Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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PROCESSES FOR PREPARING CILOSTAZOL
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of provisional application Serial Number
60/190,588, filed March 20, 2000 and provisional application Serial Number
60/225,362,
fled August 14, 2000, both of which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to processes for preparing cilostazol.
BACKGROUND OF THE INVENTION
The present invention pertains to processes for preparing 6-[4-(1-cyclohexyl-
1H
tetrazol-5-yl)butoxy]-3,4-dihydro-2(11-quinolinone of formula (I)
H
N O
N-N
N'N ~
o (I)
which is also known by the generic name cilostazol. Cilostazol inhibits cell
platelet
aggregation and is used to treat patients with intermittent claudication.
Cilostazol is described in U.S. Patent No. 4,277,479 ("the '479 patent"),
which
teaches a preparation wherein the phenol group of 6-hydroxy-3,4-
dihydroquinolinone ("6-
HQ") of formula (II) is alkylated with a 1-cyclohexyl-5-(4-halobutyl)-
tetrazole ("the
tetrazole") of formula (III). It is recommended to use an equimolar or excess
amount up to
two molar equivalents of the tetrazole (III).
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N -N .
N,
N O (II) N X (III)
HO
The '479 patent mentions a wide variety of bases that may be used to promote
the
alkylation reaction, namely, sodium hydroxide, potassium hydroxide, sodium
carbonate,
potassium carbonate, sodium bicarbonate, potassium bicarbonate, silver
carbonate,
elemental sodium, elemental potassium, sodium methylate, sodium ethylate,
triethylamine,
pyridine, N,N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine;
1,5-diaza-bicyclo[4,3,0]-non-5-ene, 1,5-diaza-bicyclo[5,4,0]-undec-7-ene
("DBU"), and
1,4-diazabicyclo[2,2,2]octane.
The '479 patent states that the alkylation may be conducted neat or in
solvent.
Suitable solvents are said to be methanol, ethanol, propanol, butanol,
ethylene glycol,
dimethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, acetone,
methylethylketone, benzene, toluene, xylene, methyl acetate, ethyl acetate,
N,N-dimethylformamide, dimethylsulfoxide and hexamethylphosphoryl triamide.
According to Examples 4 and 26 of the '479 patent, cilostazol was prepared
using
DBU as base and ethanol as solvent.
In Nishi, T. et al. Chem. Pha~m. Bull. 193, 31, 1151-57, a preparation of
cilostazol is
described wherein 6-HQ is reacted with 1.2 molar equivalents of 5-(4-
chlorobutyl)-1-
cyclohexyl-1H-tetraazole ("CHCBT," tetrazole III wherein X=Cl) in isopropanol
with
potassium hydroxide as base. Cilostazol was obtained in 74% yield.
One reason for using an excess of tetrazole as was done in Nishi et al. and
recommended by the '479 patent is that CHCBT is unstable to some bases. When
exposed
to an alkali metal hydroxide in water for a sufficient period, CHCBT undergoes
elimination and cyclization to yield byproducts (IV) and (V).
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N-N
N. \ / N_N
N,
N (IV) N CV)
Nishi et al.'s reported yield is based upon the limiting reagent 6-HQ. The
yield with
respect to CHCBT is 69 %. In the economics of producing a chemical on a large
scale,
improvements in chemical yield are rewarded with savings in the chemical's
production
cost. CHCBT is an expensive compound to prepare and should not be wasted. It
would
be highly desirable to be able to realize further improvement in yield of the
alkylation of
6-HQ with CHCBT and its halogen analogs in a way that lowers the cost of
producing
cilostazol. In other words, it would be desirable to further improve the yield
of cilostazol
by increasing the degree of conversion of CHCBT to cilostazol, as opposed to,
for
example, improving the yield calculated from 6-HQ by increasing the excess of
tetrazole
or manipulating the reaction conditions in a way that increases the conversion
of 6-HQ to
cilostazol but at the expense of poorer conversion of CHCBT to cilostazol.
Although CHCBT is unstable to hydroxide ion, it is relatively stable in the
presence
of non-nucleophilic organic bases. There are advantages to using inorganic
bases,
however, that favor their selection over organic bases. Firstly, the phenolic
proton of 6-
HQ is labile. Thus, relatively non-caustic and easily handled inorganic bases
may be used
to prepare cilostazol. Further, inorganic bases are easier to separate from
the product and
are less toxic to the environment when disposed than organic bases are.
