EA019031B1 - Process for preparing 6-{4-[3-((r)-2-methylpyrrolidine-1-yl)propoxy]phenyl}-2h-piridazin-3-one and pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention provides a short, safe, inexpensive, commercially scalable process for preparing (R)- or (S)-2-methylpyrrolidine, in particular 6-{4-[3-((R)-2-methyl-pyrrolidin-l-yl)-propoxy]-phenyl}- 2H-pyridazin-3 -one or a pharmaceutically acceptable salt thereof comprising the steps of: (Ia) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (Ib) optionally removing the hydrogenation catalyst from the mixture; (Ic) dissolving L-tartaric acid in the mixture to form a solution; (Id) crystallizing (R)-2-methylpyrrolidine L-tartrate from the solution; (Ie) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate; and (2) reacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2- methylpyrrolidine free base; and (3) reacting the (R)-2-methylpyrrolidine with 6-[4-(3-halo-propoxy)-phenyl]- 2H-pyridazin-3-one for a time and under conditions sufficient to form (R)-6-{4-[3-(2- methyl-pyrrolidin-1-yl)-propoxy] -phenyl } -2H-pyridazin-3 –one. The process further comprising the steps of: (f) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate; (g) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate; and (h) optionally repeating steps (f) and (g). The process does not require the isolation of synthetic intermediates.

Description

(K) - and (8) -2-methylpyrrolidines are the starting materials used in the synthesis of various pharmaceutical products. For example, (K) -2-methylpyrrolidine can be used to produce many H ₃ receptor ligands. For this reason, there is great interest in the development of inexpensive methods for producing (K) - and (8) -2-methylpyrrolidines. However, previously developed methods either use expensive starting materials, or many tedious synthetic steps are necessary for their implementation.

Ree et al. (Ogd. Proc. Kez. & Νον., 2005, 9, 45-50) describe the preparation of L-tartrate (K) -2 methylpyrrolidine based on fractional crystallization of racemic 2-methylpyrrolidine in the presence of L-tartaric acid. The cost of racemic 2-methylpyrrolidine is approximately 20 υδΌ per gram.

Wapye Kiy et al. (Kes1. Thau. Opt. Rauz-Waz, 1994, 113, 267-277) describe four (4) stepwise synthesis of L-tartrate (K) -2-methylpyrrolidine and Ό-tartrate (8) - 2-methylpyrrolidine from 2-methylpyrrolin (approximate cost $ 5 / gram). However, the method is disadvantageous for a number of reasons. Firstly, the process requires the preparation of three intermediates, two of which should be isolated. In addition, the method requires the separation of an intermediate salt of HC1 by removing in a vacuum glacial acetic acid and an excess of 37% aqueous hydrochloric (hydrochloric) acid, which is a time-consuming, expensive and corrosive process. Moreover, this synthesis requires isolation of the intermediate by two successive flash distillations from potassium hydroxide.

Key et al. (Te1gayeygop, 2006, 62, 4584-4589) describe four (4) stepwise synthesis of (K) -2-methylpyrrolidine hydrochloride from Ν-Boc-L-prolinol. The method is disadvantageous for a number of reasons. First, the process requires the preparation and isolation of three different synthetic intermediates. Secondly, the method uses an environmentally harmful solvent dichloromethane, as well as corrosive gaseous hydrochloric acid and phosphoric acid. Thirdly, the method uses expensive lithium iodide (approximate cost 13 $ / gram). In addition, the resulting hydrochloride salt is very hygroscopic.

Ζ1ι; · ιο et al. (1. Ogd. Siesh .. 2006, 71, 4336-4338) describe four (4) stepwise synthesis of benzenesulfonate (K) -2-methylpyrrolidine from S-Boc-L-proline. The method is disadvantageous for a number of reasons. First, the process requires the preparation and isolation of three (3) individual synthetic intermediates. Secondly, the method uses corrosive reagents such as phosphoric acid, boron trifluoride etherate, sodium hydroxide, sodium borohydride and Super-Hydride® (8regNuypie®).

There is a need for a process for the preparation of (K) - and (8) -2-methylpyrrolidines, which would be short-lived, safe, inexpensive, commercially large-scale, and which could be carried out without the need for isolation of many synthetic intermediates.

