FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003 PROVISIONAL SPECIFICATION
(See section 10; rule 13)
A PROCESS FOR THE PREPARATION OF 4-[2-[[3-(4-HYDROXYPHENYL)-l-METHYLPROPYL]AMINO]ETHYL]-l,2-BENZENEDIOL
SUN PHARMACEUTICAL INDUSTRIES LIMITED
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059,
MAHARASHTRA, INDIA.
The following specification describes the nature of this invention

The present invention relates to a process for the preparation of 4-[2-[[3-(4-hydroxyphenyl)-l-methylpropyl]amino]ethyl]-l,2-benzenediol, a compound of formula I, and its pharmaceutically acceptable salts. The compound of formula I, commonly known as dobutamine, is used in therapy as a cardiotonic for treating cardiac insufficiency.

Formula I
BACKGROUND OF THE INVENTION
United States Patent No. 3987200 (The '200 patent; equivalent Indian reference not available) discloses process for preparation of the compound of formula I by demethylation of 3,4-dimethoxy-N-[3-(4-methoxyphenyl)-l-methyl-n-propyl]-|8-phenethylamine, a compound of formula II with 48% hydrobromic acid in glacial acetic acid.

OCH,
CH,0

OCH,

Formula II
The compound of formula II is prepared by reacting a compound of formula III with a compound of formula IV in presence of hydrogenation catalyst like 5 % palladium on carbon or Raney nickel.


CH3O
OCH 3
Formula III

NH2

CH30

Formula IV

2

The process of the '200 patent has several disadvantages which makes it commercially unviable. Some of the limitations of the demethylation of compound of formula II with 48% hydrobromic acid in acetic acid are:
(1) It generates highly toxic and mutagenic methyl bromide gas.
(2) Work up is tedious, requiring distillation of HBr-acetic from reaction mixture.
(3) HBr-acetic acid is highly corrosive and cannot be recovered/reused.
(4) The compound of formula I obtained on demethylation contains ring brominated impurities and also possible impurities due to incomplete demethylation. Quality of the dobutamine hydrochloride was not consistent with ICH guidelines (International Conference on Harmonization)
(5) Energy intensive -reaction temperature of 120° C is required.
United States Patent No. 5442120 (the '120 patent equivalent Indian reference not available) discloses process for preparation of compound of formula I by reacting dopamine hydrochloride, the hydrochloride of compound of formula IIIA, with 4-(4-hydroxyphenyl)-2-butanone, a compound of formula IVA, in methanol using Pt/C and base.



NH,

OH

Formula IIIA

Formula IVA

This process uses dopamine, the compound of formula IIIA which is unstable, expensive, sensitive to oxygen and discolors rapidly. Also since the reaction is carried out under alkaline conditions it could lead to coloration of product, as phenolic compounds tend to darken under alkaline conditions.
Japanese patent application No. 04-013652 discloses process for preparing the compound of formula I by demethylating 3,4-dimethoxy-N-[3-(4-methoxyphenyl)-l-methyl-n-propyl]-/3-phenethylamine, the compound of formula II with concentrated hydrochloric acid at reflux temperature, for about 40-72 hours. This process is disadvantageous as it requires longer reaction times and generates toxic methyl chloride gas.
Hungarian patent application number HU0065437A2 discloses process for preparing compound of formula I by demethylating 3,4-dimethoxy-N-[3-(4-methoxyphenyl)-l-methyl-n-
3

propyl]- ]-p-phenethylamine, the compound of formula II with hydrochloric acid in an inert solvent like acetic acid at 140°C and pressure of 3-4 bar. This process is disadvantageous as it requires elevated temperature and pressure and generates toxic methyl chloride gas.
Polish patent application number 136711B2 discloses process for preparing compound of formula I by demethylating 3,4-dimethoxy-A^-[3-(4-methoxyphenyl)-l-methyl-n-propyl]-|8-phenylethylamine, the compound of formula II with aluminium chloride in toluene. This process is disadvantageous as it requires large quantities of aluminium chloride, approximately 10 molar equivalents with respect to compound of formula II and generates toxic methyl chloride gas.
Thus the prior art processes for preparing 4-[2-[[3-(4-hydroxyphenyl)-methylpropyl]amino] ethyl]-l,2-benzenediol, the compound of formula I entail demethylation of 3,4-dimethoxy-N-[3-(4-methoxyphenyl)-l-methyl-n-propyl]-/3-phenethylamine, the compound of formula II with hydrobromic acid or hydrochloric acid. This demethylation reaction requires high temperatures, uses corrosive reagents, leads to side product formation and generates toxic volatile by-products. Therefore there is need in the art for an improved process for preparation of the compound of formula I.
We have developed a novel process for preparing the compound of formula I which overcomes the shortcomings of prior art. The process of the present invention uses a novel intermediate, a compound of formula V, or acid addition salt thereof,

