVI>

<Formula XVII>

Wherein the variables are as indicated above.

The method is

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

Exemplary compounds that can be prepared according to the present invention include:

1- [3- (4- {4-[(2-methylpyrrolidin-1-yl) methyl] -1,3-oxazol-2-yl} phenoxy) propyl piperidine;

2-[(2- {4- [3- (2-methylpyrrolidin-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] -2-azaspiro [5.5] Cannes;

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) propyl] piperidine;

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] -1,3-oxazol-2-yl} phenoxy) propyl] piperazine ;

N, N-dimethyl-1- [4- (4- {4-[(2-methylpyrrolidin-1-yl) methyl] -1,3-oxazol-2-yl} phenoxy) butyl] py Rollidin-3-amine;

1- [2- (4- {4-[(2-methylpyrrolidin-1-yl) methyl] -1,3-oxazol-2-yl} phenoxy) ethyl] -4- (2-py Rollidin-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) azepan;

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] azane;

1- [2- (4- {4-[(2-methylpyrrolidin-1-yl) methyl} -1,3-oxazol-2-yl} phenoxy) ethyl] azane;

N- (1,3-dimethylbutyl) -N-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazole-4- One) 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-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-thiazole- 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) methyllpiperazine ;

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] pipe Razin;

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] piperi Dean;

1-[(4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyll-1,3-oxazol-5-yl) carbonyl] piperi Dean;

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-carr Acid;

N- (cyclopropylmethyl) -2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] -phenyl} -N-propyl-1,3-oxazole-4-carbox amides;

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) carr 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] carr Carbonyl} morpholine;

4-{[4-methyl-2- (4- {3-[(2S) -2-methylpyrrolidin-1-yl] propoxy} phenyl) -1,3-oxazol-5-yl] carr 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-oxazole-5 -Yl) methyl] -N-propylamine;

N-benzyl-N-[(4-methyl-2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -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- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] piperi Dean;

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- (Pyrrolidin-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] phenyll-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] deca Hydroisoquinoline;

2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -4-{[(2S) -2- (pyrrolidin-1-ylmethyl) pyrrolidine- 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] azane;

(5S) -1-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl) -1,3-oxazol-4-yl) methyl] -5- (Morpholin-4-ylmethyl) pyrrolidin-2-one;

2-methyl-N-[(2- {4- [3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] -2H- Tetraazol-5-amine;

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 ] Pyrrolidin-2-yl} methyl) morpholine;

1-[(2- {2-fluoro-4- {3- (2-methylpyrrolidin-1-yl) propoxy] phenyl} -1,3-oxazol-4-yl) methyl] piperi Dean;

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) carr 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-thiazole-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] carr 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] pyrrolidine 2-on

This includes.

Compounds of formulas (XVIII) and (XIX) and pharmaceutically acceptable salts thereof, as described in WO 2008/005338, may also be more readily prepared using the process of the invention:

In the above formula,

R ¹ and R ² are each H, C _{1 -6} acyl, C _{1 -8} alkyl, C _{2 -8} alkenyl, C _{2 -8} alkynyl, C _{3 -7-cycloalkyl,} aryl, heterocyclyl, heteroaryl, , aryl, -C _{1 -4} - independently from the group consisting of alkylenyl-alkylenyl, aryloxy -C _{1 -4-alkylenyl,} heteroaryl, -C _{1 -4-alkylenyl,} and heteroaryloxy -C _{1 -4} selected, and each of R ¹ and R ² are 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, amides, C _{2 -8} alkynyl, C _{1 -8} alkyl sulfonamide, C _1-8 alkylsulfinyl, C _{1 - 8} alkylsulfonyl, C _{1 -8} alkylthio, C _{1 - 8} alkyl urea, amino, aryl, C _{1 - 8} alkylamino, C _{2 - 8} dialkylamino, carbonyl -C _{1 -6} - alkoxy, carboxamide, carboxy, cyano, C _{3 - 7} cycloalkyl, C _{2 -8} dialkyl carboxamide, C _{2 -8} dialkyl sulfonamide, halogen, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, C _{1 - 6} haloalkyl sulfinyl, C _{1 - 6} haloalkylsulfonyl, C _{1 - 6} haloalkylthio, heterocyclyl, hydroxyl, and optionally substituted with thiol, nitro and sulfonamide 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of; Wherein each C _{1 -8} alkyl may be further substituted by a hydroxyl chamber;

