HK1185339B

HK1185339B - Processes for the resolution of nitrogen substituted (s)-5-alkoxy-2-aminotetralin derivatives

Info

Publication number: HK1185339B
Application number: HK13112756.4A
Authority: HK
Inventors: C．艾茨; A.舒勒; M．帕拉西奥; P．多伊奇; D．瓦瑟兰; N．卡里; G．帕德塔瑞; J-P．德拉提尼; M．L．易斯库德罗赫南德兹; V．皮尼拉; S．叶兰德
Original assignee: 优时比制药有限公司
Priority date: 2010-06-25
Filing date: 2011-06-24
Publication date: 2017-04-07

Description

Method for resolving nitrogen substituted (S) -5-alkoxy-2-aminotetralin derivatives

The present patent application relates to a novel process for the preparation of nitrogen substituted aminotetralins.

In particular, the present patent application relates to a novel process for the preparation of substantially optically pure nitrogen substituted aminotetralins.

In particular embodiments, the present application relates to improved processes for the preparation of rotigotine.

Rotigotine is the international non-proprietary name (INN) for the compound (-) -5,6,7, 8-tetrahydro-6- [ propyl- [2- (2-thienyl) ethyl ] -amino ] -1-naphthol having the structure shown below.

Rotigotine

Rotigotine is a non-ergoline D1/D2/D3 dopamine agonist, similar in structure to dopamine and having similar receptor properties but with higher receptor affinity.

In contrast to other non-ergoline dopamine agonists, rotigotine has significant D1 activity, which may contribute to more physiological effects.

In contrast to ergolines, rotigotine has a very low affinity for the 5HT2B receptor and therefore has a low risk of reducing fibrosis.

Effects on non-dopaminergic receptors (such as 5-HT1A agonism and A2B antagonism) may contribute to other beneficial effects such as anti-dyskinesia activity, neuroprotective activity and antidepressant action.

Rotigotine is disclosed as an active drug for the treatment of patients suffering from parkinson's disease (described in WO 2002/089777), parkinson plus syndrome (described in WO 2005/092331), depression (described in WO 2005/009424) and restless leg syndrome (described in WO 2003/092677) as well as for the treatment or prevention of dopaminergic neuronal loss (described in WO 2005/063237) and for the treatment of pain (PCT/EP 2007/005381).

International patent application WO01/38321 describes a process for the preparation of nitrogen substituted aminotetralins and in particular rotigotine.

International patent application WO2010/043571 describes a process for the preparation of rotigotine, comprising the resolution of diastereomeric salts of the aminotetralins.

Us patent 4,968,837 describes the diastereomeric resolution of 1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine with L-dibenzoyl-tartaric acid.

U.S. patent application No. 2007/185346 relates to methods and trays (tray) or kits useful for selective resolution of reagents, compositions and conditions to separate optical isomers.

Cusackn.J. et al describe in Drugsoffhefulture (Proussience, ES, Vol.18, n.11, 1January1993, pages1005-10008) a process for the preparation of rotigotine which involves the diastereomeric resolution of 2- (N-propylamino) -5-methoxytetralin.

European patent application EP1975161a1 relates to the use of heterocyclic substituted tetralin amine compounds for the treatment of diseases mediated by 5-HT7 receptor affinity.

The diastereomeric resolution of 2- (N-propylamino) -5-methoxytetralin with (R) - (-) -O-methylmandelic acid is described by Wikstoem H.et al in journal of medicinal chemistry (American chemical society, Washington, U.S.A., vol.28, n.O.2, 1january1985, pages 215-225).

Brown et al in bioorganic and medicinal chemistry (Pergamon, GB, vol.17, n.degree.11, 1June2009, pages3923-3933), Balaram Ghosh et al in journal of medicinal chemistry (American chemical society, Washington, US, vol.53,1January2010, pages1023-1037), HoveTen W. et al in journal of organic chemistry (American chemical society, Easton; US, vol.50,1January1985, pages4508-4514), Sonenson Med.et al in European journal of medicinal chemistry (Editionsscientistivientification, January 3538, Parcel, 1995) and for use as a chiral reagent in Chronic reactions and intermediates FR, inter alia, see patent application Ser. No. 25 for enantiomeric resolution and European application No. 25.

International patent application WO2010/043571 describes a process for the preparation of (S) - (-) -2- (N-propylamino) -5-methoxytetralin and (S) - (-) -2- (N-propylamino) -5-hydroxytetralin by optical resolution of the corresponding racemic mixture using an optically active organic acid such as (+) -N- (3, 5-dinitrobenzoyl) - α -phenylglycine.

SelditzU.S. et al describe the use of supercritical CO in DiePhamazie (GoviVerlag PharmazeutischerVerlag Gmbh, Eschborn, DE, vol.54, n. 3,1999, 1/183. sup. -₂Chirally separating the 2-acylaminotetralin.

Chiral separation of the 2-acetamidotetralin class is disclosed in journal of Labelled Compound and Radiopharmaceuticals (John Wiley, Chichester, GB, vol.36, n. 11,1995, 1 month 1, page 1051-.

JansenJ.M. et al describe the chiral separation of 2-acylamino tetralins using stationary cellulose-based phases in Chirality (Wiley-Liss, New York, U.S., vol.6, 1/1994, p 596-604.

The present invention provides an alternative and better process for the preparation of rotigotine.

In particular, the present invention relates to a process for the preparation of synthetic intermediates useful in the preparation of nitrogen substituted aminotetralins, and in particular useful in the synthesis of rotigotine and its salts.

In a first aspect, the present invention relates to a process for the preparation of optically enriched (S) -N-substituted aminotetralins of formula (I), wherein

R¹Is an alkyl group; and

R²and R³Independently hydrogen, alkyl, alkoxycarbonyl, aryloxycarbonyl, arylcarbonyl, or alkylcarbonyl.

The process comprises resolving an N-substituted aminotetralin of formula (II) wherein R¹、R²And R³As defined for compounds of formula (I), as shown in scheme 1.

Scheme 1

The term "optically enriched", as used herein in reference to a particular compound, means that more than 50%, preferably more than 75%, more preferably more than 85%, most preferably more than 94% of the compounds have a stereogenic center indicated by (×) in a given conformation (R) or (S).

In a second aspect, the present invention relates to a process for the preparation of substantially optically pure (S) -N-substituted aminotetralins of formula (I), wherein

R¹Is an alkyl group; and

The process comprises resolving an N-substituted aminotetralin of formula (II).

The compounds of the formulae (I), (II) and (III) according to the invention can be present as free bases or in the form of salts.

The salts are typically produced by reacting the free base of the compound with a mineral acid of the formula HX.

As used herein, the term "substantially optically pure" in reference to a particular compound means that at least 95%, preferably at least 96%, more preferably at least 97%, most preferably at least 98%, even most preferably at least 99% of the compounds have a stereocenter indicated by (×) in a given conformation (R) or (S).

The term "alkyl" as used herein is a group representing a saturated, monovalent hydrocarbon group having a straight-chain (unbranched) or branched moiety, or a combination thereof, and containing from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms; most preferably, the alkyl group has 1 to 4 carbon atoms.

An "alkyl group" according to the present invention may be unsubstituted or substituted. Preferred alkyl is C_1-4An alkyl group. Such a C_1-4Examples of alkyl are methyl, ethyl, n-propyl, isobutyl, tert-butyl.

The term "alkoxycarbonyl" as used herein refers to the group-C (O) OR^aWherein R is^aIs an alkyl group as defined above.

The term "aryloxycarbonyl" as used herein refers to the group-C (O) OR^bWherein R is^bIs an aryl group as defined herein.

The term "aryl" as used herein refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl).

The term "arylcarbonyl" as used herein refers to the group-C (O) R^bWherein R is^bIs an aryl group as defined above.

The term "alkylcarbonyl" as used herein refers to the group-C (O) R^aWherein R is^aIs an alkyl group as defined above.

The term "resolution" as used herein refers to the separation of a mixture of enantiomers into their corresponding individual enantiomers.

Enantiomers may be present in the mixture in various ratios of one enantiomer to the other.

In particular, the mixture is a racemic mixture. A racemic mixture as defined herein is a mixture comprising 50% of one enantiomer and 50% of the other enantiomer.

Resolution can be achieved by a variety of methods, including conversion to diastereomers, differential absorption, chiral recognition, biochemical methods, mechanical separation, kinetic resolution, and deracemization, as detailed in JerryMarch in advanced organic chemistry, fourth edition, Chapter 4, page 120-125.

In one embodiment, the present invention relates to a process for preparing a substantially optically pure compound of formula (I) by diastereomeric salt resolution of a compound of formula (II), as shown in scheme 2 below.

Scheme 2

In a particular embodiment according to the invention, the diastereomeric salt resolution of a compound of formula (II) is carried out as follows:

(i) reacting the free base of the compound of formula (II) with a substantially optically pure acid (IV) in a solvent to provide diastereomeric salts (V) and (V');

(ii) crystallizing the resulting diastereoisomeric salt (V) in a solvent;

(iii) reacting said diastereomeric salt (V) with a base to provide a compound of formula (I); and

(iv) (iv) optionally reacting the compound of formula (I) obtained in step (iii) with a mineral acid in a solvent to provide a salt of the compound of formula (I).

