Title of Invention

PROCESS FOR THE PREPARATION OF CHIRAL CARVEDILOL

Abstract The present invention relates to a process for the efficient preparation of highly optical pure chiral carvedilol. According to the present invention, a chiral oxazolidin-2-one or oxazolidin-2-thione having formula 2, produced from the reaction of N-protected 2-(2- methoxyphenoxy)ethylarnine with a chiral glycidol derivative is used as a key intermediate for the preparation of the chiral carvedilol. Specifically, the process for the preparation of the chiral carvedilol comprises a) reacting a compound of formula 2 with a halogenation agent, a sulfonation agent or a mitsunobu reagent to activate a hydroxyl group of the compound of formula 2, followed by nucleophilic substitution reaction with 9H-4-hydroxy carbazole to produce a compound of formula 7, and b) subjecting the obtained compound of formula 7 to a deprotection reaction in a presence of an inorganic base to produce the targeted chiral carvedilol. The process of the present invention can be accomplished in a mild condition. The process neither requires any extraordinary purification procedure, nor involves decrease of optical purity. Therefore, the process of the present invention provides highly optical pure chiral carvedilol in simple and efficient manner.
Full Text PROCESS FOR THE PREPARATION OF CHIRAL
CARVEDILOL
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a process for the preparation of carvedilol. More
specifically, the present invention relates to a process for the efficient preparation of chiral
carvedilol.
BACKGROUND OF THE INVENTION
Most of medicines that have been recently developed and commercially available are
chiral products. This is attributed to side effects or decreased efficacies caused by racemic drugs.
Therefore, in order to increase both the safety and the efficacy, studies to develop chiral drugs
containing optically pure stereoisomers has been widely attempted. In the chiral drugs, high
chemical purity and high optical purity are required for ensuring the safety and the efficacy.
Carvedilol (IUPAC NAME: l-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]
amino] -2-propanol) is a compound having formula 1:
Formula 1

wherein, * represents a chiral center.
As shown in the formula 1, the carvedilol has one chiral center, and may exist in either
(R)-isomer or (S)-isomer. Herein, as a blocker of a1-adrenoreceptor, (R)-isomer and (S)-isomer
exhibit almost the same activities. To the contrary, as a blocker of ß1-adrenoreceptor, (S)-isomer
has an enhanced, superior activity to (R)-isomer [EP 127,099; Chirality 1989, 1, 265; J. Pharm.
Exp. Then, 1992, 263, 92; Clin. Pharmacokin., 1994, 26, 335; Cardiovasc. Res., 1994, 28, 400; J.
of Chromatography B. 1996, 682, 349]. Further, the carvedilol is now used as an antioxidant,
anti-inflammatory agent, anti-apoptotic agent [The American Journal of Cardiology, 2004, 93
(9A), 3B]. For these reasons, provision of a process for the efficient preparation of highly optical
pure chiral carvedilol in an economic manner is an important task to the development of various
drugs comprising the chiral carvedilol.
Conventional processes for the preparation of the chiral carvedilol are shown in a
reaction scheme 1 :
Reaction Scheme 1

wherein, R represents hydrogen or a benzyl group.
As shown in the reaction scheme 1, the targeted carvedilol was prepared from ring
opening of a chiral epoxy-carbazole of formula 3 with an ethylamine compound of formula 4 [R
= hydrogen, US Patent Nos. 4,503,067 and 4,697,022]. However, the process leads to formation
of a bis-substituted side product that is not easy to be removable in the purification procedure.
The process requires an extraordinary purification procedure, thereby hindering the preparation of
highly optical pure carvedilol. Furthermore, loss of the targeted carvedilol is inevitable in the
purification procedure, which results in significant decrease of the yield of the carvedilol.
In order to avoid the disadvantage resulted from the bis-substituted side product, other
attempts have been performed. In order to prevent the formation of the bis-substituted side
product, a N-protected compound of formula 4 (R = benzyl) was used as a starting material in the
reaction scheme 1 and applied to ring opening of a chiral epoxy compound of formula 3 [R =
benzyl, EP 918,055]. The process produces no bis-substituted side roduct. However, it suffered
from the disadvantage that an expensive palladium catalyst should be used in order to deprotect
the benzyl group.
As an alternative, the ethylamine compound of formula 4 was used in an excess over the
compound of formula 3 to reduce the formation of the bis-substituted side product [R = hydrogen,
WO 02/00216]. Even though the process could reduce the formation of the bis-substituted side
product, there still remain problems caused from small amount of the bis-substituted side product.
In addition, the process suffered from low price competitiveness due to excess use of the
expensive ethylamine compound.
In addition, the ethylamine compound of formula 4 or its benzylated form undergoes
degradation by exposure to air and light. Therefore, the compound of formula 4 has a limitation to
the application to mass production. In order to overcome the disadvantage, acid addictive salt of
the ethylamine compound of formula 4 (R = H) was used as a starting material in the ring opening
reaction with the compound of formula 3 to increase the stability [WO 2004/041783]. The
process has an advantage applicable to mass production of the chiral carvedilol. Nonetheless, it
suffered from the formation of the bis-substituted side product and from excess use of the
ethylamine compound.
In order to avoid the formation of the bis-substituted side product, new attempt has been
tried.
The amine group of the compound of formula 4 was firstly protected with a benzyl group,
and a chloro-propanonyl group was introduced thereto. The obtained product was alkylated with
an epoxycarbazole of formula 8, followed by a reduction step and a debenzylation step to produce
the carvedilol (Korean Published Patent No. 2005-0003764). However, the process requires a
strong reducing agent such as sodium borohydride or lithium borohydride and an expensive
palladium catalyst.
Further another process for the preparation of the carvedilol known in the art comprises
reacting the amine compound of formula 4 with a carbonated compound to produce a carbamate
having two leaving groups, followed by cyclization reaction to produce a oxazolidinone
compound that is used as an intermediate for the synthesis of the carvedilol [EP 1,282,601 and
1,367,052]. In the process, the oxazolidinone compound was alkylated with 9H-4-hydroxy
carbazole and deprotected to produce the carvedilol.
Even though the above two processes effectively inhibits the formation of the bis-
substituted side product, they are not suitable for the production of chiral carvedilol.
As mentioned in the above, the conventional methods had one or more unresolved
technical problems for the application to mass production of highly optical pure chiral carvedilol.
Therefore, an efficient process for the preparation of highly optical pure chiral carvedilol is now
urgently demanded.

