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 EPINEPHRINE
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 for a process for the preparation of
epinephrine.
The following specification particularly describes the invention and the manner
in which it is to be performed.
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Field of the Invention
The present invention relates to an efficient process for the preparation of racemic epinephrine.
Background of the Invention
Epinephrine, also referred as adrenaline, is an endogenous catcholamine with combined a- and p- agonist activity. It is chemically known as 4-[1-hydroxy-2-(methylamino)ethyl]-1,2-benzenediol having the structure as depicted by formula I.
OH i HO./^J\^NH
Formula I
(-)-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.
Industrially, adrenaline is usually produced by hydrogenation of 3',4'-
dihydroxy-2-N-methylaminoacetophenone or a derivative thereof with
protected OH functions or amino function and subsequent racemate
separation.
Tetrahedron Letters 5 (1979), 425-428 describes the enantioselective process for the preparation of (-)-epinephrine, which involves by hydrogenation of 3',4'-dihydroxy-2-N-methylaminoacetophenone under a hydrogen pressure of about 50 bar using a chiral hydroxyalkylferrocenylphosphine as catalyst for about 2 to 4 days. The product obtained has enantiomeric excess of 60% ee.
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US patent 6,218,575 discloses use of a rhodium catalyst [Rh(COD)CI]2 and a chiral bidenate phosphine ligand in basic medium to obtain (R)-1-(3',4'-dihydroxyphenyl)-2-N-benzyl-N-methylethan-1 -ol) from 3',4'-dihydroxy-2-N-benzyl-N-methylamino acetophenone. Further hydrogenating (R)-1-(3',4'-dihydroxyphenyl)-2-N-benzyl-N-methylethan-1-ol) with the rhodium catalyst in acidic medium to obtain (-)-epinephrine in 98% ee.
The reported methods are not suitable for producing epinephrine on an industrial scale due to use of large amounts of expensive catalyst in the asymmetric reaction step.
Thus, there is a need to develop a cost effective process for the preparation of epinephrine.
Detailed Description of the Invention
The present invention provides for an efficient process for the preparation of racemic epinephrine from the starting material 3,4-dihydroxy phenacylchloride having the structure as shown in formula II.
The process for the preparation of epinephrine of formula I, according to the present invention comprises of:
a) reacting 3,4-dihydroxy phenacylchloride of formula II, with N-methyl
benzylamine in suitable aprotic solvent;
O HO^^^^Ji^/CI
Formula II
b) acidifying the reaction mixture;
c) isolating and purifying 3',4'-dihydroxy-2-N-benzyl-N-methylamino acetophenone of formula III from the reaction mixture thereof;
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HO v
Formula III
d) hydrogenating 3',4'-dihydroxy-2-N-benzyl-N-methylaminoacetophenone in the presence of a catalyst in a suitable organic solvent;
e) isolating epinephrine from the reaction mixture thereof.
In one embodiment of the invention the present invention provides a process for the preparation of the 3',4'-dihydroxy-2-N-benzyl-N-methylamino acetophenone of formula III, an intermediate for the preparation of epinephrine.
Another embodiment of the present invention provides an efficient cost effective process to convert the intermediate 3',4'-dihydroxy-2-N-benzyl-N-methylamino acetophenone of formula III to racemic epinephrine.
In general, the 3,4-dihydroxy phenacylchloride of formula II is treated with N-
methyl benzylamine in a suitable aprotic solvent, at a temperature in the
range of 0 to 30 °C for a period 1 to 6 hours. The suitable aprotic solvent
includes N,N-dimethyl acetamide; N,N-dimethyl formamide; dimethyl
sulphoxide; hexamethylphosphorotriamide, acetonitrile, dioxane,
tetrahydrofuran or mixtures thereof. After the reaction is complete, the reaction mass is acidified. The reaction mass may be acidified to pH -5.5 with any acid, for example, dilute hydrochloride acid, acetic acid, dilute sulphuric acid.
The solution is then basified with a basifying agent such as ammonia, methylamine to pH ~ 8.5. This solution is again acidified by said acidifying agent to pH 5.5. The product of the reaction i.e. 3\4'-dihydroxy-2-N-benzyl-N-methylamino acetophenone may be isolated from the solution by a technique
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which includes, for example, filtration, filtration under vacuum, decantation, and centrifugation.
The present invention further provides for a one pot reaction of reducing the ketone functionality to hydroxyl and debenzylating the amino functionality by using catalytic hydrogenation. The intermediate 3',4'-dihydroxy-2-N-benzyl-N-methylamino acetophenone is treated with a catalyst such as 10% Pd/C, 5% Pd/C, in presence of a hydrogen source such as hydrogen gas, ammonium formate in a suitable organic solvent. The hydrogenation reaction is performed under acidic pH ~ 1.0 to 3.0 The acidic pH is obtained with any acid, for example, dilute hydrochloride acid, dilute sulphuric acid, acetic acid, formic acid. The suitable organic solvents include methanol, ethanol, ethyl acetate, acetic acid, tetrahydrofuran, dioxane, halogenated solvents such as chloroform, methylenechloride, ethylenedichloride. On completion of the reaction the catalyst was removed by filtration and the filtrate was basified with pH ~ 8 to 9, with a basifying agent such as ammonia, methylamine and epinephrine was obtained as free base.
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 3,4-dihydroxy phenyl acetyl chloride (750 g) in N,N-dimethyl acetamide (2.1 L) at about 10-15 °C was added N-methyl benzyl amine (912 g) drop wise. After the addition temperature of the reaction mixture raised to 30-35 °C and stirred for another 2-4 hours. After completion of the reaction, the reaction mixture was filtered and washed with isopropyl alcohol (1.0 L). The filtrate is cooled to about 20 °C then the pH was adjusted to about 5.5 with dilute HCI (150 mL). Then added water (8 L) and stir for 15 min. pH of the reaction mixture adjusted to 8.5 with dilute ammonia (240 mL). The solid obtained was filtered, the solid washed with the water (4 L). The wet
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solid was suspended in water (10 L) and pH was adjusted to 5.5. The suspension was stirred for 1 hour and the solid obtained was filtered and dried at room temperature to afford 1027 g of N-benzyl epinephrine.
Example-2
N-Benzyl epinephrine (950 g) was dissolved in methanol (9.5 L) and pH was adjusted with dilute HCI (345 mL) to about 1.0-2.4 stir. To the reaction mixture was added 10% Pd/C (250 g) and applied hydrogen gas bubbling and heated to about 40 °C. Stirred at 40 °C for 30-35 hours. After completion of the reaction, the reaction mass filtered and washed with methanol (1 L). Filtrate was cooled to 10-15 °C and pH adjusted by ammonia solution (275 ml) to 8.5 to get epinephrine. The reaction mixture filtered and washed with methanol (1 L) and dried to afford 523 g of epinephrine.
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We Claim:
1. A process for the preparation of epinephrine of formula I, wherein the said
process comprises of,
a) reacting 3,4-dihydroxy phenacylchloride of formula II, with N-methyl
benzylamine in suitable aprotic solvent;

