FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"A PROCESS FOR THE PREPARATION OF ROPINIROLE INTERMEDIATES AND USE THEREOF FOR THE PREPARATION
OF ROPINIROLE"
Glenmark Pharmaceuticals Limited an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION
1

BACKGROUND OF THE INVENTION
1. Technical Field
The present invention generally relates to an improved process for the preparation of intermediates for ropinirole. More specifically, the present invention relates to an improved process for the preparation of the intermediate 2-methyl-3-nitro-phenylethyl-N,N-di-n-propyl amine and use thereof for the preparation of ropinirole and derivatives thereof.
2. Description of the Related Art
The present invention is directed to an improved process for the preparation of intermediates for ropinirole and ropinirole hydrochloride (also known as 4-[2-(dipropylamine)ethyl]-l,3-dihydro-2H-indol-2-one monohydrochloride) as represented by the structure of Formula I.

The hydrochloride salt of ropinirole is the form commercially sold under the trade name Requip®. Ropinirole hydrochloride is a non-ergoline dopamine agonist with high relative in vivo specificity and full intrinsic activity at the D2 and D3 dopamine receptors subtypes, binding with higher affinity to D3 than to D2 or D4 receptor subtypes. Ropinirole has moderate in vitro affinity for opioid receptors. Ropinirole hydrochloride is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease and for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS). See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 1482-1483, monograph 8338; and Physician's Desk Reference, "Requip," 58th Edition, p. 1604-1608 (2003).
U.S. Patent No. 4,452,808 ("the '808 Patent"), herein incorporated by reference, discloses ropinirole and its hydrochloride salt. The '808 Patent also discloses a process for preparing ropinirole and its hydrochloride salt. One process disclosed in the '808 Patent (see Example 2) generally includes (1) chlorinating and amidating 2-methyl-3-nitrophenyl acetic acid (II) to give 2-methyl-3-nitrophenyl-N,N-di-n-propyl acetamide (III), (2) reducing the acetamide (III) with borane in tetrahydrofuran (BH3-THF) to give
2

2-methyl-3-nitrophenylethyl-N,N-di-n-propyl amine (IV), (3) reacting the amine (IV) with diethyl oxalate to provide ethyl-6-(2-di-n-popylaminoethyl)-2-nitrophenylpyruvate (V), (4) hydrolyzing and decarboxylating the nitrophenylpyruvate (V) to give 2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride, and (5) reductive cyclizing the acetic acid hydrochloride to give ropinirole hydrochloride (I). This process is generally summarized in Scheme 1:
Scheme 1

I

VI

One disadvantage of this process is the use of the BH3-THF reagent which is moisture sensitive, expensive and difficult to handle on a commercial scale. Another disadvantage of this process is that the starting material, 2-methyl-3-nitrophenyl acetic acid (II), is also expensive.
SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention, a process for the preparation of a 2-alkyl-3-nitro-phenylethyl-N,N-di-n-alkylamine of Formula IV is provided:
3

N
(CH2)n


N02 (IV)j
wherein R1 is a straight or branched Ci-C6 alkyl or allyl group, R2 and R3 are
independently hydrogen or a straight or branched C1-C6 alkyl or allyl group, and n is an
integer from one to about ten, the process comprising:
(a) reacting a sulfonyl-containing halide with a 3-nitro-2-alkyl phenyl alkyl
alcohol of Formula X:
.0
HO
N02 (X)

wherein R1 has the aforestated meaning to provide a 3-nitro-2-alkyl phenyl sulfonate
ester of Formula XI:
o II
0=S R4
(CH2)n

INO,
(XI)
wherein R4 is a straight or branched C1-C6 alkyl or allyl group, or an unsubstituted or substituted phenyl group; and
(b) reacting the 3-nitro-2-alkyl phenyl sulfonate ester of Formula XI with a secondary alkyl amine to provide a compound of Formula IV.
4

In accordance with a second embodiment of the present invention, a process for the preparation of a 2-alkyl-3-nitro-phenylethyl-N,N-di-n-alkylamine of Formula IV is provided:
R3
*\/
N (CH2)n

(IV),
.1 r>2
wherein R R , R and n have the aforestated meanings, the process comprising: (a) reacting a 2-alkyl phenyl alkanoic acid alkyl ester of Formula VIII:

wherein R and R1 has the aforestated meaning, with a nitrating reagent to provide a 3-nitro-2-alkyl phenyl alkanoic acid alkyl ester of Formula IX:

(IX)
(b) reacting the 3-nitro-2-alkyl phenyl alkanoic acid alkyl ester with a reducing agent to provide a 3-nitro-2-alkyl phenyl alkyl alcohol of Formula X:
5