SUMMARY OF THE INVENTION
According to our inventors' extensive studies, it was found that efficient preparation of
highly optical pure key intermediate and provision of efficient chemical synthesis routes are
crucial to efficient mass production of the chiral carvedilol.
As a result of our inventors' profound studies, there is provided a process for the
preparation of chiral carvedilol, wherein a chiral oxazolidinone having formula 2 is used as a key
intermediate. The key intermediate of formula 2 can be effectively synthesized by reacting highly
optical pure chiral glycidol derivative with N-protected 2-(2-methoxyphenoxy)ethylamine, both
of which are commercially available and industrially mass produced.
Formula 2

wherein, * represent a chiral center and X represents oxygen or sulfur.
The preparation of the chiral carvedilol from the key intermediate of formula 2 comprises
a) reacting a compound of formula 2 with a halogenation agent, a sulfonation agent or a
mitsunobu reagent to activate a hydroxyl group of the compound of formula 2, followed by
nucleophilic substitution reaction with 9H-4-hydroxy carbazole to produce a compound of
formula 7, and b) subjecting the obtained compound of formula 7 to a deprotection reaction in a
presence of an inorganic base to produce the targeted chiral carvedilol.
Specifically, the compound of formula 2 is prepared, from a ring opening reaction and
subsequent in-situ intramolecular cyclization reaction between an amine compound of formula 4
and a chiral glycidol of formula 5, followed by deprotection reaction, and then, the chiral
carvedilol with a highly optical purity is produced from the compound of formula 2. Herein, the
amine compound of formula 4 effectively prohibits the formation of the bis-substituted side
product and produces an oxazolidin-2-one or oxazolidin-2-thione of formula 2 through a ring
opening reaction with the compound of formula 5 and subsequent in-situ intramolecular
cyclization reaction. Thereafter, the hydroxyl group of the compound of formula 2 thus obtained
is activated with aid of a halogenation agent, a sulfonation agent or a mitsunobu reagent, and
undergoes nucleophilic substitution reaction with 911-4-hydroxy carbazole to produce the
compound of formula 7 (5-(9H-carbazol-4-yloxymethyl)-3-[2-(2-methoxy-phenoxy)-ethyl]-
oxazolidin-2-one or (5-(9H-carbazol-4-yloxymethyl)-3-[2-(2-methoxy-phenoxy)-ethyl]-
oxazolidin-2-thione). The compound of formula 7 is ring-opened in a presence of an inorganic
base to produce the chiral carvedilol of formula 1.
The process of the present invention is safe and industrially applicable, and it provides
the chiral carvedilol in a highly optical pure form.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the efficient preparation of chiral carvedilol,
comprising a) reacting a compound of formula 2 with a halogenation agent, a sulfonation agent or
a mitsunobu reagent to activate a hydroxyl group of the compound of formula 2, followed by
nucleophilic substitution reaction with 9H-4-hydroxy carbazole to produce a compound of
formula 7, and b) subjecting the obtained compound of formula 7 to a deprotection reaction in a
presence of an inorganic base to produce the targeted chiral carvedilol. The process is
summarized in a reaction scheme 2:
Reaction Scheme 2

In the reaction scheme 2, * represents a chiral center and X represents oxygen or sulfur.
As shown in the reaction scheme 2, the present invention uses, as a chiral key
intermediate, chiral oxazolidin-2-one or oxazolidin-2-thione having formula 2 of which the
nitrogen atom is substituted with 2-(2-methoxy-phenoxy)ethyl group.
The key intermediate is prepared from ring opening of a chiral glycidol compound of
formula 5 by an amine compound of formula 4 and subsequent in-situ intramolecular cyclization,
followed by a hydroxy deprotection of a compound of formula 6.
Specific example of the amine compound of formula 4 used in the preparation of the
chiral key intermediate of formula 2 is as follows:
Formula 4

wherein, X represents oxygen or sulfur, and Y represent a leaving group.
The compound of formula 4 can be produced in known procedure using a corresponding /1
primary amine compound. Particularly, when X is an oxygen atom, it can be produced by reacting the primary amine compound with a carboxylic acid, a carboxylic acid ester, a carbonyl halide compound, a carboxylic acid anhydride or halo formate.
When X is a sulfur atom, the compound of formula 4 can be produced by reacting the
primary amine compound with a thiocarboxylic acid ester [J. Chem. Soc. C, 1969, 2631; Chem.
Ber. 1971, 104, 3146], or its corresponding isothiocyanate [Chem. Ber. 1914, 47, 1255; J. Am.
Chem. Soc, 1968, 90, 6008; J. Chem. Eng. Data, 1980, 25, 176]. Preferable examples of the
leaving group Y are C1~C10 alkoxy group, C6~C10 aryloxy group, allyloxy group, C7~C14
alkylaryloxy group.
Specific example of the chiral glycidol compound of formula 5 used in the preparation of
the chiral key intermediate of formula 2 is as follows:
Formula 5

In the formula 5, * represents a chiral center and R1 represents a hydroxy protecting
group. Preferable examples of R1 include C1~C10 alkyl group, C2~C10 alkenyl group, C2~C10
alkynyl group, C1~C10 alkoxy group, (C1~C10)-alkyloxycarbonyl group, C6~C10 aryl group, C3~C10
cycloalkyl group, C4~C10 cycloalkenyl group, heterocycle or polycycle group, C2~C10 carbonyl
group, C2~C10 carboxyl group, silyl group, ether group, thioether group, selenoether group, ketone
group, aldehyde group, ester group, phosphoryl group, phosphonate group, phosphine group,
sulphonyl group or -(CH2)k-R2 (wherein, R2 represents C2~C10 alkenyl group, C2~C10 alkynyl
group, C1~C10 alkoxy group, (C1~C10)-alkyloxycarbonyl group, C6~C10 aryl group, C3~C10
cycloalkyl group, C4~C10 cycloalkenyl group, heterocycle or polycycle group, C2~C10 carbonyl
group, C2~C10 carboxyl group, silyl group, ether group, thioether group, selenoether group, ketone
group, aldehyde group, ester group, phosphoryl group, phosphonate group, phosphine group,
sulphonyl group and k is an integer of 1 to 8).
The chiral glycidol of formula 5 is commercially available and can be easily produced
from a known procedure. Specifically, the chiral glycidol can be prepared from asymmetric
epoxidation reaction of an allylalcohol [US Patent Nos. 4,946,974, 5,153,338 and 5,344,947],
from chiral 3-chloro-propandiol [JP 7-165743, US 5,965,753 and 2,248,635, and DE 1,226,554],
or from asymmetric catalytic reaction using enzyme or metallic catalyst [J. Am. Chem. Soc. 1984,
106, 7250; Tetrahedron Asymmetry 1991, 2, 481; Enzyme Microb. Technol 1991, 13, 306;
Biotech.Tech, 1998, 12, 225; Tetrahedron 1994, 40, 8885; Biotech. Bioeng, 1996, 49, 70; Acta
Chem, Scand. 1996, 50, 249; Tetrahedron Asymmetry 1997, 8, 639; Biotech. Tech, 1998, 12, 225;
US 6,720,434; WO 01/89690; JP 2003-534117; EP 289,655; US 2004-0054201; JP 2004-
515356; WO 02/48162, KR 2002-01219; US 6,262,278; US 6,448,414; US 6,693,236; US
6,800,766; and WO 00/09463].
Preparation of the chiral oxazolidin-2-one or oxazolidin-2-thione of formula 2, the key
intermediate for the synthesis of the chiral carvedilol, from the compound of formula 4 and the
compound of formula 5 is summarized in a reaction scheme 3:
Reaction Scheme 3