Therefore, it
would also be highly desirable to use an inorganic base while realizing an
improvement in
conversion of CHCBT to cilostazol.
SUMMARY OF THE INVENTION
The present invention provides improved processes for preparing cilostazol (I)
by
alkylating the phenol group of 6-HQ with the ~ carbon of a 5-(4-halobutyl)-1-
cyclohexyl-
1 H-tetrazole.
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In a first aspect, the invention provides a process wherein 6-HQ and a water
soluble
base are dissolved in water A 1-cyclohexyl-5-(4-halobutyl)-tetrazole is
dissolved in a
water-immiscible organic solvent. The two solutions are combined in the
presence of a
quaternary ammonium salt phase transfer catalyst to foam a biphasic mixture in
which the
6-HQ and tetrazole react to produce cilostazol. The process may be practiced
by a variety
of procedures taught by the present invention. In one variation, a reaction
promoter, like
sodium sulfate, is added to accelerate phase transfer of 6-HQ into the organic
solvent.
Another aspect of the present invention provides a preparation of cilostazol
from a
single phase reaction mixture of 6-HQ and a 1-cyclohexyl-5-(4-halobutyl)-
tetrazole and a
mixture of inorganic bases. The base mixture comprises an alkali metal
hydroxide and
alkali metal carbonate. This process minimizes decomposition of the starting
tetrazole and
cilostazol by buffering the pH which results in improved yield calculated
based upon the
tetrazole, the more precious of the two organic starting materials. A
preferred embodiment
wherein the alkali metal hydroxide is added portionwise minimizes the
formation of
dimeric byproducts. In another preferred embodiment of the homogeneous
process, the
reaction mixture is dehydrated with molecular sieves before the tetrazole is
added.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparing cilostazol (I) by
alkylating the
phenol group of 6-HQ with the b carbon of a 5-(4-halobutyl)-1-cyclohexyl-1H-
tetrazole
("the tetrazole"). The transformation itself, depicted in Scheme 1 is known.
S cheme 1
H H
~X HO'~~y~ Ba~ of
N N
c~~n can cn
The present invention improves upon processes previously used to perform the
chemical transformation depicted in Scheme 1 which result in a greater
conversion of the
tetrazole starting material to cilostazol. The improvements may be viewed as
falling into
one of two aspects of the present invention: (1) a heterogeneous, or biphasic,
process
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employing phase transfer catalysis and improvements applicable to the
heterogeneous
process and (2) improvements applicable to a homogeneous process.
In a first aspect, the present invention provides a biphasic process for
preparing
cilostazol by alkylating the phenol group of 6-HQ with a 5-(4-halobutyl)-1-
cyclohexyl
1H-tetrazole using controlled phase transfer methodology. For a discussion of
the theory
and general application of phase transfer catalysis, See, Dehmlow, E.V.;
Dehmlow, S.S.,
Phase Tf~ahsfer Catalysis 3rd ed. (VCH Publishers: New York 1993).
According to the present inventive process, a solution of 6-HQ, a water-
soluble base
and a trialkyl ammonium phase transfer catalyst in water is contacted with a
solution of a
5-(4-halobutyl)-1-cyclohexyl-1H-tetrazole in a water-immiscible organic
solvent for a
period of time sufficient to cause the tetrazole to be substantially
completely converted to
cilostazol and then separating the cilostazol from the biphasic mixture.
The biphasic reaction mixture separates the base from the base sensitive
tetTazole.
Although not intending to be bound by any particular theory, it is believed
that the 6-HQ
phenolate anion complexes with the tetra-alkyl ammonium ion which increases
its
solubility in the water-immiscible organic solvent. The complexed phenolate
then enters
the water-immiscible phase and reacts with the tetrazole there.
Suitable phase transfer catalysts are ammonium salts such as
tricaprylylmethylammonium chloride (Aliquat~ 336) , tetra-n-butylammonium
bromide
("TBAB"), benzyltriethylammonium chloride ("TEBA"), cetyltrimethylammonium
bromide , cetylpyridinium bromide, N-benzylquininium chloride, tetra-n-
butylammonium
chloride, tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide,
tetra-ethylammonium chloride, benzyltributylammonium bromide,'
benzyltriethylammonium bromide, hexadecyltriethylammonium chloride,
tetramethylammonium chloride, hexadecyltrimethyl ammonium chloride, and
octyltrimethylammonium chloride. More preferred phase transfer catalysts are
Aliquat~
336, TBAB, TEBA and mixtures thereof, the most preferred being Aliquat~ 336.
