U.S. patent application number 11/485714 was filed with the patent office on 2006-11-09 for preparation of candesartan cilexetil.
Invention is credited to Ben-Zion Dolitzky, Marina Yu Etinger, Boris Fedotev.
Application Number | 20060252939 11/485714 |
Document ID | / |
Family ID | 34468494 |
Filed Date | 2006-11-09 |
United States Patent
Application |
20060252939 |
Kind Code |
A1 |
Etinger; Marina Yu ; et
al. |
November 9, 2006 |
Preparation of candesartan cilexetil
Abstract
The invention encompasses processes for the synthesis of
cilexetil trityl candesartan from the reaction of trityl
candesartan with cilexetil halide in the presence of a base and a
low boiling organic solvent. Optionally, the reaction may be
conducted in the presence of a phase transfer catalyst.
Inventors: |
Etinger; Marina Yu; (Nesher,
IL) ; Fedotev; Boris; (Haifa, IL) ; Dolitzky;
Ben-Zion; (Petach Tiqva, IL) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
34468494 |
Appl. No.: |
11/485714 |
Filed: |
July 12, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10968710 |
Oct 18, 2004 |
7098342 |
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11485714 |
Jul 12, 2006 |
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60512566 |
Oct 16, 2003 |
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60523524 |
Nov 18, 2003 |
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60537995 |
Jan 21, 2004 |
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60568649 |
May 5, 2004 |
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Current U.S.
Class: |
548/253 |
Current CPC
Class: |
C07D 403/10
20130101 |
Class at
Publication: |
548/253 |
International
Class: |
C07D 403/02 20060101
C07D403/02 |
Claims
1-18. (canceled)
19. A method of synthesizing cilexetil candesartan comprising:
reacting cilexetil trityl candesartan with at least one organic
acid to form cilexetil candesartan in at least one organic solvent;
and isolating the crude cilexetil candesartan.
20. The method according to claim 19, further comprising
neutralizing the excess acid in the reaction mixture with at least
one base, before isolating the crude cilexetil candesartan.
21. The method according to claim 19, further comprising adding
mineral acid.
22. The method according to claim 19, wherein the organic acid is
selected from the group consisting of: methanesulfonic acid, formic
acid, pyridine p-toluene sulphonic acid, trifluoroacetic acid,
trichloroacetic acid, or acetic acid.
23. The method according to claim 19, wherein the method is carried
out at a reaction temperature of about 15.degree. C. to about
60.degree. C.
24. The method according to claim 19, wherein the organic solvent
is substantially dry.
25. The method according to claim 24, wherein the substantially dry
organic solvent has less than about 3% by weight of water.
26. The method according to claim 25, wherein the substantially dry
organic solvent has less than about 0.5% by weight of water.
27. The method according to claim 19, wherein the substantially dry
organic solvent is an C.sub.1-C.sub.4 alkyl alcohol, ketone, ether,
hydrocarbon, or chlorinated solvent.
28. The method according to claim 27, wherein the substantially dry
organic solvent is dichloromethane, methanol, toluene, or
tert-butyl methyl ether.
29. The method according to claim 19, wherein more than one solvent
is used.
30. The method according to claim 29, wherein the ratio of first to
second solvents is from about 1:10 to about 10:1.
31. The process according to claim 20, wherein the base is at least
one of triethylamine, diisopropylethylamine, pyridine,
N,N-dimethylaniline, N-methyl-morpholine, 4-dimethylaminopyridine,
1,5-diazabicyclo-[4.3.0]non-5-ene (DBN),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
1,4-diazabicyclo[2.2.2]octane (DABCO) or NaOH.
32. The process according to claim 31, wherein the base is
NaOH.
33. A method of synthesizing cilexetil candesartan comprising:
reacting cilexetil trityl candesartan with methanol to form
cilexetil candesartan; and isolating the crude cilexetil
candesartan.
34. The method of claim 33, wherein the reaction takes place
without an acid.
35. A method of synthesizing cilexetil candesartan without an acid
comprising: deprotecting cilexetil trityl candesartan to form
cilexetil candesartan.
36. The method of claim 35, further comprising crystallizing the
cilexetil candesartan.