,o

(CHj),,
NO, (X)
(c) reacting the 3-nitro-2-alkyl phenyl alkyl alcohol with a sulfonyl-containing halide to provide a 3-nitro-2-alkyl phenyl sulfonate ester of Formula XI:
o II
S R4
(CH2)n

•N02 (XI)
wherein R4 has the aforestated meaning; and
(d) reacting the 3-nitro-2-alkyl phenyl sulfonate ester of Formula XI with a secondary alkyl amine to provide the compound of Formula IV.
The advantages of the process of the present invention include at least:
1. Synthesis of the 3-nitro-2-alkyl phenyl alkanoic acid alkyl ester is possible by
using a nitrating agent (HN03)n-ClCH2Cl at very low temperature through a
comparatively cleaner process. The selectivity of the nitration towards the 3-position of
2-methyl phenyl alkyl acetate is relatively high. Also, the 3-nitro-2-alkyl phenyl alkanoic
acid alkyl ester is available at a low cost making the overall process more cost effective.
2. The reagent BH3-THF is avoided thereby making the process easier and
cheaper.
3. Reduction of 3-nitro-2-alkyl phenyl alkanoic acid alkyl ester is possible in an
aqueous system at moderate temperature conditions, thus the anhydrous system and
nitrogen atmosphere otherwise required for borane reductions can be avoided.
Accordingly, this makes the process easier and more friendly on a commercial scale.
6

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
One aspect of the present invention is directed to a process for the preparation of an intermediate of ropinirole hydrochloride, 2-alkyl-3-nitro-phenylethyl-N,N-di-n-alkylamine of Formula IV
V/


NO, (IV)_
wherein R is a straight or branched C alkyl or allyl group, R and R are independently hydrogen or a straight or branched C1-C6 alkyl or allyl group, and n is an integer from one to about ten.
In step (a) of the process of the present invention, a sulfonyl-containing halide is reacted with a 3-nitro-2-alkyl phenyl alkyl alcohol of the general formula:
HO-
(CH2)„

wherein R1 has the aforestated meaning to provide a 3-nitro-2-alkyl phenyl sulfonate
ester of the general:
o
II 4
=S R4

(XI)
7

wherein R4 is a straight or branched C1-C6 alkyl or allyl group, or a unsubstituted or substituted phenyl group. Representatives of the 3-nitro-2-alkyl phenyl alkyl alcohol are known in the art, e.g., in U.S. Patent No. 4,452,808, the contents of which are incorporated by reference herein. In general, the 3-nitro-2-alkyl phenyl alkyl alcohol can be prepared by first selectively nitrating a 2-alkyl phenyl alkanoic acid alkyl ester of the general formula:

wherein R is a hydrocarbon group having 1 to about 30 carbon atoms and R1 and n have the aforestated meanings, with a nitrating agent to provide a 3-nitro-2-alkyl phenyl alkanoic acid alkyl ester of the general formula:
p
RO^;
(CH2)n

NO,
wherein R, R1 and n have the aforestated meanings. Suitable nitrating agents include, but are not limited to, pure nitric acid, HNO3 in H2SO4, nitric acid in acetic acid or acetic anhydride, nitric acid in chlorinated hydrocarbons such as, for example dichloromethane, dichloroethane, carbon tetrachloride and chloroform, and the like and mixtures thereof. A preferred nitrating agent is nitric acid in dichloromethane.
Generally, the 2-alkyl phenyl alkanoic acid alkyl ester starting material may be prepared by reacting a 2-alkyl phenyl acetic acid with an excess of an aliphatic alcohol in the presence of a catalyst at the boiling temperature of the alcohol used. Suitable catalysts employed in this reaction include, but are not limited to, inorganic lewis acids, e.g., concentrated sulfuric acid and HC1, and organic lewis acids, e.g., aromatic and aliphatic sulfonic acids, acetic acid and fluorinated acetic acid, and the like and mixtures
8