J is -CH ₂ CH ₂ - or a 1,2-C _{3 -7} - cycloalkyl alkylenyl group, and each C _{1 -3} alkyl, C _{1 - 4} alkoxy, carboxy, cyano, C _{1 -3} haloalkyl, Optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, hydroxyl and oxo;

^{R 3, R 4, R 5} , R 6, R 7, R 10, R 11 and R ¹² is H, C _{1 -6} acyl, C _{1 -6} acyloxy, C _{2 -8} alkenyl, respectively, 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-alkyl} sulfinyl, C _{1 - 8} alkylsulfonyl, C _1-8 alkylthio, C _1-8 alkyl, urea, amino, C _1-8 alkylamino, C _{2 - 8} dialkylamino, carbonyl -C _{1 -6} - alkoxy, carboxamide, carboxy, cyano, C _{3 -7-cycloalkyl,} C _{2 -8} dialkyl carboxamide, C _{2 -8} dialkyl sulfonamide, halogen, C _{1 -6} haloalkoxy, C _{1 -6} haloalkyl, C _{1 -6} haloalkylsulfinyl , C _{1 -6} haloalkylsulfonyl, C _{1 -6} haloalkylthio, hydroxyl, thiol, are independently selected from the group consisting of nitro and sulfonamide;

R ⁸ and R ⁹ is H, C _{1 respectively 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} - are independently selected from the group consisting of alkyl, alkylenyl, each R ⁸ and R ⁹ is C _{1 - 6} acyl, C _{1 - 6} acyl, C _{2 - 8} alkenyl, C _{1 - 6} alkoxy, C _{1 - 8} alkyl, C _{1 - 8} alkyl-carboxamide, C _{2 - 8} alkynyl carbonyl, C _{1 - 8} alkyl sulfonamide, C _{1 - 8} alkylsulfinyl, C _{1 - 8} alkylsulfonyl, C _{1 - 8} alkylthio, C _{1 - 8} alkyl urea, amino, C _{1 - 8} alkylamino, C _{2 - 8} dialkylamino, carbonyl -C _{1 -6} - alkoxy, carboxamide, carboxy, cyano, C _{3 - 7} cycloalkyl, C _{2 - 8} dialkylamino carboxamide, C _{2 - 8} dialkylamino sulfonamide, halogen, C _{1 - 6} haloalkoxy, C _{1 - 6} haloalkyl, C _{1 - 6} haloalkyl sulfinyl, C _{1 - 6} Roal kilsul sulfonyl, C _{1 -} is optionally substituted with ₆ haloalkylthio, hydroxyl, thiol, nitro, and independently selected from the group consisting of sulfonamide, 2, 3, 4, or 5 substituents.

The process for preparing (R) and (S) 2-methylpyrrolidine of the present invention can be used to more easily prepare the above-mentioned compounds. (R)-or (S) -2-methylpyrrolidine can be prepared according to the present invention, wherein (R) -2-methylpyrrolidine L-tartrate is reacted with a base to (R) -2- Methylpyrrolidine is obtained and (S) -2-methylpyrrolidine D-tartrate is reacted with a base to give (S) -2-methylpyrrolidine. The scheme below demonstrates the use of 2-methylpyrrolidine thus prepared.

In the formula, LG ^1, LG ^2, X and Y are each a leaving group, for each independently, for example, or the like halogen, triflate, R ¹⁵ is C _{1 - 8} is alkyl.