Formula V
wherein R is independently selected from hydrogen, linear, branched or cyclic (CrC6) alkyl, O-linear, branched or cyclic (Ci-C6) alkyl, aryl, O-aryl, aralkyl, halogen and hydroxyl, hitherto not
4

reported in the literature for preparing the compound of formula I.The compound of formula V or acid addition salt thereof is converted to the compound of formula I by catalytic hydrogenolysis.
The process of the present invention is advantageous as it uses mild reaction conditions, does not require corrosive reagents like hydrogen bromide and does not generate toxic by-products like methyl bromide or side products like ring brominated impurities. The work-up is simple and the product can be isolated by simply filtering the catalyst and degassing the solvent. The product obtained conforms to ICH grade purity specifications for bulk drugs, which requires that known impurity should not be more than 0.2% and unknown impurity should not be more than 0.1%.
OBJECT OF THE INVENTION
The object of the present invention is to provide a commercially viable process for the preparation of compound of formula I, which is environmentally friendly and avoids the formation of undesired side products.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of 4-[2-[[3-(4-hydroxyphenyl)-l-methylpropyl]amino]ethyl]-l,2-benzenediol, a compound of formula I or pharmaceutically acceptable salt thereof comprising

OH ^
Formula I
subjecting 3,4-bis(arylmethyloxy)-N-[3-(4-arylmethyloxy)-l-methylpropyl]-p-phenethyl amine, a compound of formula V, or acid addition salt thereof,
5

^<

Formula V
wherein R is independently selected from hydrogen, (CrC6) alkyl, O- (CrC6) alkyl, aryl, O-aryl. aralkyl, halogen and hydroxyl, to catalytic hydrogenolysis.
The present invention in one aspect provides a process for preparation of 4-[2-[[3-(4-hydroxyphenyl)-l-methylpropyl]amino]ethyl]-l,2-benzenediol, a compound of formula I or pharmaceutically acceptable salt thereof comprising


OH
OH

F

Formula I
(a) reacting a compound of formula VI with a compound of formula VII to give a compound of formula V or acid addition salt thereof
6

Nil,

Formula VI

Formula VII


Formula V
wherein R is independently selected from hydrogen, (CrCb) alkyl, O- (CrC6) alkyl, aryl, O-aryl, aralkyl, halogen and hydroxyl; and
(b) subjecting the compound of formula V or acid addition salt thereof to catalytic hydrogenolysis.
The present invention in one aspect provides a compound of formula V and acid addition salt thereof
7


Formula V
wherein R is independently selected from hydrogen, (CrC6) alkyl, O- (C:-C6) alkyl, aryl, O-aryl, aralkyl, halogen and hydroxyl.
The present invention in one aspect provides a process for preparation of 3,4-bis(arylmethyloxy)-N-[3-(4-arylmethyloxy)-l-methylpropyl]-y6-phenethylamine, a compound of formula V or acid addition salt thereof

Formula V
comprising reacting a compound of formula VI with a compound of formula VII.