thereof. In a preferred embodiment of the present invention, 2-methyl phenyl acetic acid is reacted with excess ethanol and concentrated sulfuric acid to provide 2-methyl phenyl ethyl acetate.
The nitration reaction may be carried out in a solvent such as, for example, a cyclic hydrocarbon solvent containing five to about fifteen carbon atoms, an acyclic hydrocarbon solvent containing five to about fifteen carbon atoms, a chlorinated solvent, e.g., dichloromethane, and the like and mixtures thereof. A preferred solvent is dichloromethane. The reaction may take place at a temperature ranging from about -10°C to about 80°C, preferably at a temperature ranging from about -5°C to about 30°C, and most preferably at a temperature ranging from about 0°C to about 25°C.
Next, the 3-nitro-2-alkyl phenyl alkanoic acid alkyl ester is reacted with a reducing agent to provide the starting 3-nitro-2-alkyl phenyl alkyl alcohol. Suitable reducing agents include, but are not limited to, borohydride salts of an alkali metal and the like and mixtures thereof. Representative examples of a borohydride salt of an alkali metal used herein are sodium borohydride, lithium borohydride and the like. The reaction may take place in a solvent such as a dialkyl (acyclic) ether, e.g., R5-0-R6 wherein R5 and R6 are independently a C1-C10 alkyl group, a cyclic ether, e.g., tetrahydrofuran ("THF") or dioxane, an alcoholic solvent, e.g., an aliphatic alcohol such
7 7
as one of the formula R OH wherein R may be a C1-C10 alkyl group, or an aromatic
O Q
alcohol, an aliphatic carboxylic acid, e.g., R COOH wherein R may be a straight or branched C1-C10 alkyl group, water and the like and mixtures thereof. A preferred solvent is a mixture of THF and water. The reaction may take place at a temperature ordinarily ranging from about -5°C to about 100°C and preferably from about 5°C to about 80°C.
Suitable sulfonyl-containing halides for use in step (a) of the process of the present invention can be of the general formula R4S02X, wherein R4 has the aforestated meaning and X is a halide, e.g., chloride, bromide, etc. Thus, a representative example of a sulfonyl-containing halide is a sulfonyl chloride of the formula R4S02C1, wherein R4 has the aforestated meaning. A preferred sulfonyl chloride is tosyl chloride.
The reaction in step (a) may take place in a solvent such as a dialkyl (acyclic) ether, e.g., R5-0-R wherein R5 and R6 are independently a C1-C10 alkyl group, a cyclic
9

ether, e.g., tetrahydrofuran ("THF"), dioxane and the like, a cyclic and acyclic hydrocarbon containing five to fifteen carbon atoms, a chlorinated hydrocarbon, e.g., mono-, di-, tri- or tetra- haloalkanes and alkenes, an aromatic solvent, e.g., benzene, methyl benzene, halobenzenes and the like, a polar aprotic solvent containing cyclic or acyclic sulfoxide, sulfone, amide, or keto groups, and the like and mixtures thereof. A preferred solvent for use herein is dichloromethane.
The reaction in step (a) may also take place in the presence of an inorganic base. Suitable inorganic base include, but are not limited to, salts of alkali metals, organic amine bases, e.g., primary, secondary or tertiary alkyl or arylalkyl amines, heterocyclic bases, e.g., heterocyclic base containing five and six membered ring or fused systems containing one to three nitrogen atoms in the ring. A preferred base is triethyl amine. The reaction may be carried out at a temperature ranging from about -10°C to about 100°C, preferably from about 0°C to about 30°C, and most preferable from about 10°C to about 25°C.
In step (b) of the process of the present invention, the 3-nitro-2-alkyl phenyl sulfonate ester is reacted with a secondary alkyl amine to provide the intermediate of ropinirole hydrochloride, 2-alkyl-3-nitro-phenylethyl-N,N-di-n-alkylamine. Suitable secondary alkyl amines include, but are not limited to, di-n-methylamine, di-n-ethylamine, di-n-propylamine, di-n-butylamine and the like. A preferred secondary alkyl amine is di-n-propylamine. The reaction may take place in a solvent such as a dialkyl (acyclic) ether, e.g., R5-0-R6 wherein R5 and R6 are independently a C1-C10 alkyl group, a cyclic ether, e.g., tetrahydrofuran ("THF"), dioxane and the like, a cyclic and acyclic hydrocarbon containing five to fifteen carbon atoms, a chlorinated hydrocarbon, e.g., mono-, di-, tri- or tetra- haloalkanes and alkenes, an aromatic solvent, e.g., benzene, methyl benzene, halobenzenes and the like, a polar aprotic solvent containing cyclic or acyclic sulfoxide, sulfone, amide, or keto groups, and the like and mixtures thereof. A preferred solvent is toluene.
The reaction in step (b) may also take place in the presence of an inorganic base. Suitable inorganic base include, but are not limited to, salts of an alkali metal, organic amine bases, e.g., primary, secondary or tertiary alkyl or arylalkyl amines, heterocyclic bases, e.g., heterocyclic base containing five and six membered ring or fused systems
10