The
phase transfer catalyst may be used in a stoichiometric or substoichiometric
amount,
preferably from about 0.05 to about 0.25 equivalents with respect to the
tetrazole.
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Suitable bases are soluble in water but poorly soluble or insoluble in water-
immiscible
organic solvents. Such bases are typically metal salts of inorganic
counterions. Preferred
inorganic bases are hydroxide and carbonate salts of alkali metals. More
preferred
inorganic bases are NaOH, KOH, KZCO3, Na2CO3 and NaHC03. The most preferred
inorganic base in the heterogeneous process is NaOH.
The halogen atom of 5-(4-halobutyl)-1-cyclohexyl-1H-tetrazole (X in formula
III)
may be chlorine, bromine ox iodine, preferably chlorine. Although the
tetrazole may be
used in any amount desired, it is most desirable to use a stoichiometric
amount of tetrazole
or less relative to 6-HQ, more preferably about 0.9 molar equivalents.
Prefewed water-immiscible solvents are toluene, hexanes, dichloromethane and
mixtures thereof. An excess of water to water-immiscible solvent is preferred,
although
the ratio may vary widely. Preferred ratios of water to water-immiscible
solvent range
from about 0.5:1 to about 8:1 (v/v), rnore preferably fi om about 1:1 to about
6:1.
According to one preferred procedure for preparing cilostazol, the 6-HQ, water-
soluble base and phase transfer catalyst are dissolved in water. The tetrazole
is dissolved
in the water-immiscible solvent and the two solutions are contacted and
agitated, with
optional heating, until the tetrazole is substantially consumed. Cilostazol
may be isolated
by cooling the reaction mixture to precipitate the cilostazol and then
filtering or decanting
the solutions. Cilostazol may be purified by methods shown in Table 1 or any
conventional method known in the art.
Alternatively, a biphasic mixture of the water-miscible organic solvent and
the
aqueous solution of 6-HQ, water-soluble base and the phase transfer catalyst
is mixed and
optionally heated while the tetrazole is slowly added to the stirred mixture.
The slow
addition of the tetrazole may be either continuous or portionwise.
In yet another alternative procedure, an aqueous suspension of 6-HQ and the
phase
transfer catalyst are contacted with the solution of tetrazole in the water-
immiscible
organic solvent. The biphasic mixture is agitated and optionally heated; while
the water-
soluble base is slowly added to the mixture. The slow addition may be either
continuous
as in a concentrated aqueous solution of the base or portionwise.
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Each of these preferred procedures may be modified to take advantage of a
further
improvement which is to add a reaction promoter to the aqueous phase. Reaction
promoters are salts like sodium sulfate and potassium sulfate that increase
the ionic
strength of aqueous solutions but do not form strongly acidic or basic aqueous
solutions.
The reaction promoters decrease the solubility of 6-HQ in the aqueous phase
and improve
the efficiency of phase transfer to the organic phase. The preferred reaction
promoter is
sodium sulfate. Preferably, the reaction promoter is added in the amount of
about 12-16%
(w/v) with respect to the aqueous phase.
In a second aspect, the present invention provides a process for preparing
cilostazol by
alkylating the phenol group of 6-HQ with a 5-(4-halobutyl)-1-cyclohexyl-1H-
tetrazole in a
single liquid phase reaction mixture. 6-HQ and the tetrazole may be used in
any amount,
though it is preferred that the tetrazole be the limiting reagent, preferably
used in from
about 0.9 to about 0.99 equivalents with respect to the 6-HQ. Suitable
solvents for
forming the single liquid phase reaction mixture of this aspect of the
invention are non-
aqueous hydroxylic solvents, which include 1-butanol, isopropanol, 2-butanol
and amyl
alcohol.
