FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
PROCESS FOR THE PREPARATION OF 3,4-DIHYDROXY PHENACYL CHLORIDE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a process for the preparation of 3,4-dihydroxy phenacyl chloride
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention relates to an efficient process for the preparation of a compound of formula I, a useful intermediate in the synthesis of epinephrine.
O HO. /^ J-L .CI

Formula I
Epinephrine, also referred as adrenaline, is an endogenous catcholamine with combined a- and β- agonist activity. It is chemically known as 4-[1-hydroxy-2-(methylamino)ethyl]-1,2-benzenediol having the structure as depicted by formula II.
(-)-Epinephrine is available as injection and orally inhaled dosage forms. It is used to relieve temporary shortness of breath, chest tightness, and wheezing due to bronchial asthma. Epinephrine is also available as a prescription drug used as injection in emergencies, including acute asthma attacks and severe allergic reactions.
OH | HO. /-^ ^K .NH

Formula II
3,4-dihydroxy phenacyl chloride is an intermediate involved in the synthesis of Epinephrine. Japanese patent JP 50130729A discloses a process for the preparation of 3,4-dihydroxy phenacyl chloride, which involves the reaction of catechol with chloroacetic acid in presence of POCI3 in benzene in an inert atmosphere. This drawback of this method is the use carcinogenic solvent benzene and has a moderate yield of 70%. There is a need to develop an
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efficient high yielding process for the preparation of the intermediate of formula I.
The present invention provides for an efficient process for the preparation of the compound of formula I. The process of present invention avoids prior art use of hazardous chemicals and the product is easy to isolate and handle, thus making the process amenable for commercial scale use. The product obtained by the process of the present invention is useful as a starting material for the preparation of epinephrine.

The present invention relates to reacting catechol with chloroacetyl chloride in the presence of a Lewis acid to provide 3,4-dihydroxy phenacyl chloride, an intermediate for the preparation of epinephrine as shown in the Scheme 1.
O
HO^^x O HO. ^^ >L .CI

+ JL xi
cr ^-^
HO

catechol chloroacetyl chloride

formula

Scheme -1
The process for the preparation of 3,4-dihydroxy phenacyl chloride of formula I, according to the present invention comprises of:
a) reacting catechol in a suitable organic solvent with chloroacetyl chloride in the presence of a Lewis acid;
b) acidifying the reaction mixture;
c) isolating and purifying the 3,4-dihydroxy phenacyl chloride thereof.
The Lewis acid suitable for the reaction is selected from aluminium chloride, zinc chloride, ferric chloride, stannous chloride, Boron triflouride or aluminium bromide. The suitable organic solvent includes carbon disulphide, nitrobenzene, halogenated solvent such as 1,2-dichlorothane, methylene
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chloride, chloroform, carbon tetrachloride and mixtures thereof. The reaction is carried out at a temperature in the range of -20 to 50°C.
Typically, catechol is added to a solution of aluminium chloride at 0-20 °C and the reaction mixture is stirred for 10 to 30 minutes followed by the addition of chloroacetyl chloride at a temperature in the range of 10-20 °C. The reaction mixture is stirred at room temperature for 16 to 20 hours. The reaction mixture is acidified with aqueous HCI. The solid thus obtained is dissolved in acetic acid. Upon cooling, the precipitate obtained is filtered to obtain the product i.e. 3,4-dihydroxy phenacyl chloride. The yield of the product is more than 85 %.
The compound of formula I thus obtained can be converted to epinephrine by the processes known in the art.
The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example -1
To a cooled solution of 1,2-dichloroethane (5 L) at about 10-15 °C was added aluminum chloride (1.5 Kg) and the reaction mixture was stirred for 15-30 min at 10-15 °C. To the stirred reaction mixture was added catechol (500 g) portion wise within 5-10 min and the reaction mixture stirred for 20-30 min. To the above solution chloroacetyl chloride (546 g) was added at 10-15 °C. Then temperature of the reaction mixture was raised to room temperature and stirred for 16-20 hours. After completion of the reaction, the reaction is quenched with dil HCI solution (10 L), at 5-10 °C and stirred for 2-3 hours at room temperature. The solid obtained is filtered, the wet solid was washed with water (4 L). The wet solid was suspended in dil acetic acid (mixture of acetic acid 600 mL and water 4 L) and heated to about 85-90 °C to get clear solution. To the clear solution was added carbon (15 g) and stirred for 30
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minutes. The reaction mixture was filtered hot. The solid obtained upon cooling the filtrate was filtered and washed with water (4 L) and dried to obtain 3,4-dihydroxy phenacyl chloride in 725 g, HPLC Purity: 99.83%; M.P.: 175.1-176.7 °C.
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We Claim:
1. A process for the preparation of a compound of formula I, an intermediate
useful in the synthesis of epinephrine, wherein the said process comprises
of,
a) reacting catechol in an organic solvent with chloroacetyl chloride in presence of a Lewis acid;
b) acidifying the reaction mixture;
c) isolating and purifying the 3,4-dihydroxy phenacyl chloride thereof.

2. The process of claim 1, wherein the Lewis acid is aluminium chloride.
3. The process of claim 1, wherein the organic solvent comprises halogenated solvent, carbon disulphide, nitrobenzene.
4. The process of claim 1, wherein the organic solvent is halogenated solvent.
5. The process of claim 4, wherein the organic solvent is 1,2,-dichloroethane.
6. The process of claim 1, wherein the temperature is -20 to 50°C.
Dated this 29TH day of June, 2007
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Abstract
The present invention relates to an efficient process for the preparation of a 3,4-dihydroxy phenacyl chloride, an useful intermediate in the synthesis of epinephrine.
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