US 2006O155132A1

(19) United States

(12) Patent Application Publication (10) Pub. No.: US 2006/0155132 A1
KOVacs et al. (43) Pub. Date: Jul. 13, 2006
(54) METHOD OF MAKING DORZOLAMIDE Publication Classification
HYDROCHLORIDE
(51) Int. Cl.
(76) Inventors: Laszlo Zsolt Kovacs, Debrecen (HU): C07D 495/02 (2006.01)
Csaba Szabo, Debrecen (HU); Erika (52) U.S. Cl. ................................................................ 549/23
Magyar Molnarne, Debrecen (HU);
Adrienne Kovacsne-Mezei, Debrecen (57) ABSTRACT
(HU); Claude Singer, Kfar Saba (IL);
Judith Aronhime, Rehovot (IL) Processes for the preparation of dorzolamide hydrochloride
and an intermediate of Formula IV.
Correspondence Address:
KENYON & KENYON LLP
ONE BROADWAY Formula IV
NHEt
NEW YORK, NY 10004 (US)
(21) Appl. No.: 11/326,719
N H-CI,
(22) Filed: Jan. 6, 2006
Related U.S. Application Data O
MVO
(60) Provisional application No. 60/642,166, filed on Jan.
6, 2005. are provided.
Patent Application Publication Jul. 13, 2006 US 2006/O155132 A1

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US 2006/015.5132 A1
METHOD OF MAKING DORZOLAMIDE
HYDROCHLORIDE
RELATED APPLICATIONS
0001. The present application claims benefit of U.S.
Provisional Patent Application No. 60/642,166, filed Jan. 6,
2005, the contents of which are incorporated herein in their
entirety.
FIELD OF THE INVENTION
0002 The present invention is directed to methods of
making dorzolamide hydrochloride.
BACKGROUND OF THE INVENTION
0003 Dorzolamide hydrochloride, known chemically as
5,6-dihydro-4-(S)-ethylamino-6-(S)-methyl-4H-thieno-2,
3-bithiopyran-2-sulfonamide-7,7-dioxyde hydrochloride, is
a topically effective carbonic anhydrase inhibitor useful in
the treatment of ocular hypertension.
0004 Dorzolamide hydrochloride has the structure of
Formula I:
NHEt
Formula I
O
N i NH2
S
H3C S O
MV
O O H-Cl
0005 U.S. Pat. Nos. 4,677,155 and 4,797.413 disclose
Dorzolamide. In the prior art synthesis of dorzolamide, a
chiral hydroxysulfone is used as a starting material. The
chiral hydroxysulfone starting material can be obtained
using the processes disclosed in U.S. Pat. Nos. 5,157,129,
5,474,919, and 5,760.249. In the disclosed processes, the
chiral hydroxysulfone is obtained by the asymmetric enzy
matic reduction of the corresponding ketosulfone, or by
cyclization of the chiral thienylthiobutyric acid, obtained, in
turn, from a chiral hydroxyester or lactone, and the Subse
quent stereospecific reduction of the resulting ketone.
0006 Processes for the preparation of dorzolamide
hydrochloride are described in U.S. Pat. Nos. 4,797.413,
5,157,129, and 5,688.968 and in U.S. patent application
Publication Ser. No. 2003/0220509. The disclosed processes
involve conversion of a hydroxysulfone to the correspond
ing acetamidosulfone by a Ritter reaction with retention of
configuration, followed by introduction of a sulfonamido
group, and the Subsequent reduction of the amido group to
an amine, providing the desired product.
0007. The process disclosed in U.S. Pat. No. 4,797.413
includes activation of the 4-hydoxy group of the Sulfonami
Jul. 13, 2006
nated hydroxysulfone with tosyl chloride and the introduc
tion of the desired alkylamino group by nucleophilic Sub
stitution, resulting in all diastereomeric products, which
must be separated and resolved. As a result, at least 75
percent of the product is lost when the desired product is the
more active enantiomer.
0008. There is a need in the art for a new process for the
preparation of Dorzolamide and salts thereof.
SUMMARY OF THE INVENTION
0009. In one embodiment, the present invention is
directed to a process for the preparation of a protected
derivative of Formula II, comprising: protecting the hydroxy
group of 5,6-dihydro-4-(R)-hydroxy-6-(S)-methyl-4H
thieno-2,3-bithiopyran 7,7-dioxide, having the structural
Formula II
Formula II
OH
S
HC S
4.MV\,
with a Sulfonic acid derivative, in the presence of an organic
base and a polar aprotic organic solvent, to obtain a pro
tected derivative.
0010. In another embodiment, the present invention is
directed to a process for the preparation of a compound of
Formula IV,
Formula IV
Y
NHEt
S
HC S
/MV\,
comprising: aminating the protected derivative of formula II
with an alkyl amine and an acid in the presence of a solvent
selected from the group consisting of a polar aprotic organic
solvent, water and a mixture thereof, to give 5,6-dihydro
4-(S)-ethylamino-6-(S)-methyl-4H-thieno-2,3-bithiopyran
7,7-dioxide salt of Formula IV, where Y is an organic or
inorganic acid moiety. Preferably Y is selected from the
group consisting of acetic acid, fumaric acid, tartaric acid,
Sulfuric acid, hydrochloric acid, and hydrobromic acid.
More preferably, the acid is HC1.
US 2006/015.5132 A1 Jul. 13, 2006

0011. In another embodiment, the present invention is

directed to a process for preparing dorzolamide Salt of
formula I, where Y is as defined above, Formula I
Y

NHEt
O
\ NH2.
Formula I S
H3C S O

NHEt
Y
/MV\,
O
N i NH2 The process comprises:
HC S S O
0016 (a) protecting the hydroxy group of 5,6-dihydro
4-(R)-hydroxy-6-(S)-methyl-4H-thieno-2,3-bithiopy
/MV\, ran 7,7-dioxide, having the structural Formula II

Formula II
OH
comprising: Sulfonamidating of the compound of Formula
IV by combining the compound of Formula IV with fuming
Sulfuric acid or chlorosulfonic acid, chlorinating the Sulfo
nylated intermediate by the addition of inorganic chlorinated
agent, evaporating the inorganic chlorinated agent from the HC S S
reaction mixture, adding a polar aprotic organic solvent,
adding a base and afterwards adding an acid until dorZola
/MV\,
mide salt compound of Formula I is obtained.
0012. In another embodiment, the present invention is
directed to a process of purifying dorzolamide salt by
dissolving the dorzolamide salt in water, adding a base until with a sulfonic acid derivative, in the presence of an
a basic slurry is obtained, extracting the basic slurry with an organic base and a polar aprotic organic solvent, to
aprotic polar organic solvent, which is immiscible in water, obtain a protected derivative;
until two phases are obtained, separating the organic phase,
concentrating the organic phase to obtain a residue of 0017 (b) aminating the protected derivative of formula
dorzolamide base, and cooling the residue. II with an alkyl amine and an acid in the presence of a
Solvent selected from the group consisting of a polar
0013 In another embodiment, the present invention is aprotic organic solvent, water and a mixture thereof, to
directed to a process of purifying dorzolamide salt by give 5,6-dihydro-4-(S)-ethylamino-6-(S)-methyl-4H
combining dorZolamide base with an acid and with a polar thieno-2,3-bithiopyran 7,7-dioxide salt of Formula IV.
aprotic organic solvent to obtain an acidic slurry, cooling the where Y is as defined above;
slurry to obtain a precipitate of dorzolamide salt, and recov
ering the dorzolamide salt.
Formula IV
Y
0014. In another embodiment, the present invention is
directed to a process of purifying dorzolamide salt by
dissolving the dorzolamide salt in water, adding a base until NHEt
a basic slurry is obtained, extracting the basic slurry with an
aprotic polar organic solvent, which is immiscible in water,
until two phases are obtained, separating the organic phase,
concentrating the organic phase to obtain a residue of H3C S S
dorzolamide base, cooling the residue, combining the resi /MV\,
due with an acid and with a polar aprotic organic solvent to
obtain an acidic slurry, cooling the slurry to obtain a
precipitate of dorZolamide salt, and recovering the dorZola
mide salt. and

