WO2009004593A2

WO2009004593A2 - Processes for the preparation of epinephrine

Info

Publication number: WO2009004593A2
Application number: PCT/IB2008/052677
Authority: WO
Inventors: Ramprasad Yadav; Zakir Gafoor Shaikh; Shafakat Ali Nasir Ali; Arvind Merwade; Jaweed Mukarram Siddiqui Mohammad
Original assignee: Wockhardt Research Centre
Current assignee: Wockhardt Research Centre
Priority date: 2007-07-03
Filing date: 2008-07-03
Publication date: 2009-01-08
Anticipated expiration: 2010-01-03
Also published as: WO2009004593A3

Abstract

The invention relates to efficient and cost effective processes for the preparation of pure (-)- epinephrine. More particularly, it relates to processes for the resolution of racemic epinephrine.

Description

Description PROCESSES FOR THE PREPARATION OF EPINEPHRINE

[1] Field of the Invention

[2] The invention relates to efficient and cost effective processes for the preparation of pure (-)-epinephrine. More particularly, it relates to processes for the resolution of racemic epinephrine. [3] Background of the Invention

[4] (-)-Epinephrine, also referred as adrenaline, is an endogenous catcholamine with combined a- and b- agonist activity. It is chemically known as

4-[l-hydroxy-2-(methylamino) ethyl]- 1, 2-benzenediol having the structure as depicted by Formula I.

[6] Formula I

[7] (-) -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 as 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.

[8] Summary of the Invention

[9] In one general aspect there is provided pure (-)-epinephrine having a purity of greater than about 99.0% when measured by HPLC and enantiomeric excess of more than about 95.0% . In particular, there is provided pure (-)-epinephrine having a purity more than 99.8% when measured by HPLC.

[10] In another aspect there is provided a process for the preparation of racemic epinephrine. The process includes hydrogenation and debenzylation of 3',4'-dihydroxy-2-N-benzyl-N-methylamino acetophenone at atmospheric pressure.

[11] In another aspect there is provided a process for resolving the racemic epinephrine using a chiral auxiliary to obtain (-)-epinephrine.

[12] In another aspect there is provided a process for the preparation of an intermediate

3,4-dihydroxyphenacyl chloride in high purity and yield. The process involves use of a Lewis acid in a suitable organic solvent.

[13] In another aspect there is provided a process for the conversion of

3,4-dihydroxyphenacyl chloride intermediate into 3',4'-dihydroxy-2-N-benzyl-N-methyl amino acetophenone.

[14] In another general aspect there is provided a process for the purification of

(-)-epinephrine. The process may produce (-) -epinephrine having a purity of greater than about 99.0% when measured by HPLC having enantiomeric excess of more than 95.0%. The process may produce (-) -epinephrine having enantiomeric excess of more than 95.0 % and 3% or less (+)-epinephrine.

[15] In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of pure (-)-epinephrine prepared by the process of the invention having purity more than 99.0% by HPLC and enantiomeric excess of more than 95.0%; and one or more pharmaceutically acceptable carriers, excipients or diluents.

[16] The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

[17] Detailed Description of the Invention

[18] A first aspect of the invention provides a process for the preparation of pure

(-)-epinephrine of Formula I having a purity of greater than about 99.0% when measured by HPLC and enantiomeric excess of more than 95.0%. H

[20] Formula I

[21] The process includes the steps of:

[22] a) reacting catechol with chloroacetyl chloride in the presence of a Lewis acid to get a compound of Formula II;

[24] Formula II

[25] 1. b) reacting the compound of Formula II with N-methyl benzyl amine to get

[26] a compound of Formula III;

[27]

[28] Formula III

[29] 1. c) converting the compound of Formula III to racemic epinephrine;

[30] 1. d) preparing a salt of the racemic epinephrine with a chiral auxiliary; and

[31] 1. e) isolating the (-) -epinephrine from reaction mixture thereof.