In another embodiment according to the present invention, the diastereomeric salt resolution of a compound of formula (II) is typically carried out as follows:

(ii) filtering the diastereoisomeric salt (V') from the reaction medium;

(iii) reacting the diastereoisomeric salt (V) present in the mother liquor with a base to provide a compound of formula (I); and

Alternatively, steps (iii) and (iv) in the above embodiments may be replaced by reacting the diastereomeric salt (V) with an inorganic acid to provide directly the salt of the compound of formula (I).

If the compound of formula (II) is in the form of a salt, for example the hydrochloride or hydrobromide salt, such a salt should be treated with a base prior to step (i) of the above process.

The substantially optically pure compounds of formula (I), (V) and (V') may optionally be recrystallized or reslurried in a solvent to increase the optical purity of the compounds as would be deemed necessary by one skilled in the art.

In a further specific embodiment according to the present invention and as shown in scheme 3, the undesired diastereomeric salt (V') may be regenerated to the HX salt of the compound of formula (II), which HX salt may then be subjected again to the process described in scheme 2 to provide the compound of formula (I).

Scheme 3

Such conversion typically occurs by:

(v) treating the diastereoisomeric salt (V') with a base to provide the undesired enantiomer (III);

(vi) racemizing enantiomer (III) to the free base of the compound of formula (II) by treatment with a racemizing agent;

(vii) the compound of formula (II) is treated with HX to provide the HX salt of the compound of formula (II).

These additional steps provide the particular advantage of regenerating the undesired salt (V') to the original racemic compound of formula (II), which can ultimately be converted to the desired enantiomer (I) via a repeated process, thereby increasing the overall yield of the process and reducing the formation of waste.

In a particular embodiment according to the invention, the compound of formula (II) is a racemic mixture as defined herein.

Compounds of formula (II) which are particularly suitable for undergoing diastereomeric salt resolution according to the invention are those wherein R is¹And R²Is alkyl and R³A compound of formula (II) which is hydrogen.

The compound of formula (II) may be in the form of a free base or in the form of a salt. Examples of salts of compounds of formula (II) are the hydrochloride and hydrobromide salts.

Wherein R is¹And R²Is alkyl and R³The compounds of formula (II) which are hydrogen can be obtained by reaction with amines of formula (VII) in a solvent and in the presence of hydrogen or a hydride via reductive alkylation of the corresponding tetralone (VI), wherein R²And R³As defined for the compound of formula (II), as shown in scheme 4, or obtained according to any other method known to the person skilled in the art.

Scheme 4

The compound of formula (II) obtained according to scheme 4 can be isolated as such or generated in situ in the reaction medium and converted directly into the diastereoisomeric salt (V) by reaction with a substantially optically pure acid (IV) in a solvent.

Alternatively, wherein R³The compound of formula (II) being hydrogen can be obtained by reacting an inorganic salt of tetralin of formula (X) with an aldehyde of formula (XI) according to methods known to those skilled in the art, as shown in scheme 5 below.

Scheme 5

In a further particular embodiment, the present invention relates to a process for preparing substantially optically pure (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalene-2-aminium hydrochloride (Ia) by diastereomeric salt resolution of a racemic mixture of (1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalene-2-aminium hydrochloride (IIa) in the presence of a substantially optically pure acid (IV) and in a solvent, as shown in scheme 6 below.

Scheme 6

The compound of formula (IIa) is initially converted into the corresponding free base (IIa') by reaction with a base according to methods known to those skilled in the art.

The compounds of formula (IIa) according to the invention can be obtained by reacting 5-methoxy-2-tetralone (VIa) with n-propylamine as described in journal of medicinal chemistry199134,3235-3241 or according to any other method known to the person skilled in the art.

Alternatively, the compounds of formula (IIa) according to the invention can be obtained by reacting 5-methoxy-tetralin hydrochloride (Xa) with propionaldehyde (XIa) according to methods known to those skilled in the art.

The compound of formula (IIa') is then reacted with a substantially optically pure acid of formula (IV), as outlined in step (i) of scheme 6.

Examples of solvents which may be used in step (i) of the process according to the invention are water; alcohols such as methanol, ethanol, propan-1-ol, propan-2-ol; ethers such as MTBE (methyl tert-butyl ether), THF (tetrahydrofuran), Me-THF (2-methyl THF); esters such as methyl acetate, ethyl acetate, isopropyl acetate; mixtures of two or more of these solvents.

In a particular embodiment according to the invention, the solvent is a mixture of water and an organic solvent selected from methanol, ethanol, propan-1-ol, propan-2-ol, methyl tert-butyl ether (MTBE), THF (tetrahydrofuran), Me-THF (2-methyl THF), methyl acetate, ethyl acetate or isopropyl acetate; mixtures of two or more of these solvents.

Examples of bases which can be used in step (i) of the process according to the invention are inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium hydrogen phosphate, sodium hydrogen phosphate, potassium phosphate, sodium phosphate; or an organic base such as diisopropylamine, triethylamine, piperidine, pyrrolidine.

Preferred bases are selected from sodium carbonate, potassium carbonate, diisopropylamine and triethylamine.

The proportion of substantially optically pure acid relative to the compound of formula (IIa') is generally at least 0.5 molar equivalents.

Examples of substantially optically pure acids (IV) according to the invention are (R) -2-methoxy-2-phenylacetic acid (IVa), (R) -2- (2-chlorophenyl) -2-hydroxyacetic acid (IVb), (S) -2-hydroxy-3-phenylpropionic acid (IVc), (S) - (+) -2- (6-methoxy-2-naphthyl) -propionic acid (IVd) or (R) - (-) -2- (6-methoxy-2-naphthyl) -propionic acid (IVd), and (R) -2- (5-chloro-2-oxo-2, 3-indolin-1-yl) -propionic acid (IVh).

Preferred substantially optically pure acids of formula (IV) according to the invention are (R) -2-methoxy-2-phenylacetic acid (IVa), (R) -2- (2-chlorophenyl) -2-hydroxyacetic acid (IVb) and (S) -2-hydroxy-3-phenylpropionic acid (IVc). It is noteworthy that these acids provide very good results, even though their use as resolving agents is hardly described in the literature.

Reaction of the free base (IIa ') with the substantially optically pure acid (IV) provides a mixture of diastereomeric salts (Va) and (V' a).

The desired diastereomeric salt (Va) can be crystallized or slurried directly in the reaction medium and then filtered off from the reaction medium.

The solvent used for the crystallization described in step (ii) is generally the same as that used in step (i). When a mixture of water and organic solvent is used in step (i), the aqueous phase is discarded prior to crystallization and the remaining organic phase is cooled to effect crystallization. The separation temperature is preferably between-10 ℃ and 0 ℃.

Optionally, the organic phase may be dried by drying techniques known to those skilled in the art.

In a particular embodiment, the organic phase is seeded with an optically pure compound of formula (Ia) to initiate crystallization.

The desired isolated diastereomeric salt (Va) is then further reacted with a base according to methods known to those skilled in the art to provide the free base of the compound of formula (Ia), as shown in step (iii) of scheme 6. The compound of formula (Ia) is then reacted with a mineral acid HX to provide the corresponding salt of the compound of formula (Ia) (step (iv) of scheme 6).

The solvent used in step (iii) is an alcohol such as methanol, ethanol, propan-1-ol, propan-2-ol; ethers such as MTBE (methyl tert-butyl ether), THF (tetrahydrofuran), Me-THF (2-methyl THF); esters such as methyl acetate, ethyl acetate, isopropyl acetate; mixtures of two or more of these solvents.

The base which can be used in step (iii) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium phosphate, sodium phosphate and triethylamine.

The compound of formula (Ia) may be isolated as the free base or as an inorganic salt, such as the hydrochloride or hydrobromide salt.

In a particular embodiment according to the invention, the salt of the compound of formula (Ia) is obtained by directly reacting the diastereoisomeric salt (Va) isolated under step (ii) with the mineral acid HX in a solvent without isolating the compound of formula (Ia) in free base form.

Examples of such inorganic acids are hydrochloric acid (HCl), hydrobromic acid (HBr), hydroiodic acid (HI), sulfuric acid (H)₂SO₄) And phosphoric acid (H)₃PO₄). Preferred inorganic acids are hydrochloric acid and hydrobromic acid.

Examples of solvents which may be used in step (iv) of the process according to the invention are water; ethers such as diethyl ether, MTBE (methyl tert-butyl ether), THF (tetrahydrofuran), Me-THF (2-methyl THF); aromatic hydrocarbons such as toluene, xylene; alcohols such as methanol, ethanol, propanol, butanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; mixtures of two or more of these solvents.

The preferred solvent is water; ethers such as diethyl ether, MTBE (methyl tert-butyl ether), THF (tetrahydrofuran), Me-THF (2-methyl THF); and alcohols such as methanol, ethanol, propanol, butanol or mixtures of two or more of these solvents.

In a particular embodiment, the invention also relates to diastereomeric salts (Va) resulting from combining 1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine (Ia) with any of the above acids (IV).

