WO2009056791A1

WO2009056791A1 - Processes for preparing pharmaceutical compounds

Info

Publication number: WO2009056791A1
Application number: PCT/GB2008/003427
Authority: WO
Inventors: Amir Avdagic
Original assignee: Pliva Hrvatska D.O.O.; Bucks, Teresa, Anne
Priority date: 2007-11-02
Filing date: 2008-10-09
Publication date: 2009-05-07

Abstract

The present invention relates to the preparation of N,N-disubstituted aminotetralins, such as rotigotine, as the free base form or as a pharmaceutically acceptable salt.

Description

PROCESSES FOR PREPARING PHARMACEUTICAL COMPOUNDS

FIELD OF THE INVENTION

The invention relates generally to processes for preparing nitrogen-disubstituted (N₅N- disubstituted) aminotetralins. More specifically, the invention relates to processes for the preparation of enantiomerically enriched rotigotine and enantiomerically pure rotigotine as the free base or as a pharmaceutically acceptable acid addition salt.

BACKGROUND

Aminotetralins constitute an important class of biologically active compounds. For example, the aminotetralin drug rotigotine ((S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8- tetrahydronaphthalen-1-ol) is a non-ergot (or non-ergotamine) dopamine agonist and is used for the treatment of Parkinson's disease. Rotigotine and related compounds have been synthesized by several routes.

U.S. Patent No. 4,410,519 describes the alkylation of aminotetralins depicted below where tertiary amine or an alkali metal carbonate or bicarbonate is used as the base and the reaction is heated in an inert solvent, hi this scheme, R is hydrogen or an acyl moiety; R₂ is an alkyl group of 1 to 4 carbon atoms; A is an alkylene group of 1 to 5 carbon atoms; R₃ is a variety of functional groups such as CN or N₃, and Z is a leaving group.

EP 1232152 discloses the alkylation of aminotetralins depicted below. In this reaction, an alkali metal carbonate or bicarbonate is used as the base at a molar ratio of from 0.2 to 1.9 equivalents with respect to the starting 2-aminotetralin.

In the scheme, R₁ is OA; R₂ is H or OA; A is an alkyl group having 1 to 3 carbon atoms; R₃ is selected from alkoxy and cycloalkoxy, optionally substituted with phenyl, 3-pyridyl, 4-pyridyl, and the following rings

where X is S, O or NH; R₄ is an alkyl group having 1 to 3 carbon atoms; n is an integer from 1 to 5 and Z is a leaving group.

SUMMARY

In one aspect, the present invention provides improved processes of preparing N,N-disubstituted aminotetralins in good yield and with high chemical and enantiomeric purity. In particular, the processes produce enantiomerically enriched or enantiomerically pure rotigotine, as the free base or as a pharmaceutically acceptable acid addition salt.

Surprisingly, it has been discovered that preparation of N,N-disubstituted 2-aminotetralins by alkylation of enantiomerically enriched N-monosubstituted 2-aminotetralins with an arylsulfonate derivative of an alcohol may be efficiently carried out using the 2-aminotetralins as both reactant and base at the same time. Such reactions may be performed under conditions so that the N₅N- disubstituted product remains in the filtrate, while unreacted starting material precipitates as the arylsulfonate salt and may be easily collected. The isolated salt is subsequently neutralized to liberate the unreacted starting aminotetralin for use in the next reaction. Also surprisingly, it has been discovered that by using the aminotetralin as reactant and base, only a 1-2.5 -fold molar excess, or preferably a 1.2-2.0-fold molar excess, of, for example, 2-(2-thienyl)ethanol arylsulfonate is needed for completion of the alkylation. Moreover, these reactions may be carried out at lower temperatures ranging from about 60 ⁰C to about 120 ⁰C, and preferably from about 80 ⁰C to about 110 ⁰C, in suitable solvents such as isobutyl acetate or isoamyl acetate. Workup and purification of the N,N-disubstituted aminotetralins are simpler and more economical than prior art processes. The N,N-disubstituted aminotetralin product may be converted to a naphthalene-l,5-disulfonic acid salt in situ and precipitated from the filtrate in high yield and purity. By avoiding large excesses of the arylsulfonate alkylating agent and/or base, troublesome workups and extensive purification are avoided, leading to superior chemical and enantiomeric purity of the N,N-disubstituted aminotetralins.