Summary of the invention

The authors of this application unexpectedly found that 6- {4- [3 - ((K) -2-methylpyrrolidin-1yl) propoxy] phenyl} -2H-pyridazin-3-one can be obtained in two stages from inexpensive 2methylpyrroline using non-corrosive reagents without the need for isolation of any synthetic intermediates. The present invention relates to a method for producing 6 {4- [3 - ((K) -2-methylpyrrolidin-1-yl) propoxy] phenyl} -2H-pyridazin-3-one

m including stages:

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

(lb) optionally removing the hydrogenation catalyst from the mixture;

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

(1) crystallization of L-tartrate (K) -2-methylpyrrolidine from solution;

(1e) isolation of crystalline b-tartrate of (K) -2-methylpyrrolidine;

(2) the interaction of (T) -2-methylpyrrolidine L-tartrate with a base to form the free base of (K) -2-methylpyrrolidine; and (3) the interaction of (K) -2-methylpyrrolidine with 6- [4- (3-halogenpropoxy) phenyl] -2H-pyridazin-3one for a period of time and under conditions sufficient to form (K) -6- {4- [3- (2

- 1 019031 methylpyrrolidin-1-yl) propoxy] phenyl} -2H-pyridazin-3-one.

Preferably 6- [4- (3-halogenopropoxy) phenyl] -2H-pyridazin-3-one is prepared using the following steps:

(a) contacting 1- (4-hydroxyphenyl) ethanone with 1,3-dihalogenopropane for a period of time and under conditions sufficient to form 1- [4- (3-halogenpropoxy) phenyl] ethanone; and (b) contacting 1- [ 4- (3-halo-propoxy) phenyl] ethanone with glyoxalic acid for a period of time and under conditions sufficient to obtain 6- [4- (3-halo-propoxy) phenyl] -2N-pyridazin-3-one.

Preferably, the hydrogenation catalyst is a platinum catalyst. Preferably, the platinum catalyst is platinum (IV) oxide. More preferably, the platinum catalyst is 5% P1-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 from 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 isolated (B) -2-methylpyrrolidine L-tartrate has an optical purity of at least 50%.

Optionally, the method further includes the steps of:

(I) recrystallization of the isolated (B) -2-methylpyrrolidine Ό-tartrate;

(e) isolation of the recrystallized В-tartrate of (B) -2-methylpyrrolidine; and (II) optionally repeating steps (I) and (e).

DETAILED DESCRIPTION OF THE INVENTION Definitions

The expression approximately refers to a range of values ± 10% of a certain value; for example, an expression of about 50 includes ± 10% of 50 or 45 to 55.

The term alcoholic solvent refers to a _C1-C6 alkyl alcohol or a mixture of _C1-C6 alkyl alcohols.

The term industrial scale refers to a single serving of at least 500 g.

The term crystallization refers to a process causing the formation of crystals.

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

The term heterogeneous catalyst refers to a hydrogenation catalyst that is insoluble in an alcohol solvent.

The term “homogeneous catalyst” refers to a hydrogenation catalyst that is soluble in an alcohol solvent.

The term hydrogenation catalyst refers to a composition suitable for catalysis of the reaction of 2 methylpyrroline with hydrogen to form 2-methylpyrrolidine.

The term “isolation” refers to the separation of a component (eg, reagent or product) from a mixture.

The term optical purity refers to the fraction of one enantiomer in a mixture of enantiomers, and is expressed as an enantiomeric excess (% of it), which is defined as (| K.-8 | / (K + 8)) x 100%, where B and 8 are corresponding fractions of enantiomers, so K + 8 = 1.

The term pharmaceutical product refers to a compound or composition that can be used to treat a disease, disease state or disorder in humans.

The term platinum catalyst refers to a hydrogenation catalyst that contains platinum.

The term purification refers to increasing the purity of a compound.

The term purity refers to percent by weight of one component in a mixture.

The term solution refers to a solvent containing a substance (a) that is at least partially dissolved in it; and which may contain undissolved (e.g., solid) substance (a).

All publications mentioned in this application are incorporated by reference in their entirety for all purposes.