Examples of such salts (V) are (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2-methoxy-2-phenylacetate (Vaa), (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2- (2-chlorophenyl) -2-hydroxyacetate (Vab), (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate (Vac), (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R)2- (6-methoxy-2-naphthyl) -propanoate (Vad) and (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2- (5-chloro-2-oxo-2, 3-indolin-1-yl) -propanoate (Vah).

Preferred salts of the formula (Va) according to the invention are (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ium (R) -2-methoxy-2-phenylacetate (Vaa), (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ium (R) -2- (2-chlorophenyl) -2-hydroxyacetate (Vab) and (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ium (S) -2-hydroxy-3-phenylpropionate (Vac).

In another embodiment according to the invention, the diastereoisomeric salt (V' a) may be crystallized and filtered from the reaction medium. Thus, the diastereoisomeric salt (Va) present in the mother liquor may be reacted with the base or mineral acid mentioned above to provide the corresponding free base or corresponding salt, respectively, of the compound of formula (Ia), which may be isolated from the reaction medium according to methods known to those skilled in the art.

In a particular embodiment according to the invention, the chiral acid (IV) is added to a solution of compound (IIa') in the solvent used in step (i) above. The resulting mixture was heated, then cooled and filtered.

The solvent is removed and a solution of a mineral acid, preferably hydrochloric acid, is added. The solution is heated and then cooled and the inorganic salt of the compound of formula (Ia) is isolated by filtration.

In this particular embodiment, preferably (S) -2-methoxy-2-phenylacetic acid (IVa ') is used as chiral acid (IV) and (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium- (S) -2-methoxy-2-phenylacetate (Vaa') is the diastereoisomeric salt thus obtained.

In another embodiment according to the present invention, the undesired diastereomeric salt (V' a) may be regenerated to compound of formula (IIa), as shown in scheme 7, and the compound of formula (IIa) may then be reacted according to the conditions described in scheme 6 to provide the compound of formula (Ia).

Scheme 7

Step (V) is typically achieved by treating the diastereomeric salt (V' a) present in the mother liquor after filtering off the diastereomeric salt (Va) with a base, e.g. triethylamine, to provide the undesired enantiomer (IIIa).

Alternatively, step (V) may be carried out on the separated diastereoisomeric salt (V' a), if the diastereoisomer has been filtered from the reaction medium, as described above.

The enantiomer (IIIa) can be racemized to the compound of formula (IIa) by methods known to those skilled in the art.

In a particular embodiment according to the invention, enantiomer (IIIa) is converted into the compound of formula (IIa) by free-radical-mediated racemization.

For example, enantiomer (IIIa) is reacted with an alkylthiol, such as dodecylthiol or octylthiol, in the presence of azobisisobutyronitrile in a solvent (step (vi)). The resulting free base compound of formula (IIa') is then treated with a mineral acid of formula HX, such as hydrochloric or hydrobromic acid, to provide the compound of formula (IIa).

These additional steps provide the particular advantage of regenerating the undesired salt (V' a) into the initial racemic compound of formula (IIa), which can finally be converted into the desired enantiomer (Ia) via a repeated process, thereby increasing the overall yield of the process and reducing the formation of waste.

The process steps (v) and (vi) described above can be carried out separately or jointly in batch mode or according to a continuous process, using, for example, a microreactor.

The salt resolution of the compound of formula (IIa) with a chiral acid of formula (IV) according to the invention is particularly advantageous as it allows to obtain the compound of formula (Ia) in high enantiomeric excess and in high yield.

The term "enantiomeric excess" as used herein is generally expressed as a percent enantiomeric excess, and refers to the amount of one enantiomer relative to another, and is calculated as follows

% ee = [ ([ A ] - [ B ]): ([ A ] + [ B ]) ] x100, where [ A ] is the concentration of one of the enantiomers and [ B ] is the concentration of the other enantiomer.

Typical% ee of the compounds of the inorganic acid salts of the compounds of formula (Ia) according to the invention is between 90 and 100%.

The enantiomeric excess of the compounds according to the invention is preferably at least 98%.

The term "diastereomeric excess" as used herein generally refers to a percent diastereomeric excess and refers to the amount of one diastereomer relative to the other, and is calculated as follows:

% de = [ ([ A ] - [ B ]) ] x100, where [ A ] is the concentration of one of the diastereomers and [ B ] is the concentration of the other diastereomer.

Typical% de for the compounds of formula (Va) according to the invention is between 80 and 100%.

The diastereomeric excess of the compounds according to the invention is preferably at least 90%.

The salt resolution according to the invention is generally carried out with a better resolution than that obtainable with the conventionally used chiral acids available on an industrial scale.

The term "detachability" as used herein measures the efficiency of the splitting process and is defined by Fogassy et al in J.chem.Res (S)11,346(1981) as follows.

The term "resolution" is denoted by S and is defined as the product of the yield of the resolution reaction and the diastereomeric excess of the isolated salt:

S=yXde

the value of the detachability according to the present invention is between about 0.45 and about 0.90.

Furthermore, the salt resolution process according to the present invention requires fewer crystallization steps of the compound of formula (Ia) to obtain the desired optical purity. Thus, the yield and efficiency of the process are increased relative to those described in the prior art.

In a further embodiment, the present invention relates to the use of a diastereomeric salt (Va) selected from (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2-methoxy-2-phenylacetate (Vaa), (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2- (2-chlorophenyl) -2-hydroxyacetate (Vab), (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-benzeneamine as a synthesis intermediate for the synthesis of rotigotine Levulinic acid salt (Vac), (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ium (R)2- (6-methoxy-2-naphthyl) -propionic acid salt (Vad) and (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ium (S) -2- (5-chloro-2-oxo-2, 3-dihydroindol-1-yl) -propionic acid salt (Vah).

The synthesis of rotigotine using the diastereomeric salts is particularly advantageous since such salts can be prepared on a large scale. Furthermore, their use allows to obtain the desired enantiomer of the synthetic intermediate (I) in high chiral purity, while the undesired enantiomer is easily removed from the reaction or can be easily regenerated into the desired enantiomer.

Furthermore, the process according to the invention provides compounds of formula (Ia) having better quality/purity than when prepared according to other processes.

Thus, the overall preparation method using the diastereomeric salt of formula (Va) is a cost-effective and efficient alternative synthetic route to rotigotine.

The free base or salt of the compound of formula (Ia) obtained according to any aspect of the present invention may be further converted to rotigotine as shown in the following scheme.

Scheme 8

Dealkylation, such as steps a and a' of scheme 8, is generally well described in the literature, and is achieved by reaction with strong mineral acids or derivatives containing nucleophilic counter ions, such as HBr or HI, or by reaction with lewis acids, such as BBr₃Or AlCl₃The reaction is effected by reaction with nucleophilic thiolates. Preferably, these steps are carried out by reaction with HBr, in the presence or absence of acetic acid.

Steps b and b' of scheme 10 are generally achieved by reacting a compound of formula (Ia) or a compound of formula (VIII) with 2- (2-thienyl) ethanol benzenesulfonate or 2- (2-thienyl) ethanol tosylate in the presence of an alkali metal carbonate or alkali metal bicarbonate.

The resulting salt of the compound of formula (IX) is then converted into the corresponding free base (IX) by reaction with a base according to methods known to those skilled in the art.

In another embodiment according to the invention, the resolution is achieved by differential separation, more preferably by chiral chromatographic separation, using a column packed with a Chiral Stationary Phase (CSP) and a mobile phase. Chiral chromatographic separations can be performed in batch mode or by multi-column chromatography (MCC).

The term "batch-wise" as used herein refers to a discontinuous chromatographic separation technique based on the controlled injection of a mixture onto a column packed with a stationary phase. The separated components of the mixture are then withdrawn at the outlet, and the two enantiomers are alternately collected from the system. The method will include, but is not limited to, liquid chromatography using a solvent or solvent mixture or Supercritical Fluid Chromatography (SFC) using a substance in a supercritical state with a co-solvent or co-solvent mixture.

As used herein, "supercritical state," when referring to a substance, means that the substance is at a temperature and pressure above its critical point.

Thus, supercritical fluid chromatography is a technique for enantiomeric resolution of racemic mixtures, as in the paper "TRIALSEPARATIONS SANDISOMERIDED FOR PREPARATIVE-SCALESEPARATIONSOFENATION AGERS" ("CRISEPTIONAS SERIATIONS SERIESAnnThayer,C&ENHouston, 9/5/2005, Vol 83, No.36, pp.49-53).

The term "multi-column chromatography" (MCC) as used herein refers to a continuous chromatographic separation technique based on the continuous controlled injection of a mixture onto a series of connected columns packed with a stationary phase. The separated components of the mixture are then continuously withdrawn from the system. The method will include, but is not limited to, simulated moving bed chromatography mode (SMB mode), or a mode in which the inlet and outlet ports are exchanged asynchronously, such as variacol mode, or a mode in which the inlet and outlet flow rates and/or concentrations change over time during the transition.

The Application of SMB technology to the enantiomeric resolution of racemic mixtures has been described, for example, in the paper "litmobilestimulus" Application of laser partial' from reactions [ simulated mobile ] information chimiemo No.368 (5 months 1995), pp.113-115 by r.m. nicoud.

The Varicol system is described in international patent application WO00/25885, and the mode in which the fluid flow rate varies with time during the transition is described in U.S. patent No. 5,102,553.