containing one to three nitrogen atoms in the ring. The preferred base is a dimethylamino pyridine. The reaction may be carried out at a temperature ranging from about -10°C to about 170°C, preferably from about 0°C to about 150°C and most preferable from about 100°CtoaboutllO°C.
A preferred embodiment of the process of the present invention includes at least (a) reacting 2-methyl phenyl acetic acid (Xlla) with ethanol to provide 2-methyl phenyl ethyl acetate (Villa), (b) selectively nitrating the 2-methyl phenyl ethyl acetate (Villa) to provide 3-nitro-2-methyl phenyl ethyl acetate (IXa), (c) reducing the 3-nitro-2-methyl phenyl ethyl acetate (IXa) with sodium borohydride to provide 2-methyl-3-nitrophenylethyl alcohol (Xa), (d) reacting the 2-methyl-3-nitrophenylethyl alcohol (Xa) with tosyl chloride to provide 2-methyl-3-nitrophenyl ethyl tosylate (XIa), and (e) reacting the 2-methyl-3-nitrophenyl ethyl tosylate (XIa) with di-n-propyl amine to provide 2-methyl-3-nitrophenylethyl-N,N-di-n-propylamine (IV) as generally shown in Scheme 2:
Scheme 2



Xlla

[0002] In accordance with another aspect of the present invention, the compound
of Formula IV obtained by the foregoing processes may thereafter be converted to ropinirole or a derivative thereof or a pharmaceutically acceptable salt thereof such as ropinirole hydrochloride, by methods known in the art and exemplified in the examples. See, e.g., U.S. Patent No. 4,452,808, the contents of which hare incorporated by reference
11

herein. For example, the compound of Formula IV can first be reacted with diethyl oxalate to provide ethyl-6-(2-di-n-popylaminoethyl)-2-nitrophenylpyruvate, which is then hydrolyzed and decarboxylated to provide a 2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride. Next, the 2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride is reductively cyclized to provide ropinirole hydrochloride (I).
Another aspect of the present invention is directed to a process for preparing a compound of the general formula XIII
RlO
R9—
(XIII)
7 8 0 Ift

wherein R , R , R and R independently are a straight or branched C1-C6 alkyl or allyl group, or a unsubstituted or substituted phenyl group and n is 1-3 or a pharmaceutically acceptable salt thereof, the process comprising reduction of a compound of formula XIV:

R9-

R
-N

10

(CH2)n R7
OH
(XIV)
wherein R7, R8, R9 and R10 and n have the aforestated meanings, followed by cyclization of the intermediate so formed, and, optionally, forming a pharmaceutically acceptable salt thereof, wherein the reduction of the compound of formula XIV is carried out by catalytic transfer hydrogenation in a suitable solvent in the presence of an organic base salt of formic acid as a hydrogen donor. Suitable solvents for use herein include, but are not limited to water miscible solvents such as methanol, ethanol, isopropanol, butanol,
12

isopropanol-butanol, acetonitrile, 1,4 dioxane and the like and mixtures thereof and water immiscible solvents such as esters, ethyl acetate, ethyl acetoacetate, methylene chloride, ethylene chloride, chloroform, methyl tert butyl ether, toluene and the like and mixtures thereof. Preferably the solvent is isopropyl alcohol. Suitable organic base salts of formic acid include ammonium formate, triethyl amine formate, t butyl amine formate and the like with triethyl amine formate being preferred. The reaction can be carried out at a temperature of 0-150°C preferably at the reflux temperature of the solvent used, i.e. 75-85°C when isopropanol is used as solvent for reaction, and in the presence of a suitable catalyst.
By performing the purification processes of the present invention, highly purified Ropinirole can be prepared with a degree of purity as determined by HPLC greater than about 98%, preferably greater than about 99% and most preferably greater than about 99.5% as compared to the crude product. Also, the content of free Ropinirole in the final product as determined by HPLC can be at a level of less than about 2%, preferably less than about 1% and more preferably less than about 0.5% as compared to the crude product. Moreover, the highly purified Ropinirole may be obtained substantially free of any unknown impurity, e.g., a content of less than about 0.1% of impurities. The crude Ropinirole for use herein can have purity as determined by HPLC which can ordinarily vary in the range of from about 92% to less than 98%.
Another aspect of the present invention is directed to a pharmaceutical composition containing at least the highly purified Ropinirole disclosed herein and at least one pharmaceutically acceptable excipient. Such pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectabe solution, etc.
In one embodiment, the Ropinirole or pharmaceutically acceptable salt thereof disclosed herein for use in the pharmaceutical compositions of the present invention can have a D50 and D90 particle size of less than about 400 microns, preferably less than about 200 microns, more preferably less than about 150 microns, still more preferably less than about 50 microns and most preferably less than about 15 microns. The particle sizes of
13