0015. In yet another embodiment, the present invention is 0018 (c) sulfonamidating of the compound of Formula
directed to a process for the preparation of a dorzolamide IV by combining the compound of Formula IV with
salt of structural Formula I, where Y is as defined above. fuming Sulfuric acid or chlorosulfonic acid, chlorinat
US 2006/015.5132 A1 Jul. 13, 2006

ing the sulfonylated intermediate by the addition of

inorganic chlorinated agent, evaporating the inorganic
Formula I
chlorinated agent from the reaction mixture, adding a Y
polar aprotic organic solvent, adding a base, and,
afterwards, adding an acid until dorzolamide Salt com NHEt
pound of Formula I is obtained: O

0019 (d) purifying the dorzolamide salt compound of \ NH2.

Formula I; and H3C S S
O
0020 (e) recovering the dorzolamide salt compound of /MV\,
Formula I.

0021. In another embodiment, the present invention is Comprising: protecting the hydroxy group of 5,6-dihydro
directed to a process for the preparation of a dorzolamide 4-(R)-hydroxy-6-(S)-methyl-4H-thieno-2,3-bithiopyran
salt of structural Formula I, where Y is as defined above, 7,7-dioxide, having the structural Formula II

Formula II
Formula I OH
Y

NHEt
O
N s

N i NH2 S

S
H3C S O
/MV\,
with a Sulfonic acid derivative, in the presence of an organic
base and a polar aprotic organic solvent, adding an alkyl
comprising obtaining a protected compound of formula II by amine and an acid in the presence of a solvent selected from
the group consisting of a polar aprotic organic solvent, water
the method described above and converting it to a compound and a mixture thereof, adding fuming Sulfuric acid or
of formula I. chlorosulfonic acid, adding an inorganic chlorinated agent,
0022. In another embodiment, the present invention is evaporating the inorganic chlorinated agent from the reac
tion mixture, adding a polar aprotic organic solvent, adding
directed to a process for the preparation of a dorzolamide a base, afterwards adding an acid until dorzolamide Salt
salt of structural Formula I, where Y is as defined above, compound of Formula I is obtained, purifying the dorZola
mide Salt compound of Formula I and recovering the dor
Zolamide Salt compound of Formula I.
0024. In another embodiment, the present invention is
Formula I
directed to an intermediate of the dorzolamide salt having
Y the formula (formula III):
NHEt
Formula III
O
\ i NH2.
HC S S O
/MV\,

comprising obtaining a compound of formula IV by the

method described above and converting it to a compound of
formula I.