Ml,

Formula VI Formula VII
wherein R is independently selected from hydrogen, (CrC6) alkyl, O- (C|-C6) alkyl, aryl, O-aryl, aralkyl, halogen and hydroxyl.
DESCRIPTION OF THE INVENTION
The present invention provides a process for preparing a compound of formula I via novel intermediate, a compound of formula V or acid addition salt thereof, and avoids the formation of undesired side products.
In one embodiment, the present invention provides a process for preparation of 4-[2-[[3-(4-hydroxyphenyl)-l-methylpropyl]amino]ethyl]-l,2-benzenediol, a compound of formula 1 or pharmaceutically acceptable salt thereof comprising

Formula I
subjecting 3,4-bis(arylmethyloxy)-N-[3-(4-arylmethyloxy)-l-methylpropyl]-/?-phenethyl amine, a compound of formula V, or acid addition salt thereof,
9

R

Formula V
wherein R is independently selected from hydrogen, (CrC6) alkyl, O- (C,-C6)-alkyl, aryl, O-aryl, aralkyl, halogen and hydroxyl, to catalytic hydrogenolysis.
As used herein the alkyl group refers to a saturated aliphatic hydrocarbon radical including straight chain, branched chain, and cyclic groups of 1-6 carbon atoms such as methyl, ethyl, 2-propyl, 2-butyl, cyclopropyl, cyclopentyl and the like. If the alkyl group lacks substituent then it is called unsubstituted alkyl group. Examples of 0-(C1C6) -alkyl include methoxy, ethoxy. cyclopropyloxy, cyclobutyloxy and the like.
As used herein the term halogen refers to F, CI, Br or I.
As used herein the aryl group refers to an all carbon monocyclic or fused ring polycyclic groups
of C, to Ci2 carbon atoms having a completely conjugated pi-electron system for e.g. phenyl,
naphthalenyl, and anthracenyl.
As used herein aralkyl refers to a lower alkyl, which is substituted with an aryl group. Lower
alkyl refers to a saturated aliphatic hydrocarbon radical including straight chain and branched
chain groups of 1-6 carbon atoms. The definition of aryl is as described above. Examples of
aralkyl are CH2.phenyl, (CH2)2-phenyl, (CH2)3_phenyl and the like.
As used herein O-Aryl refers to aryl oxy groups, for example, phenoxy and the like.
The catalytic hydrogenolysis of compound of formula V or acid addition salt thereof to give compound of formula I is carried out in presence of metal catalysts like palladium, platinum, ruthenium or rhodium and the like.
10

The catalytic hydrogenolysis is carried out using any suitable hydrogen source, for example, hydrogen gas.
The catalytic hydrogenolysis may be carried out in a solvent. The solvent maybe selected from alcohols such as methanol, ethanol, isopropanol, and the like; aromatic hydrocarbons such as toluene, xylene or esters such as ethyl acetate, tert-butyl acetate and the like and ether solvents such as tetrahydrofuran, 1,4-dioxane and the like or mixtures thereof.
The catalytic hydrogenolysis may be carried at atmospheric pressure or at higher pressures and at temperature between 5 and 100°C for about 0.5 to 12 hours depending on the catalyst and source selected.
The compound of formula I obtained by following the process of the present invention may be converted to a pharmaceutically acceptable salt thereof. The catalytic hydrogenolysis of compound of formula V maybe carried out in the presence of the acid corresponding to the desired pharmaceutically acceptable salt of compound of formula I.
The pharmaceutically acceptable salt of compound of formula I may be selected from hydrochloride, hydrobromide, sulfate, nitrate, acetate, fumarate, maleate, citrate and the like.
Formula I
subjecting 3,4-dibenzyloxy-N-[3-(4-benzyloxy)-l-methyl-n-propyl]-/?-phenethylamine, a compound of formula V A, or acid addition salt thereof,
11
In one embodiment, the present invention provides a process for preparation of 4-[2-[[3-(4-hydroxyphenyl)-l-methylpropyl]amino]ethyl]-l,2-benzenediol, a compound of formula I or pharmaceutically acceptable salt thereof comprising