the Ropinirole or pharmaceutically acceptable salt thereof prepared according to the present invention can be obtained by any milling, grinding micronizing or other particle size reduction method known in the art to bring the solid state Ropinirole or pharmaceutically acceptable salt thereof into any of the foregoing desired particle size range.
The dosage forms may contain the substantially pure Ropinirole disclosed herein or, alternatively, may contain the substantially pure Ropinirole as part of a composition. Whether administered in pure form or in a composition, the substantially pure Ropinirole may be in any form, for example, compacted tablets, powder suspensions, capsules, and the like. The compositions of the present invention can be administered to humans and animals in such dosage forms as oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), intracistemal, intravaginal, intraperitoneal, local (powders, ointments or drops), ophthalmic, transdermal, or sublingual forms or as a buccal or nasal spray. Oral dosage forms include, but are not limited to, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs, tablets, capsules (including soft gel capsules), ovules, solutions, and the like which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, or controlled-release such as sustained-, dual-, or pulsatile delivery applications. The highly purified form of Ropinirole disclosed herein also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes. The most preferred route of administration of the Ropinirole of the present invention is oral.
The active ingredient of the invention may also be administered via fast dispersing or fast dissolving dosage forms or in the form of high energy dispersion or as coated particles. Suitable pharmaceutical composition of the invention may be in coated or uncoated form as desired.
Tabletting compositions may have few or many components depending upon the tabletting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl
14

cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Other excipients contemplated by the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
Capsule dosages will contain the solid composition within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. The enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric coating.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.
EXAMPLE 1 Preparation of 2-methyl-3-nitro phenyl ethyl acetate
15

A solution of concentrated HNO3 (252 g) in dichloromethane (178 ml) was added to a solution of 2-methyl phenyl ethyl acetate (178 g) in dichloromethane (712 ml) at a temperature ranging from about 0°C to about 5°C over a period of about 1 to about 2 hours. The reaction mixture was then stirred at a temperature ranging from about 0°C to about 25 °C for about 6 to about 7 hours. After completion of the reaction as determined by TLC, 10% sodium sulphate solution (535 ml) was added to the reaction mixture which was stirred for about 30 minutes. The organic layer was separated and the aqueous layer was extracted with dichloromethane (178 ml). The organic layer was washed twice with demineralized water (350 ml x 2). The organic layer was concentrated on a rotavapor bath at a temperature ranging from about 40°C to about 65°C under vacuum to obtain a crystalline solid (220 g).
The crystalline solid (220 g) was stirred in 75-85% aqueous solution of ethyl alcohol at reflux for about 30 to about 45 minutes. The solution was slowly cooled to room temperature, a temperature ranging from about 25°C to about 30°C, over a period of about 2 to about 3 hours. The reaction mixture was further cooled to a temperature ranging from about 10°C to about 15°C over a period of about 1 to about 2 hours. The slurry of crystalline solids was stirred at a temperature ranging from about 10°C to about 15°C for a period of about 1 to about 2 hours. The solids were filtered, washed with 80-85% aqueous ethanol and dried at a temperature ranging from about 50°C to about 55°C under high vacuum to provide (60% molar yield) 2-ethyl-3-nitro phenyl ethyl acetate (134 g) . (HPLC purity >99%)
1HNMR (300 MHz, CDCI3), trimethyl silane (TMS) as internal standard shows
the following signals at 5 1.24-1.28 (t, 3H, ,CH3-ethyl), 2.418 (s, 3H, CH3), 3.737 (s, 2H,
CH2), 4.139-4.21 (q, 2H, CH2-ethyl), 7.26-7.31 (t, 1H, ArH), 7.42-7.44 (d, 1H, ArH, j =
6.0), 7.68-7.71 (d, 1H, ArH, j =9.0)
[0003] IR (KBr) shows signal at 1729 (CO), 2928-2980 (Ar CH3).
EXAMPLE 2 Preparation of 2-methyl-3-nitro phenyl ethyl alcohol
To a solution of 2-methyl-3-nitro phenyl ethyl acetate (223 g) of Example 1 in tetrahydrofuran (THF) (670 ml) was added water (220 ml). The reaction mixture was
16

