FORM-2
THE PATENTS ACT. 1970 (39 of 1970)
COMPLETE SPECIFICATION (Section 10, rule 13)
"A Novel processed for the preparation of 2-methyl-3-nitro-phenylethylamines
Sekhsaria Chemicals Ltd
with corporate office at 301, Corporate Enclave, B. D. Sawant Marg, Chakala, Andheri (E), Mumbai 400 099, Maharashtra, India.
an Indian Company registered under the provisions of the Companies Act, 1956.
The following specification particularly describes the nature of the invention and the manner in which it is to be performed: -

FIELD OF THE INVENTION
The present invention relates to novel processes for the preparation of 2-methyl-3-nitro-phenylethylamines 6 comprising one or more of steps (a) to (d) shown in Figures 1 and 3. The present invention also relates to novel processes for the preparation of 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-ones 9, in particular ropinirole hydrochloride 9a, comprising one or more of steps (a) to (g) shown in Figures 1 and 3.
The present invention further relates to 2-methyl-3-nitro-phenylethylamines 6 and salts thereof, and to 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-ones 9 and pharmaceutically acceptable salts and derivatives thereof, in particular ropinirole hydrochloride 9a, when prepared by processes according to the present invention. The present invention also relates to the use of 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-ones 9 and pharmaceutically acceptable salts and derivatives thereof, in particular ropinirole hydrochloride 9a, for the treatment of disorders of the central nervous system (especially Parkinson's disease), disorders which can prevent or disturb sleep, cardiovascular disorders, disorders of impaired kidney function, memory disorders or sexual dysfunction. Finally, the present invention relates to novel intermediates used in the processes of the present invention.
BACKGROUND OF THE INVENTION
The present invention relates to novel processes for the preparation of 2-methyl-3-nitro-phenylethylamines 6, processes which in themselves form part of novel processes for the preparation of 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-ones 9, and in particular 4-[2-(N,N-di-n-propylamino)ethyl]-l,3-dihydro-2H-indol-2-one, which is more commonly known by its generic name, ropinirole.
(«-Pr)2N

H
ropinirole
Ropinirole selectively interacts with dopamine D2-receptors and its hydrochloride salt is marketed under the trade name ReQuip® for the treatment of Parkinson's disease and under the trade name Adartrel® for the treatment of restless legs
syndrome.
2

A process for the preparation of ropinirole was first disclosed in US 4,452,808 (and also reported in Gallagher et al., J. Med. Chem., 1985, vol. 28, pp. 1533-1536), which was improved upon in EP 0,266,033. These documents disclose a process starting from 2-methyl-3-nitro-phenylacetic acid and proceeding via 2-methyl-3-nitro-phenylethyl-Af VV-di-«-propylamine, with a reductive cyclisation as the final step to form the indolone.
An alternative route, starting from isochroman, is disclosed in US 4,977,954, in which the indolone ring system is formed prior to displacement of a bromo group on the ethyl side chain to give ropinirole. A variation on this is provided by US 5,336,781, in which a sulphonic ester is displaced rather than a bromo group.
Yet another route is provided by WO 94/15918, in which the indolone ring system is generated by the reduction of an isatin precursor, itself generated from a 3-amino-phenylethyl compound, with the displacement of a suitable leaving group on the ethyl side chain occurring either before or after the reduction.
More recently, WO 2005/040115 disclosed a route to ropinirole starting from 4-indolcarboxaldehyde; and US 2005/0192338 disclosed an alternative means of generating the indolone ring system using O-acyl hydroxamic acid derivatives. Nevertheless, there is always a need to provide alternative processes for the manufacture of commercially valuable pharmaceuticals.
The present inventors have therefore developed novel processes for the preparation of 2-methyl-3-nitro-phenylethylamines 6, processes which in themselves form part of novel processes for the preparation of 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-ones 9, and in particular ropinirole and salts and derivatives thereof. The novel processes afford ropinirole in high yield and high purity, with a high degree of safety, on an industrial scale if desired.
SUMMARY OF THE INVENTION
A first aspect of the present invention provides a process comprising one or more of the steps of:
3

(dl) reducing a cyanide 4 to give an amine 5, and


N H,N
&.
N02 4
(d2) alkylating the amine 5 to give a 2-methyl-3-nitro-phenylethylamine 6, or a salt thereof,

R2R3N'
-CH3 ^ ^XH3
5

wherein R2 and R3 are independently hydrogen or straight-chained, branched or cyclic C1-C20 alkyl.
The process of the first aspect of the present invention preferably provides a 2-methyl-3-nitro-phenylethylamine 6. However, the present invention also encompasses the scenario where step (d2) is not present in the above process, i.e. a process for the preparation of 2-methyl-3-nitro-phenylethylamine 5.
For the purposes of the present invention, an "alkyl" group is defined as a monovalent saturated hydrocarbon, which may be straight-chained or branched, or be or include cyclic groups. An alkyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of alkyl groups are methyl, ethyl, n-propyl, n-propyl, n-butyl, n-butyl, i-butyl and n-pentyl groups. Preferably an alkyl group is straight-chained or branched. Preferably it does not include any heteroatoms in its carbon skeleton. Preferably an alkyl group is a C1-C2o alkyl group, which is defined as an alkyl group containing from 1 to 20 carbon atoms. More preferably, an alkyl group is a C1-C12 alkyl group, which is defined as an alkyl group containing from 1 to 12 carbon atoms. More preferably, an alkyl group is a C1-C6 alkyl group, which is defined as an alkyl group containing from 1 to 6 carbon atoms. An "alkylene" group is similarly defined as a divalent alkyl group.
An "alkenyl" group is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon double bond, which may be straight-chained or branched, or be or include cyclic groups. An alkenyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of alkenyl groups are vinyl,
4

allyl, but-1-enyl and but-2-enyl groups. Preferably an alkenyl group is straight-chained or branched. Preferably it does not include any heteroatoms in its carbon skeleton. Preferably an alkenyl group is a C2-C|2 alkenyl group, which is defined as an alkenyl group containing from 2 to 12 carbon atoms. More preferably an alkenyl group is a C2-C6 alkenyl group, which is defined as an alkenyl group containing from 2 to 6 carbon atoms. An "alkenylene" group is similarly defined as a divalent alkenyl group.
An "alkynyl" group is defined as a monovalent hydrocarbon, which comprises at least one carbon-carbon triple bond, which may be straight-chained or branched, or be or include cyclic groups. An alkynyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of alkynyl groups are ethynyl, propargyl, but-1-ynyl and but-2-ynyl groups. Preferably an alkynyl group is straight-chained or branched. Preferably it does not include any heteroatoms in its carbon skeleton. Preferably an alkynyl group is a C2-Ci2 alkynyl group, which is defined as an alkynyl group containing from 2 to 12 carbon atoms. More preferably an alkynyl group is a C2-C6 alkynyl group, which is defined as an alkynyl group containing from 2 to 6 carbon atoms. An "alkynylene" group is similarly defined as a divalent alkynyl group.
An "aryl" group is defined as a monovalent aromatic hydrocarbon. An aryl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton. Examples of aryl groups are phenyl, naphthyl, anthracenyl and phenanthrenyl groups. Preferably an aryl group does not include any heteroatoms in its carbon skeleton. Preferably an aryl group is a C4-C2o aryl group, which is defined as an aryl group containing from 4 to 20 carbon atoms. More preferably, an aryl group is a C4-C14 aryl group, which is defined as an aryl group containing from 4 to 14 carbon atoms. More preferably, an aryl group is a C6-Cio aryl group, which is defined as an aryl group containing from 6 to 10 carbon atoms.
For the purposes of the present invention, where a combination of groups is referred to as one moiety, for example, arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule. A typical example of an arylalkyl group is benzyl.
For the purposes of this invention, an optionally substituted alkyl, aryl or arylalkyl group may be substituted with one or more of -F, -CI, -Br, -I, -CF3, -CC13, -CB3, -CI3, -OH, -SH, -NH2, -CN, -N02, -COOH, -Ra-0-Rb, -Ra-S-Rb, -Ra-SO-Rb, Ra-S02-Rb, -Ra-S02-ORb, -RaO-S02-Rb, -Ra-S02-N(Rb)2, -Ra-NRb-S02-Rb,
5