37. The process according to claim 33, further comprising adding at
least one organic solvent.
38. The process according to claim 33, further comprising adding
water.
39. The process according to claim 33, wherein the process is
carried out at a reaction temperature of about 30.degree. C. to
about 90.degree. C.
40. The process according to claim 39, wherein the process is
carried out at a reaction temperature of about 50.degree. C. to
about 90.degree. C.
41. (canceled)
42. The method according to claim 19 further comprising
crystallizing the crude candesartan cilexetil in a solvent system
to obtain crystalline candesartan cilexetil.
43. The method according to claim 42, wherein the solvent system is
C.sub.1-C.sub.6 alcohol and aromatic compound.
44. The method according to claim 43, wherein the C.sub.1-C.sub.6
alcohol is selected from the group consisting of: methanol,
ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol,
1-pentanol, 2-pentanol and 3-pentanol.
45. The method according to any of claim 44, wherein the
C.sub.1-C.sub.6 alcohol is methanol.
46. The method according to claim 43, wherein the aromatic compound
is selected from the group consisting of: benzene, toluene,
ethyltoluene, xylene or mesitylene.
47. The method according to claim 46, wherein the aromatic compound
is toluene.
48. The method according to claim 43, wherein ratio the between the
C.sub.1-C.sub.6 alcohol to the aromatic compound is from about 20%
to about 80% by weight.
49. The method according to claim 48, wherein ratio the between the
C.sub.1-C.sub.6 alcohol to the aromatic compound is from about 10%
to about 90% by weight.
50. The method according to claim 49, wherein ratio the between the
C.sub.1-C.sub.6 alcohol to the aromatic compound is from about 5%
to about 95% by weight.
51. The method according to claim 43, further comprising
recrystallizing the crystalline candesartan cilexetil in a solvent
to obtain pure candesartan cilexetil.
52. The method according to claim 51, wherein the solvent is a
C.sub.1-C.sub.6 alcohol.
53. The method according to claim 52, wherein the C.sub.1-C.sub.6
alcohol is selected from the group consisting of: methanol,
ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol,
1-pentanol, 2-pentanol and 3-pentanol.
54. The method according to claim 51, further comprising drying the
pure candesartan cilexetil.
55-61. (canceled)
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Nos. 60/512,566, filed on Oct. 16, 2003; 60/523,524,
filed on Nov. 18, 2003; 60/537,995, filed on Jan. 21, 2004; and
60/568,649, filed on May 5, 2004.
FIELD OF THE INVENTION
[0002] The present invention encompasses preparation of candesartan
trityl cilexetil. The present invention also encompasses
preparation of candesartan cilexetil by the deprotection of
cilexetil trityl candesartan (TCC) using at least one organic
solvent and/or at least one organic acid. The present invention
encompasses crystallizing and recrystallizing the candesartan
cilexetil.
BACKGROUND OF THE INVENTION
[0003] Candesartan is a potent, long-acting, selective AT.sub.1
subtype angiotensin II receptor antagonist. Candesartan meets the
requirement of high potency but it is poorly absorbed by the body
when administered orally. To overcome the poor absorption, the
prodrug candesartan cilexetil was developed. During absorption in
the gastrointestinal tract candesartan cilexetil is rapidly and
completely hydrolyzed to candesartan. The chemical name for
candesartan is:
2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole--
7-carboxylic acid. The chemical name for candesartan cilexetil is
(.+-.)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-1-[[2'-(1H-tetrazol-
-5-yl) 1,1'biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate.
Candesartan cilexetil is a white to off-white powder and is
sparingly soluble in water and in methanol. Although candesartan
cilexetil contains an asymmetric center in the ester portion of the
molecule, candesartan cilexetil is sold as the racemic mixture.
##STR1##
[0004] Angiotensin II is formed from angiotensin I in a reaction
catalyzed by angiotensin-converting enzyme (ACE, kininase II).
Angiotensin II is the principal pressor agent of the
renin-angiotensin system, with effects that include
vasoconstriction, stimulation of synthesis and release of
aldosterone, cardiac stimulation, and renal reabsorption of sodium.