In the reaction scheme 3, * represents a chiral center, and X, Y and R1 is the same as
defined in the above.
As shown in the reaction scheme 3, N-protected compound of formula 4 participates in
the ring opening of the chiral glycidol of formula 5. As a result thereof, an intermediate
represented as formula 9 is produced. The intermediate thus produced undergoes in-situ
intramolecular cyclization reaction, thereby producing hydroxy-protected chiral oxazolidin-2-one
or oxazolidin-2-thione compound of formula 6.
Herein, the compound of formula 5 is added, based on the compound of formula 4, in an
amount of 0.8 ~ 5 equivalents, preferable 1-1.5 equivalents. The ring opening reaction and f
subsequent in-situ intramolecular cyclization reaction are carried out in a presence of a base. The
base to be used includes inorganic or organic base. For example, an alkali metal salt such as
sodium methoxide, lithium methoxide, sodium carbonate, sodium bicarbonate, potassium
carbonate, sodium hydroxide or potassium hydroxide, an imidazole, 2-6-lutidine, N,N-
dimethylamino pyridine and salts thereof, tertiary amine and its hydrate form can be used as a
base. Organic solvent to be used is not particularly limited. N,N-dimethylformamide, an aliphatic
or aromatic hydrocarbon solvent, a halogenated hydrocarbon, and an ether can be used as an
organic solvent. Specifically, an aromatic organic solvent such as toluene or benzene, a
haloalkane such as dichloromethane or chloroform, or an ether such as ethyl ether,
tetrahydrofuran or dioxane can be used. The reaction temperature is preferably adjusted to a
range of 0°C ~ 150°C, more preferably 80°C ~ 100°C at normal atmospheric pressure.
The compound of formula 6 thus obtained is applied to the next deprotection reaction
without any extraordinary purification (for example, fractional distillation or recrystallization).
Specifically, after the completion of consumption of the starting materials and intermediates
involved in the ring opening reaction and subsequent in-situ intramolecular cyclization reaction, a
deprotecting agent dependent upon the hydroxy protecting group is added to the same reactor to
produce the chiral key intermediate of formula 2 [Protecting Groups, Thieme Medical Publishers
Inc„ New York, 1994; Protective Groups in Organic Synthesis, John Wiley and Sons, Inc, 1991].
The compound of formula 2 can be also directly applied, without any purification, to an
alkylation reaction with the compound of formula 8. In order words, the hetero-ring compound of
formula 2 having a hydroxy group is prepared in a highly pure form such that it can be directly
applied, as a starting material, to the alkylation and subsequent deprotection steps for the
synthesis of the targeted carvedilol.
Preparation of a precursor compound having formula 7 from the compound of formula 2
is accomplished by reacting a compound having formula 2 with a halogenation agent, a

sulfonation agent or a mitsunobu reagent to activate a hydroxyl group of the compound having
formula 2, followed by nucleophilic substitution reaction with 9H-4-hydroxy carbazole. This is
summarized in a reaction scheme 4, wherein activation by the halogenation agent or the
sulfonation agent is expressed as pathway (1) and activation by the mitsunobu reagent as pathway
(2):
Reaction Scheme 4

In the reaction scheme 4, * represents a chiral center and Z represents a halogen group or
a sulfonate group, and X, Y and R1 is the same as defined in the above.
As shown in the above, the compound of formula 7 can be prepared by subjecting the
compound of formula 2 to halogenation or sulfonation reaction to produce a compound of
formula 10, followed by nucleophilic attack by 9H-4-hydroxy carbazole. Alternatively, it can be
prepared by mitsunobu reaction of the compound of formula 2 with 9H-4-hydroxy carbazole.
More specifically, as shown in the pathway (1) of the reaction scheme 4, the compound
of formula 2 produces a compound of formula 10 by the reaction with a halogenation agent.
Herein, examples of the halogenation agent include thionyl chloride, thionyl bromide, oxalyl
chloride, phosphorous tribromide and phosphorous trichloride. The halogenation agent is added
typically in an amount of 0.8 ~ 10 equivalents, preferably 1.1 -2.0 equivalents.
Further, the compound of formula 10 can be also prepared from the reaction of the
compound of formula 2 with a sulfonation agent (sulfonyl halide) by converting the hydroxy
group of the compound 2 to the corresponding a sulfonate group. Herein, examples of the
sulfonation agent include methanesulfonyl chloride (shortly, MsCl), p-toluenesulfonyl chloride
(shortly, TsCl), benzenesulfonyl chloride, trifluoromethanesulfonyl chloride (shortly, TfCl) and
nitrobenzenesulfonyl chloride. The sulfonation agent is added typically in an amount of 0.8 ~ 5
equivalents, preferably 1.1 - 2.0 equivalents.
The halogenation or sulfonation reaction is carried out in a presence of an organic base.
As an example of the organic base, an imidazole, 2-6-lutidine, N,N-dimethylamino pyridine and
salts thereof, or tertiary amine and its hydrate form can be mentioned. Preferable is a
trialkylamine including trimethylamine, triethylamine and diisopropylethylamine. The base is
added in an amount of 0.8 - 10 equivalents, preferably 1.0 ~ 3.0 equivalents. The reaction is
carried out in a presence of organic solvent. Sometimes, it can be carried out without any solvent.
The organic solvent to be used is not particularly limited. N,N-dimethylformamide, an aliphatic
or aromatic hydrocarbon solvent, a halogenated hydrocarbon, and an ether can be used as an
organic solvent. Specifically, an aromatic organic solvent such as toluene or benzene, a
haloalkane such as dichloromethane or chloroform, or an ether such as ethyl ether,
tetrahydrofuran or dioxane can be used. The reaction temperature is preferably adjusted to a
range of 0°C ~ 100°C, more preferably 0°C ~ 20°C at normal atmospheric pressure.

In the reaction, the compound of formula 10 is produced in a highly pure form through
typical work-up procedure. The obtained compound can be directiy subjected to the subsequent
alkylation reaction, without any extraordinary purification. This simplifies the preparation of the
chiral carvedilol and increases the yield of the reaction.
The compound of formula 10 provides a compound of formula 7, which is a precursor of
the carvedilol, through the reaction with 9H-4-hydroxy carbazole of formula 8. The 9H-4-
hydroxy carbazole of formula 8 is commercially available or can be mass produced through a
well-known procedure [DE 2,240,599 and US 4,273,711].
The specific reaction condition between the compound of formula 10 and 9H-4-hydroxy
carbazole of formula 8 is as follows. 9H-4-hydroxy carbazole of formula 8 is added, based on the
compound of formula 10, in a range of 0.5 ~ 2.0 equivalents, preferably, 1.0 - 1.1 equivalents.
First, the compound of formula 10 and 9H-4-hydroxy carbazole of formula 10 are dissolved into
an organic solvent. To the solution, 0.1 ~ 10 equivalents of a base (preferably, 0.5 ~ 2.0
equivalents) is added. Reaction temperature is adjusted to 30°C ~ 150°C, preferably 70°C ~
100°C at normal atmospheric pressure. The base to be used includes inorganic or organic base.
As an example of the inorganic base, sodium carbonate, sodium bicarbonate, potassium carbonate,
sodium hydroxide, potassium hydroxide or a metal alkoxide can be mentioned. Preferable is
potassium carbonate or sodium carbonate. For the organic base, a trialkylamine compound, for
example, trimethylamine, triethylamine or diisopropylethylamine is preferable. Organic solvent
to be used is not particularly limited. N,N-dimethylforrnamide, dimethylsulfoxide, an aliphatic or
aromatic hydrocarbon solvent, a halogenated hydrocarbon, an ether or an alcohol can be used as
an organic solvent. Preferable example of the alcohol is C1~C4 alcohol such as methanol, ethanol,
propanol, isopropanol, butanol, isobutanol or t-butanol.