-RaO-S02-ORb, -RaO-S02-N(Rb)2, -Ra-NRb-S02-ORb,

-Ra-NRb-S02-N(Rb)2,

-Ra-N(Rb)2, -Ra-N(Rb)3+, -Ra-P(Rb)2> -Ra-Si(Rb)3, -Ra-CO-Rb, -Ra-CO-ORb, -RaO-CO-Rb, -Ra-CO-N(Rb)2, -Ra-NRb-CO-Rb, -RaO-CO-ORb, -RaO-CO-N(Rb)2, -Ra-NRb-CO-ORb, -Ra-NRb-CO-N(Rb)2, -Ra-CS-Rb, -Ra-CS-ORb, -RaO-CS-Rb, -Ra-CS-N(Rb)2, -Ra-NRb-CS-Rb, -RaO-CS-ORb, -RaO-CS-N(Rb)2, -Ra-NRb-CS-ORb, -Ra-NRb-CS-N(Rb)2 or -Rb. In this context, -Ra- is independently a chemical bond, a C,-C10 alkylene, CrCi0 alkenylene or C1C10 alkynylene group. -Rb is independently hydrogen, unsubstituted Ci-C6 alkyl or unsubstituted C6-Ci0 aryl. Optional substituent(s) are not taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituent(s). Preferably a substituted group comprises 1, 2 or 3 substituents, more preferably 1 or 2 substituents, and even more preferably 1 substituent.
The term "halo" includes fluoro, chloro, bromo and iodo.
One embodiment of the first aspect of the present invention provides a process
comprising one or more of the steps of:
(a) reducing a benzoic acid 1 to give a benzyl alcohol 2,


CH,
C02H

HO

NO,

(b) converting the benzyl alcohol 2 into a compound 3,

CH,
HO

NO,

X.
a

2 3
(c) displacing the substituent X of the compound 3 to give a cyanide 4,
CH,
CH,

X^ NC.
NO,
NO,
3 4
(dl) reducing the cyanide 4 to give an amine 5,
6


H,N
CH,
CH,
NC

NO,

NO,

4 5
(d2) alkylating the amine 5 to give a 2-methyl-3-nitro-phenylethylamine 6, or a salt thereof,
R2R3N'

H2N^
NO,
^<^ i
5 6

(e) converting the 2-methyl-3-nitro-phenylefhylamine 6, or a salt thereof, into a pyruvate 7, or a salt thereof,


R2R3N
OR4
R2R3N^^
CH,
a
NO,

6 7
(f) converting the pyruvate 7, or a salt thereof, into a carboxylic acid 8, or a salt thereof, and

R2R3N^ ^| O R2R3N'
OR4

7 8
(g) reductively cyclising the carboxylic acid 8, or a salt thereof, to give a 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-one 9, or a pharmaceutical^ acceptable salt or derivative thereof,

R2R3N'' > R2R3N'
^^C02H ~NO,

C4-C20 aryl or C5-C20 arylalkyl; and R2, R3 and R4 are independently hydrogen or
wherein X is halo or -OSO2R1; R1 is substituted or unsubstituted C1-C20 alkyl, C4-C20 aryl or C5-C20 arylalkyl; and R2, R3 and R straight-chained, branched or cyclic C1-C20 alkyl.

In preferred embodiments:

7

(i) step (a) is performed in the presence of iodine; and/or
(ii) step (b) is performed using a thionyl halide in a solvent with a boiling point
of less than 95°C; and/or
(iii) step (c) is performed in the presence of a phase-transfer catalyst; and/or
(iv) step (e) is carried out over more than 24 hours; and/or
(v) step (e) is performed using a Group I metal and the reaction is quenched at
a pH of 8 to 9.5; and/or
(v) step (e) is performed using a tert-butoxide salt; and/or
(vii) the product of step (f) is isolated without distilling off more than 10% of
any solvent with a boiling point of more than 65°C present in the reaction
mixture.
A second aspect of the present invention provides a process comprising one or more of the steps of:
(a) reducing a benzoic acid 1 to give a benzyl alcohol 2,

CH,
CHi

C02H

NO,

NO,

(b) converting the benzyl alcohol 2 into a compound 3,

CH,
CH,

NO,

NO,

2 3
(c) displacing the substituent X of the compound 3 to give a cyanide 4,

CH,
CH,
NO,

NO,
3 4
(d3) hydrolysing the cyanide 4 to give a carboxylic acid 10,
NC^ H02Cs

XH, /L /CH,
NO,
NO,
10

(d4) converting the carboxylic acid 10 into a 2-methyl-3-nitro-phenylethylamide 11,
o
R2R3N
CH,
CH,
NO,
NO,

H02C.

10 11
(d5) reducing the amide 11 to give an 2-methyl-3-nitro-phenylethylamine 6, or a salt thereof,
o

R2R3N'
CH,
CH,
a
NO,
NO,

11 6
(e) converting the 2-methyl-3-nitro-phenylethylamine 6, or a salt thereof, into
a pyruvate 7, or a salt thereof,
R2R3N'^V-| RaR3N^^i O
^^N02 ^^N02
6 7
(f) converting the pyruvate 7, or a salt thereof, into a carboxylic acid 8, or a
salt thereof, and

R2R3N^ ^i O R2R3N'
vOR4 ► if "V "C02H
N02
7 8
(g) reductively cyclising the carboxylic acid 8, or a salt thereof, to give a 4-
[2-aminoethyl]-l,3-dihydro-2H-indol-2-one 9, or a pharmaceutically acceptable
salt or derivative thereof,