Thus, in another embodiment according to the invention, the resolution of the compound of formula (II) is performed by chiral chromatographic separation. In a further embodiment according to the invention, the resolution of the compound of formula (II) is carried out by MCC or SFC.

Compounds of formula (II) which are particularly suitable for undergoing chiral chromatographic separation according to the invention are those in which R¹And R²Is an alkyl radical, and R³A compound of formula (II) which is alkoxycarbonyl, alkylcarbonyl, aryloxycarbonyl or arylcarbonyl.

It is therefore also an object of the present invention to provide compounds wherein R is¹And R²Is an alkyl radical, and R³A compound of formula (II) which is alkoxycarbonyl, alkylcarbonyl, aryloxycarbonyl or arylcarbonyl.

In a particular embodiment according to the invention, the compound of formula (II) which is particularly suitable for undergoing chiral chromatographic separation according to the invention is wherein R is¹And R²Is an alkyl radical, and R³A compound of formula (II) which is an alkoxycarbonyl group.

Examples of such compounds of formula (II) are N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin, N- (ethoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin and N- (tert-butoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin, hereinafter collectively referred to as compounds of formula (IIb).

The compounds of formula (IIb) are particularly advantageous because they are surprisingly highly soluble in the mobile phase, making them easy to handle when carrying out preparative or industrial scale chiral chromatographic separations. Furthermore, the alkoxycarbonyl group can be easily removed, so that the compound of formula (Ib) obtained from the chiral chromatographic separation of the compound of formula (IIb) can be further subjected to a conversion, for example to rotigotine.

Wherein R is¹And R²Is an alkyl radical, and R³Compounds of formula (II) which are alkoxycarbonyl groups may be prepared by reacting a compound of formula (II) wherein R is¹And R²Is an alkyl radical, and R³A compound of formula (II) which is hydrogen is reacted with an alkyl chloroformate in a solvent in the presence of a base.

In a particular embodiment, the invention relates to the preparation of substantially opticalA method of purifying (S) -N- (alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Ib), which comprises chiral chromatographic separation of N- (alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (IIb), as shown in scheme 9 below, wherein R is^aIs an alkyl group.

Scheme 9

In a particular embodiment according to the invention, R^aIs C_1-4An alkyl group. C_1-4Examples of alkyl groups are methyl, ethyl, isobutyl and tert-butyl.

In a further particular embodiment, the present invention relates to a process for the preparation of substantially optically pure (S) -N- (alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Ib), which comprises MCC isolation of N- (alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (IIb).

In another further particular embodiment, the present invention relates to a process for the preparation of substantially optically pure (S) -N- (alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Ib) comprising supercritical fluid chromatography of N- (alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (IIb).

Wherein R is^aN- (alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (IIb), which is methyl, i.e., N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin, is particularly suitable for MCC or SFC chiral chromatographic separations.

N- (alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (IIb) is more stable to air oxidation than the free base of the compound of formula (IIa), making it a more robust substrate for chiral chromatographic separations.

The columns used according to the invention are generally packed with CSP comprising a silica gel backbone on which a polymeric chiral selector is coated according to techniques well known in the art.

The polymeric chiral selector may additionally be immobilized on a silica gel backbone, which gives, among other benefits, the column better resistance to solvents.

Polymeric chiral selectors according to the present invention generally include polysaccharides, such as amylose or cellulose.

The polymeric chiral selector which may be used according to the invention is cellulose tris (4-methylbenzoate) ((S))OJ), cellulose tribenzoate (CHIRALCELOB), amylose tris (3, 5-dimethylphenylcarbamate) ((III)AD orIA), cellulose tris (3, 5-dimethylphenylcarbamate) (CHIRALCELOD orIB), cellulose tris (4-methylphenyl carbamate) (OG), cellulose tris (3, 5-dichlorophenyl carbamate) ((ii)IC), amylose tris (3-chloro-4-methylphenyl carbamate) ((C)AZ), cellulose tris (3-chloro-4-methylphenyl carbamate) ((III)OZ or Lux^TMCellulose-2), amylose tris (5-chloro)-2-methylphenylcarbamate (A) ((B))AY or Lux^TMAmylose-2) and Amylose tris (5-chloro-2-methylphenyl carbamate) ((R)AZ)。

The chiral selector according to the invention may also be a donor-acceptor phase, for example Pirkle-receptor.

An example of such a donor-acceptor phase which can be used according to the invention is 1- (3, 5-dinitrobenzoylamino) -1,2,3, 4-tetrahydrophenanthrene (WHELK-O1).

In a particular embodiment, the present invention relates to a process for the preparation of (S) -N- (alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Ib) which comprises chiral chromatographic separation of N- (alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (IIb) using cellulose tris (3, 5-dimethylphenylcarbamate) coated on a silica gel backbone as a chiral stationary phase.

Examples of mobile phases that can be used for MCC separation according to the present invention are alkanes such as heptane, hexane; alcohols such as methanol, ethanol, isopropanol, n-propanol, acetonitrile and ethyl acetate. These solvents may be used alone or in combination of one with another.

When solvent mixtures are used, the proportions will depend on the type of solvent constituting the mixture, on the type of column used, and on the solubility of the compounds to be separated in those mixtures.

Examples of solvent mixtures according to the invention are mixtures of alcohols or mixtures of alcohols with alkanes or mixtures of alcohols with acetonitrile or mixtures of alcohols with ethyl acetate.

An example of a mobile phase that can be used for the chromatographic separation of supercritical fluids according to the invention is CO in the supercritical state₂With alcohols, such as methanol,Ethanol, isopropanol, and n-propanol.

When referring to CO₂By supercritical state is meant a fluid state in which carbon dioxide is maintained at or above its critical temperature and critical pressure.

Generally, according to the invention, CO₂Will remain in a fluid state above its critical temperature and critical pressure.

According to the invention, each Kg of chiral stationary phase more than 1Kg racemic mixture separation chiral chromatographic separation productivity can be achieved by liquid phase or supercritical fluid chromatography.

The (S) -N- (alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Ib) obtained according to this aspect of the invention is typically substantially optically pure. This is particularly advantageous as the use of repeated purification steps, such as crystallisation which may affect the overall process yield, is avoided.

The (R) -N- (alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (IIIb) obtained according to this aspect of the invention is typically substantially optically pure.

According to methods known to the person skilled in the art, and as illustrated in the following scheme, N- (alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (IIb) is synthesized by reacting the free base (IIa') previously or generated in situ from the reaction of the compound of formula (IIa) with the corresponding chloroformate or anhydride under basic conditions.

Scheme 10

The compound of formula (Ib) obtained according to the invention can be further converted into rotigotine as shown in the scheme below.

The use of such compounds is particularly advantageous because the commercially available chiral stationary phase does not allow chiral separation of 5,6,7, 8-tetrahydro-6- [ propyl- [2- (2-thienyl) ethyl ] -amino ] -1-naphthol by MCC.

Scheme 11

Step c of scheme 11 is typically achieved by contacting the compound of formula (Ib) with an acidic demethylating agent, such as concentrated HBr.

Alternatively, the compound of formula (Ib) may be reacted with an inorganic acid as defined above to provide a compound of formula (Ia) which is further converted to rotigotine as shown in scheme 8.

Steps a, b, c may also be performed according to any method known to the person skilled in the art.

The compounds of formula (IX) may be obtained in free form or in salt form.

The salt of the compound of formula (IX) is preferably the hydrochloride or hydrobromide salt.

The present invention therefore also relates to the use of the synthetic intermediates (Ia) and (Ib) obtained according to scheme 6 or 9 for the synthesis of N-substituted aminotetralins. In particular, the synthetic intermediates (Ia) and (Ib) obtained according to scheme 6 or 9 are useful for the synthesis of rotigotine and its salts.

It is to be understood that, according to variations and modifications of the present invention, scalability (i.e., the direct processing of an intermediate without isolation into another chemical intermediate or into another physical form or phase) including certain process steps may be achieved without departing from the scope or spirit of the present invention.

Examples

¹HNMR spectra were measured on Varian400MHz and 300MHz and Varian400MHz spectrometers at room temperature in deuterated solvents using TMS as an internal standard.

¹HNMR data are recorded in the order of chemical shift, multiplicities (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; app, apparent and/or multiple resonance), coupling constant (J) in Hertz (Hz), and number of protons.

High Performance Liquid Chromatography (HPLC) spectra were recorded on aliance waters2695 equipped with a 3 micron column of atlantis t3 (4.6X100mm), detection at 200 nm-starting solvent composition = water: 90% v/v water +1% H₃PO₄10% by volume; final solvent composition = water +1% H₃PO₄10% v/acetonitrile 90% v in 6 minutes followed by a 1min re-equilibration time to the original solvent composition.

Chiral HPLC in Chiralpak5 μm (250X4.6mm) columns were recorded on AllianceWaters2695 and detected at 229 nm.

Mass spectra were recorded on a waters3100 triploid analysis spectrometer. IR spectra were recorded with Nicolet380FT-IR (liquid pure and solid KBr pellet).

HPLC was analyzed on different systems Waters2695PDA, Agilent1100UV, Shimadzu-SCL-10 AVP.

HPLC data are reported as area%.