Angiotensin II helps maintain constant blood pressure despite
fluctuations in a person's state of hydration, sodium intake and
other physiological variables. Angiotensin II also performs
regulatory tasks such as inhibiting excretion of sodium by the
kidneys, inhibiting norephedrin reuptake, and stimulating
aldosterone biosynthesis. Candesartan blocks the vasoconstrictor
and aldosterone secreting effects of angiotensin II by selectively
blocking the binding of angiotensin II to the AT.sub.1 receptor in
many tissues, such as vascular smooth muscle and the adrenal gland.
By inhibiting angiotensin II binding to AT.sub.1 receptors,
candesartan disrupts the vasoconstriction mediated by AT.sub.1
receptors. Blocking vasoconstriction by angiotensin II has been
found to be beneficial to patients with hypertension. The United
States Food and Drug Administration has approved candesartan for
the treatment of hypertension alone or in combination with other
antihypertensive agents.
[0005] U.S. Pat. No. 5,196,444 discloses working Example 7,
1-[[(cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)
1,1'biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate was formed
by reacting
2-ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]me-
thyl]benzimidazole-7-carboxylic acid in DMF with
cyclohexyl-1-iodoethyl carbonate to form cilexetil trityl
candesartan and deprotecting with a methanolic hydrochloric acid to
form candesartan cilexetil.
[0006] U.S. Pat. No. 5,578,733, discloses the deprotection of
cilexetil trityl candesartan using mineral acids under
substantially anhydrous conditions.
SUMMARY OF THE INVENTION
[0007] One embodiment of the invention encompasses processes for
preparing cilexetil trityl candesartan comprising reacting trityl
candesartan, cilexetil halide and at least one base in a low
boiling organic solvent to form cilexetil trityl candesartan; and
isolating cilexetil trityl candesartan. The process may further
comprise adding at least one phase transfer catalyst.
[0008] In a preferred embodiment of the invention, in the process
for preparing cilexetil trityl candesartan, the low boiling organic
solvent has a boiling point of less than about 140.degree. C.
[0009] Process for preparing cilexetil candesartan comprises the
step of preparing cilexetil trityl candesartan comprising reacting
trityl candesartan, cilexetil halide and at least one base in a low
boiling organic solvent to form cilexetil trityl candesartan.
[0010] Another embodiment of the invention encompasses methods of
synthesizing cilexetil candesartan comprising providing cilexetil
trityl candesartan; reacting cilexetil trityl candesartan with at
least one organic acid to form cilexetil candesartan in at least
one organic solvent; and isolating the crude cilexetil
candesartan.
[0011] One embodiment of the invention encompasses method for
synthesizing cilexetil candesartan comprising providing cilexetil
trityl candesartan; mixing cilexetil trityl candesartan in the
presence of methanol without an acid; and isolating the crude
cilexetil candesartan.
[0012] Another embodiment of the invention encompasses
crystallizing the crude candesartan cilexetil using a solvent
system having at least two solvents to obtain a crystalline
candesartan cilexetil; and recrystallizing the crystalline
candesartan cilexetil.
DETAILED DESCRIPTION OF THE INVENTION
[0013] One embodiment of the invention encompasses processes for
the synthesis of cilexetil trityl candesartan from the reaction of
trityl candesartan with cilexetil halide in the presence of a base
and a low boiling organic solvent. Optionally, the reaction may be
conducted in the presence of a phase transfer catalyst. Preferably,
the cilexetile halide is cilexetil chloride. Another embodiment of
the invention encompasses methods of deprotecting cilexetil trityl
candesartan into cilexetil candesartan using at least one organic
acid in the presence of a substantially dry organic solvent,
optionally with addition of water. Another embodiment of the
invention encompasses methods of deprotecting cilexetil trityl
candesartan into cilexetil candesartan using at least one inorganic
acid in the presence of an aqueous solvent. Another embodiment of
the invention encompasses methods of deprotecting cilexetil trityl
candesartan into cilexetil candesartan in the presence of methanol
without an acid. Optionally, the process may further comprise the
crystallization and recrystallization of cilexetil candesartan.