[32] A second aspect of the invention provides a process for the preparation of

3,4-dihydroxyphenacyl chloride of Formula II,

[34] Formula II

[35] The process includes the steps of:

[36] 1. a) reacting catechol in a suitable organic solvent with chloroacetyl chloride in the presence of a Lewis acid; and [37] 1. b) isolating the 3,4-dihydroxyphenacyl chloride from reaction mixture thereof.

[38] Suitable Lewis acids for the reaction may include one or more of aluminium chloride, zinc chloride, ferric chloride, stannous chloride, boron triflouride, aluminium bromide, and the like.

[39] Suitable organic solvents may include one or more of carbon disulphide, nitrobenzene, halogenated solvent such as 1,2-dichloroethane, methylene chloride, chloroform, carbon tetrachloride, and mixtures thereof. The reaction may be carried out at a temperature in the range from about -2O⁰C to about 5O⁰C. The product may be isolated by breaking the Lewis acid complex formed. The Lewis acid complex may be treated with one or more acids to get 3,4-dihydroxyphenacyl chloride in 85% or more yield. The acid used for breaking the complex may be diluted with water.

[40] Suitable acids which can be used include one or more of hydrochloride acid, sulphuric acid, acetic acid, formic acid, and the like.

[41] A third aspect of the invention provides a process for the preparation of racemic epinephrine. The process includes the steps of:

[42] 1. a) reacting 3,4-dihydroxyphenacyl chloride of Formula II with N-methyl benzyl amine in a suitable aprotic solvent in the presence of a Lewis acid;

[44] Formula II [45] 1. b) isolating 3',4'-dihydroxy-2-N-benzyl-N-methylamino acetophenone of

Formula III from reaction mixture thereof ;

[47] Formula III

[48] 1. c) debenzylating and hydrogenating the

3',4'-dihydroxy-2-N-benzyl-N-methylaminoacetophenone in the presence of a catalyst; and

[49] 1. d) isolating the racemic epinephrine from reaction mixture thereof.

[50] In general, the 3,4-dihydroxyphenacyl chloride of Formula II may be treated with N- methyl benzyl amine in a suitable aprotic solvent at a temperature from about O⁰C to about 30 ⁰C.

[51] Suitable aprotic solvents may include one or more of N,N-dimethylacetamide;

N,N-dimethylformamide; dimethylsulphoxide; hexa methyl phosphorotriamide, acet- onitrile, dioxane, tetrahydrofuran, or mixtures thereof.

[52] The product may be isolated by acid base treatment. The term 'acid base treatment' refers to acidifying the reaction mixture to a pH 5 or less with acids and then basifying with a base to pH 7.2 or above.

[53] Examples of acids and bases which may be used are known to a person of ordinary skill and include hydrochloric acid, acetic acid, sulphuric acid, ammonia, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, and the like. Acids or bases can be used in the form of their solutions in water.

[54] The 3',4'-dihydroxy-2-N-benzyl-N-methylamino acetophenone may be isolated from the solution by a technique which includes, for example, filtration, filtration under vacuum, decantation, and centrifugation.

[55] In another embodiment the steps of debenzylation and hydrogenation may be carried out simultaneously in a single step. The ketone functionality may be reduced to hydroxyl and the amino functionality may be debenzylated using a catalytic hydrogenation. The intermediate 3',4'-dihydroxy-2-N-benzyl-N-methylaminoacetophenone may be treated with a catalyst such as 5% to 10% Palladium on charcoal, platinum on charcoal, and ruthenium on carbon in the presence of a hydrogen source such as hydrogen gas in a suitable organic solvent. The hydrogenation reaction may be performed under acidic conditions at pH from about 1.0 to about 3.0. The acidic pH may be obtained with any acid, for example, dilute hydrochloride acid, dilute sulphuric acid, acetic acid, and formic acid. Suitable organic solvents may include one or more of methanol, ethanol, ethyl acetate, acetic acid, tetrahydrofuran, dioxane, halogenated solvents such as chloroform, methylene chloride, ethylene dichloride, and the like.