Melting points are recorded on pomomoel dno. mp96.

The MCC used was based on an 8 x 48 model, with 2 pumps and internal recovery cycles, capable of operating with synchronous or asynchronous switching, and equipped with on-line HPLC (Agilent1100) on a panel.

SFC data were recorded on an analytical PIC-SFC system equipped with DAD and preparative separations from PIC solutions were performed on an SFC-PIClab600 system used with 50mm SFC columns.

Example 1- (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine saltPreparation of acid salt (IIa)

A2L reactor equipped with a double-jacketed temperature control was charged with 5-methoxy-2-aminotetralin hydrochloride (Xa) (161g), sodium acetate (62g), and tetrahydrofuran (750 mL). The suspension was stirred at 0 ℃. To this suspension was added glacial acetic acid (22mL), sodium triacetoxyborohydride (200g) and propanal (XIa) (48g, diluted with 50mL of tetrahydrofuran, via dropping funnel, maintaining the material temperature below 10 ℃. the resulting suspension was stirred at 0 ℃ overnight. to this suspension 25% sodium hydroxide solution (250mL) was slowly added at 0 ℃ and the resulting mixture was allowed to warm to room temperature for 30 minutes with stirring, the aqueous layer was discarded and the organic layer was washed with 6.25% sodium hydroxide solution (200mL), the aqueous layer was discarded and the organic layer was heated at 50 ℃. to this solution concentrated hydrochloric acid (77mL) was added over 20 minutes and the resulting thick suspension was diluted with 150mL of tetrahydrofuran, the suspension was kept at 50 ℃ for 30 minutes then cooled rapidly to 10 ℃ and stirred at 10 ℃ for 30 minutes, the product was isolated by filtration, washed twice with cold THF (2x200mL) and dried under vacuum at 40 ℃ until constant weight, to provide N-propyl mat hcl salt as a white solid in 78% yield.

NMR1H (dmsod6) (ppm) 0.94(3H, d),1.76(3H, m),2.04(1H, m),2.32(1H, m),2.47(1H, m),2.99(2H, m),3.17(1H, m),3.30(1H, dd),3.76(3H, s),3.86(1H, m),5.65(2H, t),6.71(1H, d),6.79(1H, d),7.12(1H, t),9.15(2H, broad-peak d) LC-MSES +220.2,161.1

EXAMPLE 2 preparation of N- (Alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (IIb)

Example 2a-N- (Methoxycarbarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Compound (IIb), wherein R ^a Is methyl) preparation

N-propyl-5-methoxy-2-aminotetralin hydrochloride (IIa) was suspended in dichloromethane (10 volumes). Triethylamine (1.64 vol, 3 equivalents) and methyl chloroformate (0.36 vol, 1.2 equivalents) were added. Additional methyl chloroformate (0.13 volumes) was added. The mixture was stirred at ambient temperature for 24 h. The product was isolated by extraction and purified by washing with acidic and neutral aqueous solutions. The organic layer was dried over magnesium sulfate and the solvent was evaporated to give a clear oil. The product was obtained in 85% yield and 100% HPLC conversion.

1HNMR (DMSO)7.05-7.11(1H, t, ArH),6.72-6.77(1H, d, ArH),6.65-6.69(1H, d, ArH),3.92-4.05(1H, brs, CH),3.75(3H, s, OMe),3.59(3H, s, OMe),3.44(1H, s, CH),3.05-3.15(2H, m, CH2),2.84-2.99(2H, m, CH2),2.65-2.75(2H, m, CH2),2.83-2.91(2H, m, CH2),1.45-1.58(2H, m, CH2) and 0.80-0.87(3H, m, CH 3). TOFMSES +278.1998[ M +1] IR (cm-1)3485.13,2957.72,1693.42,1586.48,1468.64,1437.92

Example 2b-N- (ethoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Compound (IIb), where R is ^a Is ethyl) preparation

N-propyl-5-methoxy-2-aminotetralin hydrochloride (IIa) (1 weight) was suspended in dichloromethane (10 volumes). Triethylamine (1.64 vol, 3 equivalents) and ethyl chloroformate (0.44 vol, 1.2 equivalents) were added. The mixture was stirred at ambient temperature for 24 h. Additional ethyl chloroformate (0.07 vol, 0.2 eq) was added. The product was isolated by extraction and purified by washing with acidic and neutral aqueous solutions. The organic layer was dried over sodium sulfate and the solvent was evaporated. The product was obtained in 88% yield and 100% purity as a reddish oil.

¹HNMR7.05-7.09(1H,t,ArH),6.74-6.76(1H,d,ArH),6.65-6.67(1H,d,ArH),3.90-4.10(3H,m),3.73(3H,s,OMe),3.05-3.13(2H,m,CH₂),2.83-2.98(2H,m,CH2),2.65-2.73(2H,m,CH₂),1.76-1.92(1H,m,CH2),1.57-1.67(2H,m,CH₂),1.14-1.18(3H,m,CH₃) And 0.80-0.84(3H, m, CH)₃)。

Example 2c-N- (tert-Butoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Compound (IIb), wherein R ^a Is tert-butyl)

N-propyl-5-methoxy-2-aminotetralin hydrochloride (IIa) (1 wt.) was suspended in THF H₂O (1:1) (10 vol). Addition of NaHCO₃(0.98 wt.) and Boc₂O (1.02 wt). The mixture was stirred from 0 ℃ to ambient temperature for 20 h. The product was isolated by extraction and purified by washing with aqueous solution. The organic layer was dried over magnesium sulfate and the solvent was evaporated. The product was obtained in 78% yield and 96.3% purity.

¹HNMR7.06-7.14(1H,m,ArH),6.63-6.76(2H,m,ArH),3.83(3H,s,OMe),2.78-3.25(5H,m,CH,CH₂),2.54-2.67(1H,m,CH2),1.97-2.07(1H,m,CH₂),1.76-1.92(1H,m,CH2),1.57-1.67(2H,m,CH₂),1.49(9H,s,O^tBu),1.24-1.34(1H,m,CH₂) And 0.86-0.83(3H, m, CH 3).

Example 3 preparation of 1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine hydrochloride (IIa ') from 1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine hydrochloride (IIa')

Method A

22g of the (IIa) salt was suspended in a mixture of MTBE (110mL) and aqueous sodium hydroxide (4 g in 110mL deionized water). The resulting suspension was stirred at room temperature until 2 homogeneous layers were obtained. The layers were separated and the aqueous layer was extracted with 100ml of mtbe. The organic layers were combined, washed with 100mL of deionized water, and then dried over magnesium sulfate. After filtration of the solid, MTBE was evaporated to give 18g of 1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine (IIa') as a colorless oil (yield: 95%).

NMR¹H(CDCl₃)d(ppm):0.96(3H,d),1.54(3H,q),2.07(1H,m),2.59(2H,q),2.69(2H,t),2.90(2H,m),3,01(2H,dd),3.80(3H,s),6.65(1H,d),6.71(1H,d),7.09(1H,t)。

Method B

15g of the (IIa) salt and 32g of potassium carbonate were suspended in 75g of MeTHF. The resulting suspension was stirred at the reflux temperature of MeTHF overnight. After cooling to room temperature, the suspension was filtered and the solid was discarded. The filtrate was evaporated to give 13g of 1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine (IIa') as a colorless oil (yield: 98%).

Example 4 preparation of diastereomeric salt of formula (Va)

Example 4a preparation of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium- (R) -2-methoxy-2-phenylacetate (Vaa) in methanol

A portion of 1.1g of (R) -2-methoxy-2-phenylacetic acid (IVa) is added to a solution of 2g of (IIa') in 35mL of methanol at 25 ℃. The resulting suspension was kept under stirring at 25 ℃ overnight. The solid collected by filtration was washed with 1mL of methanol to provide 1g of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium- (R) -2-methoxy-2-phenylacetate (Vaa) (yield: 29%; chiral HPLC: 95% of (Vaa); 5% of (R) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium- (R) -2-methoxy-2-phenylacetate (V' aa).

NMR1H(dmso-d6)(ppm):0.89(3H,d),1.50(3H,m),2.18(1H,m),2.47(1H,m),2.84(4H,m),3.22(1H,m),3.27(1H,s),3.76(3H,s),4.55(1H,s),6.66(1H,d),6.77(1H,d),7.08(1H,t),7.30(2H,m),7.36(2H,m)。

Example 4 b-on the nailPreparation of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium- (R) -2-methoxy-2-phenylacetate (Vaa) in alcohol-water (1:1)

A portion of 1.1g of (R) -2-methoxy-2-phenylacetic acid (IVa) is added at room temperature to a solution of 2g of (IIa') in 20mL of methanol-water (1: 1). The resulting mixture became a thick suspension. The resulting suspension was heated at 60 ℃ and then cooled to 25 ℃ and kept stirring at this temperature overnight. The solids collected by filtration were washed with 1mL of methanol-water (1:1), slurried in 20mL of methanol-water (1:1) at 60 ℃ and cooled to 25 ℃. The slurry was filtered and the collected solid was washed with 1mL of methanol-water (1:1) and then dried in vacuo to provide 1.5g of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium- (R) -2-methoxy-2-phenylacetate (Vaa) (yield: 42%; chiral HPLC: 96.5% (Vaa); 3.5% (R) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium- (R) -2-methoxy-2-phenylacetate (V' aa).