Description

The present invention relates to a method for producing (B) -6- {4- [3- (2-methylpyrrolidin-1yl) propoxy] phenyl} -2H-pyridazin-3-one, comprising the steps of:

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

(lb) optionally removing the hydrogenation catalyst from the mixture;

- 2 019031 (1c) dissolving L-tartaric acid in a mixture to form a solution;

(16) crystallization of (B) -2-methylpyrrolidine L-tartrate from solution; and (1e) isolation of (B) -2-methylpyrrolidine crystalline L-tartrate, (2) interaction of (B) -2-methylpyrrolidine L-tartrate with base with the formation of the free base of (B) -2-methylpyrrolidine; and (3) the interaction of (B) -2-methylpyrrolidine with 6- [4- (3-halogenopropoxy) phenyl] -2H-pyridazin-3one for a period of time and under conditions sufficient to form (B) -6- {4 - [3- (2methylpyrrolidin-1-yl) propoxy] phenyl} -2H-pyridazin-3-one.

Stage (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 obtained from commercial sources (for example, 8fta-A1bps11 Cogr .; 81. Bosch, MO). An important advantage of this method is that 2-methylpyrrolin is less expensive than other starting materials used to produce (B) - and (8) -2-methylpyrrolidine.

The hydrogenation catalyst used in the reaction can be obtained from commercial sources (for example, 8shta-A1bps11 Cogr .; 81. Loy, 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, carbon platinum (P1 / C), platinum (IV) oxide, and mixtures thereof. Examples of homogeneous catalysts include, but are not limited to, chlorotris (triphenylphosphine) rhodium (Wilkinson catalyst) and the catalysts described in US Patent 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% P1-C.

The alcohol solvent used in the reaction, represents a _C1-C6 alkyl alcohol or a mixture of _C1-C6 alkyl alcohols. Examples of _C1-C6 alkyl alcohols include, but are not limited to, methanol, ethanol, isopropanol and n-butanol. Preferably, the alcohol solvent includes ethanol. Preferably, the alcoholic 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 from 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 from 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 from about 2: 1 to about 3: 1 (v / v). More preferably, the alcohol solvent is a mixture of ethanol and methanol in a ratio of about 2.4: 1 (v / v).

The alcohol solvent may be present in any suitable amount in the reaction mixture in step (a). Preferably, the alcoholic solvent comprises at least about 50% (w / w) of the reaction mixture. More preferably, the alcoholic solvent comprises at least about 70% (w / w) of the reaction mixture. More preferably, the alcoholic solvent comprises at least about 90% (w / w) of the reaction mixture. More preferably, the alcoholic solvent comprises at least about 95% (w / w) of the reaction mixture. Remarkably, C ₁ -C ₆ alkyl alcohols are more easily removed from the reaction mixture as compared to acetic acid. Furthermore, _C1-C6 alkyl alcohols are not corrosive.

Hydrogen (H ₂ ) used in the hydrogenation reaction can be added to the reaction mixture in the form of a gas, as, for example, when carrying out the reaction in a hydrogen atmosphere, or it can be obtained ίη kyi, as, for example, during the treatment of Н ₂ Р1С1 ₆ or Ш1С '1 ₃ using NaBN ₄ (see ΒΐΌ \ νη ap6 81ua8apkatap, 1. At. C11st. 8os. 1962, 84, 2828). In some embodiments, the hydrogenation reaction is carried out by adding hydrogen gas to the reaction mixture. In preferred embodiments, the hydrogenation is carried out at a pressure above atmospheric. In some embodiments, the reaction is carried out upon receipt of the hydrogen ίη δίΐιι.

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

An advantage of the present process is that the hydrogenation reaction is carried out in a non-corrosive alcohol solvent. Another advantage of the present process is that the hydrogenation reaction product (i.e., 2-methylpyrrolidine) is prepared directly without the need for the preparation or isolation of intermediates, such as intermediates.

Stage (b).

