WO2007025696A2

WO2007025696A2 - Process for making substituted piperazinyl compounds

Info

Publication number: WO2007025696A2
Application number: PCT/EP2006/008401
Authority: WO
Inventors: Frédéric NOBS
Original assignee: Novartis Ag; Novartis Pharma Gmbh
Priority date: 2005-08-30
Filing date: 2006-08-28
Publication date: 2007-03-08
Also published as: WO2007025696A3; TW200745071A; GB0517637D0

Abstract

A process for making a compound of formula (I): wherein R1 is C1 to C7 alkyl. The compounds having the formula (I) may be intermediates in a process for making dipeptide compounds, for example dipeptide nitrile compounds.

Description

Process for making substituted piperazinyl compounds

The present invention relates to a new process for making substituted piperazinyl compounds.

In particular, the present invention relates to a new process for the synthesis of the compound of formula ((I)):

wherein R¹ is C₁ to C₇ alkyl.

BRIEF SUMMARY OF THE DISCLOSURE

The present invention provides a new process for making compounds of the formula ((I)).

The compounds having the formula (I) may be intermediates in a process for making dipeptide compounds, such as dipeptide nitrile compounds, for example. Such processes are described in WO 01/58886, for example, which is incorporated herein by reference.

The process of the present invention has been found able to produce surprisingly high yields. In particular, one or more of the steps of the present invention have been found to be operable to produce near quantitative yields.

The existence of a near quantitative process step makes the linear process of the present invention particularly commercially and economically viable for industrial uses such as large- scale production, e.g. the supply of intermediates. DETAILED DESCRIPTION

The present invention relates to a process for manufacturing substituted piperazinyls and steps thereof.

Advantageously, the process and/or steps thereof provide high yield, reduced cost, lower waste, fewer impurities and/or reduced environmental impact.

An example of the overall process of the present invention may be summarised below:

where R¹ is Ci to C₇ alkyl and R² is a protecting group, such as C₁ to C₄ alkyl, for example. An alternative example of the overall process of the present invention may be summarised below:

Ha

where the amino group in Via is in para or meta position; R is hydroxyl, halogen, e.g. Cl, Br; R¹ is H, C₁ to C₇ alkyl, e.g. methyl, ethyl, propyl, butyl and R² is a protecting group, such as Ci to C₄ alkyl, e.g. methyl, ethyl.

The use of protecting groups is fully described in ^"Protective Groups in Organic Chemistry^", edited by J W F McOmie, Plenum Press (1973), and ^"Protective Groups in Organic Synthesis^", 2nd edition, T W Greene & P G M Wutz, Wiley-lnterscience (1991 ).

It will be appreciated that the above process represents a particular embodiment of the present invention. Deviation, e.g. small deviation, from the above reagents may be contemplated. For example, the use of Na₂CO₃ in place of K₂CO₃ is contemplated. NaOH may be replaced by another base, as in the case by KOH or LiOHO₁, C₂ and C₃ alcohol solvents may be interchanged, if required for example.

The various steps included in the present invention are described below in more detail. - A -

(IV)

Step j

This reaction step itself forms an aspect of the present invention and involves the following sub-steps:

i) reacting piperazine with a protected 4-fluorobenzoic acid in the presence of a solvent to form a compound of formula (IV):

(IV), where R² is a protecting group; ii) treating the mixture with tertiary butyl methyl ether (TBME) and water, whereby the compound (IV) is preferentially extracted into the TBME; and iii) separating the TBME from the water.