In this process, two inorganic bases are used to catalyze the reaction. One of
the bases
is an alkali metal hydroxide such as sodium or potassium hydroxide. The other
base is an
alkali metal carbonate such as sodium or potassium carbonate. The most
preferred alkali
metal is potassium. Thus, preferred base mixtures are mixtures of potassium
hydroxide
and potassium carbonate. The alkali metal hydroxide is preferably used in an
amount of
from about 0.9 to about 1.2 equivalents with respect to the 6-HQ and the
alkali metal
carbonate is preferably used in an amount of about 0.1 to about 0.2
equivalents with
respect to the 6-HQ.
The 6-HQ, tetrazole, alkali metal hydroxide and alkali metal carbonate may be
added
to the non-aqueous solvent in any order desired and at any rate desired.
In one preferred procedure, 6-HQ, the tetrazole and the alkali metal carbonate
are
added to the hydroxylic solvent along with a portion, e.g. about a one-fourth
portion, of
the alkali metal hydroxide. Thereafter, the remainder of the alkali metal
hydroxide is
added portionwise to the reaction mixture. It has been found that portionwise
addition of
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the alkali metal hydroxide suppresses a byproduct that forms by the
substitution of the
halogen of the tetrazole by the 6-HQ lactam nitrogen.
Molecular sieves may be used to remove water from the single liquid phase
reaction
mixture before the tetrazole is added. Three and four angstrom molecular
sieves are
preferred, with three angstrom sieves being most preferred. The molecular
sieves may be
stiiTed with the solution to remove water formed by deprotonation of 6-HQ by
KOH or
adventitious water. Preferably, the molecular sieves are placed in a soxlet
extraction
funnel, the reservoir of a dropping funnel, or other suitable apparatus
mounted on the
reaction vessel that will allow circulation of vapor through the molecular
sieves and return
of the condensate to the reaction vessel. The solution is then refluxed to
circulate water
vapor over the molecular sieves. After the solution of 6-HQ phenolate has been
dehydrated, the tetrazole is added to the solution to react with the 6-HQ
phenolate to
produce cilostazol.
In the process of Nishi et al., it was necessary to separate unreacted
starting materials
and the organic base by column chromatography. It is desirable in a large
scale process to
avoid chromatography and concomitant production of spent solid phase. We have
further
discovered that cilostazol prepared according to the teachings of the present
invention or
by other methods can be selectively crystallized from certain solvents in high
purity
without the need for "clean up" chromatography to remove, for example,
unreacted
starting materials. Suitable recrystallization solvents are 1-butanol,
acetone, toluene,
methyl ethyl ketone, dichloromethane, ethyl acetate, methyl t-butyl ether,
dimethyl
acetamide-water mixtures, THF, methanol, isopropanol, benzyl alcohol, 2-
pyrrolidone,
acetonitrile, Cellosolve, monoglyme, isobutyl acetate, sec-butanol, tent-
butanol, DMF,
chloroform, diethyl ether and mixtures thereof.
The invention will now be further illustrated with the following examples.
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EXAMPLES
Example 1
Preparation of Gilostazol Using A Phase Transfer Catal.~
A 1 L reactor was charged with 6-HQ ( 16.5 g, 0.1011 moles), and NaOH (1 eq.)
in
water (90m1). To this solution was add toluene (15 ml) and CHCBT (22.22 g,
0.0915
moles), NaaS04 (17 g) and catalyst (1.9 g ) (aliquat 336). The mixture was
heated to
reflux for 8 h. After this period of time, the mixture was cooled to room
temperature, the
solid was filtered and washed with water and methanol to afford the crude
product (29 g,
yield 88%; purity by HPLC ~99%).
Example 2
Preparation of Cilostazol with Addition of CHCBT in One Portion
6-HQ (10 g, 0.0613 moles), KOH (4.05 g, 0.0722 moles), KZCO3 (1.5 g, 0.011
mole),
CHCBT (18 g, 0.0742 moles) and n-BuOH (130 ml) were heated at reflux for ~5
hours.
After cooling of the reaction mixture to room temperature the solid was
filtered, washed
with n-BuOH and water. The crude product (19.7 g, 85% yield) was
recrystallized from n-
BuOH (10 vol.) to give cilostazol crystals (yield 94%).
Example 3
Preparation of Cilostazol by Addition of The Base in Portions
6-HQ (10 g, 0.0613 moles), KOH (1.01 g, 0.018 mole), KZC03 (1.5 g, 0.011 mole)
,
CHCBT (13.4 g, 0.0552 moles) and 130 ml n-BuOH were heated at reflux for
lhour. After
1 hour, a second 1.1 g portion of KOH was added and the reflex was continued.