Formula VA
to catalytic hydrogenolysis.
In one embodiment, of the present invention the hydrochloride salt of 3,4-dibenzyloxy-N-[3-(4-benzyloxy)-l-methyl-n-propyl]-beta-phenethylamine, a compound of formula VA is subjected to catalytic hydrogenolysis with palladium/carbon in methanol and hydrochloric acid using hydrogen gas at 45-50° and atmospheric pressure for about 3 hours.
In a typical work-up, after completion of hydrogenolysis, the catalyst is removed by filtration. The compound of formula I may be isolated by degassing the solvent from the filtrate, preferably under reduced pressure. The compound of formula I thus obtained is treated with an acid to obtain a salt of compound of formula I, for example, with hydrochloric acid to obtain the hydrochloride salt of compound of formula I. The isolated salt of compound of formula I if desired, can be recrystallized from a suitable solvent(s) for example with hydrochloric acid to get substantially pure 4-[2-[[3-(4-hydroxyphenyl)-l -methylpropyl]amino]ethyl]-l ,2-benzenediol, compound of formula I.
The resultant substantially pure 4-[2-[[3-(4-hydroxyphenyl)-l-methylpropyl]amino]ethyl]-l,2-benzenediol, compound obtained by following the process of the present invention has purity of 99.5 % or greater as determined by HPLC. Preferably the resultant substantially pure 4-[2-[[3-(4-hydroxyphenyl)-l-methylpropyl]amino]ethyl]-l,2-benzenediol, compound obtained by following the process of the present invention has purity of 99.8 % or greater as determined by HPLC. The substantially pure 4-[2-[[3-(4-hydroxyphenyl)-l-methylpropyl]amino]ethyl]-l,2-benzenediol obtained by following the process of the present invention conforms to ICH grade purity
12

specifications for bulk drugs, which requires that known impurity should not be more than 0.2°/ and unknown impurity should not be more than 0.1%.
In one embodiment the present invention provides a process for preparation of 4-[2-[[3-(4-hydroxyphenyl)-l-methylpropyl]amino]ethyl]-l,2-benzenediol, the compound of formula 1 or pharmaceutically acceptable salt thereof comprising,
OH

Formula I
(a) reacting a compound of formula VI with a compound of formula VII to give a compound of formula V or acid addition salt thereof

Formula VI

Formula VII

^><

Formula V
13

wherein R is independently selected from hydrogen, (C,-C6) alkyl, O- (CrC6) alkyl, aryl.
O-aryl, aralkyl, halogen and hydroxyl; and
(b) subjecting the compound of formula V or acid addition salt thereof to catalytic
hydrogenolysis.
In one embodiment the present invention provides a process for preparation of 4-[2-[[3-(4-hydroxyphenyl)-l-methylpropyl]amino]ethyl]-l,2-benzenediol, the compound of formula I or pharmaceutically acceptable salt thereof comprising,


OH

OH

Formula I
(a) reacting a compound of formula VIA with a compound of formula VIIA to give a compound of formula VA or acid addition salt thereof; and



Ml.

Formula VIA

Formula VIIA


Formula VA
14

(b) subjecting the compound of formula VA or acid addition salt thereof to catalytic hydrogenolysis.
In one embodiment the present invention provides novel intermediate, a compound of formula V and acid addition salt thereof

Formula V
wherein R is independently selected from hydrogen, (C|-C6) alkyl, O- (C,-C(1) alkyl, aryl. O-aryl. aralkyl, halogen and hydroxyl and process for preparing it.
formula VA
15
In one embodiment the present invention provides novel intermediate, 3,4-dibenzyloxy-N-[3-(4-benzyloxy)-l-methyl-n-propyl]-beta-phenylethylamine, a compound of formula VA and acid addition salt thereof.


The novel intermediate, compound of formula V is prepared by reacting a compound of formula VI with a compound of formula VII wherein R is as defined above.

Formula VI Formula VII
The reaction of compound of the formula VI with the compound of formula VII may be carried out using hydrogen donor in presence of a catalyst or a hydride reducing agent.
A suitable catalyst for the reaction of compound of formula VI with compound of formula VII with a hydrogen donor may be selected from metals such as Raney nickel, nickel-molybdenum, platinium and the like which may be applied, if desired, to support materials, for example to carbon or calcium carbonate, for example, platinum on carbon or complexes of metals such as rhodium or iridium, for example Willikinson's catalyst, i.e. tris(triphenyphosphine)rhodium(I) chloride.
A preferred hydrogen donor is hydrogen gas and the reaction is carried out at pressures between 1 atmosphere and about 20 atmospheres and at temperatures of about 0 to about 50 ° C, the actual conditions being dependant on the substrate, catalyst and the solvent selected for the reaction.
The solvent for reaction of compound of formula VI with compound of formula VII using hydrogen donor in presence of a catalyst may be selected from alcohols such as methanol, ethanol, isopropanol, and the like; aromatic hydrocarbons such as toluene, xylene; esters such as ethyl acetate, tert-butyl acetate and the like; ether solvents such as tetrahydrofuran. 1,4-dioxane and the like
16