R2R3N
R2R3N

wherein X is halo or -OSO2R1; R1 is substituted or unsubstituted C1-C20 alkyl,
C4-C20 aryl or C5-C20 arylalkyl; and R2, R3 and R4 are independently hydrogen or
straight-chained, branched or cyclic C1-C20 alkyl;
and wherein:
(i) step (a) is performed in the presence of iodine; and/or
(ii) step (b) is performed using a thionyl halide in a solvent with a boiling point
of less than 95°C; and/or
(iii) step (c) is performed in the presence of a phase-transfer catalyst; and/or
(iv) step (d3) is performed in the presence of less than 10 equivalents H2SO4;
and/or
(v) step (d5) is performed using the product of step (d4) wherein said product
has not been purified by distillation; and/or
(vi) step (d5) is performed using a metal hydride; and/or
(vii) step (e) is carried out over more than 24 hours; and/or
(viii) step (e) is performed using a Group I metal and the reaction is quenched at
a pH of 8 to 9.5; and/or (ix) step (e) is performed using a tert-butoxide salt; and/or (x) the product of step (f) is isolated without distilling off more than 10% of
any solvent with a boiling point of more than 65°C present in the reaction
mixture; and wherein the process comprises at least one of steps (a), (b), (c), (d3), (d5), (e) or (f).
In either of the above aspects of the present invention, the selective reduction of step (a) may be performed using a hydride or a metal-hydride reagent. Preferably the reagent is BH3, NaBH4, 9-BBN, A1H3 or LiAlH4. Even more preferably, the reagent is NaBH4. Preferably NaBH4 is used in the presence of iodine, preferably in the presence of an about stoichiometric amount of iodine. Preferably NaBH4 is used in THF. Preferably the reduction is performed at or around the reflux temperature of the solvent, preferably 60-70°C.
Regarding the conversion of step (b), in a preferred embodiment, X of compound 3 is a halogen, preferably CI or Br, most preferably CI. Where X is a halogen, the conversion may be performed using an appropriate inorganic acid halide, a halogen acid, a halide salt in polyhydrogen fluoride-pyridine solution, or triphenylphosphine in CC14.
10

Preferred reagents include inorganic acid halides such as SOCl2, SOBr2, PC15, PBrs, PC13, PBr3 or P0C13; halogen acids HBr, HI or HC1 with ZnCl2 or a phase transfer catalyst, or HC1 in hexamethylphosphoramide; or halide salts NaX, KXa or NH4X in polyhydrogen fluoride-pyridine solution. In one aspect, the reagent is a thionyl halide in a solvent with a boiling point of less than 95°C. Most preferred is the use of SOCl2, preferably in DCM or toluene, preferably in the presence of DMF. Preferably the halogenation is performed under reflux conditions and/or at a temperature of 35-45°C.
In another embodiment, X of compound 3 is a sulphonic ester, preferably a tosylate, brosylate, nosylate, mesylate, triflate, nonaflate or tresylate. Where X is a sulphonic ester, the conversion may be performed using an activated sulphonic acid derivative such as a sulphonyl chloride, sulphonamide or sulphonic acid anhydride. Preferably the conversion is performed in the presence of a base, preferably pyridine. The displacement of step (c) can be achieved by using a source of cyanide ions. Preferably that source is a cyanide salt of a Group I metal, even more preferably the source is KCN or NaCN. Preferably the reaction is performed in an alcohol-water mixture, most preferably in an isopropyl alcohol-water mixture. Preferably the displacement is performed under reflux conditions.
A phase transfer catalyst may be employed in step (c) in combination with the source of cyanide ions. Suitable phase transfer catalysts include quaternary ammonium salts, quaternary phosphonium salts and crown ethers. Preferably the phase transfer catalyst is a quaternary ammonium salt, most preferably (n-Bu)4NBr. Where a phase transfer catalyst is employed, preferred solvents for the organic phase include DCM and toluene. Preferably the displacement is performed under reflux conditions. The selective reduction of step (dl) may be performed using a hydride or a metal-hydride reagent. Preferably the reagent is BH3, NaBH4, 9-BBN, AIH3 or LiBEt3H. Even more preferably, the reagent is NaBH4. Preferably NaBH4 is used in conjunction with Et2O.BF3. Preferably NaBH4 is used in THF. Preferably the reduction is performed at or around the reflux temperature of the solvent, preferably 60-70°C.
The alkylation of step (d2) may be performed using an alkyl sulphonate or preferably an alkyl halide. In either case, the use of a base is preferred. Preferably the alkyl group is 72-propyl. In a most preferred embodiment, n-PrBr is used in conjunction with Na2CO3, K2C03 or NaOH. Preferred solvents include
11

ethanol, acetonitrile, acetone, DMF and mixtures thereof. Preferably the alkylation is performed under reflux conditions.
The conversion of step (e) can be performed using a combination of a base and YCOCO2R4, wherein Y is a suitable leaving group, preferably halo or –OR4 , more preferably -OR4. Preferably R4 is C1-C6 alkyl, preferably C1-C3 alkyl. In another preferred embodiment, R4 is hydrogen, Me or Et. In a most preferred embodiment, YCOCO2R4 is diethyl oxalate. The base used is preferably R50~, preferably with R5 being the same as the R4 of YCOC02R4. Where R50~ is used, it may be generated in situ using a Group I metal in R5OH. Most preferably, EtO" is used, preferably generated in situ using sodium in ethanol. Alternatively step (e) can be performed using a tert-butoxide salt, such as potassium tert-butoxide, in the presence of a solvent such as an alcohol such as ethanol. Preferably the reaction is carried out at room temperature. Preferably the reaction is performed over a period in excess of 24 hours, 48 hours, 72 hours or 96 hours. In procedures where a Group I metal is used, the reaction is preferably quenched when desired at a pH of 8 to 9.5, more preferably at a pH of 8.5 to 9.
Pyruvate 7 can be converted into carboxylic acid 8 in step (f) using, for example, Pb(OAc)4 or alkaline H202. Preferably H202 is used with NaOH in H20. Preferably 1 to 1.25 equivalents of H202 are used, more preferably about 1.05 equivalents. Preferably the reaction is performed at a temperature of 0-5°C. Preferably the product of step (f) is isolated without distilling off more than 10% of any solvent with a boiling point of more than 65°C present in the reaction mixture. Preferably, said solvent has a boiling point of more than 80°C or more than 95°C. Preferably the product of step (f) is isolated without distilling off more than 5%, 4%, 2% or 1% of said solvent.
The reductive cyclisation of step (g) may be performed using a metal-acid combination (such as Zn, Sn or Fe and HC1), catalytic hydrogenation, AIH3-AICI3, a hydrazine-catalyst combination, [Fe3(CO)2]-MeOH, TiCl3, hot liquid paraffin, formic acid and Pd/C, sulphides or polysulphides. Preferably the reduction is performed using catalytic hydrogenation. Catalysts suitable for catalytic hydrogenation include Pd black, Pd/C and Pt202. Pd/C is the preferred catalyst, especially when used in conjunction with HCl and perchloric acid in an aqueous solution.
12