In the formula, LG ^1, LG ^2, X and Y are each a leaving group, for each independently, for example, or the like halogen, triflate, R ¹⁵ is C _{1 - 8} is alkyl.

In said formula, X is a leaving group, for example, a halogen, a triflate, etc.

In said formula, X is a leaving group, for example, a halogen, a triflate, etc.

In the above formula, LG ³ is a leaving group such as sulfonate, triflate, halogen and the like, and Z is halogen.

In the above formula, LG ³ is a leaving group such as sulfonate, triflate, halogen and the like, and Z is halogen.

Thus, another embodiment of the present invention

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst;

(1b) optionally removing a hydrogenation catalyst from the mixture;

(1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution;

(1d) crystallizing (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate from the solution;

(1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate or (S) -2-methylpyrrolidine D-tartrate; And

(2a) contacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidin free base, or (S) -2-methylpyrrolidine D- Contacting tartrate with a base to form (S) -2-methylpyrrolidine;

(3a) converting (R)-or (S) -2-methylpyrrolidine to a compound of formula XVIII or XIX

Including a method for preparing a compound of the formula XVIII and XIX comprising:

<Formula XVIII>

<Formula XIX>

Wherein the variables are as indicated above.

The method is

(1f) recrystallization of 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 repeating steps (f) and (g)

It may optionally further include.

Exemplary compounds that can be prepared according to the methods of the 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-ethoxyethyl) -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 '-(pyrrolidine-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 cyclobutylamide;

4 '-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid tert-butylamide;

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-propylbutyl) -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 '-(Aziridine-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-methoxyethyl) -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-dichlorobenzylamide;

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-dichlorobenzylamide;

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-fluorophenyl) -ethyl] -amide;

4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid (tetrahydropyran-4-ylmethyl) -amide;

Propionic acid 1- {4 '-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonyl} -piperidin-4-yl methyl 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-2H-benzo [b] [1,4, 5] oxythiazepine 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-2Hbenzo [b] [1,4,5] oxathiazepine 1,1-dioxide;

4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl] -sulfonic acid (2-hydroxyethyl) -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-oxoimidazolidin-1-yl) -ethyl] -amide ;

4 '-[2- (2-Methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonic acid [3- (2-oxopyrrolidin-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) -propane-1- On;

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-sulfonylamino} -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;

Propionic acid 2-methyl-2- {4 '-[2- (2-methyl-pyrrolidin-1-yl) -ethyl] -biphenyl-4-sulfonylamino} -propyl ester;

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

This includes.

Method and protocol

Gas Chromatography ( GC (R) -2- by Methylpyrrolidine  Chiral Purity Measurement

Column Chiraldex B-DA, 30 m × 0.25 mm, 0.25 μm df (mfr: Astec-Advanced Separation Technologies, Inc.) or equivalent

Injection temperature 150 ℃

Split ratio 40: 1

Carrier gas He, constant pressure 8 psi

Injection volume 2 μl

FID at 250 ° C detection

Flow rate hydrogen 30 ml / min

                        Air 400 ml / min

Preparation Gas Helium 30 ml / min

110 ℃ isothermal for oven program 25 minutes

Sample Preparation Trifluoroacetic anhydride (200 μl) was added to the sample (10 mg) in dichloromethane (1 mL). The reaction was carried out at 60 ° C. for 15 minutes. The solvent was slowly removed under nitrogen stream and dichloromethane (1 mL) was added to the residue.

The division between system suitability enantiomers should be ≧ 1.2.