A detailed description of the process step is now described below by way of example:

An ester of 4-fluorobenzoic acid, for example 4-fluorobenzoic acid methyl ester, may be added to a mixture, e.g. solution, of piperazine in acetonitrile and heated to an internal temperature of about 60-80⁰C, for example 70-80⁰C, typically 75°C. The solution may be stirred during 20 hours and at an internal temperature of about 70⁰C where the reaction may undergo at least 50% conversion. The total reaction duration may be for example 18 to 30 hours, for example 20 to 27 hours, such as 25 hours, for example. The reaction may be monitored by GC and on completion the reaction mixture is cooled to 50-60⁰C, for example. The cooled reaction solution may then be then transferred to a second vessel and, at an internal temperature of about 40⁰C, tertiary butyl methyl ether (TBME) may be added together with water and the resulting 2-phase mixture may then be separated and the organic layer may be washed with brine (25%), for example, to produce a solution containing (IV).

The organic phase may be reduced in volume, i.e. TBME is at least partially removed, for example by evaporation, and acetone is combined with the reduced-volume product.

The piperazine (Vl) may be present in an amount of between 3 and 10 equivalents with respect to the benzoic acid ester (V). In particular, the piperazine is present in an amount of between 4 and 10 equivalents with respect to (V), for example between 4 and 8 equivalents, typically between 5 and 6 equivalents. In one particular aspect of the invention, the piperazine is preferably present in an amount of about 5.38 equivalents.

Alternative solvents include dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP). Here, the temperature of the reaction may be between 70 and 110⁰C, for example 90 to 1 10⁰C.

The reaction is preferably carried out an internal temperature below reflux, for example approximately 3°C under the reflux temperature. This may thus avoid sublimation of piperazine. Thus, in one aspect of the present invention, the temperature of the reaction of Step 1 is under conditions in which sublimation of piperazine is avoided.

The reaction is preferably at a maximum temperature of 100⁰C.

The washing with brine is preferably done at a temperature of below 50⁰C. The brine serves to extract the piperazine hydrofluoride salt, for example.

The organic phase is preferably in solution. However, (IV) may precipitate out at temperatures below room temperature (e.g. 22 to 27 ⁰C). The TBME extraction step is used to obtain a high purity product with optimum yield. Without this extraction step some, for example up to 5%, of (IV) can be lost. (Vl) is particularly water soluble and therefore remains in the water layer and thus washing with water removes water-soluble Vl.

The presence of (V) in the final organic phase preferably does not affect the next reaction step since the next step involves the alkylation of IV.

Step 2

(IV) where X is a halide, for example chloride, bromide, iodide or fluoride.

The reaction step itself forms an aspect of the present invention and comprises:

i) N-alkylating a compound of formula (IV) with a C₁-C₇ alkyl group by treating the resultant product with an C₁-C₇ alkyl halide in the presence of a base and acetone.

Optionally, the process further includes any or each of the following:

ii) removing the acetone and treating the mixture with TBME, iii) washing the resulting TBME mixture with water, and iv) reducing the volume of TBME v) de-protecting the product The halide is preferably iodide.

The base is preferably an alkali metal carbonate.

This process step may now be described in further detail below by way of example:

The above solution of (IV) in TBME resulting from the extraction procedure of step 1 , may be reduced in volume, followed by the addition of (or to) acetone. Preferably, the solution containing (IV) has approximately three times the volume of solvent to (IV), where the solvent is TBME. In other words, the solvent:(IV) ratio is approximately 3:1 (v/w).

Thus, a mixture, e.g. a solution of (IV) in acetone may be formed. Preferably, the solvent:(IV) ratio is 10:1, where the solvent is acetone. The solution of (IV) may be stirred and a carbonate, for example an alkali metal carbonate, typically K₂CO₃ or Na₂CO₃, preferably K₂CO₃, may be added together with an alkyl halide, such as an alkyl iodide, for example, e.g. a methyl iodide or ethyl iodide or propyl iodide, typically propyl iodide, and the mixture, e.g. suspension, may be stirred over a period of about two hours, for example. The mixture may then be further stirred for a period of approximately 3 hours at a temperature of 40-50⁰C, typically 40⁰C, for example. Upon completion of the reaction, TBME and water may be added to produce a two-phase mixture. The organic phase may then be washed with water and partially evaporated. The organic phase may then be reduced in volume until the product, (II) crystallises out, for example. The organic phase may be cooled to a temperature of 0⁰C, for example, and may be stirred at this temperature for about an hour. The product may then be centrifuged or alternatively collected by filtration, for example. The product may be washed with TBME and then dried under vacuum at a temperature of approximately 40⁰C.