The hydrolysis of step (d3) may be performed using acid or base catalysed hydrolysis. Preferably acid catalysed hydrolysis is used, using for example H2S04. Most preferably, 50% aq. H2S04 in acetic acid is used, preferably under reflux conditions. Preferably step (d3) is performed in the presence of less than 10 equivalents of H2S04. More preferably 1 to 6 equivalents of H2S04 are used, more preferably about 1.5 equivalents. The conversion of step (d4) may be performed using a peptide coupling reagent (such as DCCI or TBTU) or via a reactive intermediate such as an acyl halide, an acid anhydride or a reactive ester. Preferably the reaction is performed via an acyl halide. The acyl halide may be generated using, for example, an appropriate inorganic acid halide such as SOCl2, SOBr2, PC15, PBr5, PC13, PBr3 or POCl3. Alternatively oxalyl chloride or oxalyl bromide may be used. In one aspect, the reagent is a thionyl halide in a solvent. Most preferred is the use of SOCl2, preferably in toluene. The acyl halide may then be converted to the amide by the addition of the appropriate amine. Preferably the amine is .N,N-di-n-propylamine.
The product of step (d4) may be utilised in step (d5) without purification by distillation. Preferably the product of step (d4) is purified only by means of aqueous washes of the crude product in an organic solvent, with subsequent drying and removal of the organic solvent. The conversion of step (d5) may be performed using a hydride or a metal-hydride reagent. Preferably a metal-hydride reagent is used. Preferably the reagent is NaBH4 or LiAlH4. Even more preferably, the reagent is NaBH4. Preferably NaBH4 is used in conjunction with Et2O.BF3. Preferably NaBH4 is used in THF. Preferably the reduction is performed at room temperature.
In a preferred embodiment of either of the above aspects of the present invention, R2 and R3 are the same. Preferably R2 and R3 are both alkyl. Alternatively, R2 and R3 may both be hydrogen, in which case step (d2) is not required, if a process according to the first aspect of the present invention is used. In the case where one or both of R2 and R3 are hydrogen, suitable protection of the amine group may be further employed for steps (e) to (g) of either of the above aspects of the present invention. Suitable protecting groups will be known to those skilled in the art, for example, from "Protective Groups in Organic Synthesis" by T.W. Greene and P.G.M. Wuts (Wiley-Interscience, 3rd edition, 1999) and include benzoyl, benzyl, p-methoxybenzyl or ?-butyloxycarbonyl (Boc) groups. Preferably the protecting group is not base-labile and is removed by the reaction conditions of step (g). The processes of the present invention afford 2-methyl-3-nitro-phenylethylamines 6 and 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-ones 9 in high yield and high purity, with a high degree of safety, on an industrial scale if desired.
13

Preferably 2-methyl-3-nitro-phenylethylamines 6 are obtained in an overall yield of 47% or more from benzoic acid 1 via the process of the first aspect of the present invention, or in an overall yield of 73% or more via the process of the second aspect of the present invention. Preferably 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-ones 9 are obtained in an overall yield of 20% or more from benzoic acid 1 via the process of the first aspect of the present invention, or in an overall yield of 30% or more via the process of the second aspect of the present invention.
In step (a), benzyl alcohol 2 is preferably obtained in a yield of 97% or more from benzoic acid 1. In steps (b) and (c), cyanide 4 is preferably obtained in a yield of 95% or more over two steps from benzyl alcohol 2. In steps (dl) and (d2), amine 6 is preferably obtained in a yield of 51% or more over two steps from cyanide 4. In step (d3), carboxylic acid 10 is preferably obtained in a yield of 96% or more from cyanide 4. In step (d4), amide 11 is preferably obtained in a yield of 92% or more from carboxylic acid 10. In step (d5), amine 6 is preferably obtained in a yield of 88% or more from amide 11. In step (e), pyruvate 7 is preferably obtained in a yield of 85% or more from amine 6. In step (f), carboxylic acid 8 is preferably obtained in a yield of 61% or more from pyruvate 7. In step (g), 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-one 9 is preferably obtained in a yield of 78% or more from carboxylic acid 8.
Preferably the 2-methyl-3-nitro-phenylethylamines 6 obtained are more than 85%, 90%, 98%, 99%, 99.5%, 99.7% or 99.9% pure. Preferably the 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-ones 9 obtained are more than 97%, 98%, 99%, 99.5%, 99.7% or 99.9% pure. For the purposes of the present invention, purity is measured by HPLC.
The processes of the present invention are suitable for industrial scale manufacture of 2-methyl-3-nitro-phenylethylamines 6 and of 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-ones 9. Preferably the 2-methyl-3-nitro-phenylethylamines 6 and 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-ones 9 are obtained on an industrial scale, such as in batches of 0.25kg, 0.5kg, 1kg, 5kg, 10kg, 25kg or more.
Preferably the 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-one 9 prepared is ropinirole or a pharmaceutically acceptable salt or derivative thereof. Even more preferably, the 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-one 9 is ropinirole hydrochloride. In one embodiment of the first aspect of the present invention, the process comprises both steps (dl) and (d2) of the present invention.
14

Preferably, in either of the above aspects of the invention, the process comprises two, three, four, five, six, seven, eight or nine of steps (a) to (g). Most preferably, in either aspect, the process comprises all steps (a) to (g).
In a preferred embodiment of either of the above aspects, X is CI. In another preferred embodiment, R2 and R3 are each n-Pr. In yet another preferred embodiment, R4 is Et.
A third aspect of the present invention provides a 2-methyl-3-nitro-phenylethylamine 6, or a salt or derivative thereof, when produced by a process according to the first or second aspect of the present invention. Preferably the 2-methyl-3-nitro-phenylethylamine 6, or the salt or derivative thereof, is more than 85%, 90%, 98%, 99%, 99.5%, 99.7% or 99.9% pure. In a preferred embodiment of the third aspect of the invention, the 2-methyl-3-nitro-phenylethylamine 6, or the salt or derivative thereof, is 2-methyl-3-nitro-phenylethyl-JV,jV-di-«-propylamine 6a.
A fourth aspect of the present invention provides a 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-one 9, or a pharmaceutically acceptable salt or derivative thereof, when produced by a process according to the first or second aspect of the present invention. Preferably the 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-one 9, or the pharmaceutically salt or derivative thereof, is more than 97%, 98%, 99%, 99.5%, 99.7% or 99.9% pure.
In one embodiment of the fourth aspect of the present invention, 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-one 9, or pharmaceutically salt or derivative thereof, is ropinirole, or a pharmaceutically acceptable salt or derivative thereof. Preferably the 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-one 9, or the pharmaceutically salt or derivative thereof, is ropinirole hydrochloride 9a.
Preferably the 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-one 9, or the pharmaceutically acceptable salt or derivative thereof, of the fourth aspect of the present invention is suitable for use as a medicament. Preferably the medicament is suitable for the treatment of disorders of the central nervous system (such as Parkinson's disease or acute central nervous system injury), disorders which can
15

prevent or disturb sleep (such as restless legs syndrome, apneas, hypopneas, fibromyalgia, snoring events or chronic fatigue syndrome), cardiovascular disorders (such as angina, hypertension or congestive heart failure), disorders of impaired kidney function, memory disorders (such as impaired cerebral functionality, dementia, amnesia or decreased cognitive function) or sexual dysfunction (such as male or female impotence including impaired erectile function). Most preferably, the medicament is suitable for the treatment of Parkinson's disease.
The compounds of the present invention can be used both, in their free base form and their acid addition salt form. For the purposes of this invention, a "salt" of a compound of the present invention is an acid addition salt. Acid addition salts are preferably pharmaceutically acceptable, non-toxic addition salts with suitable acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulphuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulphonic acids (for example, methanesulphonic, trifluoromethanesulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, benzenesulphonic, toluene-p-sulphonic, naphthalene-2-sulphonic or camphorsulphonic acid) or amino acids (for example, ornithinic, glutamic or aspartic acid). A preferred salt is a hydrohalogenic, sulphuric, phosphoric or organic acid addition salt. A more preferred salt is a hydrochloric acid addition salt.
In addition to pharmaceutically acceptable acid addition salts, other acid addition salts are included in the present invention, since they have potential to serve as intermediates in the purification or preparation of other, for example, pharmaceutically acceptable, acid addition salts, or are useful for identification, characterisation or purification of the free base.
The present invention encompasses pharmaceutically acceptable salts, derivatives, solvates, clathrates and/or hydrates (including anhydrous forms) of the compounds of the present invention.
16

