CLIAMS:We Claim:

1. An in-situ process for the preparation of DL-Epinephrine from N-benzyl adrenalone, which comprises:

a) reaction of N-benzyl adrenalone with sodium borohydride in presence of alcohol to provide N-benzyl adrenaline; and

b) conversion of N-benzyl adrenaline to DL-epinephrine using catalyst, for example, Pd/C in presence of hydrogen gas and alcohol.

2. The process of claim 1, wherein said sodium borohydride or Aqueous Sodium hydroxide solution of sodium borohydride is added portion wise to the reaction mixture.

3. The process of claim 1, wherein said the step a) is performed at 0 °C to 5 °C.

4. The process of claim 1, wherein said alcohol is selected from methanol, ethanol, isopropyl alcohol and n-butanol.

5. The process of claim 1, wherein said DL-epinephrine is further converted to (-)-epinephrine by using resolution technique.

6. The process of claim 1, wherein said DL-epinephrine is having purity greater than 94% by HPLC.

Dated this 26 day of March 2013 For Wockhardt Limited

(Dr Mandar Kodgule)
Authorized Signatory
,TagSPECI:DESCRIPTION

The present invention relates to an in-situ process for DL-Epinephrine from N-benzyl adrenalone, which is finally resolved to provide R-(-)-L-Epinephrine, or an addition salt thereof. Further, it relates to preparation of N-benzyl adrenaline from N-benzyl adrenalone using readily available, inexpensive and safer reducing reagent, for example, sodium borohydride.

Epinephrine, also referred as adrenaline, is an endogenous catacholamine with combined a- and b- agonist activity. Epinephrine of Formula I is chemically known as 1,2-Benzenediol, 4-[(1R)-1-hydroxy-2-(methylamino)ethyl]-, or (-)-3,4-dihydroxy-α-[2- (methylamino)ethyl]benzyl alcohol.

Formula I
Epinephrine is available as an 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 as an injection in emergencies, including acute asthma attacks and severe allergic reactions. The synthesis of epinephrine is disclosed in U.S. Patent No. 6,218,575 and Tetrahedron Letters 5 (1979), 425-428

Tetrahedron Letters 5 (1979), 425-428 discloses a method for producing adrenaline. The method, 3',4'-dihydroxy-2-N-methylaminoacetophenone is reacted to produce adrenaline by hydrogenation under a hydrogen pressure of about 50 bar using a chiral hydroxyalkylferrocenylphosphine as catalyst. The conditions of the reaction provide L-1-(3',4'-dihydroxyphenyl)-2-methylaminoethan-1-ol (adrenaline) in an enantiomeric excess over the S-enantiomer of 60% ee after about 2 to 4 days reaction.

Tetrahedron Letters 30 (1989), 367-370 and Chem. Pharm. Bull. 43 (5) (1995) 738-747 describes an asymmetric rhodium catalyst which was used in the manufacture of L-phenylephrine. Using asymmetric hydrogenation, 3'-benzyloxy-2-(N-benzyl-N-methyl)aminoacetophenone hydrochloride is reduced within 20 hours with hydrogen in the presence of [Rh(COD)Cl]2 / (2R,4R)-4-(dicyclohexylphosphino)-2-(diphenylphosphinomethyl)-N-methylamin opyrrolidine as catalyst. After filtration, concentration of the reaction mixture and cleaving of the benzyl nitrogen protecting group, phenylephrine is obtained as the product. In addition to the L-enantiomer, the D-enantiomer is also obtained in an amount of at least 7.5% as a contaminant (85% ee).

U.S.Patent No. 6,218,575 discloses process for adrenaline from 3',4'-dihydroxy-2-N-benzyl]-N-methylaminoacetophenone using asymmetric hydrogenation with [Rh(COD)Cl]2 / (2R,4R)-4-dicyclohexylphosphino)-2-(diphenylphosphinomethyl)-N-methylamino carbonylpyrrolidine (RR-MCCPM) as the catalyst system and a special sequence of subsequent steps. The abbreviation COD used in the general formula denotes cyclooctadiene.

Aforesaid processes, however, are unsuitable for producing adrenaline on an industrial scale for a number of reasons such as use of hazardous catalysts in an asymmetric hydrogenation steps, the product cannot be produced in sufficiently pure form for pharmaceutical purposes except by the use of expensive purification procedures, as this reaction produces adrenaline only as a mixture containing a relatively high proportion of the opposite enantiomer as a contaminant. Further, the use of longer reaction time for the asymmetric hydrogenation leads to expensive synthetic route and is unsafe for industrial purposes.