Retention time (R) -2-methylpyrrolidine = 11 minutes

                        (S) -2-methylpyrrolidine = 11.5 min

Example 1

Synthesis of (R) -2-methylpyrrolidine L-tartrate with 5% Pt-C

Hydrogenation of 2-methylpyrroline (2.50 g, 30.12 mmol) at 55 psi in a mixture of 5% Pt-C (250 mg, catalyst), anhydrous ethanol (62 mL) and methanol (26 mL) for 16 hours at ambient temperature I was. Gas chromatography analysis showed a 93.7% conversion from starting material to product. The mixture was filtered through Celite® (4 g) and the filtrate was put together with L-tartaric acid (3.80 g, 25.32 mmol) into a 250 mL single-neck round bottom flask with a stir bar. The mixture was heated to 25 ° C. until a solution was obtained. Certain (R) -2-methylpyrrolidine L-tartrate (10.0 mg) was added as seed crystals 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 chromatography analysis showed 55% ee, 93% overall purity.

Example 2

Synthesis of (R) -2-methylpyrrolidine L-tartrate with Pt (IV) Oxide

Hydrogenation of 2-methylpyrroline (2.50 g, 30.12 mmol) at 55 psi in a mixture of platinum (IV) oxide (250 mg, catalyst), anhydrous ethanol (62 mL) and methanol (26 mL) for 5 hours at ambient temperature I was. Gas chromatography analysis showed a 98.3% conversion from starting material to product. The mixture was filtered through Celite® (4 g) and the filtrate was put together with L-tartaric acid (3.80 g, 25.32 mmol) into a 250 mL single-neck round bottom flask with a stir bar. The mixture was heated to 25 ° C. until a solution was obtained. Certain (R) -2-methylpyrrolidine L-tartrate (100.0 mg) was added as seed crystals 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 off, 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 chromatography analysis showed 49.2% ee, 75% overall purity.

Example 3

Recrystallization of (R) -2-methylpyrrolidine L-tartrate

General Recrystallization Procedure: A portion (2.71 g) of the compound obtained in Example 1 was placed in a 100 mL single-neck round bottom flask with a stir bar with anhydrous ethanol (38 mL) and methanol (16 mL). The mixture was heated to 60 ° C. to form a solution and then cooled to ambient temperature. Certain (R) -2-methylpyrrolidine L-tartrate (2.50 mg) was added as seed crystals and the mixture was stirred at ambient temperature for 16 hours and then at 0 ° C. (ice bath) for 2 hours. The solid was filtered and dried at 60 ° C. in a vacuum oven with nitrogen stream for 1 hour at 29 in.Hg to give (R) -2-methylpyrrolidine L-tartrate (1.80 g, 66.4% recovery) It was. Chiral gas chromatography analysis showed 84.9% ee, 93% overall purity.

The obtained solid (1.79 g) was further partitioned according to a general recrystallization procedure using 25 mL of anhydrous ethanol and 11 mL of methanol to give (R) -2-methylpyrrolidine L-tartrate (1.70 g, 95.5% recovery). Obtained. Chiral gas chromatography analysis showed 93.4% ee, 97% overall purity.

The obtained solid (1.69 g) was further divided according to a general recrystallization procedure using 24 mL of anhydrous ethanol and 10 mL of methanol to obtain (R) -2-methylpyrrolidine L-tartrate (1.58 g, 93.5% recovery). Obtained. Chiral gas chromatography analysis showed 96.7% ee, 98% overall purity.

The obtained solid (1.57 g) was further partitioned according to the general recrystallization procedure using 22.5 mL of anhydrous ethanol and 9.5 mL of methanol except that seeding was not performed, and the obtained crystals were dried for 4 hours (R). 2-methylpyrrolidine L-tartrate (1.49 g, 94.9% recovery, 6.334 mmol, 21.0% overall yield from 2-methylpyrroline) was obtained. Chiral gas chromatography analysis showed 98.4% ee, 99% overall purity.

As will be appreciated by those skilled in the art, many modifications and variations of the invention are possible in the above teachings. Accordingly, in view of the appended claims, the invention may be practiced otherwise than as specifically described herein, and the scope of the invention is intended to include such modifications.