A fifth aspect of the present invention provides a pharmaceutical composition, comprising a compound, or a pharmaceutically acceptable salt or derivative thereof, according to the fourth aspect of the present invention, and a pharmaceutically acceptable carrier or diluent.
Preferably the pharmaceutical composition is suitable for the treatment of disorders of the central nervous system (such as Parkinson's disease or acute central nervous system injury), disorders which can prevent or disturb sleep (such as restless legs syndrome, apneas, hypopneas, fibromyalgia, snoring events or chronic fatigue syndrome), cardiovascular disorders (such as angina, hypertension or congestive heart failure), disorders of impaired kidney function, memory disorders (such as impaired cerebral functionality, dementia, amnesia or decreased cognitive function) or sexual dysfunction (such as male or female impotence including impaired erectile function). Preferably, the pharmaceutical composition is suitable for the treatment of Parkinson's disease.
The medicament employed in the present invention can be administered by oral, parental (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), transdermal, airway (aerosol), rectal, vaginal or topical (including buccal, mucosal and sublingual) administration. Preferably the medicament is suitable for oral administration.
For oral administration, the compounds of the invention will generally be provided in the form of tablets, capsules, hard or soft gelatine capsules, caplets, troches or lozenges, as a powder or granules, or as an aqueous solution, suspension or dispersion. The compounds of the invention are provided in the form of tablets or capsules, more preferably tablets. Tablets and capsules for oral use contain ropinirole hydrochloride as active ingredient.
Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose. Corn starch, alginic acid and croscarmellose sodium are suitable disintegrating agents. Binding agents may include starch and gelatine. Lubricating agents, if present, may be magnesium stearate, stearic acid or talc. Preferred excipients include lactose, microcrystalline cellulose, croscarmellose sodium
17

and magnesium stearate. If desired, the tablets may be coated with a material, for example, to delay absorption in the gastrointestinal tract.
Capsules for oral use include hard gelatine capsules in which the active ingredient is mixed with a solid diluent, and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil. Tablets and capsules for oral use may be adapted for controlled or delayed release. For example, tablets may be coated with a material to delay absorption in the gastrointestinal tract. Preferred coating agents are hypromellose, hydroxypropylmefhyl cellulose and polyethylene glycol.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. For parenteral use, the compounds of the present invention will generally be provided in a sterile aqueous solution or suspension, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride or glucose. Solutions or suspensions for parenteral use preferably contain ropinirole in free base form as active ingredient. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and rc-propyl p-hydroxybenzoate. The compounds of the invention may also be presented as liposome formulations.
For topical and transdermal administration, the compounds of the invention will generally be provided in the form of ointments, cataplasms (poultices), pastes, powders, dressings, creams, plasters or patches. Suitable suspensions and solutions can be used in inhalers for airway (aerosol) administration.
In general, a suitable dose will be in the range of 0.05 to 30 mg of active ingredient (measured as ropinirole free base) per day, preferably 0.1 to 24 mg per day, more preferably 0.2 to 9 mg per day. The desired dose is preferably
presented once, twice or three times a day, but may even be dosed as four, five,
18

six or more sub-doses administered at appropriate intervals throughout the day.
These doses and sub-doses may be administered in unit dosage forms, for
example, containing 0.05 to 10 mg, preferably 0.25 to 5 mg, and more preferably
0.25, 0.5, 1, 2 or 5 mg of active ingredient (measured as ropinirole free base) per
unit dosage form.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention is exemplified by reference to the accompanying drawings in
which:
Figure 1 is a schematic illustration of a first process of the present invention.
Figure 2 is a schematic illustration of a first preferred process.
Figure 3 is a schematic illustration of a second process of the present invention.
Figure 4 is a schematic illustration of a second preferred process.
Synthetic examples
Examples and details of processes of the invention are found in the experimental procedures outlined below. Preparation of 2-methyl-3-nitro-benzyl alcohol 2
To a stirring suspension of sodium borohydride (263 g, 6.94 mol) in THF (750 ml) at 15-20°C was added over 1 hour a solution of 2-methyl-3-nitro-benzoic acid 1 (1.0 kg, 5.52 mol) in THF (3.0 1). The creamy yellow suspension was then stirred for a further 0.5 hour, before a solution of iodine (710 g, 2.80 mol) in THF (1.5 1) was added dropwise over a period of 4.5 hours. After completion of the addition, the suspension was refluxed for around 3 hours. The reaction mass was then cooled to about 15°C and slowly quenched with water (3.8 1). The resulting clear yellow solution was concentrated to remove the THF under reduced pressure. The pH of the residual mass was adjusted to 10-11 with 50% aq. sodium hydroxide solution (380 ml), followed by the addition of dichloromethane (DCM). The clear biphasic layer was stirred and allowed to stand for layer separation. Separation of the organic layer and back extraction of the aqueous solution with DCM, followed by water washing and concentration of the organic layer gave 2-methyl-3-nitro-benzyl alcohol 2.
Yield: 895 g (97.0%), Melting point: 65-66°C [Lit. (Askam et al., J. Chem. Soc. (C), 1969, pp. 1935-1936): 68-69°C]
19

Alternatively, the DCM layer may be taken to the next step without concentration.
Preparation of 2-methyl-3-nitro-benzyl chloride 3a (X = CI) To a stirring solution of 2-methyl-3-nitro-benzyl alcohol 2 (895 g, 5.35 mol) in DCM (5.0 1) was added dimethylformamide (3.5 ml, 0.0452 mol). Thionyl chloride (431 ml, 5.91 mol) was slowly added over 1 hour. The resulting dark brown solution was refluxed for 3-4 hours. Then the DCM was distilled off, and fresh DCM was charged and distilled as before. Then the brownish viscous liquid was degassed for around 30 minutes under vacuum. The product of this stage was taken to the subsequent stage without isolation on a 100% yield basis.
Preparation of 2-methyl-3-nitro-benzyl cyanide 4
2-Methyl-3-nitro-benzyl chloride 3a was converted to 2-methyl-3-nitro-benzyl
cyanide 4 by the following two methods A and B.
Method A: To the above dark viscous liquid 3a was charged isopropyl alcohol (4.97 1). Potassium cyanide (418 g, 6.41 mol) was charged, followed by the addition of water (1.98 1). The solution was refluxed for 6 hours. After completion of the reaction, the isopropyl alcohol was distilled under vacuum. Toluene (2.0 1) and water (1.0 1) were charged and the resulting solution was stirred, then allowed to stand. The biphasic layers were separated. The aqueous layer was back extracted with toluene (2 x 1.0 1). The combined toluene layers were washed well with water and concentrated to yield a crude solid, which was recrystallised from a 1:2 toluene:hexane mixture to give cyanide 4. Yield over two steps: 903.6 g (95.9%), Melting point: 83-85°C
Alternatively, the toluene layer above may be concentrated partially and the product precipitated by the addition of hexane.
Method B: To 2-methyl-3-nitro-benzyl chloride 3a (88 g, 0.474 mol) were charged sequentially DCM (88 ml) (alternatively toluene may be used), potassium cyanide (37.7 g, 0.578 mol), tetra-«-butyl ammonium bromide (1.71 g, 0.006 mol) and water (88 ml). The resulting solution was stirred under reflux for
20