[0014] Typically, the process for the synthesis of cilexetil trityl
candesartan comprises reacting trityl candesartan, cilexetil
halide, and at least one base in a low boiling organic solvent for
a sufficient time and at a sufficient temperature and isolating
cilexetil trityl candesartan. Preferably, the cilexetil halide is
cilexetil chloride. The process advantageously uses a low boiling
point organic solvent which is easier to remove from the product
mixture and environmentally safer than solvents previously used in
the synthesis. Not to be limited by theory, however, it is believed
that in some of the processes of the invention, the base may be
insoluble in the low boiling organic solvent and a two-phase system
may be formed. Because the reaction may occur at the interface
between the two phases, the rate of such an interfacial reaction
may be greatly increased by use of a phase transfer catalyst
(PTC).
[0015] The solvents used in the process are solvents with a low
boiling point. Typically, a low boiling organic solvent has a
boiling point of less than about 140.degree. C. and preferably a
boiling point of less than about 120.degree. C. Alternatively, the
low boiling organic solvent is a pharmaceutically acceptable low
boiling point organic solvent having a boiling point from about
140.degree. C. to about 70.degree. C., and preferably a boiling
point from about 120.degree. C. to about 80.degree. C. Typically,
the solvents include, but are not limited to, at least one of
hydrocarbon aliphatic solvents, aromatic solvents, or ethers. In a
preferred embodiment, one solvent may be acetonitrile, which has a
boiling point of 81.degree. C. to 82.degree. C., or toluene, which
has a boiling point of 110.degree. C. In contrast, the solvents
used in the prior art, such as dimethylforamide, has a boiling
point of 153.degree. C. However, if DMF is used in the reaction of
the invention, then the reaction temperature may be from about
50.degree. C. to about 55.degree. C. and not the reflux
temperature.
[0016] The base in the reaction may be at least one of an inorganic
base or an organic base. Inorganic bases used in the reaction
include, but are not limited to, lithium hydroxide, sodium
hydroxide, potassium hydroxide, cesium hydroxide, lithium
carbonate, sodium carbonate, potassium carbonate, cesium carbonate,
lithium hydrogen carbonate, sodium hydrogen carbonate, potassium
hydrogen carbonate, and silver carbonate. Organic bases used in the
reaction include, but are not limited to, triethylamine,
diisopropylethylamine, pyridine, N,N-dimethylaniline,
N-methyl-morpholine, 4-dimethylaminopyridine,
1,5-diazabicyclo-[4.3.0]non-5-ene (DBN),
1,8-diazabicyclo[5.4.0]undec-1-ene (DBU), or
1,4-diazabicyclo[2.2.2]octane (DABCO). Preferably, the base is
potassium carbonate.
[0017] Several classes of compounds are known to be capable of
acting as phase transfer catalysts, for example quaternary ammonium
compounds and phosphonium compounds, to mention just two. Phase
transfer catalysts include, but are not limited to, at least one of
tetrabutylammonium bromide, TEBA, tetrabutylammonium
hydrogensulfate, tricaprylylmethylammonium chloride,
benzyltriethylammonium chloride, 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, or octyltrimethylammonium
chloride. Preferably, the phase transfer catalyst includes, but is
not limited to, at least one of tetrabutylammonium bromide, TEBA,
tricaprylylmethylammonium chloride, or tetrabutylammonium
hydrogensulfate. The phase transfer catalysts are
either-commercially available or readily synthesized by one of
ordinary skill in the art. For example tricaprylylmethylammonium
chloride, commonly know as Aliquat.RTM. 336, is manufactured by
Aldrich Chemical Company, Inc. Milwaukee, Wis.
[0018] The lower boiling point organic solvent used in the reaction
allows for lower reaction temperatures for the synthesis of
cilexetil trityl candesartan. Based on the low boiling solvent.
Typically, the reaction temperature is from about 25.degree. C. to
about 110.degree. C., and preferably from about 40.degree. C. to
about 90.degree. C. The reaction time will depend upon the amount
of reactants, reaction temperature, and other variables commonly
known to one of ordinary skill in the art.