Stage (b) is an optional stage. In step (b), the hydrogenation catalyst is removed from the hydrogenation reaction mixture. Preferably, the hydrogenation catalyst is removed from the hydrogenation reaction mixture after step (a). Preferably, step (b) is carried out before step (6), in particular when the hydrogenation catalyst is a heterogeneous catalyst. Suitable methods for removing the hydrogenation catalyst include, but are not limited to, filtration, decantation, and centrifugation. In some

- 3 019031 embodiments, the hydrogenation catalyst is removed by filtration. Although the base of the hydrogenation catalysts is usually precious metals, an advantage of the present invention is that the hydrogenation catalyst can be removed from the mixture, recycled, and reused in subsequent hydrogenation reactions (see, for example, U.S. Patent 5,554,353 (8cbnl e !. a1); EP 1739104 A1 (KoauakY e a1); 8eyu-R1stap, etc., Ca 1 MO1 !. A:.... Siete, 1999, 144 (1), 159-163.

Stage (s).

In step (c), b-tartaric acid is dissolved in the reaction mixture obtained by hydrogenation to form a solution. If the desired product is (K) -2-methylpyrrolidine, then L-tartaric acid is used. L-tartaric acid used in the present process can be obtained from commercial sources (for example, 8fta-A1bps11 Comp.; 81. Lb. MO).

Preferably, the solution obtained in step (e) is homogeneous. If the solution is not homogeneous (for example, contains undissolved particles), the solution is preferably heated to facilitate dissolution.

An advantage of the present method is that it does not require isolation of the 2-methylpyrrolidine obtained from the hydrogenation reaction from the reaction mixture before adding tartaric acid. This makes the method simpler, faster, less expensive and less wasteful than the methods previously known in the art.

Stage (b).

In step (b), (K) -2-methylpyrrolidine L-tartrate is crystallized from the solution obtained in step (c). If b-tartaric acid is added in step (c), then the b-tartrate of (K) -2-methylpyrrolidine is crystallized from the solution in step (b). Any suitable method can be used to crystallize L-tartrate (K) -2-methylpyrrolidine from solution. In some embodiments, the solution is heated to facilitate dissolution, and then cooled to cause crystallization.

Stage (e).

In step (e), crystalline L-tartrate (K) -2-methylpyrrolidine is isolated. If tartaric acid is added in step (c), then (K) -2-methylpyrrolidine b-tartrate is crystallized from the solution in step (b) and isolated in step (e). Suitable methods for isolating crystalline L-tartrate (K) -2-methylpyrrolidine include, but are not limited to, filtration, decantation and centrifugation. An advantage of the present method is that the product can be isolated by simple filtration. Preferably, L-tartrate (K) -2 methylpyrrolidine is isolated by filtration. It should be understood that the isolated L-tartrate (K) -2 methylpyrrolidine probably contains some L-tartrate (8) -2-methylpyrrolidine, which will reduce the optical purity of the isolated product. Preferably, the isolated L-tartrate of (K) -2-methylpyrrolidine has an optical purity of at least 40%. More preferably, the isolated L-tartrate (K.) - 2-methylpyrrolidine is of optical purity having at least 50% of it. More preferably, the isolated L-tartrate (K.) - 2-methylpyrrolidine has an optical purity of at least 55%.

Optional additional stages

The present method for producing L-tartrate (K) -2-methylpyrrolidine is advantageous because it uses inexpensive and non-corrosive reagents and solvents, it can be conveniently and inexpensively carried out at temperatures ranging from 0 and 25 ° C, it is necessary to obtain only one intermediate compound, it does not require the isolation of intermediate synthesis compounds, recycling of the catalyst is permissible, and it leads to a product that can be isolated by simple filtration and then used in subsequent sp persons.

The isolated product is an addition salt of tartaric acid and the free base of (K) -2-methylpyrrolidine. If desired, the salt can be converted to the free base of (K) 2-methylpyrrolidine. The resulting free base can be isolated using methods known in the art. Preferably, the free base can form ίη δίΐιι and be used in the next synthetic step without isolation. The methods described in this invention can be used both for the isolated free base of 2-methylpyrrolidine and for the free base of 2-methylpyrrolidine obtained by ίη δίΐιι in the reaction mixture.

Thus, in some embodiments, the method further comprises the step of reacting the isolated b-tartrate of (K) -2-methylpyrrolidine with a base to produce (K) -2methylpyrrolidine. Suitable bases for use in this reaction include, but are not limited to, ammonium hydroxide, alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkyl amines (e.g. triethylamine, diisopropylethylamine), and mixtures thereof. Suitable solvents for use in this reaction include, but are not limited to, diethyl ether and dichloromethane. In addition, the free base of 2-methylpyrrolidine can be obtained from the corresponding tartaric acid salt using an ion exchange resin by methods known in the art.