10 hours. After the completion of the reaction, cyanide 4 was isolated from the
organic phase by layer separation, followed by aqueous work up and
concentration.
Yield over two steps: 83 g (99.4%), Melting point: 85.2-86.6°C
Preparation of 2-methyl-3-nitro-phenylethyl-N,N-di-n-propylamine 6a (R2 = R3 = n-Pr) 2-Methyl-3-nitro-benzyl cyanide 4 was converted to 2-methyl-3-nitro-phenylethyl-./V, N-di-H-propylamine 6a by the following two routes 1 and 2.
Route 1 (Scheme 2):
Preparation of 2-methyl-3-nitro-phenylethylamine 5
To a stirring suspension of 2-methyl-3-nitro-benzyl cyanide 4 (330 g, 1.87 mol) in THF
(1.65 1) was charged sodium borohydride (142 g, 3.75 mol). A solution of boron
trifluoride etherate (710 g, 5.00 mol) in THF (497 ml) was slowly added over 5 hours.
The solution was stirred for 8 hours and then cooled to 5°C and slowly quenched with
methanol. The solids were removed by filtration, and the methanol layer was then
concentrated to give 2-methyl-3-nitro-phenylethylamine 5 as a solid.
Yield: 337.5 g(100%)
Preparation of 2-methyl-3-nitro-phenylethyl-N,N-di-n-propylamine 6a (R2 = R3 = n-Pr) The above solid 5 (234 g, 1.30 mol) was refluxed for 8 hours in acetonitrile (1.75 1) with «-propyl bromide (1064 g, 8.65 mol) in the presence of sodium carbonate (629 g, 5.93 mol) and benzyltriefhylammonium chloride (34.3g, 0.150 mol). After completion of the reaction, the organic layer was separated and concentrated. The residue was dissolved in M-diisopropyl ether and was washed well with water. The product 6a was isolated as a brownish yellow oil on concentration of the n-diisopropyl ether under vacuum. Yield: 176 g (51.3%), Purity (HPLC): 88.6%
Route 2 (Scheme 4):
Preparation of 2-methyl-3-nitro-phenylacetic acid 10
To 2-methyl-3-nitrobenzyl cyanide 4 (100 g, 0.56 mol) was charged gradually 50% aq. sulfuric acid (91 ml, 1.5 eq.) and acetic acid (160 ml). The resulting suspension was refluxed under stirring for 3 hours, after which it was poured hot under stirring onto ice-water slush (1.2 1). The product, 2-methyl-3-nitrophenyl acetic acid 10, was filtered, washed with water to pH 4 and subsequently dried for 12 hours. Yield: 106.6 g (96.2%)
21

Preparation of 2-(2-methyl-3-nitrophenyl)-N,N-di-n-propylacetamide 11a (R = R3 = n-Pr)
To a stirring solution of 2-methyl-3-nitrophenylacetic acid 10 (715 g, 3.66 mol) in toluene (715 ml) was charged thionyl chloride (321 ml, 4.40 mol, 1.2 eq.) over 1 hour. The solution was then refluxed for 3 hours. The toluene was distilled off under reduced pressure. Fresh toluene (715 ml) was charged and distillation was resumed, after which the reaction mass was degassed for 1 hour. DCM (1.43 1) was charged and the solution was cooled to 0-5°C under stirring. 9% Aq. sodium carbonate (3.58 1) was charged under very slow stirring over 1.5 hours, followed by gradual addition of JV,iV-di-w-propylamine (426 g, 4.21 mol, 1.15 eq.) in DCM (608 ml) while maintaining the temperature at 0-5°C. The reaction mixture was then slowly warmed to room temperature (28±2°C). The organic phase was separated and washed sequentially with 2% aq. sodium carbonate (715 ml), 2N HC1 (715 ml), water (715 ml), then brine (715 ml). The organic layer was concentrated to give 2-(2-methyl-3-nitrophenyl)-A/,A/-di-«-propylacetamide 11a as brownish yellow solid on long standing or chilling. Yield: 945 g (92.7%), Melting point: 49-50°C
Alternately, the organic layer may be concentrated partially and then triturated with hexane. The oily mass starts solidifying on cooling to about 10°C under stirring. The solid can then be filtered and dried under vacuum.
Preparation of 2-methyl-3-nitro-phenylethyl-N,N-di-n-propylamine 6a (R2 = R3 = n-Pr) To a stirring suspension of 2-(2-methyl-3-nitrophenyl)-Af A/-di-«-propylacetamide 11a (500 g, 1.80 mol) and sodium borohydride (102 g, 2.70 mol, 1.5 eq.) in THF (2.5 1), was added over 5.5 hours a solution of boron trifluoride etherate (455 ml, 3.59 mol, 2.0 eq.) in THF (565 ml). The suspension was stirred for 4.5 hours at room temperature (28±2°C). The reaction mass was then cooled to about 5°C, then quenched gradually with methanol (940 ml) (alternatively 1.9 1 water may be used). The solids were filtered off and the solution was concentrated to dryness. The resulting mass was basified to pH 10-11 with 50% aq. sodium hydroxide solution (85 ml). The separated oil was briefly stirred with rc-diisopropyl ether (1 1). The «-diisopropyl ether layer was then separated from the aqueous solution and acidified with 7.5% aq. HC1 (1 1) to pH 1. The aqueous layer was back
22

extracted with «-diisopropyl ether (2 x 200 ml). The acidic aqueous solution was basified under stirring with 10% aq. sodium hydroxide (1.25 1) to pH 10-11. The oil was extracted in n-diisopropyl ether (1 1). The rc-diisopropyl ether layer was washed with water, brine and finally concentrated at 50-55°C under reduced pressure to yield 2-methyl-3-nitro-pheneylethyl-A/,Ar-di-«-propylamine 6a as brownish orange viscous liquid. Yield: 422 g (88.7%), Purity (HPLC): 97.3%
Preparation of ethyl [2-nitro-6-[2-(N,N-di-n-propylamino)ethyl]phenyl]pyruvate 7a (R2 = R3 = n-Pr, R4 = Et)
Sodium metal (91.5 g, 3.98 mol) was slowly charged to ethanol (1680 ml). After
complete dissolution of the metal, the turbid solution was cooled to ambient
temperature (28±2°C). Then, 2-methyl-3-nitro-phenylethyl-JV)./V-di-«-propylamine
6a (350 g, 1.32 mol) and diethyl oxalate (1743 ml, 12.8 mol) were sequentially
charged in one lot. The resulting dark brown solution was stirred at room
temperature for 96 hours, after which it was poured gradually onto ice-water
slush (14 1) under stirring whilst maintaining the pH at 8.5-9. Hexane (1400 ml)
was then charged and the brown liquid was stirred for 15 minutes during which
time the colour of the suspension acquired an orange tinge. The suspension was
filtered under suction and the orange solid slurry washed with hexane (700 ml).
The solid was sucked well under vacuum and then dried at 45°C for 6 hours to
constant weight to give ethyl [2-nitro-6-[2-(N,N-di-n-
propylamino)ethyl]phenyl]pyruvate 7a. The hexane layer was separated from the filtrate, washed once with water followed by brine and then concentrated to yield 42.6 g (12.2%) of unreacted 2-methyl-3-nitro-phenylethyl-N,N-di-n-propylamine 6a.
Yield of 7a: 366 g (86.4% based on 6a reacted), Melting point: 84-88°C
Alternative preparation of ethyl [2-nitro-6-[2-(N,N-di-n-
propylamino)ethyl]phenyl]pyruvate 7a (R = R = n-Pr, R - Et) Potassium tert-butoxide (62.5 g, 0.56 mol) was slowly charged to ethanol (240 ml). After complete dissolution, the turbid solution was cooled to room temperature (28±2°C). Then, 2-methyl-3-nitro-phenylethyl-N,N-di-n-propylamine 6a (50 g, 0.19 mol) and diethyl oxalate (88 ml, 0.57 mol) were sequentially charged in one lot. The resulting dark brown solution was stirred at room temperature for 96 hours, after which it was poured gradually onto ice-water slush (2 1) under stirring whilst
23