The obtained compound can be directly subjected to one-pot deprotection reaction,
without any extraordinary purification. This attributes to the facts that the procedure proceeds in a
very pure meaner and that small amount of impurities can be easily removed from the purification
procedure of the subsequent deprotection reaction.
According to the present invention, the compound of formula 7 can be also prepared from
direct coupling of the compound of formula 2 with 9H-4-hydroxy carbazole of formula 8. That is,
the compound of formula 2 can be directly converted into the compound of 7 through coupling
with the compound of formula 8, without any procedures to increase the leaving ability of the
hydroxy group mediated by halogenation or sulfonation. Such a procedure is expressed as
pathway (2) in the reaction scheme 4. As a result of the pathway (2), the carvedilol can be
produced through reduced steps, compared to the pathway (1).
Mitsunobu reaction can be applicable to the direct coupling of the compound of formula
2 with the compound of formula 8, via the pathway (2) of the reaction scheme 4. In the mitsunobu
reaction, activation of the hydroxy group of the compound 2 and in situ nucleophilic substitution
are carried out as one pot reaction [Advanced Organic Chemistry 3rd Ed. Part B.. Plenum Press,
1993; Advanced Organic Chemistry 4th Ed. A Wiley-Interscience Publication, 1992].
The preparation of the compound of formula 7 through the pathway (2) is explained in
detail. The hetero-ring compound of formula 2 having the hydroxy group is dissolved into an
organic solvent, and a mitsunobu reagent comprised of a phosphine compound of formula 11 and
a dialkyl azocarboxylate of formula 12 is added to activate the hydroxy group. To the solution,
9H-4-hydroxy carbazole of formula 8 is added. Nucleopliilic attack of 9H-4-hydroxy carbazole of
formula 8 to the activated hydroxy group produces the compound of formula 7.
Specific examples of the compound of formula 11 and the compound of formula 12 are
as follows:

Formula 11

wherein, R', R" and R1" represent substituents. Preferably, R', R" and R'" each
independently represent C1~C6 alkyl group, C3~C6 cycloalkyl group, C2~C6 alkenyl group, C2~C6
alkynyl group, C1~C6 alkoxy group, C6~C10 aryl group or (CH2)L-R3(wherein, R3 represents C3~C6
cycloalkyl group, C2~C6 alkenyl group, C2~C6 alkynyl group, C1~C6 alkoxy group or C6~C10 aryl
group and L is an integer of 1 to 8).
Formula 12

wherein, A and B each independently represent C1~C6 alkyl group, C3~C6 cycloalkyl
group, C2~C6 alkenyl group or C2~C6 alkynyl group.
The compound of formula 7, prepared through the pathway (2) of the reaction scheme 2
can be also applicable to the subsequent deprotection reaction, without any purification
procedure, because the phosphine oxide produced as a byproduct can be easily removed from the
purification procedure of the following deprotection reaction. That is, the compound of formula 7
can be directly applied, without any purification, to the deprotection as one pot reaction. This
provides simplicity of the process and increase of the yield.
The preparation of the carvedilol from the compound of formula 7 is illustrated in a
reaction scheme 5:
Reaction Scheme 5

As mentioned in the above, the conversion of the compound of formula 7 to the
carvedilol is accomplished by adding a base, optionally in combination with a reaction solvent, to
the reactor inside which the compound of formula 7 is produced as shown in the reaction scheme
4. Generally, an oxazolidin-2-one or oxazolidin-2-thione compound undergoes a hydrolysis
reaction in a basic condition, thereby producing an aminoalcohol [hydrolysis of oxazolidin-2-one:
J. Org. Chem., 1986, 51, 713; J. Org. Chem., 1988, 53, 3865; Tetrahedron Lett., 1990, 57, 7407;
Tetrahedron 1998, 54, 7221; hydrolysis of oxazolidin-2-thione: J. Org. Chem., 1992, 57, 4331; J.
Am. Chem. Soc, 1994, 116, 5607]. According to the present invention, the compound of formula
7 was found to be applicable to the deprotection reaction to produce the targeted carvedilol. As
shown in the reaction scheme 5, after the starting material of the reaction scheme 4 has been
completely consumed, a base or a combination of a base and a solvent is added to the same
reactor under stirring to complete the deprotection reaction. According to preferred embodiment
of the present invention, a base was added, under stirring, to the reaction mixture of the
nucleophilic substitution reaction between the compound of formula 2 and the compound of
formula 8, followed by addition of a solvent such as water, alcohol and a mixture thereof. Herein,
the reaction temperature is typically in a range of 0°C ~ 150°C, preferably 30°C ~ 70°C at normal
atmospheric pressure.
The base is added, based on the compound of formula 2, in an amount of 0.8 ~ 10
equivalents, preferably 1.0 ~ 3.0 equivalents. As an inorganic base to be used, inorganic carbonate
(for example, sodium carbonate, potassium carbonate, cesium carbonate or sodium bicarbonate)
or inorganic hydroxide (for example, sodium hydroxide, potassium hydroxide or lithium
hydroxide) can be mentioned.
As a solvent added in admixture with the base, water, alcohol or mixture thereof is
generally used. Preferable example of the alcohol is C1~C4 alcohol such as methanol, ethanol,
propanol, isopropanol, butanol, iso-butanol or t-butanol.
As mentioned in the above, the present invention is distinguished from the prior art, in
that the targeted chiral carvedilol of formula 1 is eiTectively prepared from the chiral key
intermediate of formula 2 in a highly optical purity and in a mild condition applicable to
industrial mass production. Further, the chiral key intermediate is prepared, without any change of
the chirality, from the optically pure chiral glycidyl derivative.
To the contrary, according to the conventional processes for the preparation of the chiral
carvedilol as explained in the reaction scheme 1, the starting material, 4-(2,3-epoxypropyl)
carbazole of formula 3, is not obtainable in a highly optical pure form. Specifically, the compound
of formula 3 is prepared from the nucleophilic substitution reaction of chiral glycidyl m-
nitrobenzenesulfonate with 9H-4-hydroxy carbazole of formula 8. Even though the reaction had
been reported to proceed in a stereoselective manner such that chiral configuration of the product
had been retained [J. Org. Chem., 1989, 54, 1295; Tetrahedron: Asymmetry 1992, 3, 539], Dubois
et al. reported that optical purity of the compound of formula 3 was significantly reduced in some
cases [J. Med. Chem., 1996, 39, 3256]. Further, according to our inventors' studies, the optical

purity of the product was found to be very sensitive 10 the reaction condition. Therefore, the
process is believed to require very strict reaction condition. As a result, the process is not
applicable to industrial mass production.
According to the present invention, the key intermediate of formula 2 with a highly
optical purity is prepared from the optically pure chiral glycidol derivative, without any
deterioration of optical purity. Further, decrease of the optical purity does not occur in the
preparation of the chiral carvedilol from the key intermediate of formula 2. Therefore, the process
of the present invention provides the carvedilol in a highly optical pure form, compared to the
conventional ones.
In addition, the process of the present invention does not require any extraordinary
purification of the intermediate products involved in the preparation of the targeted chiral
carvedilol. This implies that the process of the present invention is a very simple and economic
one. Besides, the process of the present invention is carried out in a mild condition such that it
neither requires vigorous reaction condition nor a strong oxidizing or reducing agent. As a result,
the process of the present invention is suitable for the application to industrial mass production.
Conclusively, we established the process for the preparation of highly optical pure
carvedilol from the chiral compound of formula 2, without any decrease of chirality and in an
industrially applicable manner.
In the following, the present invention will be more fully illustrated referring to
Examples. However, it should be understood that these Examples are suggested only for
illustration and should not be construed to limit the scope of the present invention. Numerous
modifications could be made without departing from the scope and the spirit of the invention.