The hydride reducing agent for the reaction of compound of formula VI with compound of formula VII may be selected from diborane, aluminum hydride and borohydride which may also be in complexed form. A suitable borohydride or a complexed borohydride is, for example, an alkali metal borohydride such as sodium borohydride or lithium borohydride; an earth alkali metal borohydride such as calcium borohydride; an alkali metal cyanoborohydride, such as sodium cyanoborohydride or lithium cyanoborohydride, an alkali metal tri-(C l-C7alkoxy)-borohydride such as sodium triacetoxyborohydride; a tetra-Cl-C7-alkylammonium-(cyano)-borohydride such as tetrabutylammonium-borohydride or tetrabutylammonium-cyanoborohydride; aluminum hydrides or complexed aluminum hydrides such as lithium aluminum hydride, diisobutylaluminum ahydride, Red-Al and Vitride®.
The reaction of the compound of formula VI with the compound of formula VII using hydride reducing agent such as sodium cyanoborohydride and sodium triacetoxyborohydride may be carried out in a solvent selected from the group consisting of aromatic hydrocarbons such as toluene, xylene; esters such as ethyl acetate, tert-butyl acetate and the like; ether solvents such as tetrahydrofuran, tetrabutyl methyl ether and the like.
Formula VIII
17
Alternatively, the compound of formula VI may be reacted with the compound of formula VII to give a compound of formula VIII wherein R is same as defined earlier.


The reaction of the compound of formula VI with the compound of formula VII to give the compound of formula VIII may be carried out by any method known in the art. For example equimolar amounts of compounds of formula VI and VII are taken in an inert solvent such as toluene, in the presence of an acid catalyst, such as p-toluenesulfonic acid and the water generated in the condensation reaction is removed by azeotropic distillation to obtain the compound of formula VIII.
The compound of formula VIII obtained may be reduced to the compound of formula V by treatment with hydrogen donor in presence of a catalyst i.e. catalytic hydrogenation or a hydride reducing agent by using reagents as described earlier. Alternatively, the compound of formula VIII can be subjected to concomitant hydrogenation/ hydrogenolysis reaction using a suitable catalyst such as palladium/carbon and hydrogen gas as hydrogen donor to obtain directly the compound of formula I.
formula IX formula X
18
Alternatively the novel intermediate, compound of formula V, can be prepared by amidation of 3,4-bis(arylmethyloxy)phenylacetic acid of formula IX with 3-[4-(arylmethyloxy)phenyl]-l-methylpropylamine of formula X to the amide of formula XI, which can be reduced with a hydride reducing agent such as diborane to the compound of formula V.



Formula XI
The novel intermediate, compound of formula V, obtained by any of the methods described above may be converted to its acid addition salt. The acid addition salts may be selected from hydrochloride, maleate, hydrobromide, sulfate, nitrate, acetate, fumarate, maleate, citrate and the like. The acid addition salt may be prepared by reacting the compound of formula V with the respective acid. For example the hydrochloride salt of compound of formula V may be obtained, with hydrochloric acid.
The compound of formula V or acid addition salt thereof prepared by the process of the present invention need not necessarily be isolated and may be converted directly to the compound of formula I in the same pot. For example if the compound of formula V is prepared by reacting the compound of formula VI with the compound of formula VII using hydrogen donor in presence of catalyst, a suitable catalyst such as palladium on carbon can be used which will catalytically hydrogenate as well as cause simultaneous hydrogenolysis of the generated compound of formula V to give the compound of formula I in the same pot. If compound of formula V is prepared by using hydride reducing agent then hydrogenolysis catalyst can be added in the same pot after formation of compound of formula V to obtain the compound of formula I.
Alternatively the compound of formula V or acid addition salt thereof can be isolated and then converted to the compound of formula I by catalytic hydrogenolysis as disclosed earlier.
In one embodiment of the process of the present invention the compound of formula VIA is reacted with the compound of formula VIIA using acetic acid and sodium triacetoxyborohydride in tetrahydrofuran by heating at 50-55°C for about 1 to 4 hours to give 4-[2-[[3-(4-
19

