(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization

International Bureau

(43) International Publication Date (10) International Publication Number

8 January 2009 (08.01.2009) PCT WO 2009/004593 A2
(51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA,
C07C 213/02 (2006.01) C07C 215/52 (2006.01) CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE,
C07C 213/10 (2006.01) EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID,
(21) International Application Number: IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK,
PCT/IB2008/052677 LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW,
MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT,
(22) International Filing Date: 3 July 2008 (03.07.2008)
RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ,
(25) Filing Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM,
(26) Publication Language: English ZW
(30) Priority Data:
1265/MUM/2007 3 July 2007 (03.07.2007) IN (84) Designated States (unless otherwise indicated, for every
1268/MUM/2007 3 July 2007 (03.07.2007) IN kind of regional protection available): ARIPO (BW, GH,
1272/MUM/2007 3 July 2007 (03.07.2007) IN GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
(71) Applicant (for all designated States except US): WOCK-
European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
HARDT RESEARCH CENTRE [IN/IN]; D 4, Midc In
FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,MC, MT, NL,
dustrial Area, Chikalthana, Aurangabad 431210 (IN).
NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG,
(71) Applicants and CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
(72) Inventors: YADAV, RAMPRASAD [IN/IN]; At Post
Mawaiya, Village Lakhanpur, Mirzapur 231001 (IN). Published:
SHAIKH, ZAKIR GAFOOR [IN/IN]; Village & Post — without international search report and to be republished
- Warigaon, Tehsil- Kopargaon, Ahmednagar 413708 upon receipt of that report
(IN). NASIR ALI, SHAFAKAT ALI [IN/IN]; At Post
Sawara (machanpur), Taluka : Akot, Dist : Akola (IN).
MERWADE, ARVIND [IN/IN]; Rajendra Prasad Road,
Gadag Betgeri, Gadag Betgeri 582102 (IN). SIDDIQUI
MOHAMMAD, JAWEED MUKARRAM [IN/IN];
House No. 4-8-65, Nawabpura, Near Nagina Masjid,
Aurangabad 431001 (IN).
(81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,

(54) Title: PROCESSES FOR THE PREPARATION OF EPINEPHRINE

(57) 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
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 ep i
nephrine. 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 d e
scription 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%.

[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, n i
trobenzene, 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 -2O 0C to about 5 O0C. 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 ep i
nephrine. 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 hydro
genation. 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 ep i
nephrine. 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 d i
astereomeric 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 enan
tiomeric 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 4 O 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 pre
cipitation 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 b i
sulphite ( 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 -2O 0C to about
5 O0C.
[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 enan
tiomeric excess of more than about 95.0%; and one or more pharma
ceutically acceptable carriers, excipient or diluents.