0023. In yet another embodiment, the present invention is 0025. In another embodiment, the present invention is
directed to a process for the preparation of a dorzolamide directed to an intermediate of the dorzolamide hydrochloride
salt of structural Formula I, where Y is as defined above, having the formula (formula IV):
US 2006/015.5132 A1
Formula IV
NHEt
\, H–C
HC S S
/MV\,
BRIEF DESCRIPTION OF THE DRAWING
0026 FIG. 1 illustrates the characteristic XRD pattern of
the compound of Formula IV.
DETAILED DESCRIPTION OF THE
INVENTION
0027. As used herein, the term “fuming sulfuric acid
refers to a sulfuric acid containing 10-25% free SO.
0028. The present invention provides a process for the
preparation of dorZolamide and salts thereof that uses a
chiral starting material, thus avoiding the need for an optical
resolution process to obtain the final product. The process
includes transformation of one intermediate to another in a
process that is almost one pot, hence isolation of only one
intermediate is required. Moreover, the process can be
adapted to industrial scale.
0029. In one embodiment, the present invention is
directed to a process for the preparation of a protected
derivative of Formula II, comprising: protecting the hydroxy
group of 5,6-dihydro-4-(R)-hydroxy-6-(S)-methyl-4H
thieno-2,3-bithiopyran 7,7-dioxide, having the structural
Formula II
Formula II
OH
S HC
H3C
O
S
M \,O
with a Sulfonic acid derivative, in the presence of an organic
base and a polar aprotic organic solvent, to obtain a pro
tected derivative.
0030 Preferably, the sulfonic acid derivative is arylsul
fonyl or alkylsulfonyl chloride. More preferably, the aryl
sulfonyl chloride is benzylsulfonyl chloride, tosyl chloride
or toluenesulfonyl chloride. Most preferably, the arylsulfo
nyl chloride is benzylsulfonyl chloride. When the arylsul
fonyl chloride is benzylsulfonyl, the obtained protected
compound is a compound of Formula III.
Jul. 13, 2006
Formula III
's
- O
N
Preferably, the process is performed at a temperature of up
to about 0°C. More preferably, the process is performed at
a temperature of from about -30° to about 0°C. for about
2 to about 4 hours. Preferably, the organic base is selected
from the group consisting of pyridine, triethylamine, and
N,N-diisipropylethylamine. More preferably, the organic
base is triethylamine. Preferably, the polar aprotic organic
Solvent is selected from the group consisting of acetone,
dioxane, acetonitrile, tetrahydrofuran, ethyl acetate, 2-me
thyltetrahydrofuran, and pyridine. More preferably, the polar
aprotic organic solvent is tetrahydrofuran or ethyl acetate.
After the addition of the base, the sulfonic acid derivative,
and the polar aprotic organic solvent, the reaction mixture is
stirred and triethylamine HCl salt may be obtained. Prefer
ably, the obtained triethylamine HCl salt is filtered. Follow
ing filtration, the protected compound is preferably used in
the next step of the synthesis without further processing.
0031. In another embodiment, the present invention is
directed to a process for the preparation of a compound of
Formula IV, where Y is as defined above,
Formula IV
Y
NHEt
S
S
4./V\,
comprising: aminating the protected derivative of formula II
with an alkyl amine and an acid in the presence of a solvent
selected from the group consisting of a polar aprotic organic
solvent, water and a mixture thereof, to give 5,6-dihydro
4-(S)-ethylamino-6-(S)-methyl-4H-thieno-2,3-bithiopyran
7,7-dioxide salt of Formula IV.
0032 Preferably, the amination is carried out at a tem
perature of about 20° C. to about 30° C. for about 16 hours
to about 20 hours. Preferably, the alkylamine is ethylamine.
Preferably, the acid is an organic acid or an inorganic acid.
Preferably, the organic acid is selected from the group
consisting of acetic acid, fumaric acid, and tartaric acid.
US 2006/015.5132 A1
Preferably, the inorganic acid is selected from the group
consisting of Sulfuric acid, hydrochloric acid and hydrobro
mic acid. More preferably, the inorganic acid is HC1. Pref
erably, the polar aprotic organic solvent is selected from the
group consisting of acetone, dioxane, acetonitrile, tetrahy
drofuran, ethyl acetate, 2-methyltetrahydrofuran, and pyri
dine. More preferably, the polar aprotic organic solvent is
tetrahydrofuran or ethyl acetate. Preferably, the acid is added
until a pH of about 2 to about 2.5 is obtained. Preferably, the
acid is added to the solution formed with alkyl amine and the
solvent. Preferably, the solution is heated to a temperature of
about 40° C. prior to the addition of HC1. Preferably, the
solvent is removed from the reaction mixture. Preferably, the
reaction mixture, containing alkyl amine, an acid and a
solvent, is cooled to a temperature of about -15°C. to about
10°C., more preferably, to a temperature of about -8°C.
Formula I
Y H3C
NHEt
O
N i NH2
S
HC S O
4./V\,
0033. In another embodiment, the present invention is
directed to a process for preparing dorzolamide Salt of
Formula I, where Y is as defined above comprising: sul
fonamidating of the compound of Formula IV by combining
the compound of Formula IV with fuming sulfuric acid or
chlorosulfonic acid, chlorinating the Sulfonylated interme
diate by the addition of inorganic chlorinated agent, evapo
rating the inorganic chlorinated agent from the reaction
mixture, adding a polar aprotic organic Solvent, adding a
base and afterwards adding an acid until the dorZolamide
salt compound of Formula I is obtained.
0034 Preferably, the compound of Formula IV under
goes sulfonylation at a temperature of about -10°C. to about
25°C. for about 2 to about 24 hours. Preferably, the resulting
sulfonylated intermediate is not isolated, but is used directly
in the next stage of step, which comprises chlorination of the
sulfonylated intermediate by the addition of inorganic chlo
rinated agent at a temperature of from about -10° to about
25°C. Preferably, the inorganic chlorinated agent is selected
from the group consisting of thionyl chloride, SOCl, PCls,
and POCl. The sulfonylated intermediate can be isolated by
addition of an alcohol. Such as n-butanol, and then reacted
with an inorganic chlorinated agent. Preferably, after the
addition of the inorganic chlorinated agent, the reaction
mixture is heated to a temperature of about 60° C. to about
65° C. Preferably, after the chlorination is completed, the
excess of inorganic chlorinated agent is removed from the
reaction mixture, preferably, by evaporation. Preferably, a
residue is obtained after the evaporation. Preferably, after
the evaporation of the inorganic chlorinated agent, a residue
or diluted residue is obtained. Preferably, the polar aprotic
organic solvent is selected from the group consisting of
acetone, dioxane, acetonitrile, tetrahydrofuran, ethyl acetate,
2-methyltetrahydrofuran, and pyridine. More preferably, the
polar aprotic organic solvent is tetrahydrofuran or ethyl
Jul. 13, 2006
acetate. Preferably, the base is added at a temperature of
about -15° C. to about 30C. Preferably, the residue or
diluted residue is added to the base. Preferably, the base is
an organic base or an inorganic base. Preferably, the organic
base is ammonia. Preferably, the ammonia is an aqueous
ammonia. Preferably, the inorganic base is selected from the
group consisting of NaOH, KOH, KCO, and NaCO.
Preferably, the organic solvent is removed from the reaction
mixture. Optionally, the acid is added in an alcohol Such as
ethanol. Preferably, the dorzolamide salt is dorzolamide
HC1.
Formula IV
NHEt
\, H–C
S
S
/V
O O
0035) In another embodiment, the present invention is
directed to a process of purifying dorzolamide salt by
dissolving the dorzolamide salt in water, adding a base until
a basic slurry is obtained, extracting the basic slurry with an
aprotic polar organic solvent, which is immiscible in water,
until two phases are obtained, separating the organic phase,
concentrating the organic phase to obtain a residue of
dorzolamide base, and cooling the residue.
0036 Preferably, the dorzolamide hydrochloride is dis
solved in water at a temperature of about 20°C. to about 25°
C. Preferably, the base is an organic base or an inorganic
base. Preferably, the organic base is ammonia. Preferably,
the ammonia is an aqueous ammonia. Preferably, the inor
ganic base is selected from the group consisting of NaOH.
KOH, KCO, and NaCO. Preferably, the base is added
until a pH of about 8.0 to about 8.5 is obtained. Preferably,
the aprotic polar organic solvent, which is immiscible in
water, is selected from the group consisting of isobutyl
acetate, ethyl acetate, and dichloromethane. More prefer
ably, the aprotic polar organic solvent, which is immiscible
in water, is ethyl acetate. Optionally, the concentration
continuous until a dry dorzolamide base is obtained. Option
ally, the concentration continuous until a diluted dorZola
mide base is obtained. Preferably, the residue is cooled to a
temperature of about 10° C. to about 30° C., more prefer
ably, to a temperature of about 20° C. to about 25°C.
0037. In another embodiment, the present invention is
directed to a process of purifying dorzolamide salt by
combining dorZolamide base with an acid and with a polar
aprotic organic solvent to obtain an acidic slurry, cooling the
slurry to obtain a precipitate of dorzolamide salt, and recov
ering the dorzolamide salt.
0038 Preferably, the acid is an organic acid or an inor
ganic acid. Preferably, the organic acid is selected from the
group consisting of acetic acid, fumaric acid, and tartaric
acid. Preferably, the inorganic acid is selected from the
group consisting of Sulfuric acid, hydrochloric acid and
hydrobromic acid. More preferably, the inorganic acid is
HC1. Preferably, the slurry is cooled to a temperature of
about 0° C. to about 4° C. Preferably, the cooled slurry is
US 2006/015.5132 A1
stirred for about at least 4 hours, more preferably, for about
5 hours. Preferably, the acid is added in C to C alcohol.
Preferably, the C to C alcohol is ethanol. Preferably, after
cooling the slurry, the slurry is filtered until obtaining a
precipitate. Preferably, the precipitate is recovered by wash
ing it with a polar aprotic organic solvent, and drying it at a
temperature of about 55° C. to about 60° C.
0039. In another embodiment, the present invention is
directed to a process of purifying dorzolamide salt by
dissolving the dorzolamide salt in water, adding a base until
a basic slurry is obtained, extracting the basic slurry with an
aprotic polar organic solvent, which is immiscible in water,
until two phases are obtained, separating the organic phase,
concentrating the organic phase to obtain a residue of
dorzolamide base, cooling the residue, combining the resi
due with an acid and with a polar aprotic organic solvent to
obtain an acidic slurry, cooling the slurry to obtain a
precipitate of dorZolamide salt, and recovering the dorZola
mide salt.
0040. In yet another embodiment, the present invention is