[0019] Another embodiment of the invention encompasses methods for
the deprotection of cilexetil trityl candesartan (I) using a
mixture of at least one organic solvent and at least one organic
acid to form crude cilexetil candesartan (II). In another
embodiment, the organic solvent may be substantially dry organic
solvent. Yet, in another embodiment, the methods include a mineral
acid in addition to the organic acid. Another embodiment of the
invention encompasses neutralizing the excess acid in the reaction
mixture with at least one base, after adding the organic solvent.
Not to be limited by theory, however, it is believed that the
organic acid is easily removed from the reaction mixture during
regular work-up. Accordingly, as a general matter, organic acids
are easier to be used in an industrial scale. The present invention
uses an organic solvent with at least one organic acid to deprotect
the cilexetil trityl candesartan. As used herein, the term
"substantially dry organic solvent" refers to an organic solvent
having less than about 3% water by weight, and preferably less than
about 0.5% water by weight.
[0020] The method encompasses deprotecting cilexetil trityl
candesartan comprising: mixing cilexetil trityl candesartan and at
least one organic acid in at least one organic solvent for a
suitable time and at a suitable temperature to synthesize cilexetil
candesartan; and isolating the crude cilexetil candesartan. The
deprotecting step is depicted in Scheme I. ##STR2##
[0021] Organic acids contemplated for the method of the invention
include, but are not limited to, at least one of C.sub.6-C.sub.10
aromatic sulfonic acids, haloacetic acids, C.sub.1-C.sub.6 alkyl
sulfonic acids, or C.sub.1-C.sub.6 carboxylic acids. Preferably,
the organic acids include, but are not limited to, at least one of
methanesulfonic acid, formic acid, pyridine p-toluene sulphonic
acid, trifluoroacetic acid, trichloroacetic acid, or acetic acid.
Preferably, when using an organic acid, the reaction temperature
may be from about 15.degree. C. to about 60.degree. C. Reaction
time may easily be determined by monitoring the reaction progress
and/or completion by thin layer chromatography (TLC). Typical
reactions times may be from about 4 hours to about 20 hours.
[0022] Organic solvents include, but are not limited to, at least
one alcohol, ketone, ether, hydrocarbon, or chlorinated solvent.
Preferably, organic solvents include at least one C.sub.1-C.sub.4
alkyl alcohol, ketone, ether, or chlorinated solvent. In
particular, organic solvents include, but are not limited to,
dichloromethane, methanol, toluene, or tert-butyl methyl ether. In
one embodiment, wherein more than one solvent is used, the ratio of
first to second solvents is from about 1:10 to about 10:1.
[0023] After the trityl group has been removed, the reaction
mixture is neutralized using a base. Bases include those enumerate
above, and preferably, the base is NaOH. The isolation of the
cilexetil candesartan can be carried out by extraction,
evaporation, crystallization, or other techniques commonly used to
isolate an organic compound of interest from a reaction mixture. In
a preferred embodiment, the solvent may be evaporated under reduced
pressure, and thereafter, the residue is diluted with water and
extracted with a suitable organic solvent, such as ethyl acetate.
The organic extracts are combined, dried, and the solvent removed
to obtain crude compound II.
[0024] One embodiment of the invention encompasses deprotecting
cilexetil trityl candesartan comprising: mixing cilexetil trityl
candesartan in the presence of methanol without an acid; and
isolating the cilexetil candesartan. The deprotecting step of the
trityl group can be performed in presence of water. The
deprotecting step of the trityl group can be performed in presence
of organic solvent to facilitate the precipitation of the compound
at the end of the reaction. This deprotection process comparatively
yields a clean product.
[0025] Typically, the deprotection step comprises heating to reflux
trityl candesartan cilexetil in methanol. Optionally, the
deprotection solvent mixture further comprises an organic solvent,
such as toluene, and/or an acid, such as formic acid. The cilexetil
trityl candesartan is heated to reflux until a clear solution is
obtained. Typically, the reaction temperature is from about
30.degree. C. to about 90.degree. C., preferably from about
50.degree. C. to about 90.degree. C., and the heating takes place
for about 5 to about 19 hours, preferably for about 8 to about 12
hours. Thereafter, the solvents are removed by evaporation to
obtain crude deprotected candesartan cilexetil. The solvents may be
removed at a temperature of about 30.degree. C. to about 70.degree.