PCT application Publication No. 2009/004593A2 discloses a process for the preparation of epinephrine, which involves debenzylation and hydrogenation using catalyst in presence of acid to provide racemic epinephrine, which is further subjected to resolution of racemic epinephrine to provide R-(-)-L-Epinephrine.

Therefore, there is a need to develop a process for preparing epinephrine or addition salt thereof, and its intermediate, for example, DL-Epinephrine from N-benzyl adrenalone that are lower cost alternative, simple and industrially applicable, result in high yield and high purity of the intermediate as well as epinephrine.

The present inventors found that the use of sodium borohydride, which is inexpensive and safe, as hydrogen source for conversion of N-benzyl adrenalone to N-benzyl adrenaline. Further, the present inventors found that the in-situ process for the conversion of N-benzyl adrenalone to DL-Epinephrine leads to greater yield and purity of the intermediate, which is further resolved to provide pure Epinephrine without effecting the quality and quantity of yield.

An aspect of the present invention is to provide an in-situ process for the preparation of DL-Epinephrine from N-benzyl adrenalone, which comprises:
a) reaction of N-benzyl adrenalone with sodium borohydride in presence of alcohol to provide N-benzyl adrenaline; and
b) conversion of N-benzyl adrenaline to DL-epinephrine using catalyst, for example, Pd/C in presence of hydrogen gas and alcohol.

The step a) involves reaction of N-benzyl adrenalone with sodium borohydride in presence of alcohol to provide N-benzyl adrenaline.

The use of sodium borohydride for the step a) as a hydrogen source reduces the time cycle of the reaction. The reaction involves portion wise addition of sodium borohydride to eliminate exothermic reaction at a lower temperature, for example, below room temperature such as 0-5°C. The quantity of sodium borohydride may range from 1 to 5 molar equivalents, or 2.5 molar equivalents per the molar equivalent of N-benzyl adrenalone.

The alcoholic solvent used for the formation of N-benzyl adrenaline includes but are not limited to methanol, ethanol, isopropyl alcohol, n-butanol and its mixture thereof with or without tetrahydrofuran the like. Additionally, The reaction is performed, may be at temperature range of about -5 to 30 °C for a period of about 3 hours or more for the completion of the reaction.

After completion of the reaction, the reaction mixture is treated with aqueous or alcoholic acid, for example methanolic hydrochloric acid to attain the pH in between 0.5 to 2.5 to affect the precipitation of unwanted solid. The resultant reaction suspension is filtered to afford filtrate which comprises N-benzyl adrenaline.

The step b) involves conversion of N-benzyl adrenaline to DL-epinephrine using catalyst, for example, Pd/C in presence of hydrogen gas and alcohol. Isolation of N- benzyl adrenaline and its further debenzylation using solvents like water and range of alcohols has also been attempted.

The N-benzyl adrenaline is prepared in-situ from the step a) to react directly with the catalyst, for example, 10% Pd/C to provide DL-epinephrine.

The solvent for the step a) and b) is the same which is selected from alcohol such as methanol, ethanol, isopropyl alcohol and the like.

The reaction is performed at a temperature of about 30 to about 50 °C, or 35 to 45°C for a period of 6 to 12 hours.

After completion of the reaction, the reaction mixture is filtered and the resultant filtrate is subjected for precipitation of solid using aqueous or may be alcoholic ammonia solution.

The resultant DL-epinephrine may have purity greater than or equal to 94%, which is easily resolved to provide R-(-)-L-epinephrine using the known process in the art, for example, WO 2009/004593 A2.

The overall process of the present invention is depicted in the following scheme:

The present invention is further illustrated by the following example, which does 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 application.

EXAMPLES

Example -1: Preparation of DL-Epinephrine:

N-Benzyl-Adrenalone (100 gm) was charged into methanol (400 ml) and applied ice-salt cooling to reaction mass. Sodium borohydride was added portion wise at 0°C. After complete addition of Sodium borohydride, reaction mixture was stirred under ice cooling for 3 hours. Methanol.HCl was added to the reaction mixture to break the borate complex and bring pH between 0.5-2.5. The reaction mixture was filtered to remove inorganic solid of borate complex.

10% Pd-C (50% Wet; 6 gm) was added to the above filtrate and then purged hydrogen gas under stirring at 25-50 °C. The reaction mixture was stirred for 8-12 hours, filtered and then washed with methanol (50 ml). The filtrate was cooled with ice-water and then added aqueous ammonia solution (25%) to bring pH of between 7.5-9.5.The obtained suspension was stirred for 30 minutes, filtered and then washed with methanol (100 ml).

The compound obtained was dried under vacuum at 38-40 °C for 4-5 hours.

Dry solid: 63.6 gm (m/c: 1.76%)