directed to a process for the preparation of a dorzolamide
salt of structural Formula I, where Y is as defined above,
Formula I
Y
NHEt
O 0046) The preferred reaction of the compound of Formula
\ NH2.
H3C S S
O derivative is arylsulfonyl or alkylsulfonyl chloride. More
/MV\,
The process comprises:
0041 (a) protecting the hydroxy group of 5,6-dihydro
4-(R)-hydroxy-6-(S)-methyl-4H-thieno-2,3-bithiopy
ran 7,7-dioxide, having the structural Formula II
Formula II
OH
N s
HC S N
with a sulfonic acid derivative, in the presence of an
organic base and a polar aprotic organic solvent, to
obtain a protected derivative;
0042 (b) aminating the protected derivative of formula
II with an alkyl amine and an organic salt in the
presence of a solvent selected from the group consist
ing of a polar aprotic organic solvent, water and a
mixture thereof, to give 5,6-dihydro-4-(S)-ethylamino
6-(S)-methyl-4H-thieno-2,3-bithiopyran 7,7-dioxide
salt of Formula IV, where Y is as defined above;
Jul. 13, 2006
Formula IV
Y
NHEt
HC S S
/MV\,
and
0043 (c) sulfonamidating of the compound of Formula
IV by combining the compound of Formula IV with
fuming Sulfuric acid or chlorosulfonic acid, chlorinat
ing the sulfonylated intermediate by the addition of
inorganic chlorinated agent, evaporating the inorganic
chlorinated agent from the reaction mixture, adding a
polar aprotic organic solvent, adding a base and after
wards adding an acid until dorzolamide salt compound
of Formula I is obtained;
0044) (d) purifying the dorzolamide salt compound of
Formula I; and
0045 (e) recovering the dorzolamide salt compound of
Formula I.
II with the sulfonic acid derivative in step (a) provides a
Sulfonic acid protecting group. Preferably, Sulfonic acid
preferably, the arylsulfonyl chloride is benzylsulfonyl chlo
ride, tosyl chloride or toluenesulfonyl chloride. Most pref
erably, the arylsulfonyl chloride is benzylsulfonyl chloride.
When the arylsulfonyl chloride is benzylsulfonyl, the
obtained protected compound is a compound of Formula III.
Formula III
S=
> O
HC S S
/\,
Step (a) is preferably performed at a temperature of up to
about 0° C. More preferably, step (a) is performed at a
temperature of from about -30° to about 0°C. for about 2
to about 4 hours. Preferably, the organic base is selected
from the group consisting of pyridine, triethylamine, and
N,N-diisipropylethylamine. More preferably, the organic
base is triethylamine. Preferably, the polar aprotic organic
Solvent is selected from the group consisting of acetone,
dioxane, acetonitrile, tetrahydrofuran, ethyl acetate, 2-me
US 2006/015.5132 A1
thyltetrahydrofuran, and pyridine. More preferably, the polar
aprotic organic solvent is tetrahydrofuran or ethyl acetate.
After the addition of the base, the sulfonic acid derivative,
and the polar aprotic organic solvent, the reaction mixture is
stirred, and the triethylamine HCl salt may be obtained.
Preferably, the obtained triethylamine HCl salt is filtered.
Following filtration, the protected compound is preferably
used in the next step of the synthesis without further
processing.
0047 Preferably, the amination in step b) is carried out at
a temperature of about 20° C. to about 30° C. for about 16
hours to about 20 hours. Preferably, the alkyl amine is ethyl
amine. Preferably, the acid is an organic acid or an inorganic
acid. Preferably, the organic acid is selected from the group
consisting of acetic acid, fumaric acid, and tartaric acid.
Preferably, the inorganic acid is selected from the group
consisting of Sulfuric acid, hydrochloric acid and hydrobro
mic acid. More preferably, the inorganic acid is HC1. Pref
erably, the polar aprotic organic solvent is selected from the
group consisting of acetone, dioxane, acetonitrile, tetrahy
drofuran, ethyl acetate, 2-methyltetrahydrofuran, and pyri
dine. More preferably, the polar aprotic organic solvent is
tetrahydrofuran or ethyl acetate. Preferably, the acid is added
until a pH of about 2 to about 2.5 is obtained. Preferably, the
acid is added to the solution formed with alkyl amine and the
solvent. Preferably, the solution is heated to a temperature of
about 40° C. prior to the addition of HC1. Preferably, the
solvent is removed from the reaction mixture. Preferably, the
reaction mixture, containing alkyl amine, an acid and a
solvent, is cooled to a temperature of about -15°C. to about
10°C., more preferably, to a temperature of about -8°C.
0.048 Preferably, in step (c), the compound of Formula
IV undergoes sulfonylation at a temperature of about -10°
C. to about 25°C. for about 2 to about 24 hours. Preferably,
the resulting sulfonylated intermediate is not isolated, but is
used directly in the next stage of step, which comprises
chlorination of the sulfonylated intermediate by the addition
of inorganic chlorinated agent at a temperature of from about
-10° to about 25° C. Preferably, the inorganic chlorinated
agent is selected from the group consisting of thionyl
chloride, SOCl, PCls, and POCl. The sulfonylated inter
mediate can be isolated by addition of an alcohol. Such as
n-butanol, and then reacted with inorganic chlorinated agent.
Preferably, after the addition of the inorganic chlorinated
agent, the reaction mixture is heated to a temperature of
about 60° C. to about 65° C. Preferably, after the chlorina
tion is completed, the excess of inorganic chlorinated agent
is removed from the reaction mixture, preferably, by evapo
ration. Preferably, a residue is obtained after the evaporation.
Preferably, after the evaporation of the inorganic chlorinated
agent, a residue or diluted residue is obtained. Preferably, the
polar aprotic organic solvent is selected from the group
consisting of acetone, dioxane, acetonitrile, tetrahydrofuran,
ethyl acetate, 2-methyltetrahydrofuran, and pyridine. More
preferably, the polar aprotic organic solvent is tetrahydro
furan or ethyl acetate. Preferably, the base is added at a
temperature of about -15°C. to about 30° C. Preferably, the
residue or diluted residue is added to the base. Preferably,
the base is an organic base or an inorganic base. Preferably,
Jul. 13, 2006
the organic base is ammonia. Preferably, the ammonia is an
aqueous ammonia. Preferably, the inorganic base is selected
from the group consisting of NaOH, KOH, KCO, and
NaCO. Preferably, the organic solvent is removed from the
reaction mixture. Optionally, the acid is added in an alcohol
such as ethanol. Preferably, the dorzolamide salt is dorzola
mide HC1.
Formula IV
NHEt
Y H-c
HC S S
/MV\,
0049. The purification in step d) of the dorzolamide salt
comprises: dissolving the dorzolamide Salt in water, adding
a base until a basic slurry is obtained, extracting the basic
slurry with an aprotic polar organic solvent, which is immis
cible in water, until two phases are obtained, separating the
organic phase, concentrating the organic phase to obtain a
residue of dorzolamide base, cooling the residue, combining
the residue with an acid and with a polar aprotic organic
Solvent to obtain an acidic slurry, cooling the slurry to obtain
a precipitate of dorzolamide salt, and recovering the dor
Zolamide salt.
0050 Optionally, the obtained dorzolamide salt may be
purified by crystallizing it from water or a mixture of
isopropyl alcohol-methanol (as described in example 1).
0051. In yet another embodiment, the present invention is
directed to a process for the preparation of a dorzolamide
salt of structural Formula I, where Y is as defined above,
0 Y
Formula I
NHEt
O
N i NH2.
HC S S O
/MV\,
Comprising: protecting the hydroxy group of 5,6-dihydro
4-(R)-hydroxy-6-(S)-methyl-4H-thieno-2,3-bithiopyran
7,7-dioxide, having the structural Formula II
US 2006/015.5132 A1
Formula II
OH
N s
S
HC
with a Sulfonic acid derivative, in the presence of an organic
base and a polar aprotic organic solvent, adding an alkyl
amine and an acid in the presence of a solvent selected from
the group consisting of a polar aprotic organic solvent, water
and a mixture thereof, adding fuming Sulfuric acid or
chlorosulfonic acid, adding an inorganic chlorinated agent,
evaporating the inorganic chlorinated agent from the reac
tion mixture, adding a polar aprotic organic solvent, adding
a base, afterwards adding an acid until dorzolamide Salt
compound of Formula I is obtained, purifying the dorZola
mide Salt compound of Formula I and recovering the dor
Zolamide Salt compound of Formula I.
0.052 The final purified dorzolamide hydrochloride pre
pared by this method does not contain more than 0.1% by
weight of the corresponding 4R,6S dorzolamide.
0053. In another embodiment, the present invention is
directed to a process for the preparation of a dorzolamide
salt of structural Formula I, where Y is as defined above,
0 Y
Formula I
NHEt
O The intermediate of formula IV may be further characterized
N i NH2
S stantially as depicted in FIG. 1. The intermediate of formula
H3C S O
/MV\,
comprising obtaining a protected compound of formula II by
the method described above and converting it to a compound
of formula I.
0054. In another embodiment, the present invention is
directed to a process for the preparation of a dorzolamide
salt of structural Formula I, where Y is as defined above,
Formula I
0 Y
NHEt
O
\ i NH2.
HC S S O
/MV\,
comprising obtaining a compound of formula IV by the
method described above and converting it to a compound of
formula I.
Jul. 13, 2006
0055. In another embodiment, the present invention is
directed to an intermediate of the dorzolamide salt having
the formula (formula III):
Formula III
Sl
- O
N
H3C S S
/\,
0056. In another embodiment, the present invention is
directed to an intermediate of the dorzolamide hydrochloride
having the formula (formula IV):
Formula IV
NHEt
N H-Cl
S
HC S
/MV\,
by a powder XRD pattern with peaks at 9.6, 12.6, 16.4, 17.1,
19.1, 21.9, 25.3, 26.1, 27.7 and 30.2+0.1 degrees 20, sub
IV may be further characterized by a "H NMR (DMSO-d)
with peaks at: 89.74 (m, 2H), 8.12 (d. 1H), 7.65 (d. 1H), 4.68
(m. 1H), 4.20 (m, 1H), 3.16 (m. 1H), 3.05 (m. 1H), 2.78 (d.
1H), 2.53 (m, 1H), 1.37 (t, 3H), and 1.30 (t, 3H). The
intermediate of formula IV may be further characterized by
a 'C NMR (DMSO-d) with peaks at: 8 139.4, 138.5, 132.7,
129.7, 52.2, 50.0, 41.4, 31.8, 11.9, and 10.9. The interme
diate of formula IV may be further characterized by MS:
M+H of 246.06. The intermediate of formula IV may be
further characterized by an IR (KBr): L. (cm) 3120, 3000
2850, 2800-2500, 1560, 1540, 1522, 1300, 1264, 1140,
750,and 710.
0057 The following non-limiting examples are merely
illustrative of the preferred embodiments of the present
invention, and are not to be construed as limiting the
invention, the scope of, which is defined by the appended
claims.
EXAMPLE 1.
0058. A compound of Formula IV, 6-dihydro-4-(S)-ethy
lamino-6-(S)-methyl-4H-thieno-2,3-bithiopyran 7,7-diox
ide hydrochloride can be synthesized according to the fol
lowing scheme.
US 2006/015.5132 A1 Jul. 13, 2006