Examples
Example 1: Preparation of (S)-3-[2-(2-methoxyphenoxy)ethyl]-5-
(hydroxymethyl)oxazolidin-2-one [Formula 2, X = oxygen]
Isobutyl-2-(2-methoxyphenoxy)ethylcarbamate 106.9 g (0.4 mol) and lithium-r-
butoxide 6.40 g (0.08 mol) were dissolved into N,N-dimethylformamide (200 mL) and stirred at
room temperature for 10 min. To the mixture, 69.5 g (0.44 mol) of (S)-2-oxyranylmethoxy-
tetrahydropyran was added and stirred at 80°C for 24 hours. The reaction mixture was cooled
down to room temperature and was adjusted to pH 1 using 20% methyl alcohol sulfuric acid
solution. The reaction mixture was further stirred at room temperature for 5 hours and neutralized
using triethylamine. To the solution, water (400 mL) and dichloromethane (1000 mL) were added.
After organic layer was separated from the mixture solution, it was dried with anhydrous
magnesium sulfate and filtrated. Evaporation under reduced pressure gave the targeted compound
of formula 2 in a liquid phase. The obtained product was subjected without any purification to the
next deprotection reaction.
Yield: 104.6 g (98%)
1H NMR (300MHz, CDCl3): d 2.32 (br s, 1H), 3.65-3.74 (m, 4H), 3.80-3.92 (m, 2H),
3.85 (s, 3H), 4.18 (t, J = 7.8Hz, 2H), 4.60 (m, 1H), 6.89-6.99 (m, 4H).
Example 2: Preparation of (R)-3-[2-(2-methoxyphenoxy)ethyl]- 5 -hydroxymethyl
oxazolidin-2-one [Formula 2, X = oxygen]
Using N,N-dimethylformamide solution of isobutyl-2-(2-ethoxyphenoxy)
ethylcarbamate 53.46 g (0.2 mol), lithium-r-butoxide 3.20 g (0.04 mol) and (R)-2-
oxyranylmethoxy-tetrahydropyran 34.76 g (0.22 mol), the procedures as described in Example
1 were carried out to obtain the targeted product.
Yield: 51.2 g (96%)
Example 3: Preparation of (S)-3-[2-(2-methoxyphenoxy)ethyl]-5-
(hydroxymethyl)oxazolidin-2-one [Formula 2, X = oxygen]
Using N,N-dimethylformamide solution of isobutyl-2-(2-
methoxyphenoxy)ethylcarbamate 26.7 g (0.1 mol), lithium-r-butoxide 1.60 g (0.02 mol) and (S)-
2-t-butoxymethyl-oxiran 14.3 g (0.11 mol), the procedures as described in Example 1 were
carried out to obtain the targeted product.
Yield: 25.6 g (96%)
Example 4: Preparation of (R)-3-[2-(2-methoxyphenoxy)ethyl]-5-(hydroxymethyl
oxazoIidin-2-one [Formula 2, X = oxygen]
Using N,N-dimethylformamide solution of isobutyl-2-(2-
methoxyphenoxy)ethylcarbamate 53.46 g (0.2 mol), lithium-t-butoxide 3.2 g (0.04 mol) and (R)-
2-t-butoxymethyl-oxiran 28.6 g (0.22 mol), the procedures as described in Example 1 were
carried out to obtain the targeted product.
Yield: 50.7 g (95%)
Example 5: Preparation of (S)-3-[2-(2-methoxyphenoxy)ethyl]-5-(hydroxymethyI)
xazoIidin-2-thione [Formula 2, X = sulfur]

Using N,N-dimethylformamide solution of ethyl-2-(2-
methoxyphenoxy)ethylthiocarbamate 25.5 g (0.1 mol) [J. Chem. Soc, 1952, 2076; J. Chem.
Soc, 1952, 2079; Tetrahedron Lett., 1969, 3631], lithium-r-butoxide 1.6 g (0.02 mol) and (S)-2-
oxyranylmethoxy-tetrahydropyran 17.38 g (0.11 mol), the procedures as described in Example
1 were carried out to obtain the targeted product.
Yield: 21.5 g (76%)
Example 6: Preparation of (R)-3-[2-(2-methoxyphenoxy)ethyl]-5-(hydroxymethyl)
xazolidin-2-thione [Formula 2, X = sulfur]
Using N,N-dimethylformamide solution of ethyl-2-(2-
methoxyphenoxy)ethylthiocarbamate 51.0 g (0.2 mol), lithium-f-butoxide 3.2 g (0.04 mol) and
(R)-2-oxyranylmethoxy-tetrahydropyran 34.76 g (0.22 mol), the procedures as described in
Example 1 were carried out to obtain the targeted product.
Yield: 42.5 g (75%)
Example 7: Preparation of (S)-{3-[2-(2-methoxyphenoxy)ethyl]-2-oxooxazolidin-5-
yl}methyl methanesulfonate [Formula 7, X = oxygen, Z = methanesulfonate]
The compound of formula 2 prepared in the Example 1 53.4 g (0.2 mol) and triethylamine
30.36 g (0.3 mol) were added to dichloromethane (300 mL), and the obtained solution was cooled
down to 0°C. To the solution, methanesulfonyl chloride 25.2 g (0.22 mol) was
dropwisely added under stirring. The reaction solution was stirred for 3 hours and water (300 mL)
was added thereto. After organic layer was separated from the mixture solution, it was dried with
anhydrous magnesium sulfate and filtrated. Evaporation under reduced pressure gave the targeted

compound of formula 7 in a liquid phase. The obtained product was subjected without any
purification to the next procedure.
Yield: 68.4 g (99%)
Example 8: Preparation of (R)-{3-[2-(2-methoxyphenoxy)ethyl]-2-oxooxazolidin-5-
yl}methyl methanesulfonate [Formula 7, X = oxygen, Z = methanesulfonate]
Using dichloromethane solution of the compound of formula 2 prepared in Example 2
80.1 g (0.3 mol), triethylamine 45.5 g (0.45 mol) and methanesulfonyl chloride 37.8 g (0.33 mol),
the procedures as described in Example 7 were carried out to obtain the targeted product.
Yield: 102.5 g (99%)
Example 9: Preparation of (S)-{3-[2-(2-methoxyphenoxy)ethyl]-2-oxothiooxazolidin-
5-yl}methyl methanesulfonate [Formula 7, X = sulfur, Z = methanesulfonate]
Using dichloromethane solution of the compound of formula 2 prepared in Example 5
28.33 g (0.1 mol), triethylamine 15.18 g (0.15 mol) and methanesulfonyl chloride 12.6 g (0.11
mol), the procedures as described in Example 7 were carried out to obtain the targeted product.
Yield: 35.7 g (99%)
Example 10: Preparation of (R)-{3-[2-(2-methoxyphenoxy)ethyl]-2-
oxothiooxazolidin-5-yl}methyl methanesulfonate [Formula 7, X = sulfur, Z =
methanesulfonate]