This reaction may also take place with triethylamine and tributylamine instead of potassium carbonate. In addition, the reaction may also take place in acetone, ethylmethylketone or other tertiary amines .

The preferred concentration of the base solution is from about 1 to 10 equivalents, for example between 1 and 5 equivalents. In once aspect of the present invention, the preferred concentration of the base solution is from about 1.5 to 3 equivalents. In a further aspect of the present invention, the concentration of the base solution is at least one equivalent.

The amount of (III) in the product (II) is preferably very small, for example less than 1%. The small amount of (III) in the final product ((H)) is desired since (III) is a potential mutagen.

Alternatively, compounds of formula (II) may also be produced in a second route: Alternative process has e.g. the advantage not to use the potential mutagen III.

i) N-alkylating a compound of formula (Via) with haloderivatives

Optionally, the process further includes any or each of the following:

ii) removing the organic solvent and treating the mixture with TBME, iii) washing the resulting TBME mixture with water or buffered water, and iv) reducing the volume of TBME Reaction can be done in different solvents such as xylene, methylenchloride or thionylchloride.

(H) (I)

This step is the deprotection of compound (II) and itself forms an aspect of the present invention. In embodiments, the process comprises de-esterification, e.g. by treating compound (II) with an aqueous base, e.g. with aqueous sodium hydroxide.

A mixture, for example a suspension, of (II) in methanol and water may be treated with sodium hydroxide solution (30%v/v) and the mixture may be warmed to a temperature of 60- 8O⁰C, for example 70-75⁰C (internal temperature). Preferably, the sodium hydroxide is added after a period of heating of 30 to 40 minutes. The reaction mixture may then be stirred for approximately 60 to 90 minutes at a temperature of 90 to 11O⁰C, typically 100⁰C (e.g. an internal temperature of 75⁰C). The reaction may be monitored by chromatography. Once the reaction has neared completion, the internal temperature may be reduced to approximately 50⁰C and the cooled reaction mixture may be optionally filtered and transferred to a new vessel whereby the reaction mixture may be treated with glacial acetic acid over a period of 10 to 20 minutes. The reaction mixture may be stirred. After a period of approximately 60 minutes the internal temperature may be reduced to approximately 2O⁰C and then after a further 60 minutes the internal temperature may be reduced to O⁰C where the mixture may be further stirred for approximately 2 hours. The product (I) should precipitate out, for example. The resulting suspension may be centrifuged or filtered and washed with cold water. The product is dried under vacuum at a temperature of approximately 5O⁰C.

Preferably, upon addition of acetic acid, the product (I) precipitates out as a white powder and is filtered and dried.

A compound (I) may undergo further conversion into a salt, prodrug or a N-oxide. Whether or not further converted, the compound may be formulated into a pharmaceutical formulation.

Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", means "including but not limited to", and is not intended to (and does not) exclude other moieties, additives, components, integers or steps.

Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

EXAMPLES

EXAMPLE 1 : Synthesis of 4-(piperazin-1-yl)-benzoic acid methyl ester

A mixture of piperazine (6Og) in acetonitrile (200ml) was heated to a temperature of 75-8O⁰C (internal temperature) and then further heated to a temperature of 8O⁰C once the piperazine was in solution. The mixture was then treated with 4-fluoro-benzoic acid-methyl ester (2Og) within a period of 15 minutes. The reaction mixture was then stirred for about 20 hours. The reaction mixture was then cooled to a temperature of 4O⁰C and TBME (300ml) and water (200ml) were added at this temperature. Brine (100ml) was then added to the reaction mixture and the 2-phase mixture was stirred for approximately 5 minutes. The water phase was then extracted with TBME (100ml). The combined organic layers were then washed with a further solution of brine (2 x 100ml). The resulting organic phase may be used directly in the next step. GC: 14% of (V).