hydroxyphenyl)-l-methylpropyl]amino]ethyl]-l,2-benzenediol, the compound of formula VA. The compound of formula VA obtained by following the process of the present invention is converted to the hydrochloride salt by reacting with hydrochloric acid. The hydrochloride salt of compound of formula VA is converted to the compound of formula I by subjecting it to catalytic hydrogenolysis with palladium/carbon in methanol and hydrochloric acid using hydrogen gas at 45-50° and atmospheric pressure for about 2 to 5 hours.
The starting material for example, compound of formula VIA can be prepared by any method known in the art such as by reacting 4-(4-hydroxyphenyl)but-2-one, a compound of formula IVA with benzyl chloride and potassium carbonate in N,N-dimethylforrnamide.

Formula IVA Formula VIA
The starting material for example, compound of formula VIIA can be prepared by any method known in the art such as by reacting compound of formula XII with diborane generated from sodium borohydride and borontrifluoride etherate.

Formula XII Formula VIIA
The patents and patent applications described in this application are herein incorporated by reference only.
The invention is illustrated but not restricted by the description in the following examples.
20

Examples
Example 1 : Preparation of 3,4-dibenzvloxv-N-[3-(4-benzvloxvM-methvl-n-propvl|-3-phenvl ethvlamine hydrochloride, compound of formula VA
A suspension of 2-(3,4-dibenzyloxyphenyl)ethylamine (75g, 0.225mol), compound of formula
VIIA, and 4-(4-benzyloxyphenyl)-2-butanone compound of formula VIA, (68.65g, 0.27mol),
acetic acid (19.3ml) and 46%w/w solution of sodium tnacetoxyborohydride (247ml, 0.4mol)
in tetrahydrofuran (300ml) was heated to 50-55°C for 2 hours. The slurry was cooled to 30-
35°C and it was quenched by addition of water (225ml). The pH was adjusted to 10.0-10.5 by
adding caustic lye at 10-15°C, and the product was extracted into isopropyl acetate (225ml) at
30-35°C. The organic extract was concentrated at 50-55°C under reduced pressure and then
degassed under vacuum. Resulting residue was dissolved in methanol (375ml), cooled to 10-
15°C and treated with concentrated hydrochloric acid (12.5ml). Water (225ml) was charged to
the slurry, the product was filtered, washed with water (150ml), and dried in air oven at 55-
60°C till constant weight, yield 1 l0g. The product was dissolved in ethyl acetate (550ml) at
75-80°C, cooled to 30-35°C and the crystallized product, compound of formula VA as the
hydrochloride salt is filtered, washed with ethyl acetate (220ml), and dried in air oven at 55-
60°C till constant weight. Yield 74g, purity >97.0%.
Example 2: Preparation of 4-[2-H3-(4-hvdroxvphenvl)-l-methvlpropyl|aminolethvl|-l,2-benzenediol, compound of formula I
A slurry of 3,4-dibenzyloxy-N-[3-(4-benzyloxy)-l-methyl-n-propyl]-/?-phenethylamine
hydrochloride, compound of formula VA as the hydrochloride salt (75g, 0.131mol), 5% Pd/
C (7.5g) and hydrochloric acid (7.5ml) in methanol (600ml) was hydrogenated at 45-50°C at
atmospheric pressure for 3hours.The catalyst was filtered, and the filtrate concentrated at 50-
55°C under reduced pressure. 4N Hydrochloric acid (75ml) was added and distilled out at
55-60°C and then degassed under high vacuum to get white solid product. 4N Hydrochloric
acid (2460ml) was added to the solid, heated to 100-105°C to get a clear solution, and then
cooled gradually to 30-35°C. The crystallized product was filtered, washed with 0.5N
hydrochloric acid (75ml) and dried in air oven at 55-60°C till constant weight, 36g, white
solid with purity of 99.8% as determined by HPLC with individual impurities below 0.1%,
as determined by HPLC.
21