Using dichloromethane solution of the compound of formula 2 prepared in Example 6
42.45 g (0.15 mol), triethylamine 22.8 g (0.225 mol) and methanesulfonyl chloride 18.9 g (0.165
mol), the procedures as described in Example 7 were carried out to obtain the targeted product.
Yield: 53.67 g (99%)
Example 11: Preparation of (S)-{3-[2-(2-methoxyphenoxy)ethyl]-2-oxooxazoIidin-5-
yl}methyl toluenesulfonate [Formula 7, X = oxygen, Z = toluenesulfonate]
Using dichloromethane solution of the compound of formula 2 prepared in Example 1
26.7 g (0.1 mol), triethylamine 15.18 g (0.15 mol) and p-toluenesulfonyl chloride 21.0 g (0.11
mol), the procedures as described in Example 7 were carried out to obtain the targeted product.
Yield: 38.7 g (92%)
Example 12: Preparation of (R)-{3-[2-(2-methoxyphenoxy)ethyl]-2-oxooxazolidin-5-
yl}methyl toluenesulfonate [Formula 7, X = oxygen, Z = toluenesulfonate]
Using dichloromethane solution of the compound of formula 2 prepared in Example 2
42.7 g (0.16 mol), triethylamine 24.3 g (0.24 mol) and p-toluenesulfonyl chloride 33.6 g (0.176
mol), the procedures as described in Example 7 were carried out to obtain the targeted product.
Yield: 62.6 g (93%)
Example 13: Preparation of (S)-{3-[2-(2-methoxyphenoxy)ethyl]-2-
oxothiooxazoIidin-5-yl}methyl toluenesulfonate [Formula 7, X = sulfur, Z =
toluenesulfonate]

Using dichloromethane solution of the compound of formula 2 prepared in Example 5
28.3 g (0.1 mol), triethylamine 15.18 g (0.15 mol) and p-toluenesulfonyl chloride 21.0 g (0.11
mol), the procedures as described in Example 7 were carried out to obtain the targeted product.
Yield: 40.64 g (93%)
Example 14: Preparation of (R)-{3-[2-(2-methoxyphenoxy)ethyl]-2-
oxothiooxazolidin-5-yI}methyl toluenesulfonate [Formula 7, X = sulfur, Z =
toluenesulfonate]
Using dichloromethane solution of the compound of formula 2 prepared in Example 6
25.5 g (0.09 mol), triethylamine 13.66 g (0.135 mol) and p-toluenesulfonyl chloride 19.0 g (0.1
mol), the procedures as described in Example 7 were carried out to obtain the targeted product.
Yield: 35.4 g (90%)
Example 15: Preparation of (S)-5-chloromethyl-3-[2-(2-methoxyphenoxy)ethyl]
oxazoIidin-2-one [Formula 7, X = oxygen, Z = chloride]
Using dichloromethane solution of the compound of formula 2 prepared in Example 1
26.7 g (0.1 mol), triethylamine 10.1 g (0.1 mol) and thionyl chloride 35.7 g (0.3 mol), the
procedures as described in Example 7 were carried out to obtain the targeted product.
Yield: 26.3 g (92%)

Example 16: Preparation of (S)-5-chloromethyl-3-[2-(2-methoxyphenoxy)ethyl]
oxazolidin-2-thione [Formula 7, X = sulfur, Z = chloride]
Using dichloromethane solution of the compound of formula 2 prepared in Example 5
28.3 g (0.1 mol), triethylamine 10.1 g (0.1 mol) and thionyl chloride 35.7 g (0.3 mol), the
procedures as described in Example 7 were carried out to obtain the targeted product.
Yield: 28.0 g (93%)
Example 17: Preparation of (S)-carvedilol
51.75 g (0.15 mol) of (S)-{3-[2-(2-methoxyphenoxy)ethyl]-2-oxooxazolidin-5-yl}methyl
methanesulfonate prepared in Example 7 and 27.45 g (0.15 mol) of 9H-4-hydroxy carbazole were
dissolved into 450 mL of anhydrous ethyl alcohol. To the solution, 31.10 g (0.225 mol) of
potassium carbonate was added and refluxed for 16 hours under stirring. After the compound of
formula 7 was completely consumed, the reaction temperature was adjusted to room temperature.
To the mixture, 4N KOH aqueous solution 150 mL was added and then refluxed for 6 hours under
stirring. The reaction mixture was cooled down to room temperature and the ethyl alcohol was
evaporated under reduced pressure. To the residue, water (200 mL) and dichloromethane (500
mL) were added and stirred for 30 min. Organic layer was separated, dried with anhydrous
magnesium sulfate and filtrated. Evaporation under reduced pressure gave solid residues. To the
obtained residue, ethyl acetate 150 ml was added and stirred. Through filtration and washing, the
targeted (S)-carvedilol of formula 1 was obtained.
Yield: 44.5 g (73%)

1H NMR (300MHz, CDCl3): d 1.85 (br s, 1H), 2.97 (m, 1H), 3.10 (m, 3H), 3.83 (s, 3H),
4.15 (t, J= 7.7Hz, 2H), 4.18-4.29 (m, 3H), 6.66 (d, J = 8.1Hz, 1H), 6.85-6.97 (m, 4H), 7.04 (d, J
= 8.1Hz, 1H), 7.25-7.38 (m, 3H), 8.19 (br s, 1H), 8.26 (d. J= 7.8Hz, 1H).
Optical purity: > 99% ee [HPLC: Chirolsil SCA(-), effluent: mixture solvent of
acetonitrile:methyl alcohol = 2:1 containing 0.1%) trieth} lamine, rate of effluent = 1 mL/min, UV
detector: 254 nm, retention time of (S)-isomer, ts = 23.2 min, retention time of (R)-isomer, tR =
20.6 min]
Example 18: Preparation of (R)-carvedilol
Using 34.5 g (0.1 mol) of (R)-{3-[2-(2-methoxyphenoxy)ethyl]-2-oxooxazolidin-5-yl}
methyl methanesulfonate prepared in Example 8, 18.3 g (0.1 mol) of 9H-4-hydroxy carbazole and
20.7 g (0.15 mol) of potassium carbonate, the procedures as described in Example 17 were
carried out to obtain the targeted (R)-carvedilol.
Yield: 28.8 g (71%)
Example 19: Preparation of (S)-carvedilol
Using 36.1 g (0.1 mol) of (S)-{3-[2-(2-methoxyphenoxy)ethyl]-2-oxothiooxazolidin-5-
yl}methyl methanesulfonate prepared in Example 9, 18.3 g (0.1 mol) of 9H-4-hydroxy carbazole
and 20.7 g (0.15 mol) of potassium carbonate, the procedures as described in Example 17 were
carried out to obtain the targeted (S)-carvedilol.
Yield: 28 g (69%)