EXAMPLE 2: Synthesis of 4-(4-propyl-piperazin-1-yl)-benzoic acid methyl ester

(IV) (37g) in TBME (approx 200ml) is partly reduced in volume under reduced pressure (approx 300mbar) at a maximum temperature of 5O⁰C. The resulting residue was then treated with absolute acetone (370ml) to eventually produce a solution. Then, postassium carbonate (30.2g) is added to the reaction mixture at a temperature of 40-50⁰C (internal temperature). Then, within 2 hours, propyl iodide (37.1) is added. After 3 hours the reaction mixture is tested by GC to determine the reaction completion. Where the GC indicates that less than 5% (IV) remains the reaction mixture is then reduced in volume at a temperature of 4O⁰C (internal temperature) and that a reduced pressure of 300mbr. The product is crystallised with TBME (320ml) together with water (270ml) where the reaction mixture is stirred for 5 minutes at a temperature of 4O⁰C (internal temperature) to produce a clear solution. The upper organic phase is separated and then washed with water (100ml). Then the TBME-phase is reduced in volume at a temperature of 40-5O⁰C (internal temperature) under reduced pressure of 300mbar where the product (II) precipitates out. The reaction mixture is further agitated at O⁰C for approximately 2 hours and then filtered. The filter-cake is then washed with cold TBME and dried at a temperature of 5O⁰C (internal temperature) under reduced pressure of 50mbar for 15 hours. Yield: 37.4g (85% of theory) GC: 99.6F% ((IV) 0.1%, (V) 0.03%, (III) less than 0.01%)

Titration: 99.2% (HCI)

EXAMPLE 3: Alternative synthesis of 4-(4-propyl-piperazin-1-yl)-benzoic acid methyl ester

Piperazine (696mmol) , 4-Fluorobenzoic acid methyl ester (1 29mmol) are suspended in Acetonitrile ( 200 ml) and refluxed 24h; the reaction mixture is transferred into TBME (t-Butylmethylether) and diluted brine . The organic phase is washed with brine; a solution with 168 mmol 4-(piperazin-1 -yl) benzoic acid methylester is concentrated at vacuo and TBME replaced by 370 ml acetone ; after addition of 218 mmol K₂CO₃ and 218 mmol n-propyliodide the reaction mixture is stirred 3h at 50°. After partial evaporation of acetone and replacement by TBME, the organic phase is washed with water and concentrated until 4-(4-propyl-piperazin-1 -yl) benzoic acid methylester cristallised; after filtration is obtained a colourless powder.

NMR (CDCI₃): 7.9 (d/ 2H), 6.9 (d/ 2H), 3.9 (s/3H), 3.4 (m/4H), 2.6 (m/ 4H), 2.4 (t/2H), 1 .6 (m/2H), 0.9 (t/3H).

EXAMPLE 4: Synthesis of 4-(4-propyl-piperazin-1-yl) benzoic acid

123 mmol 4-(4-propyl-piperazin-1 -yl) benzoic acid methylester is taken up in 100 ml methanol and 100 ml water and treated with 130 mmol NaOH (as a 30% solution in water) at 70⁰C. After the reaction, addition of 130mmol acetic acid precipitates the product which is filtered and dried (white powder). mp: 240-242

NMR (DMSO): 7.8 (d/ 2H), 7.0 (d/ 2H), 3.3 (m/4H), 2.5 (m/ 4H), 2.3 (t/2H), 1 .4

(m/2H) 0.9 (t/3H)

EXAMPLE 5: Synthesis of 4-(4-propyl-piperazin-1-yl)-benzoic acid (alternative)

5 g methyl-4-aminobenzoate in 50 ml methylisobutylketon and 6.6 g triethylamine and 12.0 g IHa are stirred over night at 1 1 5°C. The yield of the title compound after extraction with TBME and washing with water/Na2CO3 at pH 10 and evaporation was 3.7g. mp: 102-103

NMR (CDCI₃): 7.9 (d/ 2H), 6.9 (d/ 2H), 3.9 (s/3H), 3.4 (m/4H), 2.6 (m/ 4H), 2.4

(t/2H), 1.6 (m/2H), 0.9 (t/3H).