[56] A fourth aspect of the invention provides a process for the resolution of racemic epinephrine. The process includes the steps of:

[57] 1. a) reacting racemic epinephrine with a chiral auxiliary to form a mixture of di- astereomeric salts of epinephrine;

[58] 1. b) separating the diastereomer of (-)-epinephrine from reaction mixture thereof;

[59] 1. c) converting the separated diastereomeric salt of (-)-epinephrine to

(-)-epinephrine; and

[60] 1. d) isolating the (-)-epinephrine.

[61] In general, easily available chiral auxiliaries may be used for resolution of the racemic epinephrine to (-)-epinephrine. The term 'chiral auxiliary' refers to enantio- merically pure organic acids having at least one chiral centre.

[62] Examples of chiral auxiliaries for optically resolving epinephrine may include 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, and the like.

[63] In general, the reaction of epinephrine free base with a chiral auxiliary may be carried out in an organic solvent. The organic solvent may include one or more solvents for example, methanol, ethanol, isopropanol, butanol, acetonitrile, dioxane, di- methylformamide, dimethylsulphoxide, halogenated solvents such as dichloromethane, chloroform and mixtures thereof. The solvent mixture also includes aqueous organic solvent mixtures. The reaction of epinephrine free base with a chiral auxiliary in an organic solvent may result in the formation of two diastereomeric salts of epinephrine. The separation of the diastereomeric salt from the reaction mixture may be carried out by filtration. Desired isomer may be c onverted into a free base by treating the separated diastereomeric salt with a basifying agent. T he steps of formation of the diastereomeric salt, separation of the desired salt and subsequent conversion of the salt to the free base can be repeated t o enrich the optical purity of (-)-epinephrine free base.

[64] The basifying agent may include bases such as ammonia, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide and similar bases to liberate the diastereomer.

[65] A fifth aspect of the invention provides a process for the preparation of pure (-)

[66] -epinephrine having a purity of greater than about 99.0% when measured by HPLC and enantiomeric excess of more than about 95.0% . . The process includes the steps of

[67] 1. a) obtaining a solution or suspension of (-)-epinephrine; [68] 1. b) acidifying the solution or suspension of (-)-epinephrine;

[69] 1. c) basifying; and

[70] 1. d) isolating the pure (-) -epinephrine free base from reaction mixture thereof.

[71] In general, a solution or suspension of (-) -epinephrine may be obtained in water or may be obtained directly from the reaction mixture in which (-)-epinephrine is formed. The solution or suspension of (-)-epinephrine in water may be acidified. Suitable acids which may be used for acidification include acids such as hydrochloric acid, sulphuric acid, acetic acid, formic acid, and the like.

[72] In general, the solution or suspension of (-)-epinephrine may be acidified up to pH about 4 with an acid. The reaction mixture may be basified with one or more bases. Examples of bases may include one or more of ammonia, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, and the like.

[73] The product may be isolated by a technique which includes, for example, filtration, filtration under vacuum, decantation, and centrifugation.

[74] The pure (-)-epinephrine may have a chemical purity more than 99% and enantiomeric excess of more than 95%. It may have 3% or less (-ι-)-epinephrine.

[75] The present invention is further illustrated by the following examples 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.