Example 20: Preparation of (R)-carvedilol
Using 43.3 g (0.12 mol) of (R)-{3-[2-(2-methoxyphenoxy)ethyl]-2-oxothiooxazolidin-5-
yl}methyl methanesulfonate prepared in Example 10. 22.0 g (0.12 mol) of 9H-4-hydroxy
carbazole and 24.8 g (0.18 mol) of potassium carbonate, the procedures as described in Example
17 were carried out to obtain the targeted (R)-carvedilol.
Yield: 32.6 g (67%)
Example 21: Preparation of (S)-carvedilol
Using 42.1 g (0.1 mol) of (S)-{3-[2-(2-methoxyphenoxy)ethyl]-2-oxooxazolidin-5-yl}
methyl toluenesulfonate prepared in Example 11, 18.3 g (0.1 mol) of 9H-4-hydroxy carbazole and
20.7 g (0.15 mol) of potassium carbonate, the procedures as described in Example 17 were
carried out to obtain the targeted (S)-carvedilol.
Yield: 26.4 g (65%)
Example 22: Preparation of (S)-carvedilol
Using 56.8 g (0.13 mol) (S)-{3-[2-(2-methoxyphenoxy)ethyl]-2-oxothiooxazolidin-5-
yl}methyl toluenesulfonate prepared in Example 13, 23.8 g (0.13 mol) of 9H-4-hydroxy carbazole
and 26.9 g (0.195 mol) of potassium carbonate, the procedures as described in Example 17 were
carried out to obtain the targeted (S)-carvedilol.
Yield: 32.7 g (62%)

Example 23: Preparation of (S)-carvedilol
Using 28.6 g (0.1 mol) of (S)-5-chloromethyl-3-[2-(2-methoxyphenoxy)ethyl]oxazolidin-
2-one prepared in Example 15, 18.3 g (0.1 mol) of 9H-4-hydroxy carbazole, 0.17 g (0.001 mol) of
potassium iodide and 20.7 g (0.15 mol) of potassium carbonate, the procedures as described in
Example 17 were carried out to obtain the targeted (S)-carvedilol.
Yield: 26.8 g (66%)
Example 24: Preparation of (S)-carvedilol
Using 42.8 g (0.15 mol) of (S)-5-chloromethyl-3-[2-(2-methoxyphenoxy)ethyl]
oxazolidin-2-thione prepared in Example 16, 27.45 g (0.15 mol) of 9H-4-hydroxy carbazole,
0.249 g (0.0015 mol) of potassium iodide ? and 31.1 g (0.225 mol) of potassium carbonate, the
procedures as described in Example 17 were carried out to obtain the targeted (S)-carvedilol.
Yield: 37.8 g (62%)
Example 25: Preparation of (S)-carvedilol
26.7 g (0.1 mol) of (S)-3-[2-(2-methoxyphenoxy)ethyl]-5-(hydroxymethyl)oxazolidin-2-
one was dissolved into tetrahydrofuran (100 mL), and then, triphenylphosphine (31.44 g, 0.12
mol) and diisopropyl azodicarboxylate (24.2 g, 0.12 mol) were successively added to the solution.
The mixture solution was stirred for 1 hour at room temperature. To the mixture solution,
tetrahydrofuran solution (50 mL) containing 18.3 g (0.1 mol) of 9H-4-hydroxy carbazole was
dropwisely added and stirred for 12 hours at room temperature. After the starting material, the
compound of formula 2, was completely consumed, the reaction solution was evaporated under

reduced pressure. To the remaining residue, ethyl alcohol 300 mL and 4N KOH aqueous solution
100 mL were added and refluxed for 6 hours under stirring. The reaction mixture was cooled
down to room temperature and the ethyl alcohol was evaporated under reduced pressure. To the
residue, water (200 mL) and dichloromethane (300 mL) were added and stirred for 30 min.
Organic layer was separated, dried with anhydrous magnesium sulfate and filtrated. Evaporation
under reduced pressure gave solid residues. To the obtained residue, ethyl acetate 150 ml was
added and stirred. Through filtration and washing, the targeted (S)-carvedilol of formula 1 was
obtained.
Yield: 21.1 g (52%)
Example 26: Preparation of (R)-carvedilol
Using (S)-3-[2-(2-methoxyphenoxy)ethyl]-5-(hydroxymethyl)oxazolidin-2-thione (32 g,
0.12 mol) prepared in Example 5, triphenylphosphine (37.7 g, 0.144 mol), diisopropyl
azodicarboxylate (29.0 g, 0.144 mol) and 9H-4-hydroxy carbazole (22.0 g, 0.12 mol), the
procedures as described in Example 25 were carried out to obtain the targeted (R)-carvedilol.
Yield: 23.4 g (48%)
The present invention provides an efficient process for the preparation of the targeted
chiral carvedilol of formula 1, starting from the compound of formula 2, which is the key
intermediate for the synthesis of the chiral carvedilol, either through increasing the leaving ability
of the hydroxy group, alkylation with 9H-4-hydroxy carbazole and subsequent deprotection, or
through direct coupling with 9H-4-hydroxy carbazole and subsequent deprotection.

In the above process, the key intermediate of formula 2 can be easily prepared in a highly
optical pure form from commercially available starting materials, which is one of the advantages
of the present invention. That is, the chiral glycidol or its derivatives of formula 5 and N-
protected amine compound of formula 4, which are starling materials of the key intermediate of
formula 2, are commercially available or industrially produced in a simple manner. Further, the
preparation of the key intermediate of formula 2 from the starting materials is carried out without
any decrease of optical purity such that the key intermediate can be produced in a highly optical
pure form.
Furthermore, according to the present invention, the process does not involve any
procedure which reduces the optical purity, during the conversion from the key intermediate of
formula 2 to the carvedilol. The process is carried out in a simple manner, in a mild condition and
without any extraordinary purification, thereby providing the chiral carvedilol in an economic
manner.
Therefore, the present invention established an efficient process for the preparation of the
chiral carvedilol with high optical purity, using the compound of formula 2 as a key intermediate
for the synthesis of the chiral carvedilol, without any change of chirality and in a manner suitable
for an industrial mass production.

