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 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 a cost efficient process for the preparation of (-)-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.
(-)-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.

Formula I
Tetrahedron Letters 5 (1979), 425-428 describes the enantioselective process for the preparation of (-)-epinephrine, 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.
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'-
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dihydroxyphenyl)-2-N-benzyl-N-methylethan-1-ol) with the rhodium catalyst in acidic medium to obtain (-)-epinephrine.
Thus, there is a need to develop a cost effective process for the preparation of (-)-epinephrine with high chemical and optical purity without using expensive reagents, which is suitable for industrial scale preparation.
Detailed Description of the Invention
The present invention provides for an efficient process for the preparation of (-)-epinephrine of formula I.
In one aspect the present invention provides a process for the resolution of racemic epinephrine. The process for the preparation of (-)-epinephrine of formula I, according to the present invention comprises of:
a) reacting epinephrine with a chiral auxiliary to form a mixture of diastereomeric salts of epinephrine;
b) separating the diastereomer of (-)-epinephrine from the reaction mixture of step a);
c) converting the separated diastereomeric salt of (-)-epinephrine to (-)-epinephrine.
Another aspect of the present invention is to provide the process for the purification of (-)-epinephrine free base. The process of purifying (-)-epinephrine free base comprises of acidifying a solution of (-)-epinephrine free base with an acid, treating the solution with charcoal and sodium bisuphite and isolating the pure (-)-epinephrine free base by basifying the reaction mixture with a base.
The present invention uses easily available, chiral auxiliary for the resolution of racemic epinephrine to (-)-epinephrine. The chiral auxiliary refers to enantiomerically pure organic acids having at least one chiral centre. Examples of chiral auxiliary for optically resolving epinephrine may include D-
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tartaric acid, L-tartaric acid, D-camphor-10-sulfonic acid, L-camphor-10-sulfonic acid, D-dibenzoyltartaric acid, L-dibenzoyltartaric acid, D-mandelic acid, L-mandelic acid and the like.
The reaction of epinephrine free base with a chiral auxiliary in an organic solvent results in formation of two diastereomeric salts of epinephrine. The organic solvent for the reaction may include solvents for example methanol, ethanol, isopropanol, butanol, acetonitrile, dioxane, dimethylformamide, dimethylsulphoxide, halogenated solvents such as dichloromethane, chloroform and mixtures thereof. The solvent mixtures also includes aqueous organic solvent mixtures. The two diastereomeric salts are separated by means of difference in their solubility properties. One of the salt precipitates out and the other salt remains in the solution. The separation of the diastereomeric salt from the reaction mixture is carried out by filtration. The desired isomer is converted into the free base by treating the separated diastereomeric salt with a basifying agent. The steps of formation of the diastereomeric salt, separation of the desired salt and subsequent release of the free base from the salt can be repeated to enrich the optical purity of (-)-epinephrine free base. The basifying agent includes bases such as ammonia, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide and similar bases to liberate the diastereomer.
Typically, the racemic epinephrine is treated with L-tartaric acid in methanol and the reaction is stirred at room temperature for a period of 4 to 36 hours. The precipitate obtained is filtered to obtain epinephrine tartrate. The epinephrine tartrate is basified with the basifying agent, in presence of sodium meta bisulphite at a temperature in the range of -10 to 30 °C. The solid obtained is filtered to provide the (-)-epinephrine free base. The chiral purity of the epinephrine is obtained by chiral HPLC. To further enrich the chiral purity, the steps of formation of epinephrine tartrate and isolation of (-)-epinephrine from epinephrine tartrate can be repeated.
The process of purifying (-)-epinephrine free base by the process comprising, a) acidifying (-)-epinephrine free base solution with an acid;
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b) basifying the solution with a base;
c) isolating the pure (-)-epinephrine free base from the reaction mixture thereof.
The (-)-epinephrine free base is purified by acidifying the suspension of (-)-epinephrine free base in water upto pH 4 with an acid such as hydrochloric acid, sulphuric acid, acetic acid, formic acid, to obtain a clear solution. Treating the solution with carbon for 30 min and filtering the reaction mixture to remove any impurities. The filtrate is cooled to -10 to 20 CC and basified. The solid obtained is filtered and dried under vacuum to afford pure (-)-epinephrine. The (-)-epinephrine thus obtained has a chemical purity more than 99% and enantiomeric excess of more than 95%. The free base can be further subjected to extraction, washing, drying and the like to purify further the (-)-epinephrine.
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
Step A: To a solution of epinephrine (crude) (500 g) in methanol (1.0 L) was added L-tartaric acid (820 g). The reaction was stirred and after 1-3 hours, a thick precipitation was observed. Methanol (1.5 lit) was added and stirred for 24-30 hours at room temperature. The reaction mixture filtered and washed with a mixture of methanol-ethanol (1 L) and dried on to obtain epinephrine tartrate (wet. wt) 464 g as solid.
Step B: Epinephrine tartrate (wet. wt) (464 g) was dissolved in purified water (4.5 L) and sodium meta bisulphite (4 g) was added and the reaction mixture was cooled to 5-10 °C. The pH of the reaction mixture was adjusted with ammonia sol (270 mL) to about 8.5. The reaction stirred for 15 min and filtered. The solid obtained was washed with water (500 mL) followed by
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methanol (500 mL) and dried to obtain (-)-epinephrine base 232 g as solid. The reaction sequence of Step A and Step B is repeated twice to enrich the optical purity. The crude (-)-epinephrine is used in the next step.
Example –2
To a 5-10 °C cooled suspension of epinephrine base obtained from Example-
1 (130 g) in purified water (1.3 L) was added HCI (55 mL) to adjust the pH to ~
2 to 2.5 to get clear solution. To the clear solution was added carbon (5 g) and sodium meta bisulphite (1 g), the reaction stirred for 30 min. The reaction mass filtered and washed with water (200 mL). The filtrate was cooled to 5-10 °C then added dilute ammonia solution (105 mL) to adjust pH about 8.5. The reaction was stirred for 15 min, the reaction mixture was filtered and washed with water (400 mL) then methanol (400 mL) and dried to get pure epinephrine 103 g as a solid with chemical purity 99.88 %, Enantiomeric excess 95.34 %.
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We Claim:
1. A process for obtaining pure (-)-epinephrine from racemic epinephrine, the
process comprising:
a) reacting epinephrine with a chiral auxiliary to form a mixture of diastereomeric salts of epinephrine;
b) separating the diastereomer of (-)-epinephrine from the reaction mixture of step a);
c) converting the separated diastereomeric salt of (-)-epinephrine to (-)-epinephrine.