mixture is warmed to 25°-5°C., and aged for 16 to 20 hours.

After aging, the mixture is cooled to -5°-5°C., and 300 ml
of 4 molar aqueous hydrochloric acid is added to reduce the

OH
Sull
u
pH to about 2.5, while maintaining the temperature at
-5'-t5° C. The acidified reaction mixture is then concen
trated to remove THF, and 800 ml of ethyl acetate is added.
The resulting slurry is cooled to -7°-5°C. After stirring the
N suspension at -7°-5°C. for 8 to 18 hours, the resulting solid
S THF is filtered and dried at 50° C. under vacuum. The process has
HC S been shown to provide a yield of a crude aminated inter
/\, mediate of Formula IV of 70 to 80 percent with a chromato
graphic purity of 98.5 to 99.5 percent.
O \,
\
1. 0061 The dorzolamide hydrochloride product is pre
pared from the aminated intermediate of Formula IV by the
following scheme.
N
S
H3C
O
7\
O
HN1)-
H-CI fuming
N H2SO4
0059. In the process of the invention, a solution of
4-(R)-hydroxy-5,6-dihydro-6-(S)-methyl-4H-thieno 2,3-b S S
thiopyran-7.7-dioxide, i.e., a compound of Formula II, in
THF is prepared by mixing 20 g, 91.6 mmol, of the 4\,
compound with 200 ml of anhydrous THF. The solution is
cooled to about -20°-5°C. Triethylamine in an amount of N1.
19.4 ml is then added gradually, while maintaining the O
temperature at -20°+3°C. A solution of C-toluenesulfonyl N { OH SOCl.
chloride in an amount of 21.62 g, 109.9 mmol, in 66 ml of S O
anhydrous THF is added in portions under an inert atmo
sphere, while maintaining the temperature at -18°+3° C. O
\
O
The reaction mixture is stirred for 2 to 2.5 hours, and the
resulting triethylamine hydrochloride salt is filtered under an
inert atmosphere. The cake is washed with 40 ml of cooled
in 1a
O
THF, and the combined filtrate is used immediately without
further processing in the next step of the synthesis, accord
ing to the following scheme. S
N (c. N's
S O