Preferably, the obtained (K) -2-methylpyrrolidine L-tartrate, (K) -2-methylpyrrolidine has

- 4 019031 optical purity of at least 50% of it. This means that the main enantiomer is 75% of the mixture, and the minor enantiomer is 25% (50% = ((0.75-0.25) / (0.75 + 0.25) x100%). This purity level is often is sufficient to use the product as a reagent in a subsequent synthetic process.For example, when L-tartrate (K) -2-methylpyrrolidine, having an optical purity of 50%, is used to obtain a compound having an additional stereogenic center (s) (s), the reaction will result in a mixture of diastereomers, and the minor (s) diastereomer (s) formed from (8) -2-methylpyrrolidine, can be removed during routine purification of the main (s) diastereomer (s) formed from (K) -2-methylpyrrolidine.

If a higher level of optical purity is desired, the obtained L-tartrate (K) -2 methylpyrrolidine can be recrystallized. Accordingly, in some embodiments, the method may further include the steps of:

(I) recrystallization of the isolated b-tartrate of (K) -2-methylpyrrolidine;

(e) isolation of recrystallized b-tartrate of (K) -2-methylpyrrolidine; and (II) optionally repeating steps (1) and (e).

Stage (ί).

At stage (ί), the recrystallization of L-tartrate (K) -2-methylpyrrolidine isolated in stage (e) is carried out. Suitable methods for recrystallizing the recovered L-tartrate (K) -2-methylpyrrolidine include, but are not limited to, dissolving the recovered tartaric acid salt in a suitable solvent and then cooling the solution to cause crystallization. Suitable solvents for recrystallization include, but are not limited to, alcoholic solvents. Preferably, the recrystallization solvent is an alcoholic 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 from 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 from 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 from about 1: 1 to about 5: 1 (v / v). More preferably, the recrystallization solvent is an alcohol solvent comprising at least about 90% (vol./about.) Ethanol and methanol in a ratio of from about 1: 1 to about 2: 1 to about 3: 1 (vol./about. )

Stage (d).

At stage (e), recrystallized L-tartrate (K) -2-methylpyrrolidine is isolated. Suitable methods for isolating the recrystallized tartaric acid salt include, but are not limited to, filtration, decantation and centrifugation. Preferably, recrystallized L-tartrate (K) -2-methylpyrrolidine is isolated by filtration.

Exposure of the tartaric acid salt isolated in step (e) to one recrystallization sequence in accordance with steps (ί) and (e) preferably provides isolated (K) -2-methylpyrrolidine L-tartrate having an optical purity of at least 80% her. More preferably, L-tartrate (K) -2-methylpyrrolidine isolated in step (e) has an optical purity of at least 85%. An optical purity of 85% of it means that the main enantiomer is more than 92% of the mixture, and the minor enantiomer is less than 8% (84% of it = ((0.9250.075) / (0.925 + 0.075) x100%), which is often It is of sufficient purity for use in subsequent synthetic methods.

Stage (1).

If a higher optical purity is desired, the recrystallization sequence (i.e., steps (ί) and (e)) can be repeated one or more times to increase the optical purity of L-tartrate (K) -2-methylpyrrolidine. After two recrystallizations, the (K) -2-methylpyrrolidine L-tartrate preferably has an optical purity of at least 90%. More preferably, the recrystallized (K) -2-methylpyrrolidine L-tartrate recovered has an optical purity of at least 93%. After three (3) recrystallizations, L-tartrate (K) -2-methylpyrrolidine preferably has an optical purity of at least 95%. More preferably, the recrystallized (K) -2-methylpyrrolidine L-tartrate recovered has an optical purity of at least 97%. After four (4) recrystallizations, the (K) -2-methylpyrrolidine L-tartrate preferably has an optical purity of at least 98%.

Free base

Optionally, the method may further include the step of reacting the selected trans

- 5 019031 crystallized L-tartrate of (B) -2-methylpyrrolidine with a base to obtain (B) -2 methylpyrrolidine. Suitable bases for use in this reaction include, but are not limited to, ammonium hydroxide, alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkylamines (e.g. triethylamine, diisopropylethylamine) and mixtures thereof. Suitable solvents for use in this reaction include, but are not limited to, diethyl ether and dichloromethane. In addition, the free base of 2-methylpyrrolidine can be obtained from the corresponding tartaric acid salt using an ion exchange resin by methods known in the art.