Formula II
b) acidifying the reaction mixture;
c) isolating and purifying 3',4'-dihydroxy-2-N-benzyl-N-methylamino acetophenone of formula III from the reaction mixture thereof;

Formula III
d) hydrogenating 3',4'-dihydroxy-2-N-benzyl-N-methylaminoacetophenone in presence of a catalyst in a suitable organic solvent;
e) isolating epinephrine from the reaction mixture thereof;
2.The process of claim 1, wherein the aprotic solvent comprises N,N-dimethyl
acetamide; N,N-dimethyl formamide; dimethyl sulphoxide;
hexamethylphosphorotriamide, acetonitrile, dioxane, tetrahydrofuran or mixtures thereof.
3. The process of claim 2, wherein the aprotic solvent is N,N-dimethyl
acetamide.
4. The process of claim 1, wherein the catalyst is 10% Pd/C or 5% Pd/C.
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5. The process of claim 1, wherein the solvent for hydrogenation reaction is methanol, ethanol, ethyl acetate, acetic acid, tetrahydrofuran, dioxane, halogenated solvents such as chloroform, methylenechloride, ethylenedichloride.
6. The process of claim 1, wherein the pH of the hydrogenation reaction is in the range of 1.0 to 3.0

Dated this 29TH day of June, 2007


Abstract
The present invention provides for an efficient process for the preparation of racemic epinephrine from the starting material 3,4-dihydroxy phenacylchloride. The present invention provides a process for the preparation of the 3',4'-dihydroxy-2-N-benzyl-N-methylamino acetophenone, an intermediate for the preparation of epinephrine. The invention further provides an efficient cost effective process to convert the intermediate 3',4'-di hydroxy-2-N-benzyl-N-methylamino acetophenone to racemic epinephrine.
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