2. The process of claim 1, wherein the chiral auxiliary is selected from D-tartaric acid, L-tartaric acid, D-camphor-10-sulfonic acid, L-camphor-10-sulfonic acid, D-dibenzoyltartaric acid, L-dibenzoyltartaric acid, D-mandelic acid, L-mandelic acid, L-lactic acid, L-malic acid and the like.
3. The process of claim 1, wherein the organic solvent comprises of methanol, ethanol, isopropanol, butanol, acetonitrile, dioxane, dimethylformamide, dimethylsulphoxide, halogenated solvents and mixtures thereof.
4. The process of purifying (-)-epinephrine free base by the process
comprising,
a) acidifying (-)-epinephrine free base solution with an acid;
b) basifying the solution with a base;
c) isolating the pure (-)-epinephrine free base from the reaction mixture thereof.

5. The process of claim 4, wherein the acid used for acidifying comprises of hydrochloric acid, sulphuric acid, acetic acid, formic acid.
6. The process of claim 4, wherein in the step a) the pH of the reaction mixture is below 4.
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7. The process of claim 4, wherein the pure (-)-epinephrine free base is isolated by basifying the reaction mixture with a base.
8. The process of claim 4 or 7, wherein the base comprises of ammonia, sodium carbonate, sodium hydroxide, potassium carbonate or potassium hydroxide.
9. (-)-Epinephrine having less than 3% of (+)-epinephrine.
10. (-)-Epinephrine having enantiomeric excess of more than 95 %, obtained
by using a chiral auxiliary.

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Abstract
The present invention relates to a cost efficient process for the preparation of (-)-epinephrine. The process comprises of resolution of racemic epinephrine using an organic acid.
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