cooled to a temperature ranging from about 10°C to about 15°C. Solid sodium borohydride (97 g) was added to the reaction mixture in small lots under an inert atmosphere over a period of about 1 to about 2 hours. The reaction mixture was heated to reflux temperature and stirred for about 6 to about 7 hours. After completion of the reaction as determined by TLC, reaction mixture was cooled to a temperature ranging from about 10°C to about 15°C. Acetone (110 ml) was added to the reaction mixture, which was stirred for about 30 minutes. Dichloromethane (450 ml) and water (1150 ml) were added to the reaction mixture at a temperature ranging from about 10°C to about 15°C. The reaction mixture was stirred for about 30 minutes. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane (110 ml x 2). The organic layer was concentrated on a rotavapor bath at a temperature ranging from about 40°C to about 65°C under vacuum to obtain 2-ethyl-3-nitro phenyl ethyl alcohol (172 g, 95% molar yield)) ( HPLC purity >98%) as a viscous oily liquid.
'H-NMR (300 MHz, CDC13), TMS as internal standard shows the following signals at 5 2,439 (s, 3H, CH3), 2.979-3.023 (t, 2H, Ar-CH2-), 3.85-3.90 (m, 3H, CH2-OH), 7.24-7.29 (t, 1H, ArH), 7.41-7.43 (d, 1H, ArH, j =6.0), 7.61-7.64 (d, 1H, ArH, j =9.0)
EXAMPLE 3
Preparation of 2-methyl-3-nitro phenyl ethyl tosylate
To a solution of 2-methyl-3-nitro phenyl ethyl alcohol (181 g) of Example 2 in dichloromethane (360 ml) was added triethylamine (126.5 g) and dimethyl aminopyridine (2.75 g). The reaction mixture was cooled to a temperature ranging from about 5°C to about 10°C under inert atmosphere. The freshly prepared solution of the tosyl chloride (238 g) in dichloromethane (180 ml) was added to the reaction mass at a temperature ranging from about 5°C to about 10°C over a period of about 1 to about 2 hours. The reaction mixture was stirred at a temperature ranging from about 5°C to about 25°C for about 3 to about 4 hours. The reaction mixtures was heated at reflux temperature and stirred for about 4 to about 5 hours. After completion of the reaction as determined by TLC, reaction mixture was cooled to a temperature ranging from about 20°C to about 25°C. Water (360 ml) was added to the reaction mixture, which was stirred for 30
17