WE CLAIM:
1. A process for the preparation of chiral carvedilol, comprising:
a) reacting an amine compound of formula 4 with a chiral glycidol of formula
5 in a reaction temperature range of 0°C~150°C at normal atmospheric pressure for
ring opening of the chiral glycidol of formula 5 by the amine compound of formula 4
and subsequent in-situ intramolecular cyclization, followed by deprotection of a
hydroxy-protecting group from the obtained compound to produce a compound of
formula 2;
b) reacting a compound of formula 2 with a halogenation agent, a sulfonation
agent or a mitsunobu reagent in a reaction temperature range of 0°C~100°C at normal
atmospheric pressure to activate a hydroxyl group of the compound of formula 2,
followed by nucleophilic substitution reaction with 9H-4-hydroxy carbazole in a
reaction temperature range of 30°C~150°C at normal atmospheric pressure to produce
a compound of formula 7, wherein said halogenation agent is selected from the group
consisting of thionyl chloride, thionyl bromide, oxalyl chloride, phosphorous
tribromide and phosphorous trichloride, said sulfonation agent is selected from the
group consisting of methanesulfonyl chloride, p-toluenesulfonyl chloride,
benzenesulfonyl chloride, trifluoromethanesulfonyl chloride and nitrobenzenesulfonyl
chloride, and said mitsunobu reagent is comprised of a phosphine compound of
formula 11 and a dialkyl azocarboxylate of formula 12; and
c) subjecting the obtained compound of formula 7 to a deprotection reaction in
a reaction temperature range of 0°C~150°C at normal atmospheric pressure to produce
the targeted chiral carvedilol of formula 1:


wherein, * represents a chiral center,
X is oxygen or sulfur,
Y is a leaving group selected from the group consisting of
C1-C10 alkoxy group, C6-C10 aryloxy group, allyloxy group and C7-C14
alkylaryloxy group, and
R1 is a hydroxy-protecting group,

wherein,
R', R" and R'" each independently represent C1-C6 alkyl group, C3-C6
cycloalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, C6-
C10 aryl group or (CH2)L-R3 (wherein, R3 represents C3-C6 cycloalkyl group, C2-C6
alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group or C6-C10 aryl group and L is
an integer of 1 to 8),

wherein,
A and B each independently represent C1-C6 alkyl group, C3-C6 cycloalkyl
group, C2-C6 alkenyl group or C2-C6 alkynyl group.
2. The process as claimed in claim 1, wherein the deprotection reaction of step
(c) is carried out in a presence of an alkali metal salt selected from the group
consisting of sodium methoxide, lithium methoxide, sodium carbonate, sodium
bicarbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.



The present invention relates to a process for the efficient preparation of highly optical
pure chiral carvedilol. According to the present invention, a chiral oxazolidin-2-one or
oxazolidin-2-thione having formula 2, produced from the reaction of N-protected 2-(2-
methoxyphenoxy)ethylarnine with a chiral glycidol derivative is used as a key intermediate for the
preparation of the chiral carvedilol. Specifically, the process for the preparation of the chiral
carvedilol comprises a) reacting a compound of formula 2 with a halogenation agent, a
sulfonation agent or a mitsunobu reagent to activate a hydroxyl group of the compound of
formula 2, followed by nucleophilic substitution reaction with 9H-4-hydroxy carbazole to
produce a compound of formula 7, and b) subjecting the obtained compound of formula 7 to a
deprotection reaction in a presence of an inorganic base to produce the targeted chiral carvedilol.
The process of the present invention can be accomplished in a mild condition. The process neither
requires any extraordinary purification procedure, nor involves decrease of optical purity.
Therefore, the process of the present invention provides highly optical pure chiral carvedilol in
simple and efficient manner.

Documents:

00254-kol-2006-abstract.pdf

00254-kol-2006-claims.pdf

00254-kol-2006-description complete.pdf

00254-kol-2006-form 1.pdf

00254-kol-2006-form 2.pdf

00254-kol-2006-form 3.pdf

00254-kol-2006-form 5.pdf

254-KOL-2006-ABSTRACT 1.1.pdf

254-KOL-2006-ABSTRACT.pdf

254-kol-2006-amanded claims.pdf

254-KOL-2006-AMANDED PAGES OF SPECIFICATION.pdf

254-kol-2006-assignment.pdf

254-KOL-2006-CLAIMS 1.1.pdf

254-KOL-2006-CLAIMS.pdf

254-kol-2006-correspondence-1.1.pdf

254-KOL-2006-CORRESPONDENCE.pdf

254-KOL-2006-DESCRIPTION (COMPLETE).pdf

254-KOL-2006-DESCRIPTION COMPLETE 1.1.pdf

254-kol-2006-examination report.pdf

254-KOL-2006-FORM 1 1.1.pdf

254-KOL-2006-FORM 1.pdf

254-kol-2006-form 13-1.1.pdf

254-KOL-2006-FORM 13.pdf

254-kol-2006-form 18.pdf

254-KOL-2006-FORM 2 1.1.pdf

254-KOL-2006-FORM 2.pdf

254-kol-2006-form 3-1.1.pdf

254-KOL-2006-FORM 3.pdf

254-kol-2006-form 5.pdf

254-KOL-2006-FORM-27-1.1.pdf

254-KOL-2006-FORM-27.pdf

254-kol-2006-gpa.pdf

254-kol-2006-granted-abstract.pdf

254-kol-2006-granted-claims.pdf

254-kol-2006-granted-description (complete).pdf

254-kol-2006-granted-form 1.pdf

254-kol-2006-granted-form 2.pdf

254-kol-2006-granted-specification.pdf

254-KOL-2006-INTERNATIONAL EXM REPORT.pdf

254-kol-2006-international preliminary examination report.pdf

254-kol-2006-international search report.pdf

254-kol-2006-others-1.1.pdf

254-KOL-2006-OTHERS.pdf

254-KOL-2006-PETITION UNDER RULE 137.pdf

254-KOL-2006-REPLY TO EXAMINATION REPORT 1.1.pdf

254-kol-2006-reply to examination report-1.2.pdf

254-KOL-2006-REPLY TO EXAMINATION REPORT.pdf

254-KOL-2006-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf


Patent Number 246835
Indian Patent Application Number 254/KOL/2006
PG Journal Number 11/2011
Publication Date 18-Mar-2011
Grant Date 16-Mar-2011
Date of Filing 24-Mar-2006
Name of Patentee AHN-GOOK PHARMACEUTICAL CO., LTD.
Applicant Address # 993-75, DAELIM-DONG YOUNGDUNGPO-KU SEOUL 150-953
Inventors:
# Inventor's Name Inventor's Address
1 QUAN LONG GUO # 304 VENTURE TOWN JANGYOUNGSILGWAN 1688-5 SINIL -DONG DAEDUK-GU DAEJEON 306-230 KOREA
2 KIM SEONG JIN # 607-1504 YEOLMAEMAEUL 880 JIJOK-DONG YUSUNG-KU DAEJEON 305-330 KOREA
3 JONG CHANG WOO # 103-204 KOLONHANEULCHAE APARTMENT JUNGHWASANDONG-2-GA WANSAN-KU JEONJU-SI JEOLLABUK-DO 560-742 KOREA
4 JIN KYUNG YONG # 176-29 SEOKGWAN-1-DONG SEONGBUK-GU SEOUL 136-151 KOREA
5 KANG HYUN BIN # 102-201 DAEJU APARTMENT SIPJEONG-DONG BUPYEONG-GU INCHEON 403-130 KOREA
6 AUH JIN # 13-104 HYUNDAI APARTMENT 369-1 APGUJEONG-DONG KANGNAM-KU SEOUL 135-110 KOREA
7 WON DUK KWON # 132-903 HYUNDAI APARTMENT GGOTMEYANGGIMAEUL HWASEO-DONG PALDAL-KU SUWON GYEONGGI-DO 442-150 KOREA
8 MOON BYUNG HYUN # 104-406 POONGLIM-3 APARTMENT 922 DONGCHUN-1-DONG YEONSU-KU INCHEON 406-801 KOREA
PCT International Classification Number C07D 209/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 KR 10-2006-0017781 2006-02-23 Republic of Korea