Example 3: Preparation of 4-(4-benzvloxv)but-2-one, compound of formula VIA
A suspension of 4-(4-hydroxyphenyl)but-2-one (200g, 1.22mol), benzyl chloride (162g. 1.428mol) and potassium carbonate (250g, 2.17mol) in N,N-dimethylformamide (400ml) was heated at 90-95°C for 2hours. The mixture was cooled to 30-35°C, water (1200ml) was then added while maintaining the temperature between 30-35°C. The crystallized product was filtered, washed with water (500ml), and dried in air oven at 45-50°C till constant weight, 306g, (96.8% yield), purity >98.0%.
Example 4
Preparation of 2-(3,4-dibenzyloxyphenvl)ethvlamine compound of formula VI1A
To a suspension of sodium borohydride (49.72g, 1.31mol) in tetrahydrofuran (600ml) was added slowly borontrifluoride etherate (235.8g, 1.66mol) at 0-15°C. The temperature was raised to 25-30°C and stirred for 15min, and solution of 2-(3,4-dibenzyloxyphenyl)nitroethylene (l00g, 0.276mol) in tetrahydrofuran (400ml) was added to the above mixture at reflux temperature. After 4 hours stirring at 60-65°C the reaction mixture was cooled to 0-5°C and was quenched by addition of 1.5N hydrochloric acid (600ml) while maintaining the temperature between 25-30°C. The pH was adjusted to 9.0-9.5 by addition of caustic lye at 25-30°C. The inorganic salts were filtered and the organic layer was separated. Aqueous layer was extracted with isopropyl acetate (200ml), and combined organic layers were concentrated at 65-70°C under reduced pressure. The residue was heated in a mixture of toluene (150ml) and cyclohexane (300ml) at 85-90°C and then gradually cooled to 30-35°C. After stirring for 2hours at 30-35°C the product was filtered, washed with a mixture of toluene-cyclohexane (1:1, 200ml), and dried to constant weight, 83g, (90.2% yield), purity >98.0%.
Example 5: Comparative Example (as per United States Patent No.US3987200)
Preparation of 4-|2-H3-(4-hvdroxvphenvl)-l-methvlpropyllamino|ethvl|-l,2-benzenediol, compound of formula I
A solution of trimethoxy dobutamine, compound of formula II (50g, 0.131mol) in acetic acid (150ml) and hydrobromic acid (150ml) was heated to reflux for six hours. The mixture of acetic-acid and hydrobromic acid was distilled out under reduced pressure at 90-95°C. Water (120ml) was added to the residual solid and heated to get a clear solution. Concentrated hydrochloric acid (120ml) was added to it and heated to 90-95°C for 2-3 hours and slowly cooled to 25-30°C. The
22

product was filtered, washed with 0.5 N hydrochloric acid (50ml), dried in air oven at 55-60 C till constant weight. Yield 40g (89.8%), purity 99.0% with individual impurities >0.1% as determined by HPLC.
LC-MS analysis of the impurities indicated presence of ring brominated impurity (ES+ m/z at 380), ring chlorinated impurity (ES+ m/z at 336) besides other impurities.
Example 6: Comparative Example (as per Polish Patent No. PL1367U)
Preparation of 4-[2-[[3-(4-hvdroxvphenvl)-l-methvlpropvl]amino|ethvl]-l,2-benzenediol,
compound of formula I
A slurry of trimethoxy dobutamine, compound of formula II (10g, 0.0263mol) and anhydrous aluminum chloride (33.37g, 0.25mol) in toluene (156ml) was stirred for 1.5 hour at 25-30°C. The mixture was heated at 100-105°C for 2 hours, then cooled to 0-5°C and quenched into chilled water (150ml). Stirred for l hour at 25-30°C and the solid was filtered and washed with water. The solid was suspended in water (125ml), heated at 95-100°C to get clear solution, added concentrated hydrochloric acid (10ml) to it and then cooled to 25-30°C. The crystallized product was filtered, washed with 0.5 N hydrochloric acid (50ml), dried in air oven at 55-60"C till constant weight, yield 7.4g, purity 99.0% individual impurities were >0.1%.
23

The present invention particularly relates to:
A] A process for preparation of 4-[2-[[3-(4-hydroxyphenyl)-l -methylpropyl]amino]
ethyl]-1,2-benzenediol, a compound of formula I or pharmaceutically acceptable salt thereof comprising
on