The
procedure was repeated with two additional 1.1 g portions of KOH. After the
addition of
the whole KOH the reaction was continued for an additional hour. The reaction
mixture
was cooled to room temperature, the solid was f ltered and washed with n-BuOH
and dried
to afford the product ( 15.6 g, 56 %yield).
Example 4
Preparation of Cilostazol Using Molecular Sieves as Dehydratin;~Agent
A three neck flask equipped with condenser and a soxlet extraction funnel
containing
molecular sieves 3~ (28 g) was charged with 6-HQ (10 g, 0.0613 moles) , KOH
(4.05 g,
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0.0722 moles) and KZC03 (1.5 g, 0.011 moles) and 130 ml n-BuOH. The mixture
was
heated to reflux and the reflux was maintained passing the solvent over the
molecular
sieves. After 30 minutes, CHCBT (18 g, 0.0742 moles, 1.2 equivalents) was
added and the
reflux was continued for about Sh. Then, the reaction mixture was cooled and
the product
was filtered and washed with n-BuOH. The yield after drying was 14.4 g (62%).
Example 5
Pret~aration of Cilostazol Using an Excess of 6-HQ
6-HQ (10 g, 0.0613 moles), KOH (4.05 g, 0.0722 moles), KZC03 (1.5 g, 0.011
mole),
CHCBT (13.4 g, 0.0552 moles) and 130 ml n-BuOH were heated at reflux for 5
hours.
After cooling of the reaction mixture to room temperature the solid was
filtered and
washed with n-BuOH and water; the material was dried to give the product
cilostazol
(15.93 g, 76.2% yield).
Examples 6-28
Table 1 provides conditions for selectively crystallizing cilostazol from
mixtures
containing minor amounts of 6-HQ and CHCBT. Cilostazol is obtained with small
particle size and narrow particle size distribution.
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Table 1
Example Solvent Volume'Recommended Procedure
6 n-BuOH 10
7 n-BuOH 20
8 Acetone 20 Slurry. Reflex. Cool to r.t.
9 Toluene 20 Dissolve at reflex. Cool
to r.t.
Methyl etlryl 11 Dissolve at reflex. Cool
ketone to r.t.
11 CHZC12 4 Dissolve at reflex. Cool
to r.t.
12 Ethyl acetate 10 Slurry at reflex 1h. Cool
to r.t.
10 13 MTBE 10 Slurry at reflex 1h. Cool
to r,t,
14 2:1 DMA-H20 10 Dissolve in DMA at ~70-80C.
Add water.
Cool to r.t. Precipitate
at 65C
THF 13 Dissolve at reflex. Cool
to r.t.
16 Methanol 3 Dissolve at reflex. Cool
to r.t..
Precipitate at 55C
17 Acetone 2.5 Slurry at reflex for 1 h.
Cool to r.t.
15 18 Ethanol 12.5 Dissolve at reflex. Cool
to r.t.
19 Isopropanol 19 Dissolve at reflex. Cool
to r.t.
Acetone 33 Dissolve at reflex. Cool
to 40C
21 Benzyl alcohol 2 Dissolve at 55C. Cool to
r.t.
22 2-Pyrrolidone 3.5 Dissolve at 65C. Cool to
r.t.
20 23 Acetonitrile 6.5 Dissolve at reflex. Cool
to 30C
24 2-BuOH 5 Dissolve at ~ 90C. Cool to
r.t.
Cellosolve 3 Dissolve at 100C. Cool to
r.t.
26 Monoglyme 13 Dissolve at reflex. Cool
to r.t.
27 iso-butyl-acetate23 Dissolve at reflex (115C).
Cool to r.t.
25 28 n-BuOH 20 Dissolve at reflex. Treat
with decolorizing
agents, (SXl activated carbon
and tonsil
silicate). Cool to r.t.
' Relative
to the volume
of cilostazol
It should be understood that some modification, alteration and substitution is
anticipated and expected from those skilled in the art without departing from
the teachings
of the invention. Accordingly, it is appropriate that the following claims be
construed
broadly and in a manner consistent with the scope and spirit of the invention.
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