[76] Example -1: 3.4-Dihvdroxyphenyl acetyl chloride

[77] To a cooled solution of 1,2-dichloroethane (5 L) at about 10-15 ⁰C, aluminum chloride (1.5 Kg) was added and the reaction mixture was stirred at 10-15 ⁰C for about 15-30 minutes. To the stirred reaction mixture, catechol (500 g) was added portion wise within about 5-10 minutes and the reaction mixture was further stirred for about 20-30 minutes. To the above solution, chloroacetyl chloride (546 g) was added at 10-15 ⁰C. The temperature of the reaction mixture was raised to room temperature and further stirred for about 16-20 hours. After completion of the reaction, the reaction was quenched with dilute hydrochloric acid solution (10 L) at 5-10 ⁰C and stirred for 2-3 hours at room temperature. The solid so obtained was filtered and the wet solid was washed with water (4 L). The w et solid was suspended in dilute acetic acid (mixture of acetic acid 600 mL and water 4 L) and heated to about 85-90 ⁰ C tO get a clear solution. To the clear solution, carbon (15 g) was added and stirred for 30 minutes. The reaction mixture was filtered hot. The filtrate was cooled and the solid so obtained was filtered and washed with water (4 L). It was dried to obtain 3,4-dihydroxyphenacyl chloride.

[78] Yield: 725 g;

[79] HPLC Purity: 99.83%; [80] M.P.: 175.1-176.7 ⁰C.

[81] Example -2: N-benzyl epinephrine

[82] To a cooled solution of 3,4-dihydroxyphenyl acetyl chloride (750 g) in N,N-dimethyl acetamide (2.1 L), N-methyl benzyl amine (912 g) was added drop wise at about 10-15 0C. After the addition, temperature of the reaction mixture was raised to 30-35 ⁰C 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 was cooled to about 20 ⁰C and the pH was adjusted to about 5.5 with dilute HCl (150 mL). Water (8 L) was added and further stirred for 15 minutes. pH of the reaction mixture was adjusted to 8.5 with dilute ammonia (240 mL). Solid so obtained was filtered and wet solid was washed with water (4 L). The wet 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.

[83] Yield: 1027 g

[84] Example- 3: Racemic epinephrine

[85] N-Benzyl epinephrine (950 g) was dissolved in methanol (9.5 L) and pH was adjusted with dilute HCl (345 mL) to about 1.0-2.4 and stirred. To the reaction mixture, 10% Pd/C (250 g) was added and hydrogen gas was bubbled through the reaction mixture. It was heated to about 4O ⁰ C and stirred for about 30-35 hours at 40 0C . After completion of the reaction, the r eaction mass was filtered and washed with methanol (1 L). The filtrate was cooled to 10-15 ⁰C and pH was adjusted by ammonia solution (275 ml) to 8.5. The reaction mixture was filtered, washed with methanol (1 L) and dried to get epinephrine.

[86] Yield: 523 g

[87] Example -4: (-) -Epinephrine

[88] Step A: To a solution of racemic 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.

[89] wet wt. 464 g

[90] 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 ⁰C. 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 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. [91] To a 5-10 ⁰C cooled suspension of epinephrine base obtained from Example-1 (130 g) in purified water (1.3 L) was added HCl (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 ⁰C 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.

[92] Yield: 103 g;

[93] Purity: 99.88 %:

[94] enantiomeric excess: 95.34 %.

[95] While the present invention has been described in terms of its specific embodiments, 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.

Claims

[1] A process for the preparation of (-)-epinephrine of Formula I, the process comprising:

Formula I a) reacting catechol with chloroacetyl chloride in the presence of a Lewis acid to get a compound of Formula II;

Formula II b) reacting the compound of Formula II with N-methyl benzyl amine to get a compound of Formula III;

Formula III c) converting the compound of Formula III to racemic epinephrine; d) preparing a salt of the racemic epinephrine with a chiral auxiliary; and e) isolating the (-) -epinephrine from reaction mixture thereof.

[2] The process of claim 1, wherein the Lewis acid comprises one or more of aluminium chloride, zinc chloride, ferric chloride, stannous chloride, boron triflouride and aluminium bromide.

[3] The process of claim 1, wherein the chiral auxiliary comprises one or more of 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, and L-malic acid.