/\,
O
Y-1a N1.
o1 V O
O 1. EtNH2/THF
2. aq. HCI Y 4 HC
N S S \,
HC S S /\,
O
W\O HN1\
NH HCI O
N (N, HCI
N S S \,
HC S S
/\,
/\,
0062) The aminated intermediate of Formula IV, in an
0060 A 2 molar solution of ethylamine in THF in an amount of 20 g, is added in portions under an inert atmo
amount of 674 ml is added to a cold solution of the sphere to 40 ml of fuming Sulfuric acid at room temperature.
compound of Formula III prepared according to the method The reaction mixture is stirred for 2 to 3 hours at 20°-5°C.
discussed above in one portion at 0°-5° C. The resulting Thionyl chloride in an amount of 160 ml is then added in one
US 2006/015.5132 A1
portion, and the resulting mixture is refluxed for 3 to 6 hours.
Excess thionyl chloride is evaporated, and the residue is
stirred into a mixture of aqueous ammonia and THF (300
300 ml) in portions, under an inert atmosphere, while
maintaining the temperature at -5°-5°C.
0063. After stirring the reaction mixture for 75+15 min
utes, the resulting ammonium sulfate is filtered. The cake is
then washed with two 80 ml volumes of THF, the filtrate is
concentrated to remove THF, and extracted with four 300 ml
Volumes of ethyl acetate. The organic layers are combined,
concentrated to 300 ml, and stirred well, as 16 ml of
concentrated hydrochloric acid is added slowly. The slurry is
stirred for 40+15 minutes, filtered, and washed with two 40
ml volumes of ethyl acetate. The resulting white solid is
dried under vacuum at 50° C. The process has been shown
to provide a yield of crude dorzolamide HCl of 70 to 75
percent. The crude salt is recrystallized from water or a
mixture of isopropyl alcohol-methanol. The amount of the
4R,6S dorzolamide (at RRt 1.09) is lower than 0.1 percent.
0064. The sulfonylated intermediate is isolated as fol
lows: The aminated intermediate of Formula IV, in an
amount of 2 g, is added in portions under an inert atmo
sphere to 4 ml of fuming Sulfuric acid at room temperature.
The reaction mixture is stirred for 2 to 3 hours at 20°-5°C.
then stirred into 240 ml of n-butanol. After stirring the
suspension at -7°-5°C. for 8-18 hours, the resulting solid
is filtered, washed with n-butanol, and dried at 50° C. under
vacuum to give 1.80 g of the desired product in 80 percent
yield. This material can be transformed to the final dorzola
mide hydrochloride.
EXAMPLE 2
0065 Preparation of 5,6-dihydro-4-(S)-ethylamino-6-
(S)-methyl-4H-thieno-2,3-bithiopyran 7,7-dioxide hydro
chloride salt (Formula IV)
0.066 Tetrahydrofuran (501) and triethylamine (4.81) are
added to 4-(R)-hydroxy-5,6-dihydro-6-(S)-methyl-4H
thieno2.3bthiopyran-7,7-dioxide (5 Kg) and stirred under a
nitrogen atmosphere at room temperature. The solution is
cooled to -10° C. Benzylsulfonyl chloride (5.4 Kg) solved
in THF (151) is added to the DRZ-19 THF solution in
portions while maintaining the temperature below 0°C. The
feeding funnel is washed with THF (21). The reaction
mixture is stirred at 0° C. for 2-4 hours. The formed TEA
HCl is filtered and the cake is washed with THF (2x10 l)
Ethylamine in THF (30%, 63.7 l) is added to the filtrate and
the reaction mixture is stirred at 20°-25° C. for 16 hours.
Ethylamine gas prepared by heating of 70% EtNHe water
solution (50 l) is absorbed in cooled THF (301). Water (20
1) is added to the reaction mixture and THF is evaporated
from the filtrate at 40+5° C. under vacuum. The residue is
cooled to 20°-25°C., ethyl acetate (601) is added to it and
stirred vigorously. After phase separation, the organic phase
is washed with water (201). The ethyl acetate phase is heated
to 40+2° C. and hydrochloric acid (4M, -8-10 l) is added
to it during stirring to set pH 2.0-2.5. The formed slurry is
cooled to -8°+2° C. and stirred for 3 hours at this tempera
ture. The slurry is filtered, the precipitated HCl salt is
washed with ethyl acetate (30 l) and dried at 55°-60° C.
under vacuum for 4-8 hours to give the desired salt (-5 Kg).
Jul. 13, 2006
0067 Preparation of dorzolamide hydrochloride product
from the aminated intermediate of Formula IV
0068. Fuming sulfuric acid (20%, 51) is cooled to -7°+2°
C. and the aminated intermediate of Formula IV (2.5 Kg) is
added to it in portions during stirring. The temperature of the
reaction mixture is increased to 20°-5°C. during addition of
the aminated intermediate of Formula IV. The reaction
mixture is stirred for 22 hours at 20°-5°C. Thionyl chloride
(201) is added to the stirred reaction mixture at 20°-5°C.
The reaction mixture is heated to 60°-65° C. and stirred for
24 hours at this temperature. The mixture is cooled back to
40+2° C. and the excess amount of thionyl chloride is
evaporated at this temperature under vacuum. (The Volume
of the residue: -91.) The residue is cooled to -5°+2° C.
0069. Ethyl acetate (751) is cooled to -10°+5° C. and the
residue is added to it at this temperature. The temperature of
the diluted solution: 10°-25°C. Aqueous ammonia (25%, 75
1) is cooled to -10+5° C. and the residue is added to it at
this temperature during effective stirring, while maintaining
the temperature below 30° C. The final pH: -11. The slurry
is cooled to 0°-2° C. and stirred for 14 hours at this
temperature. The formed ammonium sulfate is filtered and
the cake is washed with ethyl acetate (2x20 land 101). Ethyl
acetate is evaporated from the filtrate at 38°+2° C. under
vacuum. The residue is heated to 38+2° C., washed with
toluene (3x37.51) at this temperature. Water (251) is added
to the aqueous phase, cooled to 20°-25° C. and extracted
with ethyl acetate (3x751, 37.51, and 37.51). The collected
ethyl acetate phase is concentrated to ~100 1 at 38°+2° C.
under vacuum. The residue is cooled to 20°-25° C. and
hydrogen chloride in ethanol (5%, 10.8 l) is added to it
during stirring. The formed slurry is stirred for 1 hour at
20°-25° C. then cooled to 0°-4° C. and stirred for 5 hours at
this temperature. The slurry is filtered, the precipitated HCl
salt is washed with ethyl acetate (2x20 l) and dried at
55°-60° C. under vacuum for 4-8 hours to give Dorzolamide
hydrochloride salt (-2 Kg).
0070 Crude Dorzolamide hydrochloride salt (9 Kg) is
solved in water (225 l) at 20°-25° C. and the pH is set to
8.0-8.5 by addition of 25% of aqueous ammonia (21). The
formed slurry is extracted with ethyl acetate (5x721). The
collected ethyl acetate phase is concentrated to 1801 by
vacuum distillation. The residue is cooled to 20°-25° C.,
ethyl acetate (451) and hydrogen chloride in ethanol (5%,
22.51) are added to it during stirring (pH:-1.0). The formed
slurry is stirred for 1 hour at 20°-25° C. then cooled to 0°-4°
C. and stirred for 5 hours at this temperature. The slurry is
filtered, the precipitated HCl salt is washed with ethyl
acetate (2x301), and dried at 55°-60° C. under vacuum for
4-8 hours to give purified Dorzolamide hydrochloride salt
(-8.2 Kg).
0071 Purified Dorzolamide hydrochloride salt (8 Kg)
dissolved in water (24 l) at 95°-105° C. and treated with
active carbon (80 g). After filtration, the water solution is
cooled gradually to 0-4°C. and stirred for 3-5 hours at this
temperature. The slurry is filtered, the precipitated HCl salt
is washed with cooled water (2x51) and dried at 55°-60° C.
under vacuum for 4-8 hours to give crystallized DRZ HCl
salt (-6.6 Kg).
0072 While it is apparent that the invention disclosed
herein is well calculated to fulfill the objects stated above, it
will be appreciated that numerous modifications and
US 2006/015.5132 A1
embodiments can be devised by those skilled in the art.
Therefore, it is intended that the appended claims cover all
Such modifications and embodiments as falling within the
true spirit and scope of the present invention.
What is claimed:
1. A process for the preparation of a protected compound,
comprising: protecting the hydroxy group of 5,6-dihydro
4-(R)-hydroxy-6-(S)-methyl-4H-thieno-2,3-b thiopyran
7,7-dioxide, having the structural Formula II
Formula II
OH
S
H3C S chloric acid and hydrobromic acid.
/ \,
with a Sulfonic acid derivative, in the presence of an organic
base and a polar aprotic organic solvent, to obtain a pro
tected derivative of the compound of Formula II.
2. The process of claim 1, wherein the sulfonic acid
derivative is arylsulfonyl or alkylsulfonyl chloride.
3. The process of claim 2, wherein the arylsulfonyl
chloride is benzylsulfonyl chloride, tosyl chloride or tolu
enesulfonyl chloride.
4. The process of claim 3, wherein the arylsulfonyl
chloride is benzylsulfonyl chloride.
5. The process of claim 1, wherein the process is per
formed at a temperature of up to about 0°C.
6. The process of claim 5, wherein the process is per
formed at a temperature of from about -30° to about 0°C.
7. The process of claim 1, wherein the organic base is
selected from the group consisting of pyridine, triethy
lamine, and N,N-diisipropylethylamine.
8. The process of claim 7, wherein the organic base is
triethylamine.
9. The process of claim 1, wherein the polar aprotic
organic solvent is selected from the group consisting of
acetone, dioxane, acetonitrile, tetrahydrofuran, ethyl acetate,
2-methyltetrahydrofuran, and pyridine.
10. The process of claim 9, wherein the polar aprotic
organic solvent is tetrahydrofuran or ethyl acetate.
11. A process for the preparation of a compound of
Formula IV
Formula IV
Y 23. The process of claim 21, wherein the sulfonylation is
NHEt
H3C S S
4./V\,
comprising: aminating a protected derivative of formula II,
wherein Y is an acid moiety, with an alkyl amine and an acid
in the presence of a solvent selected from the group con
Jul. 13, 2006
sisting of a polar aprotic organic Solvent, water and a
mixture thereof, to give 5,6-dihydro-4-(S)-ethylamino-6-
(S)-methyl-4H-thieno-2,3-bithiopyran 7,7-dioxide salt of
Formula IV.
12. The process of claim 11, wherein the amination is
carried out at a temperature of about 20° C. to about 30° C.
13. The process of claim 11, wherein the amination is
carried out for about 16 hours to about 20 hours.
14. The process of claim 11, wherein the alkyl amine is
ethyl amine.
15. The process of claim 11, wherein the acid is an organic
acid or an inorganic acid.
16. The process of claim 15, wherein the organic acid is
selected from the group consisting of acetic acid, fumaric
acid, and tartaric acid.
17. The process of claim 15, wherein the inorganic acid is
selected from the group consisting of Sulfuric acid, hydro
18. The process of claim 17, wherein the inorganic acid is
hydrochloric acid.
19. The process of claim 11, wherein the polar aprotic
organic solvent is selected from the group consisting of
acetone, dioxane, acetonitrile, tetrahydrofuran, ethyl acetate,
2-methyltetrahydrofuran, and pyridine.
20. The process of claim 19, wherein the polar aprotic
organic solvent is tetrahydrofuran or ethyl acetate.
21. A process for preparing dorzolamide Salt of formula I
Formula I
Y
NHEt
O
N NH2
S
HC S O
//V\,
comprising: Sulfonamidating of the compound of Formula