The resulting free base can be isolated using methods known in the art. Preferably, the free base can be obtained ίπ δίΐιι and used in the next synthetic step without isolation. The methods described in this application are applicable for both the isolated free base of 2-methylpyrrolidine and the free base of 2-methylpyrrolidine obtained by ίπ δίΐιι in the reaction mixture.

Additional connections

In addition to the development of convenient methods for the preparation of (B) -2-methylpyrrolidine and its corresponding tartaric acid salt, the present invention also relates to methods for introducing 2-methylpyrrolidine into other compounds, in particular to pharmaceutically useful compounds. (B) -2-methylpyrrolidine b-tartrate obtained after steps (e), (e) or (s) can be used. In some embodiments, the initial conversion step may be to transform the salt form of the (B) -2-methylpyrrolidine L-tartrate to the form of the corresponding free base (i.e. (B) -2 methylpyrrolidine) by reacting with a base or ion exchange resin. This (B) -2 methylpyrrolidine, either isolated or obtained ίπ δίΐπ. can then be used to produce a number of pharmaceutical compounds, for example, histamine-3 receptor ligands known in the art.

This compound can be obtained from (B) -2-methylpyrrolidine obtained in accordance with the above methods. Scheme 3 shows an illustrative process for the preparation of 6- {4- [3 - ((B) -2methylpyrrolidin-1-yl) propoxy] phenyl} -2H-pyridazin-3-one.

Scheme 3 about

In accordance with Scheme 3, in step 1, a mixture of 1- (4-hydroxyphenyl) ethanone and 3-bromo-1-chloropropane in CH ₃ COCH _{3 is} heated at 65 ° C. overnight. The mixture is filtered, washed with acetone and concentrated to dryness. The crude product is dissolved in CH ₂ Cl ₂ and washed with a saturated solution of αHCO ₃ , solution No. 1 Cl and dried over No. 1 ₂ 8O ₄ . Concentration to dryness in a vacuum results in a product.

A mixture of the product from step 1 and glyoxalic acid monohydrate was stirred in 15 ml of acetic acid at 100 ° C for 2 hours. The solvent was evaporated, water was added to the residue and cooled to 0 ° C, while adding concentrated aqueous ΝΗ ₄ ΟΗ to pH 8. Hydrazine hydrate was added to this mixture and heated at 100 ° C for 1 h. The resulting solid could be filtered and washed with water. The crude material can be dissolved in a mixture of CH ₂ Cl ₂ / MeOH and purified by column chromatography using CH ₂ Cl ₂ to 10% MeOH in CH ₂ Cl ₂ .

A mixture of the product from step 2, K ₂ CO ₃ , 100 mg Να1 and B-2-methylpyrrolidine hydrochloride in acetonitrile is heated at 80 ° C for 2 days. The reaction mixture was then filtered, washed with CH2C12 and concentrated. The residue was dissolved in CH ₂ Cl ₂ and washed with saturated NaΗCΟ ₃ solution, saturated No. C1, dried over No. 1 ₂ 8O ₄ and concentrated. The residue can be purified by 18CO gradient chromatography using from 100% CH ₂ Cl ₂ to a mixture of 5% MeOH: 95% CH ₂ Cl ₂ in 2-aminopropane and then a mixture of 10% MeOH: 90% CH ₂ Cl ₂ in 2-aminopropane, receiving the product. The free base of the product can be converted to the HCl salt by dissolving in MeOH and adding 0.5 n HCl to E1OH, followed by evaporation of the solvent and crystallization from a mixture of MeOH: E1 ₂ O.

The above methodology can be adapted to obtain the compounds described in application for US patent 2008/0027041 A1.

Methods of obtaining (B) 2-methylpyrrolidine of the present invention can be used to more easily obtain the above compounds. (B) -2-methylpyrrolidine can be obtained in accordance with the present invention and the interaction of the b-tartrate of (B) -2-methylpyrrolidine with a base to obtain (B) -2-methylpyrrolidine.