Formula I
subjecting 3,4-bis(arylmethyloxy)-N-[3-(4-arylmethyloxy)-l-methylpropyl]-beta-phenethyl amine, a compound of formula V, or acid addition salt thereof,

Formula V
wherein R is independently selected from hydrogen, (CrC6) alkyl, O- (CrC6) alkyl, aryl, O-aryl, aralkyl, halogen and hydroxyl, to catalytic hydrogenolysis.
B] A process as defined in 'A' above, for preparation of 4-[2-[[3-(4-hydroxy phenyl)-
l-methylpropyl]amino]ethyl]-1,2-benzenediol, a compound of formula I or pharmaceutically acceptable salt thereof comprising
24

OH

Formula I
subjecting 3,4-dibenzyloxy-N-[3-(4-benzyloxy)-l-methyl-n-propyl]-y5-phenethylamine, a compound of formula VA, or acid addition salt thereof,

Formula VA to catalytic hydrogenolysis.
C] A process as defined in 'A' above , wherein the resultant 4-[2-[[3-(4-hydroxyphenyl)-
l-methylpropyl]amino]ethyl]-l,2-benzenediol, the compound of formula I or pharmaceutically acceptable salt thereof has purity of 99.5 % or greater as determined by HPLC.
D] A process for preparation of 4-[2-[[3-(4-hydroxyphenyl)-l-methylpropyl]amino]ethyl]-l,2-
benzenediol, a compound of formula I or pharmaceutically acceptable salt thereof
comprising
25

Oil

Formula I
(a) reacting a compound of formula VI with a compound of formula VII to give a compound of formula V or acid addition salt thereof


NIN


Formula VI

Formula VII


Formula V
wherein R is independently selected from hydrogen, (CrC6) alkyl, O- (CrC6) alkyl, aryl, O-aryl, aralkyl, halogen and hydroxyl; and (b) subjecting the compound of formula V or acid addition salt thereof to catalytic hydrogenolysis.
26

E] A process as defined in 'D' above for preparation of 4-[2-[[3-(4-hydroxyphenyl)-l-
methylpropyl]amino]ethyl]-l,2-benzenediol, a compound of formula I or pharmaceutically acceptable salt thereof comprising
OH


Formula VIA Formula VIIA
Formula I
(a) reacting a compound of formula VIA with a compound of formula VIIA to give a compound of formula VA or acid addition salt thereof; and


Formula VA
(b) subjecting the compound of formula VA or acid addition salt thereof to catalytic hydrogenolysis.
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F] A process as defined in 'D' above, wherein, step 'a' is carried out using a hydride
reducing agent or a hydrogen donor in presence of a catalyst.
G] A compound of formula V and acid addition salt thereof.

Formula V
wherein R is independently selected from hydrogen, (CrC6) alkyl, O- (CrC6) alkyl, aryl, O-aryl, aralkyl, halogen and hydroxyl.
Formula VA
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H] 3,4-dibenzyloxy-N-[3-(4-benzyloxy)-l-methyl-n-propyl]-P-phenyl ethylamine, a compound of formula VA and acid addition salt thereof.


I] A process for preparation of 3,4-bis(arylmethyloxy)-N-[3-(4-arylmethyloxy)-l-methylpropyl]-/?-phenethyl amine , a compound of formula V or acid addition salt thereof

Formula V
comprising reacting a compound of formula VI with a compound of formula VII,

Formula VI Formula VII
wherein R is independently selected from hydrogen, (Ci-C6) alkyl, O- (CrC6) alkyl, aryl, O-aryl, aralkyl, halogen and hydroxyl.
J] A process as defined in T above for preparation of 4-[2-[[3-(4-hydroxyphenyl)-methylpropyl]amino]ethyl]-l,2-benzenediol, a compound of formula V or acid addition salt thereof,
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Formula VA
comprising reacting a compound of formula VIA with a compound of formula VIIA.

Formula VIA

Formula VIIA

Dated this 10th day of July, 2006

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DILIP SHANGHVI CHAIRMAN AND MANAGING DIRECTOR SUN PHARMACEUTICAL INDUSTRIES LTD
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