DETAILED DESCRIPTION

Processes for the preparation of N,N-disubstituted aminotetralins, specifically, for the preparation of enantiomerically enriched or enantiomerically pure rotigotine as the free base or as pharmaceutically acceptable acid addition salt are provided herein. In one aspect, the processes include the step of:

a) reacting an enantiomerically enriched compound of Formula (I),

with 2-(2-thienyl)ethanol arylsulfonate of Formula (II),

(H)

to provide a compound of Formula (IV),

(IV) wherein each R is independently selected from hydrogen or a methyl group. The reaction may be performed without added base because Formula (I) serves as both the reactant and the base at the same time. In some embodiments, the compound of Formula (II) can be 2-(2-thienyl)ethanol benzenesulfonate or 2-(2-thienyl)ethanol toluenesulfonate. The reaction is typically carried out in an organic solvent, heated to a temperature of from about 60 ⁰C to about 120 ⁰C, and preferably from about 80⁰C to about 110 ⁰C. Suitable solvents that may be heated to such temperatures include but are not limited to isopropyl acetate, isobutyl acetate, isoamyl acetate, toluene and xylene. Preferably, isobutyl acetate or isoamyl acetate are used. In some embodiments, the amount of the compound of Formula (II) is present at about 1 to about a 2.5-fold molar excess, preferably from about a 1.2 to about a 2.0-fold molar excess with respect to the amount the compound of Formula (I).

Advantageously, unreacted starting aminotetralin precipitates from the reaction mixture as the salt of Formula (III):

(III)

Thus, the present processes may further comprise the following step:

b) filtering the reaction mixture to isolate the precipitate comprising the salt having Formula (III). The filtrate will therefore comprise the product, the compound of Formula (IV).

The present processes may further comprise the following step:

c) contacting the salt having Formula (III) with a suitable base to convert it to the compound of Formula (II). Suitable bases are well known in the art and include, for example, alkali metal hydroxides, carbonates. For example, 10% aqueous NaOH may be used to neutralize the salt and allow the compound of Formula (II) to be extracted into an organic solvent such as dichloromethane or the like.

The present processes may further comprise the following step: d) treating the filtrate containing the compound of Formula (IV) with 1,5-naphthalenedisulfonic acid or its hydrates, to give the enantiomerically enriched or enantiomerically pure salt having Formula (V),

(V)

wherein R is as defined above. The salt having Formula (V) is a useful intermediate in the synthesis allowing ready purification of the N,N-disubstituted aminotetralin by crystallization, and avoiding the use of chromatography.

Treatment of the filtrate is optionally conducted with the addition of an organic solvent, such as acetone, methanol or isopropanol. Optionally, the salt having Formula (V) is recrystallized.

The processes for preparing N,N-disubstituted aminotetralins may further include the following step:

e) contacting the salt of Formula (V) with a suitable base to provide the enantiomerically enriched or enantiomerically pure compound of Formula (IV). Suitable bases for salt neutralization are well known in the art and include for example, alkali metal hydroxides and carbonates.

The free base from step (e) may be converted to a pharmaceutically acceptable salt. Thus, processes of the invention may further include.

f) contacting the enantiomerically enriched or enantiomerically pure compound of Formula (FV) from step (e) with a pharmaceutically acceptable acid and isolating the resulting salt. In some embodiments, the salt is the hydrochloride salt having Formula (VI):

(VI)

wherein R is as defined above.

The synthetic processes described herein possess several advantages over prior art procedures. First, the present methods avoid the use of a large excess of alkylation agent, which is commonly greater than three-fold molar excess with respect to the starting 2-aminotetralins. Not only is this cheaper and more efficient, but extensive purification of the final product is avoided, thus simplifying the procedure. Second, the present methods avoid the use of temperatures higher than 120 ⁰C for prolonged periods of time and thus avoid increased amounts of impurities that are problematic to remove from the final product. Finally, the unreacted starting material is readily recovered in a salt form that simplifies workups and subsequent purification of the product, which remains in the filtrate after the reaction.

Thus, one embodiment of the processes of the invention may be represented as in Scheme I.

Scheme I

Definitions of terms used herein are provided below.

By the use of the term enantiomerically enriched it is meant that the enantiomeric excess (ee) is greater than 80%. In some embodiments greater than 90% or greater than 95%.

By use of the term enantiomerically pure it is meant that the enantiomeric excess (ee) is greater than 98%, ideally greater than 99% and ideally enantiomerically pure means greater than 99.5%.

Pharmaceutically acceptable salts of the invention compounds are considered within the scope of the present invention. When the compound of the invention has a basic group, such as, for example, an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid).

As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as "up to," "at least," "greater than," "less than," and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth.

While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims.

All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.