maintaining the pH at 8.5-9.0. Hexane (300 ml) was charged and the brown liquid was stirred for around 15 minutes during which time the colour of the suspension acquired an orange tinge. The suspension was filtered under suction and the orange solid slurry was washed with hexane (100 ml). The solid was sucked well under vacuum and dried at 45°C for 6 hours to constant weight to give ethyl [2-nitro-6-[2-(N,N-di-n-propylamino)ethyl]phenyl]pyruvate 7a. The hexane layer was separated from the filtrate, washed once with water followed by brine and then concentrated to yield 8.9 g (17.8%) of unreacted 2-methyl-3-nitro-phenylethyl-N;N-di-n-propylamine 6a. Yield of 7a: 48.6 g (85.8% based on 6a reacted), Melting point: 84-88°C
Preparation of [2-nitro-6-[2-(N,N-di-n-propylamino)ethyl]phenyl]pyruvic acid 7b (7 with R2 = R3 = n-Pr, R4 = H)
Sodium metal (6.55 g, 2.19 mol) was slowly charged to ethanol (120 ml). After complete dissolution of the metal, the turbid solution was cooled to room temperature (28±2°C). Then, 2-methyl-3-nitro-phenylethyl-N,N-di-n-propylamine 6a (25 g, 0.0946 mol) and diethyl oxalate (41.5 ml, 0.306 mol) were sequentially charged in one lot. The resulting dark brown solution was stirred at room temperature for 96 hours, after which it was poured gradually onto ice-water slush (300 ml) under stirring. Hexane (100 ml) was charged, then 20% aq. sodium hydroxide (50 ml) was added and the suspension was stirred for 2 hours, during which time the colour of the suspension acquired a buff tinge. The suspension was filtered and the biphasic layer was separated. The hexane layer, after water washing, was concentrated for recovery of the unreacted 2-methyl-3-nitro-phenylethyl-N-N-di-n-propylamine 6a (5.3 g, 21.2%). The aqueous layer was concentrated to one third volume and then acidified with HCl (25 ml). The suspension was chilled. The solid was then filtered under suction and dried to give [2-nitro-6-[2-N,N-n-propylamino)ethyl]phenyl]pyruvic acid 7b (7 with R2 = R3 = n-Pr, R4 = H). Yield of 7b: 23.4 g (92.8% based on 6a reacted)
Preparation of 2-nitro-6-(2-di-n-propylaminoethyl)-phenylacetic acid hydrochloride 8a (R2 = R3 = n-Pr)
To a stirring solution of sodium hydroxide (39.51 g, 0.987 mol) in water (360 ml) at 0-5°C was charged solid 7a (100 g, 0.274 mol). The dark brown solution was stirred for 1 hour at this temperature. Hydrogen peroxide (15% aq., 64.5 ml, 1.04 eq.) was added through a dropping funnel over 60 minutes whilst maintaining the above temperature. The pH of the solution, after stirring further for 4 hours at this temperature (28±2°C), was adjusted to 8-9 with cone. HCl (50 ml). The alkaline solution was then extracted thrice with rc-diisopropyl ether (3 x 200 ml). The alkaline solution obtained after the n-
24

diisopropyl ether extraction was carefully acidified under stirring with cone. HC1 to pH
about 1.5 and stirred for about 1 hour. The solid obtained was filtered and washed with
chilled water under suction. The wet solid (76 g) on drying yielded crude 2-nitro-6-(2-
di-«-propylaminoethyl)-phenylacetic acid hydrochloride 8a as an off-white solid.
Yield: 76.0 g (80.38%), Melting point: 179°C, HPLC purity: 97.97%
The above solid (75 g) was dissolved in methanol (225 ml) at reflux. The hot solution
was filtered to remove insolubles. The filtrate was then concentrated and triturated with
ethyl acetate (150 ml) to obtain pure 2-nitro-6-(2-di-«-propylaminoethyl)-phenylacetic
acid hydrochloride 8a.
Recovery: 63.0 g (84.0%), Melting point: 179°C, HPLC purity: 99.69%
Preparation of ropinirole hydrochloride 9a (R2 = R3 = n-Pr)
2-Nitro-6-(2-di-n-propylaminoethyl)-phenylacetic acid hydrochloride 8a (176 g, 0.510 mol) was dissolved in water (2665 ml) containing a catalytic amount of perchloric acid. The pH of the solution was adjusted to 2.5 with 10% aq. sodium hydroxide solution. Wet 10% Pd/C (39.6 g, 22.5% w/w) was charged and the resulting solution hydrogenated at 75 psi for 10 hours at 28°C. After completion of the hydrogenation, the acidic solution was filtered through a Celite® pad under vacuum. The filter cake was washed well with water. The aqueous layer was basified to pH 12 with 25% aq. sodium hydroxide solution (105 ml) and then extracted with diisopropyl ether (2 x 352 ml, 1 x 176 ml). The organic layers were combined, washed free of excess alkali and concentrated to 212 ml. The resultant solution was added over 0.5 hours to a solution of isopropyl alcohol (212 ml) (alternatively acetone may be used) containing concentrated hydrochloric acid (47 ml) and maintained at 10-15°C under stirring. The resulting suspension was stirred further at this temperature for 1 hour, after which it was filtered, washed with isopropyl alcohol (2 x 212 ml), sucked well under vacuum and dried to a constant weight at 60-80°C to obtain ropinirole hydrochloride 9a. Yield: 119.5 g (78.9%) , Melting point: 240-242°C [Lit. (Gallagher et al., J. Med. Chem., 1985, vol. 28, pp. 1533-1536): 241-243°C]
Alternatively, 9a can be prepared without the use of perchloric acid and without the subsequent pH adjustment.
Manufacture of ropinirole tablets
Ropinirole tablets comprising lmg, 2mg and 5mg equivalents of ropinirole respectively were prepared in accordance with the compositions set out in Table.
25

Ingredients (mg/tablet) lmg Tablet 2mg Tablet 5mg Tablet
Core
Ropinirole hydrochloride (eq. to ropinirole) 1.14 (1.0) 2.28 (2.0) 5.70 (5.0)
Lactose monohydrate 44.70 44.40 43.30
Microcrystalline cellulose 97.16 96.32 94.00
Croscarmellose sodium 6.00 6.00 6.00
Magnesium stearate 1.00 1.00 1.00
Core total 150.0 150.0 150.0
Coating
Opadry green 3.0 - -
Opadry pink - 3.0 -
Opadry blue - - 3.0
Total 153.0 153.0 153.0
26

WE CLAIM:

1. A process comprising one or more of the steps of: (dl) reducing a cyanide 4 to give an amine 5, and
h . (|VCH3
N02 ^^N02
4 5
(d2) alkylating the amine 5 to give a 2-methyl-3-nitro-phenylethylamine 6, or a salt thereof,

wherein R and R are independently hydrogen or straight-chained, branched or
cyclic C1-C20 alkyl.
2. A process as claimed in claim 1, comprising one or more of the steps of:
(a) reducing a benzoic acid 1 to give a benzyl alcohol 2,
CO2H HO(A — ciCH3
^^N02 ^NOj
(b) converting the benzyl alcohol 2 into a compound 3,
CH, _ J^ XH,
(X
N02 v N02
2 3
(c) displacing the substituent X of the compound 3 to give a cyanide 4,
X^ NC.
IX
N02 ^^^N02
3 4
27

CH,
(dl) reducing the cyanide 4 to give an amine 5,
H,N
CH,
NO,
NCNO,

4 5
(d2) alkylating the amine 5 to give a 2-methyl-3-nitro-phenylethylamine 6, or a salt thereof,

H,N
R2R3N
CH,
CH,

NO,

(e) converting the 2-methyl-3-nitro-phenylethylamine 6, or a salt thereof, into a pyruvate 7, or a salt thereof,
R2R3N'^^I R2R3N'
OR4
(X
NO,

6 7
(f) converting the pyruvate 7, or a salt thereof, into a carboxylic acid 8, or a
salt thereof, and

R2R3N^ ^i O R2R3N'
""OR4 ► f ^f "COzH
~N02
7 8
(g) reductively cyclising the carboxylic acid 8, or a salt thereof, to give a 4-
[2-aminoethyl]-l,3-dihydro-2H-indol-2-one 9, or a salt or derivative thereof,
R2R3N'^ R2R3N'

NO,

H

J. Dl
wherein X is halo or -OS02R1 ; R is substituted or unsubstituted C1-C20 alkyl, C4-C20 aryl or C5-C20 arylalkyl; and R2, R3 and R4 are independently hydrogen or straight-chained, branched or cyclic C1-C20 alkyl.
3. A process as claimed in claim 2, wherein:
(i) step (a) is performed in the presence of iodine; and/or
(ii) step (b) is performed using a thionyl halide in a solvent with a boiling point of
less than 95°C; and/or
28

(iii) step (c) is performed in the presence of a phase-transfer catalyst; and/or
(iv) step (e) is carried out over more than 24 hours; and/or
(v) step (e) is performed using a Group I metal and the reaction is quenched at a pH
of 8 to 9.5; and/or (vi) step (e) is performed using a tert-butoxide salt; and/or (vii) the product of step (f) is isolated without distilling off more than 10% of any
solvent with a boiling point of more than 65 °C present in the reaction mixture.
4. A process comprising one or more of the steps of:
(a) reducing a benzoic acid 1 to give a benzyl alcohol 2,

CH,
CH,

CO,H

NO,

HO.

NO,

CH,
(b) converting the benzyl alcohol 2 into a compound 3,
HO^ X^
CH,,

NO,

(C)
displacing the substituent X of the compound 3 to give a cyanide 4,
CH,
CH,

X^ NC.
NO,
NO,
3 4
(d3) hydrolysing the cyanide 4 to give a carboxylic acid 10,
CH,
CH,
NO,
NO,

NC^ H02C^

4 10
(d4) converting the carboxylic acid 10 into a 2-methyl-3-nitro-phenylethylamide 11,
O
RZRJN
CH,
NO,
HOjC,

29

(d5) reducing the amide 11 to give a 2-methyl-3-nitro-phenylethylamine 6, or a salt thereof,
o
R2R3NT > R2R3N^^
^Hj _ /lxH3
N02 ^^N02
11 6
(e) converting the 2-methyl-3-nitro-phenylethylamine 6, or a salt thereof, into a pyruvate 7, or a salt thereof,
R2R3N" > R2R3N" ^I p
CH,
NO,
"OR4
(f) converting the pyruvate 7, or a salt thereof, into a carboxylic acid 8, or a salt thereof, and


R2R3N
OR4
R2R3N"~>
ry^co2H

(g) reductively cyclising the carboxylic acid 8, or a salt thereof, to give a 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-one 9, or a salt or derivative thereof,

R2R3N'^vi R2R3N'
ipV^COjH -
^^N02
8
wherein X is halo or -OSO2R1; R1 is substituted or unsubstituted C1-C20 alkyl,
C4-C20 aryl or C5-C20 arylalkyl; and R2, R3 and R4 are independently hydrogen or
straight-chained, branched or cyclic C1-C20 alkyl;
and wherein:
(i) step (a) is performed in the presence of iodine; and/or
(ii) step (b) is performed using a thionyl halide in a solvent with a boiling
point of less than 95°C; and/or
(iii) step (c) is performed in the presence of a phase-transfer catalyst; and/or
(iv) step (d3) is performed in the presence of less than 10 equivalents H2S04; and/or
(v) step (d5) is performed using the product of step (d4) wherein said product has
not been purified by distillation; and/or
(vi) step (d5) is performed using a metal hydride; and/or
30

(vii) step (e) is carried out over more than 24 hours; and/or
(viii) step (e) is performed using a Group I metal and the reaction is quenched at a pH
of 8 to 9.5; and/or
(ix) step (e) is performed using a tert-butoxide salt; and/or
(x) the product of step (f) is isolated without distilling off more than 10% of any
solvent with a boiling point of more than 65°C present in the reaction mixture;
and wherein the process comprises at least one of steps (a), (b), (c), (d3), (d5),
(e) or (f).
5. A process as claimed in claim 4, wherein step (d5) is performed using NaBH4.
6. A process as claimed in any one of claims 2 to 6, wherein X is CI and R4 is hydrogen, Me or Et and R2 and R3 are each n-Pr.
7. A process as claimed in any one of claims 2 to 5, wherein step (a) is performed using NaBH4 in the presence of iodine.
8. A process as claimed in any one of claims 1 to 7, for the preparation of a 2-methyl-3-nitro-phenylethylamine 6, or a salt or derivative thereof.
9. A process as claimed in claim 8, wherein the 2-methyl-3-nitro-phenylethylamine 6, or the salt or derivative thereof, is 2-methyl-3-nitro-phenylethyl-N,N-n-propylamine 6a.
10. A process as claimed in any one of claims 1 to 9, for the preparation of a 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-one 9, or a salt or derivative thereof.
11. A process as claimed in claim 10, wherein the 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-one 9, or salt or derivative thereof, is ropinirole or a salt or derivative thereof.
12. A process as claimed in claim 11, wherein the 4-[2-aminoethyl]-l,3-
dihydro-2H-indol-2-one 9, or the salt or derivative thereof, is ropinirole
hydrochloride 9a.
Dated this 1st May, 2007

31

Abstract
The present invention relates to novel processes for the preparation of 2-methyl-3-nitro-phenylethylamines 6, which in themselves form part of novel processes for the preparation of 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-ones 9 and in particular ropinirole and ropinirole hydrochloride.
The present invention also relates to the use of 4-[2-aminoethyl]-l,3-dihydro-2H-indol-2-ones 9 and pharmaceutical^ acceptable salts and derivatives thereof, in particular ropinirole and ropinirole hydrochloride, for the treatment of disorders of the central nervous system (especially Parkinson's disease), disorders which can prevent or disturb sleep, cardiovascular disorders, disorders of impaired kidney function, memory disorders or sexual dysfunction.