- 6 019031

Examples

Methodology and Protocols

Determination of chiral purity (K) -2-methylpyrrolidine by gas chromatography (GC)

Column СЫга14ех Β-ϋΑ, 30 mx 0.25 mm, diameter 0.25 μm (manufacturer: Azbes - Aschapsece Zerahyop Tesenpoleus, 1 ps.) Or equivalent Injector temperature 150 ° C Degree of cleavage 40: 1 Carrier gas Not, constant pressure 8 ft / sq. Inch Injected volume 2 μl Detection ΕΊϋ at 250’s Flow Hydrogen at 30 ml / min Air at 400 ml / min Injection gas Helium at 30 ml Heater program 110 ° isothermal for 25 minutes Sample preparation Add trifluoroacetic anhydride (200 μl) to the sample (10 mg) in dichloromethane (1 ml). Interaction at 60 ° C for 15 minutes. Remove the solvent under a gentle stream of nitrogen and add dichloromethane (1 ml) to the residue. System suitability Separation between enantiomers should be > 1.2

Retention Times: (K) -2-methylpyrrolidine = 11 minutes (3) -2-methylpyrrolidine = 11.5 minutes

Example 1. Synthesis of L-tartrate (K) -2-methylpyrrolidine using 5% P1-C

2-Methylpyrroline (2.50 g, 30.12 mmol) was hydrogenated at 55 psi at ambient temperature for 16 hours in a mixture of 5% P1-C (250 mg, catalytic amount), absolute ethanol (62 ml) and methanol (26 ml). Analysis by gas chromatography showed 93.7% conversion of the starting material to the product. The mixture was filtered through CcShc® (4 g) and the filtrate was placed in a 250 ml single-neck round-bottom flask with stirrer together with L-tartaric acid (3.80 g, 25.32 mmol). The mixture was heated to 25 ° C. until a solution formed. Authentic L-tartrate (K) -2 methylpyrrolidine (10.0 mg) was added as germ crystals to initiate crystallization, and the mixture was stirred at ambient temperature for 16 hours. The mixture was cooled to 0 ° C. using an ice bath and further stirred for 12 hours. The solids were filtered off and then dried in air for 1 hour to obtain L-tartrate (K.) - 2 methylpyrrolidine (3.55 g, 15.09 mmol, 50.1%). Analysis by chiral gas chromatography showed 55% of it and an overall purity of 93%.

Example 2. Synthesis of L-tartrate (K) -2-methylpyrrolidine using oxide Ρΐ (ΐν)

2-Methylpyrrole (2.50 g, 30.12 mmol) was hydrogenated at 55 psi at ambient temperature for 5 hours in a mixture of platinum (IV) oxide (250 m, catalytic amount), absolute ethanol (62 ml) and methanol (26 ml). Analysis by gas chromatography showed 98.3% conversion of the starting material to the product. The mixture was filtered through CcShc® (4 g) and the filtrate was placed in a 250 ml single-neck round-bottom flask with stirrer together with L-tartaric acid (3.80 g, 25.32 mmol). The mixture was heated to 25 ° C. until a solution formed. Authentic L-tartrate (K) -2-methylpyrrolidine (100.0 mg) was added as germ crystals to initiate crystallization, and the mixture was stirred at 25 ° C. for 8 hours. The mixture was allowed to cool to ambient temperature and stirred for an additional 16 h. The mixture was cooled to 0 ° C. using an ice bath and stirred for an additional 2 hours. The solids were filtered off, washed with methanol (5 ml) and then dried in air for 1 hour to obtain L-tartrate (K) -2-methylpyrrolidine ( 2.85 g, 12.12 mmol, 40.3%). Analysis by chiral gas chromatography showed 49.2% of it and an overall purity of 75%.

Example 3. Recrystallization of L-tartrate (K) -2-methylpyrrolidine

General recrystallization method:

A portion of the product obtained in Example 1 (2.71 g) was placed in a 100 ml one-neck round-bottom flask with a stirrer together with absolute ethanol (38 ml) and methanol (16 ml). Heat mixture

- 7 019031 Wali to 60 ° C with the formation of a solution and then left to cool to ambient temperature. Authentic L-tartrate (K) -2-methylpyrrolidine (2.50 mg) was added as seed crystals to initiate crystallization and the mixture was stirred at ambient temperature for 16 hours and then at 0 ° C (ice bath) for 2 more hours. The solids were filtered and dried at 60 ° C in a vacuum oven in a stream of nitrogen at 29 inches of mercury. within 1 h to obtain L tartrate (K) -2-methylpyrrolidine (1.80 g, 66.4% isolation). Analysis by chiral gas chromatography showed 84.9% of it and an overall purity of 93%.