It will be appreciated from the aforegoing that in one aspect, the process of the present invention provides a process which comprises a near quantitative step.

The term "near quantitative" is, for example, taken to mean a yield of a value of greater than 80% of the theoretical yield, for example a value of greater than 85% of the theoretical yield, for example a value of greater than 90% of the theoretical yield.

Preferably at least one process step of the present invention yields between 90 and 100% of the theoretical yield, for example over 90% of the theoretical yield. Over 90% of the theoretical yield means any value, integer or otherwise, over 90%, in particular it means 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.

The term "process step" within the meaning of the present disclosure may be taken to mean any particular reaction undergone during the linear process. Therefore, a "process step" does not necessarily require any product isolation. In other words, a process step may be a step normally conducted in situ, i.e. a step where the product of the process step, for which the near quantitative yield has been found to exist, may not necessarily normally be isolated.

Claims

1. A process for making a compound of formula (I):

wherein R¹ is C₁ to C₇ alkyl, the process comprising the steps of a) reacting piperazine with a protected 4-fluorobenzoic acid in the presence of a solvent to form a compound of formula ((IV));

((IV)), where R² is a protecting group, b) treating the mixture with tertiary butyl methyl ether (TBME) and water, whereby the compound ((IV)) is preferentially extracted into the TBME; c) separating the TBME from the water; d) N-alkylating the compound of formula ((IV)) which was extracted into the TBME with a C₁- C₇ alkyl group; and e) de-protecting the product.

2. The process of claim 1 , where the alkylation process (d) comprises the steps:

(d1) treating the resultant product with an C₁-C₇ alkyl halide in the presence of a base and acetone.

3. The process of claim 2, where the halide is iodide.

4. The process of claim 2 or 3, where the base is an alkali metal carbonate.

5. The process of any preceding claim, wherein the compound of formula ((IV)) is not isolated prior to reaction step (c).

6. The process of any of claims 2 to 5, wherein the reaction mixture of step (d1 ) is a solution.

7. The process of any one of claims 2 to 6, wherein the process further comprises the following steps between N-alkylation and deprotection: f) removing the acetone and treating the mixture with TBME, g) washing the resulting TBME mixture with water, and h) reducing the volume of TBME.

8. The process of any preceding claim, wherein R² is methyl.

9. The process of any preceding claim, wherein R¹ is propyl.

10. The process of any preceding claim further comprising converting the product into a salt, N-oxide or prodrug.

11. The process of any preceding claim further comprising converting the product into a pharmaceutical formulation.

12. The process of any preceding claim wherein at least one of the process steps a)-f) produce a near quantitative yield of more than 80% of the theoretical yield.

13. A process substantially as hereinbefore described under the headings "Step 1", "Step 2" or "Step 3" or comprising one or more of said steps.

14. A process substantially as hereinbefore described in the Examples.

15. A process for making a compound of formula (I):

wherein R¹ is Ci to C₇ alkyl, the process comprising the steps of a) N-alkylating a compound of formula (Via)

Via

wherein R2 is a protecting group; with a compound of formula HIa

wherein R is hydroxyl, halogen; and R1 is H, C₁ to C₇ alkyl; in the presence of a solvent to form a compound of formula (II);

wherein R1 is H, C₁ to C₇ alkyl; and R2 is a protecting group; and b) de-protecting compound of formula II.