IV, wherein Y is an acid moiety, by combining the compound
of Formula IV with fuming sulfuric acid or chlorosulfonic
acid, chlorinating the sulfonylated intermediate by the addi
tion of inorganic chlorinated agent, evaporating the unre
acted inorganic chlorinated agent from the reaction mixture,
adding a polar aprotic organic Solvent, adding a base and
afterwards adding an acid corresponding to Y until dorZola
mide salt compound of Formula I is obtained.
22. The process of claim 21, wherein the sulfonylation is
at a temperature of about -10° C. to about 25°C.
for about 2 to about 24 hours.
24. The process of claim 21, wherein the inorganic
chlorinated agent is selected from the group consisting of
thionyl chloride, SOCl, PCls, and POCl.
25. The process of claim 21, wherein the inorganic
chlorinated agent is added at a temperature of from about
-10° to about 25° C.
26. The process of claim 21, wherein after the addition of
the inorganic chlorinated agent, the reaction mixture is
heated to a temperature of about 60° C. to about 65° C.
27. The process of claim 21, wherein the polar aprotic
organic solvent is selected from the group consisting of
US 2006/015.5132 A1
acetone, dioxane, acetonitrile, tetrahydrofuran, ethyl acetate,
2-methyltetrahydrofuran, and pyridine.
28. The process of claim 27, wherein the polar aprotic
organic solvent is tetrahydrofuran or ethyl acetate.
29. The process of claim 21, wherein the base is an
organic base or an inorganic base.
30. The process of claim 29, wherein organic base is
ammonia.
31. The process of claim 29, wherein the inorganic base
is selected from the group consisting of NaOH, KOH,
KCO, and NaCO.
32. The process of claim 21, wherein the base is added at
a temperature of about -15° C. to about 30C.
33. The process of claim 21, wherein after the addition of
the polar aprotic organic solvent, the reaction mixture is
added to the base.
34. The process of claim 21, wherein the dorzolamide salt
compound of Formula I is dorzolamide HCl, of Formula I,
Formula I
NHEt
O due with an acid and with a polar aprotic organic solvent to
N i- NH2
S
H3C S O
MVO
O H-Cl
35. A process of purifying dorzolamide salt by dissolving
the dorzolamide Salt in water, adding a base until a basic
slurry is obtained, extracting the basic slurry with aprotic
polar organic solvent, which is immiscible in water, until
two phases are obtained, separating the organic phase,
concentrating the organic phase to obtain a residue of
dorzolamide base, and cooling the residue.
36. The process of claim 35, wherein the dorzolamide
hydrochloride is dissolved in water at a temperature of about
20° C. to about 25° C.
37. The process of claim 35, wherein the base is an
organic base or an inorganic base.
38. The process of claim 37, wherein the organic base is
ammonia.
39. The process of claim 37, wherein inorganic base is
selected from the group consisting of NaOH, KOH, KCO,
and NaCO.
40. The process of claim 35, wherein the aprotic polar
organic solvent, which is immiscible in water, is selected
from the group consisting of isobutyl acetate, ethyl acetate,
and dichloromethane.
41. The process of claim 35, wherein the aprotic polar
organic solvent, which is immiscible in water, is ethyl
acetate.
42. The process of claim 35, wherein the concentration
continuous until a diluted dorzolamide base is obtained.
43. The process of claim 35, wherein the concentration
continuous until a dry dorzolamide base is obtained.
44. The process of claim 35, wherein the residue is cooled
to a temperature of about 10° C. to about 30° C.
45. A process of purifying dorzolamide Salt by combining
dorzolamide base with an acid and with a polar aprotic
organic solvent to obtain an acidic slurry, cooling the slurry
to obtain a precipitate of dorZolamide salt, and recovering
the dorzolamide salt.
Jul. 13, 2006
46. The process of claim 45, wherein the acid is an organic
acid or an inorganic acid.
47. The process of claim 46, wherein the organic acid is
selected from the group consisting of acetic acid, fumaric
acid, and tartaric acid.
48. The process of claim 46, wherein the inorganic acid is
selected from the group consisting of Sulfuric acid, hydro
chloric acid and hydrobromic acid.
49. The process of claim 48, wherein the inorganic acid is
hydrochloric acid.
50. The process of claim 45, wherein the slurry is cooled
to a temperature of about 0°C. to about 4°C.
51. The process of claim 45, wherein the acid is added in
C to C alcohol.
52. A process of purifying dorZolamide salt by dissolving
the dorzolamide Salt in water, adding a base until a basic
slurry is obtained, extracting the basic slurry with aprotic
polar organic solvent, which is immiscible in water, until
two phases are obtained, separating the organic phase,
concentrating the organic phase to obtain a residue of
dorzolamide base, cooling the residue, combining the resi
obtain an acidic slurry, cooling the slurry to obtain a
precipitate of dorZolamide salt, and recovering the dorZola
mide salt.
53. A process for the preparation of dorzolamide salt of
structural Formula I,
Formula I
Y
NHEt
: O
N i- NH2.
H3C S S
O
/MV\,
wherein Y is an acid moiety, comprising:
(a) protecting the hydroxy group of 5,6-dihydro-4-(R)-
hydroxy-6-(S)-methyl-4H-thieno-2,3-bithiopyran 7.7-
dioxide, having the structural Formula II
Formula II
OH
N
HC S
with a sulfonic acid derivative, in the presence of an
organic base and a polar aprotic organic solvent, to
obtain a protected derivative;
(b) aminating the protected derivative of formula II with
an alkyl amine and an organic salt in the presence of a
Solvent selected from the group consisting of a polar
aprotic organic solvent, water and a mixture thereof, to
US 2006/015.5132 A1
13
give 5,6-dihydro-4-(S)-ethylamino-6-(S)-methyl-4H
thieno-2,3-bithiopyran 7,7-dioxide salt of Formula IV;
Formula IV
Y selected from the group consisting of Sulfuric acid, hydro
NHEt
S
HC S sisting of acetone, dioxane, acetonitrile, tetrahydrofuran,
/MV\,
and
(c) sulfonamidating of the compound of Formula IV by
combining the compound of Formula IV with fuming
Sulfuric acid or chlorosulfonic acid, chlorinating the
sulfonylated intermediate by the addition of inorganic
chlorinated agent, evaporating the inorganic chlori
nated agent from the reaction mixture, adding a polar
aprotic organic solvent, adding a base and afterwards
adding an acid until dorzolamide Salt compound of
Formula I is obtained;
(d) purifying the dorzolamide salt compound of Formula
I; and
(e) recovering the dorzolamide Salt compound of Formula
I.
54. The process of claim 53, wherein the sulfonic acid
derivative in step (a) is arylsulfonyl or alkylsulfonyl chlo
ride.
55. The process of claim 54, wherein the arylsulfonyl
chloride is benzylsulfonyl chloride, tosyl chloride or tolu
enesulfonyl chloride.
56. The process of claim 55, wherein the arylsulfonyl
chloride is benzylsulfonyl chloride.
57. The process of claim 53, wherein step (a) is performed
at a temperature of up to about 0°C.
58. The process of claim 57, wherein step (a) is performed
at a temperature of from about -30° to about 0°C.
59. The process of claim 53, wherein the base in step (a)
is selected from the group consisting of pyridine, triethy
lamine, and N,N-diisipropylethylamine.
60. The process of claim 53, wherein the base in step (a)
is triethylamine.
61. The process of claim 53, wherein the polar aprotic
organic solvent in step (a) is selected from the group
consisting of acetone, dioxane, acetonitrile, tetrahydrofuran,
ethyl acetate, 2-methyltetrahydrofuran, and pyridine.
62. The process of claim 61, wherein the polar aprotic
organic solvent tetrahydrofuran or ethyl acetate.
63. The process of claim 53, wherein the amination in step
(b) is carried out at a temperature of about 20° C. to about
30° C.
64. The process of claim 53, wherein the amination in step
(b) is carried out for about 16 hours to about 20 hours.
65. The process of claim 53, wherein the alkyl amine in
step (b) is ethyl amine.
66. The process of claim 53, wherein the acid in step (b)
is an organic acid or an inorganic acid.
Jul. 13, 2006
67. The process of claim 66, wherein the organic acid is
selected from the group consisting of acetic acid, fumaric
acid, and tartaric acid.
68. The process of claim 66, wherein the inorganic acid is
chloric acid and hydrobromic acid.
69. The process of claim 68, wherein the inorganic acid is
HC1.
70. The process of claim 53, wherein the polar aprotic
organic solvent in step b) is selected from the group con
ethyl acetate, 2-methyltetrahydrofuran, and pyridine.
71. The process of claim 70, wherein the polar aprotic
organic solvent is tetrahydrofuran or ethyl acetate.
72. The process of claim 53, wherein the compound of
Formula IV in step (c) undergoes Sulfonylation at a tem
perature of about -10° C. to about 25° C.
73. The process of claim 53, wherein the sulfonylation in
step (c) is for about 2 to about 24 hours.
74. The process of claim 53, wherein the chlorination in
step (c) is at a temperature of from about -10° to about 25°
C.
75. The process of claim 53, wherein the inorganic
chlorinated agent in step (c) is selected from the group
consisting of thionyl chloride, SOCl, PC1, and POCl.
76. The process of claim 53, wherein after the addition of
the inorganic chlorinated agent in step c), the reaction
mixture is heated to a temperature of about 60° C. to about
650 C.
77. The process of claim 53, wherein the polar aprotic
organic solvent in step (c) is selected from the group
consisting of acetone, dioxane, acetonitrile, tetrahydrofuran,
ethyl acetate, 2-methyltetrahydrofuran, and pyridine.
78. The process of claim 77, wherein the polar aprotic
organic solvent is tetrahydrofuran or ethyl acetate.
79. The process of claim 53, wherein the base in step (c)
is an organic base or an inorganic base.
80. The process of claim 79, wherein the organic base is
ammonia.
81. The process of claim 79, wherein the inorganic base
is selected from the group consisting of NaOH, KOH,
KCO, and NaCO.
82. The process of claim 51, wherein the base in step (c)
is added at a temperature of about -15° C. to about 30° C.
83. The process of claim 53, wherein after the addition of
the polar aprotic organic solvent, the reaction mixture is
added to the base.
84. The process of claim 53, wherein the purification in
step (d) of the dorzolamide Salt comprises: dissolving the
dorzolamide Salt in water, adding a base until a basic slurry
is obtained, extracting the basic slurry with aprotic polar
organic solvent, which is immiscible in water, until two
phases are obtained, separating the organic phase, concen
trating the organic phase to obtain a residue of dorZolamide
base, cooling the residue, combining the residue with an acid
and with a polar aprotic organic solvent to obtain an acidic
slurry, cooling the slurry to obtain a precipitate of dorZola
mide salt, and recovering the dorzolamide salt.
US 2006/015.5132 A1 Jul. 13, 2006