NMR¹H(dmsod6)(ppm):0.89(3H,d),1.50(3H,m),2.18(1H,m),2.47(1H,m),2.84(4H,m),3.22(1H,m),3.27(1H,s),3.76(3H,s),4.55(1H,s),6.66(1H,d),6.77(1H,d),7.08(1H,t),7.30(2H,m),7.36(2H,m)。

EXAMPLE 4c preparation of (S) -1,2,3, 4-tetrahydro-5-methoxy-n-propyl-naphthalen-2-ammonium (R) -2- (2-chlorophenyl) -2-hydroxyacetate (Vab) in ethanol

A portion of 0.85g of (R) -2- (2-chlorophenyl) -2-hydroxyacetic acid (IVb) is added to a solution of 1g of (IIa') in 5mL of pure ethanol. The resulting mixture was refluxed and then cooled to 35 ℃. The resulting solid was filtered, rinsed with 2mL of ethanol and dried in a vacuum oven to provide 0.31g of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2- (2-chlorophenyl) -2-hydroxyacetate (Vab) (yield: 17%; chiral HPLC: 96.8% of (Vb); 3.2% of (R) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2- (2-chlorophenyl) -2-hydroxyacetate (V' ab).

NMR¹H(dmsod6)(ppm):0.88(3H,d),1.54(3H,m),2.18(1H,m),2.47(1H,m),2.84(4H,m),3.22(1H,m),3.76(3H,s),4.96(1H,s),6.66(1H,d),6.77(1H,d),7.11(1H,t),7.19(1H,m),7.33(2H,m)。

EXAMPLE 4d preparation of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2- (2-chlorophenyl) -2-hydroxyacetate (Vab) in Ethyl acetate

A portion of 0.85g of (R) -2- (2-chlorophenyl) -2-hydroxyacetic acid (IVb) is added to a solution of 1.0g of (IIa') in 5mL of ethyl acetate. The resulting mixture was filtered until a clear solution was obtained, which was then allowed to cool to 50 ℃. The resulting solid was filtered, washed twice with 2mL ethyl acetate, and dried in a vacuum oven to provide 0.45g of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2- (2-chlorophenyl) -2-hydroxyacetate (Vab) in ethyl acetate (yield: 30.6%; chiral HPLC: 96.1% of (Vab); 3.9% of (R) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2- (2-chlorophenyl) -2-hydroxyacetate (V' ab))

NMR1H(dmsod6)(ppm):0.88(3H,d),1.54(3H,m),2.18(1H,m),2.47(1H,m),2.84(4H,m),3.22(1H,m),3.76(3H,s),4.96(1H,s),6.66(1H,d),6.77(1H,d),7.11(1H,t),7.19(1H,m),7.33(2H,m)。

Melting Point-DSC: 134.0 deg.C (start)

EXAMPLE 4e preparation of (S) -1,2,3, 4-tetrahydro-5-methoxy-n-propyl-naphthalen-2-ammonium (R) -2- (2-chlorophenyl) -2-hydroxyacetate (Vab) in Me-tetrahydrofuran

A portion of 2.1g of (R) -2- (2-chlorophenyl) -2-hydroxyacetic acid (IVb) is added to a solution of 2.5g of (IIa') in 10mL of methyl-THF. The resulting mixture was heated to 75 ℃ until a clear solution was obtained, and then cooled to room temperature. The resulting solid was filtered, rinsed twice with 5mL of methyl-THF, and dried in a vacuum oven to provide 1.1g of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2- (2-chlorophenyl) -2-hydroxyacetate (Vab) (yield: 24.7%; chiral HPLC: 97.9% of (Vab); 2.1% of (R) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2- (2-chlorophenyl) -2-hydroxyacetate (V' ab)).

Melting Point-DSC: 136.3 deg.C (start)

Example 4f preparation of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2- (2-chlorophenyl) -2-hydroxyacetate (Vab) in ethyl acetate (AcOEt)

136g triethylamine was added to 250g of the (IIa) salt suspended in a mixture of water (750mL) and AcOEt (1000 mL). The resulting mixture was refluxed for 45 minutes. After cooling at 10 ℃, the layers were separated and the aqueous phase was discarded. The organic layer was washed twice with 500mL of water and then azeotropically dried to constant volume. The resulting solution of (IIa') is then cooled to 55-60 ℃ and 183g of (R) -2- (2-chlorophenyl) -2-hydroxyacetic acid (IVb) are added in one portion. Crystallization was initiated by seeding with 2.5g of essentially optically pure (Vab) seed. The resulting suspension was stirred at 50 ℃ for 4 hours and then cooled to 0 ℃ (in 50 ℃). The solid was isolated by filtration and washed twice with 250ml acoet. Slurrying the solids with 720mlac oet; the slurry suspension was refluxed for 2 hours and then cooled to 0 ℃ over 4 hours to be filtered. The isolated solid was washed with 300mL of AcOEt and dried under vacuum to provide 136g of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2- (2-chlorophenyl) -2-hydroxyacetate (Vab) (yield: 34%; chiral HPLC: 99.4% of (Vab); 0.6% of (R) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2- (2-chlorophenyl) -2-hydroxyacetate (V' ab)).

Example 4g preparation of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate (Vac) in isopropanol

A portion of 0.38g of (S) -2-hydroxy-3-phenylpropionic acid (IVc) is added to a solution of 1g of (IIa') in 5mL of isopropanol. The resulting mixture was refluxed and cooled to 25 ℃. Before it was filtered, the suspension was diluted with 1mL of isopropanol; the resulting solid was rinsed three times with 2mL of isopropanol and dried in a vacuum oven to provide 0.59g of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate (Vac) (yield: 34%; chiral HPLC: 95.2% of (Vac); 4.8% of 1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate (V' ac)).

NMR1H(dmsod6)(ppm):0.93(3H,d),1.65(3H,m),2.22(1H,m),2.48(1H,m),2.66(1H,m),2.84(4H,m),3.00(1H,dd),3.10(1H,dd),3.23(1H,m),3.76(3H,s),3.86(1H,m),6.69(1H,d),6.77(1H,d),7.11(1H,t),7.21(5H,m)

Melting Point-DSC 118.5 deg.C (onset)

EXAMPLE 4h preparation of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate (Vac) in THF

A portion of 0.38g of (S) -2-hydroxy-3-phenylpropionic acid (IVc) is added to a solution of 1g of (IIa') in 5ml of THF. The resulting mixture was refluxed and cooled to 25 ℃. The solid obtained was filtered, washed three times with 2ml THF, and dried in a vacuum oven to provide 0.72g of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate (Vc) (yield: 41%; chiral HPLC: 91.4% of (Vac); 8.6% of (R) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate (Vac).

Melting Point-DSC 111.9 deg.C (onset)

Example 4i preparation of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate (Vac) in THF

A portion of 2.3g of (S) -2-hydroxy-3-phenylpropionic acid (IVc) is added to a solution of 6g of (IIa') in 60ml of THF. The resulting mixture was refluxed and cooled to 20 ℃ over 10 hours. The resulting solid was filtered, washed twice with 6mL THF, and oven dried to provide 4.8g of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate (Vac) (chiral HPLC: 80.2% of (Vc); 19.8% of (R) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate (V' ac))

4.7g of (Vac) are suspended in 75mL of tetrahydrofuran. The resulting suspension was refluxed until a slightly cloudy solution was observed and then cooled to 5 ℃. The solid obtained was filtered once cooled, rinsed twice with 5mL fresh THF, and dried in a vacuum oven to provide 4g of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate (Vac) (overall yield: 38%; chiral HPLC: 98.7% of (Vac); 1.3% of (R) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate (V' ac)).

Melting Point-DSC 121.2 deg.C (onset)

EXAMPLE 4j preparation of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ium (S) -2-hydroxy-3-phenylpropionate (Vac) in 2-methyl THF

A solution of 60g of (S) -2-hydroxy-3-phenylpropionic acid (IVc) in 365mL is added to a solution of 143g of (IIa') in 360mL of THF. The resulting suspension was stirred at 70 ℃ for 1 hour, then cooled to 25 ℃ over 7.5 hours and aged at 25 ℃ for 8 hours. The solid was collected by filtration, rinsed twice with 70 mM ME-THF, and oven dried to provide 113g of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate (Vac) (yield: 45%; chiral HPLC: 98.7% of (Vac); 1.3% of (R) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate (V' ac)).

EXAMPLE 5 preparation of essentially optically pure ((S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalene-2-aminium hydrochloride (Ia) from salt (Va) described in the above example

Example 5a preparation of substantially optically pure ((S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalene-2-aminium hydrochloride (Ia) from salt (Vac)

The isolated diastereoisomeric salt (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate (Vac) was suspended in a mixture of Me-THF (5 vol) and water (2 vol). Sodium hydroxide (1.1 eq) was added as a solid. The resulting suspension was stirred at room temperature until completely dissolved. The layers were allowed to separate and the aqueous layer was discarded. The organic layer was washed twice with deionized water (2 volumes) and then heated at 60 ℃. (Ia) was formed by the addition of a 37% hydrochloric acid solution (1.1 equiv.). After cooling at 0-10 ℃, the resulting solid was filtered, washed twice with Me-THF and dried under vacuum to afford (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine hydrochloride (Ia) (yield: 84%; chiral HPLC: 100% of (Ia)).