Claims (22)

(a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (b) optionally removing a hydrogenation catalyst from said mixture; (c) dissolving L-tartaric acid in the mixture to form a solution; (d) crystallizing (R) -2-methylpyrrolidine L-tartrate from the solution; And (e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate A method for producing (R) -2-methylpyrrolidine L-tartrate comprising a. The process of claim 1 wherein the hydrogenation catalyst is a platinum catalyst. The process of claim 2 wherein the platinum catalyst is 5% Pt-C. The process of claim 2 wherein the platinum catalyst is platinum (IV) oxide. The process according to any of claims 1 to 4, wherein the alcohol solvent is a mixture of ethanol and methanol. 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 process according to claim 1, wherein step (a) is carried out at ambient temperature. The process according to claim 2, wherein the platinum catalyst is removed by filtration in step (b). The method of any one of claims 1 to 8, wherein the optical purity of the isolated (R) -2-methylpyrrolidine L-tartrate is at least 50% ee. The method according to any one of claims 1 to 9, (f) recrystallizing the isolated (R) -2-methylpyrrolidine L-tartrate; (g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate; And (h) optionally repeating steps (f) and (g) How to include more. The method of claim 10, further comprising reacting the isolated recrystallized (R) -2-methylpyrrolidine L-tartrate with a base to provide (R) -2-methylpyrrolidine. 10. The method of claim 1, further comprising converting the prepared (R) -2-methylpyrrolidine L-tartrate into an H ₃ receptor ligand. 11. 12. The method of claim 10 or 11, further comprising 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 ligand is 6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H -Pyridazin-3-one.

(1a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (1b) optionally removing a hydrogenation catalyst from the mixture; (1c) dissolving L-tartaric acid in the mixture to form a solution; (1d) crystallizing (R) -2-methylpyrrolidine L-tartrate from the solution; (1e) isolating crystalline (R) -2-methylpyrrolidine L-tartrate; And (2) reacting (R) -2-methylpyrrolidine L-tartrate with a base to form (R) -2-methylpyrrolidine free base; And (3) sufficient time to form (R) -6- {4- [3- (2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one Reacting (R) -2-methylpyrrolidin with 6- [4- (3-halo-propoxy) -phenyl] -2H-pyridazin-3-one during and under conditions A process for producing 6- {4- [3-((R) -2-methyl-pyrrolidin-1-yl) -propoxy] -phenyl} -2H-pyridazin-3-one comprising a.

The compound of claim 15, wherein 6- [4- (3-halo-propoxy) -phenyl] -2H-pyridazin-3-one is substituted. (a) 1,3- (4-hydroxy-phenyl) -ethanone for a time and under conditions sufficient to form 1- [4- (3-halo-propoxy) -phenyl] -ethanone; Contacting with dihalopropane; And (b) 1- [4- (3-halo-propoxy) for a time and under conditions sufficient to produce 6- [4- (3-halo-propoxy) -phenyl] -2H-pyridazin-3-one. Contacting) -phenyl] -ethanone with glyoxalic acid Prepared by. The method of claim 15, (f) recrystallizing the isolated (R) -2-methylpyrrolidine L-tartrate; (g) isolating recrystallized (R) -2-methylpyrrolidine L-tartrate; And (h) optionally repeating steps (f) and (g) How to include more. (a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (b) optionally removing a hydrogenation catalyst from said mixture; (c) dissolving D-tartaric acid in the mixture to form a solution; (d) crystallizing (S) -2-methylpyrrolidine D-tartrate from the solution; And (e) isolating crystalline (S) -2-methylpyrrolidine D-tartrate A method for producing (S) -2-methylpyrrolidine D-tartrate comprising a. The method of claim 18, wherein the hydrogenation catalyst is a platinum catalyst. The method of claim 19, wherein the platinum catalyst is 5% Pt-C. The method of claim 20, wherein the platinum catalyst is platinum (IV) oxide. 22. The method of any one of claims 18 to 21, wherein the alcohol solvent is a mixture of ethanol and methanol.