[4] A process for the preparation of a compound of Formula II,

Formula II the process comprising: a) reacting catechol in an organic solvent with chloroacetyl chloride in the presence of a Lewis acid; and b) isolating the 3,4-dihydroxy phenacyl chloride from reaction mixture thereof.

[5] The process of claim 4, wherein the Lewis acid comprises of one or more of aluminium chloride, zinc chloride, ferric chloride, stannous chloride, Boron triflouride, and aluminium bromide.

[6] The process of claim 4, wherein the organic solvent comprises one or more of halogenated solvents, carbon disulphide and nitrobenzene. [7] The process of claim 6, wherein the halogenated comprises one or more of chloroform, methylene chloride and 1,

2,-dichloroethane. [8] The process of claim 5, wherein temperature is from about -2O⁰C to about 5O⁰C. [9] A process for the preparation of racemic epinephrine, the process comprising: a) reacting 3,4-dihydroxyphenacyl chloride of Formula II with N-methyl ben- zylamine in a suitable aprotic solvent in presence of a lewis acid;

Formula II b) isolating 3',4'-dihydroxy-2-N-benzyl-N-methylamino acetophenone of

Formula III from reaction mixture thereof ;

Formula III c) debenzylating and hydrogenating the

3',4'-dihydroxy-2-N-benzyl-N-methylamino acetophenone in the presence of a catalyst; and d) isolating the racemic epinephrine from reaction mixture thereof. [10] The process of claim 9, wherein the catalyst comprises one or more of 5 to

10% palladium, platinum and ruthenium on carbon. [11] The process of claim 9, wherein the aprotic solvent comprises one or more of N,N-dimethyl acetamide; N,N-dimethyl formamide; dimethyl sulphoxide; hexamethylphosphorotriamide, acetonitrile, dioxane, tetrahy- drofuran or mixtures thereof. [12] The process of claim 9, wherein pH of the hydrogenation reaction is 3 or below. [13] A process for preparing pure (-)-epinephrine, the process comprising: a) reacting racemic epinephrine with a chiral auxiliary in one or more organic solvents to form a mixture of diastereomeric salts of epinephrine; b) separating the diastereomer of (-)-epinephrine from reaction mixture thereof; c) converting the separated diastereomeric salt of (-)-epinephrine to (-)-epinephrine; and d) isolating the (-)-epinephrine.

[14] The process of claim 13, wherein the chiral auxiliary comprises one or more of

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, and L-malic acid.

[15] The process of claim 13, wherein the organic solvent comprises one or more of methanol, ethanol, isopropanol, butanol, acetonitrile, dioxane, dimethyl- formamide, dimethylsulphoxide, halogenated solvents, and mixtures thereof.

[16] A process for the preparation of pure (-)-epinephrine having a purity of greater than about 99.0% when measured by HPLC and enantiomeric excess of more than about 95.0% , the process comprising: a) obtaining a solution or suspension of (-)-epinephrine; b) acidifying the solution or suspension of (-)-epinephrine; c) basifying; and d) isolating the pure (-) -epinephrine free base from reaction mixture thereof. [17] The process of claim 16, wherein the acid used for acidifying comprises one or more of hydrochloric acid, sulphuric acid, acetic acid and formic acid. [18] The process of claim 16, wherein pH of reaction mixture at step b) is below

4. [19] The process of claim 16, wherein the base used for basifying comprises one or more of ammonia, sodium carbonate, sodium hydroxide, potassium carbonate and potassium hydroxide. [20] (-)-Epinephrine having a purity of greater than about 99.0% when measured by

HPLC and enantiomeric excess of more than about 95.0%.

[21] (-)-Epinephrine of claim 20, having less than 3% of (+)-epinephrine.

[22] A pharmaceutical composition that includes a therapeutically effective amount of pure (-)-epinephrine prepared by the process of claim 13 or 16 a purity of greater than about 99.0% when measured by HPLCand enantiomeric excess of more than about 95.0%; and one or more pharmaceutically acceptable carriers, excipient or diluents.