NMR1H (dmsod6) (ppm) 0.94(3H, d),1.76(3H, m),2.04(1H, m),2.32(1H, m),2.47(1H, m),2.99(2H, m),3.17(1H, m),3.30(1H, dd),3.76(3H, s),3.86(1H, m),5.65(2H, t),6.71(1H, d),6.79(1H, d),7.12(1H, t),9.15(2H, broad d)

Melting Point-DSC: 282 deg.C (Start)

EXAMPLE 5b preparation of ((S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalene-2-ammoniumsalt (Ia) from salt (Vab)

The separated diastereoisomeric salt (Vab) was suspended in a mixture of THF (5 vol) and water (1 vol). The resulting suspension was heated to 65 ℃, thereby obtaining a transparent solution. A 37% hydrochloric acid solution (1.1 eq) was added over 15 minutes and after approximately one third of the acid was added, Ia began to crystallize. The resulting suspension was refluxed for 1 hour, then cooled to 60 ℃ and held at this temperature for 1 hour, then finally cooled to 0 ℃ over 6 hours. The resulting solid was filtered, washed twice with THF (1 vol) and dried under vacuum to afford (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine hydrochloride (Ia) (yield: 94%; chiral HPLC: 100% of (Ia)).

Example 6 preparation of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine hydrochloride (Ia) via separation of (S) - (1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium- (S) -2-methoxy-2-phenylacetate with (S) -2-methoxy-2-phenylacetate in mother liquor of resolution of (IIa)

A portion of 3.4g of (S) -2-methoxy-2-phenylacetic acid (IVa ') is added to a solution of 4g of (IIa') in 25mL of methanol and 25mL of water. The resulting suspension was refluxed, cooled to 25 ℃, and then filtered to provide a solution of a mother liquor containing (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium- (S) -2-methoxy-2-phenylacetate (chiral HPLC: 98.04% of (Vaa '); 1.96% of (R) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-methoxy-2-phenylacetate (V ' aa ').

The solution obtained from the mother liquor was evaporated to dryness by distillation. The residue obtained is diluted with 10ml of THF and heated to 70 ℃. Hydrochloric acid solution (2 eq) was added and a solid precipitated out. The solid formed was isolated by filtration, washed with THF (2X1mL) and dried in vacuo to provide 1.8g of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine hydrochloride (Ia) (overall yield from IIa': 38.5%; chiral HPLC: 99.7% of (Ia)).

NMR1H (dmsod6) (ppm) 0.94(3H, d),1.76(3H, m),2.04(1H, m),2.32(1H, m),2.47(1H, m),2.99(2H, m),3.17(1H, m),3.30(1H, dd),3.76(3H, s),3.86(1H, m),5.65(2H, t),6.71(1H, d),6.79(1H, d),7.12(1H, t),9.15(2H, broad d).

Example 7 preparation of (RS) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine hydrochloride (IIa) from the diastereomeric salt (V' a)

7.1. Preparation of (R) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine (III)

To a stirred solution of 1 equivalent of any of the undesired diastereomeric salts described in example 5 (V' a) are added water (3 volumes relative to 1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine) and triethylamine (1 equivalent relative to 1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine). The biphasic system was stirred and decanted at room temperature. The lower aqueous layer was allowed to sink and separate. The organic layer was washed twice with water. The organic layer was dried by azeotropic distillation.

Preparation of (RS) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine hydrochloride (IIa)

(R) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-amine (III) (1 eq) obtained in example 7.1 was adjusted to-9.5 volumes of dilution in EtOAc. 1-dodecylmercaptan (1.2 equiv.) was added and the solution was heated to reflux under a nitrogen atmosphere. A solution of AIBN (0.1 eq) in 0.5 volume of EtOAc was added dropwise over 5 min. The solution was stirred for 30min after reflux.

37% w: wHCl in water (1.1 equiv.) was added dropwise to the resulting mixture at reflux for 5min to precipitate N-propyl MAT. The suspension was cooled down to 20 ℃ (Tramp = -20 ℃/h). The suspension was stirred after 20 ℃ for a minimum of 30min and filtered. The filter cake was washed twice with EtOAc (2 × 1 volumes). The wet solid was dried under vacuum at 40 ℃ to afford an off-white solid. Yield: 95.0% from (III)

Example 8 preparation of (S) - (alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Ib) by chiral chromatography of N- (alkoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (IIb)

The method A comprises the following steps: reacting N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Compound (IIb), wherein R is ^a Is methyl) into (S) -N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Ib) and (R) -N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (IIIb)

Preparation of 10.5kg of N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Compound (IIb), where R is^aIs methyl) in ethanol and stirred under nitrogen until complete dissolution is achieved. The solution was continuously injected into an MCC system equipped with six identical columns of 11.1cm length and 4.8cm inner diameter in a 1-2-2-1 configuration. Each column contained 125g of chiral stationary phase containing cellulose tris (3, 5-dimethylphenylcarbamate) coated on a silica gel backbone and the enantiomers were separated using ethanol as the mobile phase.

Substantially optically pure (S) -N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Ib) and (R) -N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (IIb) are extracted from the effluent and are obtained in an enantiomeric excess of greater than 99%.

The chiral separation of the compound of formula (IIb) according to Process A yielded 3.4Kg of (IIb) per Kg of chiral stationary phase per day.

The method B comprises the following steps: reacting N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Compound (IIb), wherein R is ^a Is methyl) into (S) -N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Ib) and (R) -N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (IIIb)

Preparation of 10.5kg of N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Compound (IIb), where R is^aIs methyl) in ethanol and stirred under nitrogen until complete dissolution is achieved. The solution was continuously injected into an MCC system equipped with five identical columns of 11.1cm length and 4.8cm inner diameter in a configuration of 1-1.5-1.75-075. Each column contained 125g of chiral stationary phase containing cellulose tris (3, 5-dimethylphenylcarbamate) coated on a silica gel backbone and the enantiomers were separated using ethanol as the mobile phase.

The chiral separation of the compound of formula (IIb) according to Process B yielded 4.15Kg of (IIb) per Kg of chiral stationary phase per day.

The method C comprises the following steps: reacting N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Compound (IIb), wherein R is ^a Is methyl) The resolution is (S) -N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Ib) and (R) -N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (IIIb)

Preparation of 3.6g of N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin (Compound (IIb), wherein R is^aIs methyl) in IPA and stirred under nitrogen until complete dissolution is achieved. The solution was injected discontinuously in a batch mode into an SFC system equipped with a column 26cm long and 5cm internal diameter. The column contained 300g of chiral stationary phase comprising cellulose tris (3, 5-dimethylphenylcarbamate) coated on a silica gel backbone and was purified using IPA15% and CO₂85% separated the enantiomers as a mobile phase.

(S) -N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin and (R) -N- (methoxycarbamoyl) -N-propyl-5-methoxy-2-aminotetralin are extracted from the effluent in substantially optically pure form and are obtained in an enantiomeric excess of greater than 99%.

The chiral separation of the compound of formula (IIb) according to method C yielded 1.5Kg of (IIb) per Kg of chiral stationary phase per day.

Example 9 preparation of a Compound of formula (VIII) from a Compound of formula (Ib)

15g of the compound of the formula (Ib) are dissolved in 30ml (2 vol.) of AcOH. Aqueous 48% HBr (52.6 mL, 8.6 equiv.) was heated to 60-70C and the solution of (Ib) was added slowly over 25 minutes. The reaction mixture was then heated (jacket temperature 90 ℃) and stirred for 30 minutes. The jacket temperature was then raised to 125 ℃ and stirred for 6 hours. Once the reaction was complete, the mixture was cooled to 20 ℃ and 30ml water (2 vol) was added. The precipitated salt was filtered, washed with 15mL (1 volume) and dried under vacuum at 40 ℃ to constant weight. The yield is 88.6 percent

¹HNMR(DMSO)9.40(1H,s,OH),8.58(2H,brs,NH.HBr),6.93–6.96(1H,m,ArH),6.63–6.65(1H,m,ArH),6.55–6.57(1H,m,ArH),3.40(1H,m,CH),3.10–3.14(1H,m,CH),2.98(2H,m,CH2),2.81(2H,m,CH2),2.45(1H,m,CH),2.23(1H,m,CH),1.67(3H,m),0.93-0.96(3H,m,CH₃)

Example 10 preparation of rotigotine from a Compound of formula (Ia)

Example 10.1 conversion of (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalene-2-aminium hydrochloride (Ia) to (S) -1,2,3, 4-tetrahydro-5-hydroxy-N-propyl-naphthalene-2-ammoniumhydrobromide (VIII)

Will be provided with(S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalene-2-aminium hydrochloride (Ia)(60.9g), sodium bisulfite (0.61g), aqueous HBr (48%,345.6g) and glacial acetic acid (103.3g) were combined. The batch was gradually heated to reflux and aged at this temperature for a minimum of 2 hours. At the completion of the reaction, the batch was cooled to 20 ± 5 ℃ and aged at this temperature for a minimum of 1 hour. The batch was filtered, washed with water (120mL) and dried to provide 60.5g (88.8% yield)

HPLC analysis confirmed a purity of >99% and the content was determined to be 99% compared to the reference standard.