The resulting solids (1.79 g) were further dissolved in accordance with the general recrystallization method using 25 ml of absolute ethanol and 11 ml of methanol to obtain L-tartrate (K) -2-methylpyrrolidine (1.70 g, 95.5% selection). Analysis by chiral gas chromatography showed 93.4% of it and an overall purity of 97%.

The resulting solids (1.69 g) were further dissolved according to the general recrystallization method using 24 ml of absolute ethanol and 10 ml of methanol to obtain L-tartrate (K) -2-methylpyrrolidine (1.58 g, 93.5% selection). Analysis by chiral gas chromatography showed 96.7% of it and an overall purity of 98%.

The resulting solids (1.57 g) were further dissolved in accordance with the general recrystallization method using 22.5 ml of absolute ethanol and 9.5 ml of methanol, except that the introduction of germ crystals was not carried out, and the obtained crystals were dried for 4 h, obtaining L-tartrate (K) -2-methylpyrrolidine (1.49 g, 94.9% isolation, 6.334 mmol, 21.0% based on 2-methylpyrroline). Analysis by chiral gas chromatography showed 98.4% of it and an overall purity of 99%.

As will be appreciated by those skilled in the art in light of the above indications, numerous modifications and variations of the present invention are possible. Therefore, it should be understood that within the scope of the appended claims, the invention may be practiced in a different way than is specifically described in this application, and it is intended that the scope of the invention covers all such variations.

Claims (8)

CLAIM 1. The method of obtaining 6- {4- [3 - ((K) -2-methylpyrrolidin-1-yl) propoxy] phenyl} -2H-pyridazin-3-one or its pharmaceutically acceptable salt, comprising the steps of: (la) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (lb) optionally removing the hydrogenation catalyst from the mixture; (lc) dissolving L-tartaric acid in the mixture to form a solution; (16) crystallizing L-tartrate (K) -2-methylpyrrolidine from solution; (1e) isolating crystalline L-tartrate of (K) -2-methylpyrrolidine and (2) reacting L-tartrate of (K) -2-methylpyrrolidine with a base to form the free base of (K) -2-methylpyrrolidine; and (3) reacting (K) -2-methylpyrrolidine with 6- [4- (3-halogenopropoxy) phenyl] -2H-pyridazin-3one for a time and under conditions sufficient to form (K) -6- {4- [3- (2-methylpyrrolidin-1yl) propoxy] phenyl} -2H-pyridazin-3-one. 2. The method according to claim 1, further comprising the step of converting the product from step (3) into a salt HC1. 3. The method according to claim 1 or 2, where 6- [4- (3-halogenopropoxy) phenyl] -2H-pyridazin-3-one is obtained by stages, including: (a) contacting 1- (4-hydroxyphenyl) ethanone with 1,3-dihalo-propane for a time and under conditions sufficient to form 1- [4- (3-halo-propoxy) phenyl] ethanone; and (b) contacting 1- [4- (3-halo-propoxy) phenyl] ethanone with glyoxalic acid for a time and under conditions sufficient to obtain 6- [4- (3-halo-propoxy) phenyl] -2H-pyridazin-3- she. 4. The method according to claim 1 or 2, further comprising the steps of: (I) recrystallizing the isolated b-tartrate of (K) -2-methylpyrrolidine; (e) isolating the recrystallized L-tartrate of (K) -2-methylpyrrolidine; and (II) optionally repeating steps (1) and (e). 5. The method according to claim 4, where the selected b-tartrate (K) -2-methylpyrrolidine has an optical purity of at least 50% e.i. - 8 019031 6. The method according to claim 1, where the hydrogenation catalyst is a platinum catalyst. 7. The method according to claim 6, where the platinum catalyst is 5% P1-C. 8. The method according to claim 6, where the platinum catalyst is a platinum oxide (IV). About Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2