minutes. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane (90 ml x 2). The organic layer was washed twice with 0.5% sodium bicarbonate solution (90 ml x 2) followed by water (180 ml x 2). Organic layer was concentrated on a rotavapor bath at a temperature in the ranging from about 40°C to about 65°C under vacuum to obtain 2-ethyl-3-nitro phenyl ethyl tosylate (285 g, 85% molar yield) (HPLC purity=95-97%) as a crystalline solid.
The crystalline solid of 2-ethyl-3-nitro phenyl ethyl tosylate was dissolved in ethanol (285 ml) at a reflux temperature and cooled slowly to a temperature ranging from about 10°C to about 15°C over a period of about 2 to about 3 hours. The reaction mixture was stirred at this temperature for about 1 hour. The solids were filtered, washed with ethanol and dried to obtain pure 2-ethyl-3-nitro phenyl ethyl tosylate (252 g) (HPLC purity >99).
*H-NMR (300 MHz, CDC13), TMS as internal standard shows the following signals at 5 2.268 (s, 3H, CH3), 2.426 (s, 3H, CH3), 3.05-3.09 (t, 2H, Ar-CH2-), 4.18-4.22 (m, 3H, -CH2-OS02), 7.20-7.33 (m, 4H, ArH), 7.61-7.64 (m, 3H, ArH).
EXAMPLE 4 Preparation of 2-methyl-3-nitro phenylethyl-N,N-di-n-propylamine To a solution of 2-methyl-3-nitro phenyl ethyl tosylate (335 g) of Example 3 in toluene (1000 ml), dimethyl aminopyridine (0.85 g) was added at a temperature ranging from about 15°C to about 20°C. Di-n-propylamine (303 g) was added to the reaction mixture. The reaction mixture was heated to reflux temperature (about 110°C to about 120°C) and was maintained for a period of about 5 to about 6 hours. After completion of the reaction as determined by TLC, the reaction mixture was cooled to a temperature ranging from about 45°C to about 50°C. Water (1000 ml) was added to the reaction mixture, which was stirred for about 30 minutes and the pH was adjusted to 2-3 using concentrated HC1. The organic layer was separated and the aqueous layer was extracted twice with toluene (165 ml x 2). The organic layer was washed twice with water (2X 165 ml). The combined aqueous layer was washed twice with toluene (2X165 ml). The pH of the aqueous layer was adjusted to 9-10 using aqueous ammonia and extracted with toluene. The toluene layer was separated and concentrated on a rotavapor bath at a
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temperature ranging from about 50°C to about 75°C under vacuum to obtain 2-methyl -3-nitro phenyl ethyl-N,N-di-n-propylamine (238 g, 90% molar yield) as a viscous oil (HPLC purity >98%).
^-NMR (300 MHz, CDC13), TMS as internal standard shows the following signals at 8 0.867-0.937 (m, 6H, 2CH3), 1.438-1.513 (m, 4H, 2-CH2), 2.43-2.48 (m,7H, -CH2-N-CH2-, CH3), 2.618-2.648 (m, 2H, -CH2-N), 2.82-2.87 (m, 2H, Ar-CH2), 7.206-7.27 (t, 1H, ArH), 7.36-7.38 (d, 1H, ArH, j =6.0), 7.58-7.61 (d, 1H, ArH, j =9.0).
EXAMPLE 5 Preparation of 2-nitro-6-N,N-di-n-propyl-phenyl ethyl pyruvate To a solution of 2-methyl-3-nitro phenylethyl-N,N-di-n-propylamine (238 g) of Example 4 in toluene (1500 ml), dimethyl sulphoxide (550 ml) was added and stirred for 30 minutes. Diethyl oxalate (230 gm) was added to the reaction mixture and the reaction mass was cooled to a temperature of 0 to 5°C. To the cooled solution was charged sodium ethoxide (107 gm) in lots within 4 hours at a temperature ranging from 0-10°C. The reaction mass was stirred for 5 hours at temperature 0-10°C. The temperature was raised to 20-30°C, and the reaction mass stirred for 12 hours at 20-30°C. After completion of the reaction as determined by TLC, the reaction mixture was cooled to a temperature ranging from about 0°C to about 15°C. Toluene (700 ml) and water (3800 ml) were added to the reaction mixture at a temperature ranging from 0-10°C. Tetrabutylammonium bromide (TBAB) (4 gm) and 35 % sodium hydroxide solution (35 ml) were added to the reaction mixture and stirred for 3 hours at a temperature ranging from about 0-10°C. After completion of the reaction as determined by TLC, the layers were separated. The aqueous layer was cooled to 10-15°C and 30% hydrogen peroxide solution (380 ml) was slowly added at a temperature ranging from 5-15°C. The reaction mixture was stirred at a temperature ranging from 20-30°C for 5 hours. The temperature to 40-50°C was then raised and the reaction mixture was stirred for 3 hours at 40-50°C. After completion of the reaction as determined by TLC, the reaction mixture was cooled to a temperature ranging from about 20°C to about 30°C and washed with ethyl acetate (320 ml). The pH of the reaction mixture was adjusted to a range from 4.25 to 4.50 with aqueoua HC1 at a temperature ranging from 15-20°C and then stirred for 5 hours. The
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solids were filtered, washed with water (165 ml) and acetone (165)and dried to obtain crude 2-nitro-6-N,N-di-n-propyl-phenyl ethyl pyruvate, which on purification in isopropanol (IPA) (950ml) and methanol(950 ml) provided the 2-nitro-6-N,N-di-n-propyl-phenyl ethyl pyruvate ( 105 gm, 38% molar yield ) and having a HPLC purity > 97%.
1HNMR (300 MHz, DMSO), TMS as internal standard shows the following signals at 5 0.922-0.875( t, 6H, 2CH3), 1.725-1.691 (m, 4H, 2-CH2), 3.404-3.228 (m,6H, -3 CH2), 3.612-3.56 (m, 2H, -CH2), 3.796 (S.2H,CH2), 7.436-7.383 (t, 1H, ArH), 7.62-7.60 (d, 1H, ArH, J =7.2), 7.77-7.74 (d, 1H, ArH, J =9).