Example 10.2 conversion of (S) -1,2,3, 4-tetrahydro-5-hydroxy-N-propyl-naphthalene-2-ammonium hydrobromide (VIII) to rotigotine hydrochloride

10.2.1.2 preparation of 2- (2-thienyl) ethyl-4-tosylate

4-Toluenesulfonylchloride (162g), toluene (363.3g), and 2- (2-thienyl) ethanol (104g) were combined. Triethylamine (93g) was added while maintaining the temperature below 45 ℃. After 4 hours, the mixture was washed with aqueous phosphoric acid, aqueous sodium hydroxide, and then water. The organic phase is distilled off under vacuum. Isopropanol (314g) and heptane (365.9g) were added. The batch was crystallized by cooling and isolated at-15 ℃. The crystals were filtered and washed with heptane (175 mL). The crystals were then dried under vacuum at room temperature until a melting point of 30 ℃ or higher was obtained.

Yield (214 g): 93.6 percent

HPLC analysis confirmed a purity of >99% and the content was determined to be 100%, compared to the reference standard.

10.2.2. (S) -1,2,3, 4-tetrahydro-5-hydroxy-N-propyl-naphthalen-2-aminium hydrobromide (VIII) to rotigotine hydrochloride

(S) -1,2,3, 4-tetrahydro-5-hydroxy-N-propyl-naphthalene-2-ammonium hydrobromide (VIII) (44.5g), sodium carbonate (24.0g), o-xylene (390g) and purified water (320g) were heated to 70-80 ℃ and stirred until all solids were dissolved. The pH of the aqueous phase was adjusted to 9.5-10.5 with phosphoric acid (25%). The phases were separated and the organic phase was washed with water (105 g). The organic phase was incompletely distilled and added to sodium carbonate (20 g). To the organic phase were added 2- (2-thienyl) ethyl-4-tosylate (64g) obtained in 10.2.1, sodium carbonate (0.2g) and o-xylene (130g) and heated to reflux. When the reaction was complete by HPLC, the batch was cooled and water (290mL) was added. The pH of the aqueous phase was adjusted to 9.5-10.5 with phosphoric acid (25%) at 75-85 ℃.

The organic layer was then washed with water (290 mL). The organic layer was extracted with a pre-mixed solution of water (220mL) and phosphoric acid (25%,91g), and then twice with water (54mL) and phosphoric acid (25%,18g) at 70-90 ℃. The aqueous phase was passed through charcoal and celite, and then toluene (270g) and NaOH (50%,30g) were added. The pH of the aqueous phase is adjusted to 5.5-6.5 at 75-85 ℃ and the phases are separated. The organic phase is washed with water and then incompletely distilled. 2-propanol (72g) and rotigotine hydrochloride seeds were added at 45-55 ℃. Hydrochloric acid (37%,14g) was added slowly. After crystallization, the batch was cooled to 15-25 ℃, filtered and washed with a premixed solution of toluene (60g) and 2-propanol (20 g). The product was then dried under vacuum to a constant weight of 44.8 g.

The yield thereof was found to be 82%.

HPLC analysis confirmed the purity to be greater than, and the content was determined to be 100.8%, compared to the reference standard.

10.3 conversion of rotigotine hydrochloride to rotigotine

Water (295g) and rotigotine hydrochloride (120g), followed by aqueous ammonia (25%,111g) and cyclohexane (295g) were heated to reflux and stirred for 30-50 minutes. The mixture was cooled to 55-65 ℃ and the phases separated. Water (250mL) was charged and the batch was heated to reflux for 30-50 minutes. The batch was cooled to 55-65 ℃ and the phases separated. The batch was then heated to reflux and cyclohexane/water distilled until no more water was collected. The batch was then cooled to 70-78 ℃. If the volume of cyclohexane distilled off exceeds 15mL, an equivalent amount of cyclohexane to the distilled off is charged back to the batch. The organic phase was filtered through activated carbon and celite, rinsing with cyclohexane (110 g). The filtrate was adjusted to 60-70 ℃. The batch is stirred at this temperature for 30 to 50 minutes. The batch was then cooled to 54-60 ℃ and rotigotine seeds were added. After 15 minutes, the batch temperature was reduced to 37 ℃ in an interval of 5 ℃ every 60 minutes. After stirring at 37 ℃ for 1h, the batch is cooled to 25 ℃ and kept at this temperature for 1 h. The batch was then cooled and stirred at 6-12 ℃ for at least two hours. The slurry was then filtered and washed with cyclohexane (48 g). 101.5g rotigotine was obtained.

The yield is 94.4%

HPLC analysis confirmed >99% purity, assay 100.2%, compared to reference standard.

Claims

1. A process for the preparation of substantially optically pure 2-aminotetralins of formula (I) by resolution of diastereomeric salts of a compound of formula (II),

wherein the salt resolution of the compound of formula (II) is performed according to the following steps:

(i) reacting the free base of the compound of formula (II) with a substantially optically pure acid (IV) selected from the group consisting of (R) -2-methoxy-2-phenylacetic acid, (R) -2- (2-chlorophenyl) -2-hydroxyacetic acid, (S) -2-hydroxy-3-phenylpropionic acid and (R) - (-) -2- (6-methoxy-2-naphthyl) -propionic acid in a solvent to provide diastereomeric salts (V) and (V');

(ii) crystallizing the resulting diastereoisomeric salt (V) in a solvent; and

(iii) (iii) reacting the diastereomeric salt (V) obtained as a result of step (ii) with a mineral acid to provide a salt of the compound of formula (I); and is

Wherein HX is hydrochloric acid or hydrobromic acid, R¹And R²Is an alkyl radical, and R³Is hydrogen.

2. The process according to claim 1, wherein when the compound of formula (II) is in the form of a salt, said compound is treated with a base prior to step (i).

3. A process according to claim 1, wherein the diastereoisomeric salt (V') is regenerated to the HX salt of the compound of formula (II) by performing the following steps:

(vii) treating the compound of formula (II) with a mineral acid of formula HX to provide the corresponding HX salt of the compound of formula (II);

wherein HX, R¹、R²And R³Have the meaning defined in claim 1.

4. The process according to claim 1, wherein the compound of formula (II) is 1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-aminium hydrochloride (IIa).

5. The process according to claim 1, wherein the salt of the compound of formula (I) is substantially optically pure (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-aminium hydrochloride (Ia).

6. The process according to claim 1, wherein the diastereomeric salt of formula (V) is selected from (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2-methoxy-2-phenylacetate, (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R) -2- (2-chlorophenyl) -2-hydroxyacetate, (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (S) -2-hydroxy-3-phenylpropionate and (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-ammonium (R)2- (6-methoxy-2-naphthyl) -propanoic acid salt.

7. The process according to claim 2, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium hydrogen phosphate, sodium hydrogen phosphate, potassium phosphate, sodium phosphate, diisopropylamine, triethylamine, piperidine and pyrrolidine.

8. The process according to claim 1, wherein the solvent used in step (i) is selected from the group consisting of water, methanol, ethanol, propan-1-ol, propan-2-ol, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, isopropyl acetate, and mixtures of two or more of these solvents.

9. The process according to claim 8, wherein a mixture of water and an organic solvent is used.

10. A process according to claim 9, wherein the aqueous phase is discarded before the crystallization of the diastereoisomeric salt (V) and the remaining organic phase is cooled at a temperature between-10 ℃ and 0 ℃.

11. A process according to claim 3, wherein step (vi) is free radical mediated racemisation.

12. A process according to any one of claims 1 to 11, having a dissociability between 0.45 and 0.90, and wherein the dissociability is represented by S and is defined as the product of the yield of the diastereomeric salt and the diastereomeric excess of the isolated diastereomeric salt.

13. A process for the preparation of rotigotine (IX) or a salt thereof, comprising the steps of:

(1) a process for the preparation of substantially optically pure 2-aminotetralins of formula (I) by resolution of diastereomeric salts of a compound of formula (II),

(ii) crystallizing the resulting diastereoisomeric salt (V) in a solvent; and

(iii) (iii) reacting the diastereomeric salt (V) obtained as a result of step (ii) with a mineral acid to provide a salt of the compound of formula (I);

wherein R is¹And R²Is an alkyl radical, and R³Is a hydrogen atom, and is,

wherein the salt of the compound of formula (I) is substantially optically pure (S) -1,2,3, 4-tetrahydro-5-methoxy-N-propyl-naphthalen-2-aminium hydrochloride (Ia), and

(2) preparing rotigotine (IX) or a salt thereof starting from a compound of formula (Ia):

(a) reacting a compound of formula (Ia) with aqueous HBr in the presence of acetic acid;

(b) reacting the compound of formula (VIII) obtained as a result of step (a) with 2- (2-thienyl) ethanol benzenesulfonate or 2- (2-thienyl) ethanol tosylate in the presence of an alkali metal carbonate or alkali metal bicarbonate;

wherein HX is hydrochloric acid.