EXAMPLES

a) (-)-5-Hydroxy-N-n-propyl-2-aminotetralin (3.02 g, 14.7 mmol) and 2-(2-thienyl)ethanol toluenesulfonate (8.30 g, 29.4 mmol) were suspended in isobutylacetate (30 mL) under an inert atmosphere. The reaction mixture was heated at 110 ⁰C for 10 hours and then filtered while hot to give 2.62 g (6.96 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin toluenesulfonate and filtrate. The filtrate was evaporated to dryness, dissolved in a mixture of acetone-isopropanol when 1.91 g (5.30 mmol) of 1,5-naphthalenedisulfonic acid was added, and the resulting mixture was stirred at room temperature. The product was filtered, washed with 2-PrOH (30 mL) and dried under reduced pressure to yield 2.92 g (6.36 mmol, 43.2% yield based on starting 2-aminotetralin) of (S)-6-(propyl(2-thiophen-2- yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen- 1 -ol heminaphthalene- 1 ,5-disulfonate.

b) 2.62 g (6.96 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin toluenesulfonate was suspended in a mixture of 10% NaOH (30 mL) and dichloromethane (30). The mixture was stirred for 30 minutes; the organic layer was separated, and the aqueous layer was washed again with dichloromethane (30 mL). The combined organic layers were dried with Na₂SO₄, filtered and evaporated to yield 1.41 g (6.87 mmol) of (-)-5-hydroxy-N-n-propyl- 2-aminotetralin.

c) (-)-5-Hydroxy-N-n-propyl-2-aminotetralin (1.41 g, 6.87 mmol) and 2-(2-thienyl)ethanol toluenesulfonate (3.88 g, 13.74 mmol) were suspended in isobutylacetate (15 mL) under an inert atmosphere. The reaction mixture was heated at 110 ⁰C for 10 hours and then filtered while hot to give 1.09 g (2.88 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin toluenesulfonate and filtrate. The filtrate was evaporated to dryness, dissolved in a mixture of acetone-isopropanol when 0.87 g (2.40 mmol) of 1,5-naphthalenedisulfonic was added, and the resulting mixture was stirred at room temperature. The product was filtered, washed with 2-PrOH (15 mL) and dried under reduced pressure to yield 1.26 g (2.74 mmol, 39.9% yield based on starting 2-aminotetralin) of (S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)- 5,6,7,8-tetrahydronaphthalen- 1 -ol heminaphthalene- 1 ,5-disulfonate.

d) 1.09 g (2.88 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin toluenesulfonate was transformed to 0.56 g (2.75 mmol) of (-)-5-hydroxy-N-n-propyl-2-aminotetralin in the same manner as described in Example (b).

e) (-)-5-Hydroxy-N-n-propyl-2-aminotetralin (0.56 g, 2.75 mmol) and 2-(2-thienyl)ethanol toluensulfonate (1.55 mg, 5.50 mmol) were suspended in isobutylacetate (7 mL) under an inert atmosphere. The reaction mixture was heated at 110 ⁰C for 10 hours and then filtered while hot to give 0.41 g (1.10 mmol) of (-)-5-hydroxy-N-n-propyl -2-aminotetralin toluenesulfonate and filtrate. The filtrate was evaporated to dryness, dissolved in a mixture of acetone-isopropanol when 0.35 g (0.96 mmol) of 1,5-naphtalenedisulfonic acid was added and the resulting mixture was stirred at room temperature.. The product was filtered, washed with 2-PrOH (8 mL) and dried under reduced pressure to yield 0.48 g (1.04 mmol, 37.8% yield based on starting 2-aminotetralin) of (S)-6-(propyl(2-thiophen-2- yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-l-ol heminaphthalene-l,5-disulfonate.

f) (S)-6-(Propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen- 1 -ol heminaphthalene-l,5-disulfonate from a), c) and e) was collected to give 4.66 g (10.1 mmol, 68.7% yield based on starting 2-aminotetralin) and suspended in dichloromethane (60 mL). The suspension was adjusted with 10% NaOH to pH 11.0, the organic layer separated, and the water layer was washed again with dichloromethane (30 mL). The organic layers were dried with Na₂SO₄ and evaporated to give (S)-6-(propyl(2-thiophen-2- yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-l-ol which was converted in the usual manner to its hydrochloride salt form, with yield of 3.15 g (8.96 mmol, 60.9%). HPLC analysis on Chiralcel OD-H column, hexane/EtOH/DEA=100/4/0.2 revealed more than 99.5 % ee.

Claims

CLAIMSWhat is claimed is:

1. A process comprising reacting an enantiomerically enriched compound of Formula (I),

with a 2-(2-thienyl)ethanol arylsulfonate of Formula (II),

without added base, to provide an enantiomerically enriched compound of Formula (IV),

(IV) wherein each R is independently selected from hydrogen or a methyl group.

2. The process of claim 1 wherein the compound of Formula (I) is 5-hydroxy-N-n-propyl-2- aminotetralin.

3. The process of claim 1 wherein the compound of Formula (II) is 2-(2-thienyl)ethanol toluenesulfonate.