EXAMPLE 6
Preparation of Ropinirole Hydrochloride
IPA (5000 ml) and 2-nitro-6-N,N-di-n-propyl-phenyl ethyl pyruvate of Example 5 (473 gm) was added in a round bottom flask. A slurry of 10% pd-carbon in IPA (500 ml) was added under nitrogen in one lot at a temperature of 20-30°C. The temperature was slowly raised to 70-75°C and ammonium formate (393 gm) was added. The reaction mixture was stirred for 2 hours at a temperature of 75-80°C. After completion of the reaction as determined by TLC, the reaction mixture was cooled to a temperature of about 60°C. The catalyst was filtered, and wash with IPA (500 ml). The IPA was distilled out under reduced pressure below 50°C. Toluene (1400 ml) was added to the reaction mixture at 40-50°C. The reaction mixture was cooled to 20-30°C. Water (1000 ml) was added to the reaction mixture, stirred, allowed to settle and then the upper organic layer was separated. The toluene layer was washed with 2%aq. NaOH solution (900 ml), followed with water (900 ml). The pH was adjusted to 7-8 of toluene layer with 0.025N HC1 solution. The organic layer was separated and the pH of the organic layer was adjusted to 1-1.5 with 0.5N HC1 solution. The pH of the aqueous layer was adjusted to 8-8.5 with sodium bicarbonate, and stirred for 1 hour at 25-30°C. The solids were filtered, washed with chilled water (215 ml) and acetonitrile (215 ml). The solid cake was then immersed in acetonitrile (1700ml), and the reaction mixture was cooled to 5-10°C. To the reaction mixture was added 20 % IPA.HC1 solution at 10-15°C, and stirred for 7 hours at 10-15°C. The solids were filtered, washed with chilled acetonitrile
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(30 ml) and dried to give crude ropinirole hydrochloride. The crude ropinirole hydrochloride in toluene (1750 ml).was heated to 65-70°C and methanol (1000ml) was slowly added to obtain a clear solution. The reaction mixture was gradually cooled to 10-15°C. The solids were filtered, washed with acetonitrile (50 ml) and dried to get pure ropinirole hydrochloride (140 g, 30% molar yield) having a HPLC purity >99.5%.
!H-NMR (300 MHz, DMSO), TMS as internal standard shows the following signals at 8 0.946-0.897( t, 6H, 2CH3), 1.746-1.670 (m, 4H, 2-CH2), 3.034-2.946 (m,6H, N-(CH2)3), 3.186-3.162 (m, 2H, -CH2),3.557(S,2H,CH2),6.738-6.714(d,lH, Ar-H,J=7.2), 6.87-6.84(d, 1H, ArH,J=7.8), 7.169-7.117 (t, 1H, ArH),10.45(S,lH,NH),10.70(bs,lH ,HC1).
EXAMPLE 7
Preparation of Ropinirole Free Base
IPA (400 ml) and 2-nitro-6-N,N-di-n-propyl-phenyl acetic acid (100 gm) was added in a round bottom flask. A slurry of 10% pd-carbon (catalyst) in IPA (50 ml) was added under nitrogen in one lot at a temperature of 20-3 0°C and the temperature was slowly raised to 70-75°C. Triethyl amine formate (190 gm) was added in lots at a temperature of 70-75°C and the reaction mixture was stirred for 2 hours at 75-80°C. After completion of the reaction as determined by TLC, the reaction mixture was cooled to a temperature of about 30°C. The catalyst was filtered and wash with IPA (100 ml). IPA was distilled out under reduced pressure below 50°C. Next, toluene (400 ml) was added to the reaction mixture and a solid was obtained. The solid was further cooled to 10-20°C and filtered and washed with IPA to provide a ropinirole formic acid salt of base or mixture there of.
Ropinirole formic acid salt thus obtained was dissolved in water (200 ml) and basified using aq. NaOH solution until a pH of 9-10 was reached. The solution was extracted into toluene (200 ml) and washed with 5X 200 ml of 2% aq. sodium hydroxide solution and water (100 ml). Next, water (200 ml) was added to the organic layer and pH was adjusted to 7-8. The layers were separated out and the aqueous layer was basified to a pH of 8.0-8.5 using sodium bicarbonate at 25-30°C. The solids obtained were filtered,
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washed with chilled water (215 ml) and toluene (100 ml) to give 60-75 gm of suck dried material as ropinirole free base.
EXAMPLE 8
Preparation of Ropinirole HC1
The ropinirole free base of Example 7 was taken in toluene (600ml), and the reaction mixture was cooled to 5-10°C. 20 % IPA-HCl solution was added at 10-15°C and stirred for 5-7 hours at 10-15°C. The solids were filtered, washed with chilled toluene (50 ml) and dried to give crude ropinirole hydrochloride. The crude ropinirole hydrochloride was taken in toluene(350 ml) and the reaction mixture was heated to 65-70°C. Methanol (200ml) was slowly added to obtain a clear solution. Next, the reaction mixture was gradually cooled to 10-15°C. The solids were filtered, washed with a toluene/methanol mixture (50 ml) and dried to provide pure Ropinirole hydrochloride (45 gm) having a HPLC purity >99.5%.
'H-NMR (300 MHz, DMSO), TMS as internal standard shows the following signals at 5 0.946-0.897( t, 6H, 2CH3), 1.746-1.670 (m, 4H, 2-CH2), 3.034-2.946 (m,6H, N-(CH2)3), 3.186-3.162 (m, 2H, -CH2),3.557(S,2H,CH2),6.738-6.714(d,lH, Ar-H,J=7.2), 6.87-6.84(d, 1H, ArH,J=7.8), 7.169-7.117 (t, 1H, ArH),10.45(S,lH,NH),10.70(bs,lH ,HC1).
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention.
Dated this Seventh (07th) day of April, 2006
(Signed)
NITIN SHARAD CHANDRA PRADHAN
VICE PRESIDENT
GLENMARK PHARMACEUTICALS LIMITED
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