85. A process for the preparation of dorzolamide salt of 88. An intermediate of the dorzolamide salt having the
structural Formula I, formula (formula III):

Formula I Formula III

Y

NHEt
O
\ i NH2. O
S
- =O
S
HC S O
//V\, N
wherein Y is an acid moiety, comprising: protecting the HC S S
hydroxy group of 5,6-dihydro-4-(R)-hydroxy-6-(S)-methyl /\,
4H-thieno-2,3-bithiopyran 7,7-dioxide, having the struc
tural Formula II 89. An intermediate of the dorzolamide hydrochloride
having the formula (formula IV):
Formula II
OH
Formula IV
NHEt
N
N H-C.
7\ S
O O
7\
O O

with a Sulfonic acid derivative, in the presence of an organic
base and a polar aprotic organic solvent, adding an alkyl
amine and an acid in the presence of a solvent selected from
the group consisting of a polar aprotic organic solvent, water
and a mixture thereof, adding fuming Sulfuric acid or
chlorosulfonic acid, adding an inorganic chlorinated agent,
evaporating the inorganic chlorinated agent from the reac
tion mixture, adding a polar aprotic organic solvent, adding
a base, afterwards adding an acid until dorzolamide Salt
compound of Formula I is obtained, purifying the dorZola
mide Salt compound of Formula I and recovering the dor
Zolamide Salt compound of Formula I.
86. The process of claim 1, further comprising converting
the protected compound of formula II to a compound of
formula I.
87. The process of claim 11, further comprising convert
ing the compound of formula IV to a compound of formula
I.
90. The intermediate of the dorzolamide hydrochloride of
claim 89, characterized by a powder XRD pattern with peaks
at 9.6, 12.6, 16.4, 17.1, 19.1, 21.9, 25.3, 26.1, 27.7 and
30.2+0.1 degrees 20.
91. The intermediate of the dorzolamide hydrochloride of
claim 89, having a powder XRD pattern as depicted in FIG.
1.
92. The intermediate of the dorzolamide hydrochloride of
claim 89, characterized by a "H NMR (DMSO-d) with
peaks at: 89.74 (m, 2H), 8.12 (d. 1H), 7.65 (d. 1H), 4.68 (m,
1H), 4.20 (m, 1H), 3.16 (m, 1H), 3.05 (m, 1H), 2.78 (d. 1H),
2.53 (m, 1H), 1.37 (t, 3H), and 1.30 (t, 3H).
93. The intermediate of the dorzolamide hydrochloride of
claim 89, characterized by a 'C NMR (DMSO-d) with
peaks at: 8 139.4, 138.5, 132.7, 129.7, 52.2, 50.0, 41.4, 31.8,
11.9, and 10.9.
94. The intermediate of the dorzolamide hydrochloride of
claim 89, characterized by MS: M+H of 246.06.
k k k k k