C., preferably at a temperature of about 50.degree. C., and at a
reduce pressure of about 30 mbar.
[0026] As used herein, the term "crude" refers to the product
obtained from the deprotection reaction. The crude candesartan
cilexetil may be either a solid form or an oil form.
[0027] Typically, crude candesartan cilexetil is dissolved in a
minimal amount of the solvent system, thereafter the solution is
cooled slowly until a crystalline candesartan cilexetil precipitate
appears. Crystallization may be induced by seeding, etching,
cooling, or other techniques commonly known to one of ordinary
skill in the art. Optionally, during the crystallization step, the
solution may be stirred. Thereafter, the crystalline candesartan
cilexetil obtained during the first crystallization is allowed to
dry. The drying step may be performed by heating the crystalline
candesartan cilexetil, optionally under reduced pressure, until a
constant weight is obtained. Typically, drying is performed at a
temperature of about 45.degree. C. to about 65.degree. C., and
preferably at a temperature of about 50.degree. C. to about
60.degree. C. When present, the reduce pressure, includes, but is
not limited to, about 30 mbar.
[0028] The solvent system comprises at least two solvents, wherein
one solvent is an alcohol and another solvent is an aromatic
compound. Typically, the alcohol is at least one C.sub.1-C.sub.6
alcohol including, but not limited to, methanol, ethanol, propanol,
isopropanol, butanol, sec-butanol, tert-butanol, 1-pentanol,
2-pentanol, or 3-pentanol. Preferably, the alcohol is methanol. The
aromatic compound is at least one compound with a phenyl ring
including, but not limited to, substituted or unsubstituted
benzene, toluene, ethyltoluene, xylene, or mesitylene. Preferably,
the aromatic compound is toluene. Generally, the solvent system
comprises an alcohol and aromatic compound in a ratio of about 20%
alcohol to 80% aromatic by weight; preferably, the ratio of alcohol
to aromatic compound is about 10% alcohol to 90% aromatic by weight
of the solvent mixture. More preferably, the weight ratio of
alcohol to aromatic compound is about 5% alcohol to 95% aromatic by
weight.
[0029] The recrystallizing of crystalline candesartan cilexetil
comprises dissolving the crystalline candesartan cilexetil in a
solvent and recrystallizing to obtain a substantially pure
candesartan cilexetil. Optionally, during the recrystallization,
the solution may be stirred. Typically, the solvent comprises at
least one C.sub.1-C.sub.6 alcohol including, but not limited to,
methanol, ethanol, propanol, isopropanol, butanol, sec-butanol,
tert-butanol, 1-pentanol, 2-pentanol, or 3-pentanol. Preferably,
the alcohol is methanol.
[0030] Optionally, the process may further comprise a drying step
wherein after the second recrystallization, the substantially pure
candesartan cilexetil is dried at a suitable temperature and for a
suitable time to obtain a substantially pure dry candesartan
cilexetil of a constant weight. Generally, the drying temperature
should be sufficient to remove undesired solvents until the weight
of the crystalline candesartan cilexetil does not fluctuate. For
example, the drying temperature may be about 50.degree. C. to
65.degree. C., and preferably, the drying temperature is about
50.degree. C. Optionally, the drying step may be performed at a
reduced pressure including, but not limited to, about 8 mbar.
[0031] Having described the invention with reference to certain
preferred embodiments, other embodiments will become apparent to
one skilled in the art from consideration of the specification. The
invention is further defined by reference to the following examples
describing in detail the preparation of the composition and methods
of deprotection of the invention. It will be apparent to those
skilled in the art that many modifications, both to materials and
methods, may be practiced without departing from the scope of the
invention.
EXAMPLES
Example 1
Method of Making Cilexetil Trityl Candesartan in a Low Boiling
Solvent
[0032] A suspension of trityl candesartan (2.0 g, 2.93 mmol),
cilexetil chloride (1.21 g, 5.86 mmol), potassium carbonate (0.81
g, 5.86 mmol) and acetonitrile (19 g) was stirred at 40.degree. C.
for about 8 h, and the reaction was monitored by TLC. The
acetonitrile was removed at 30.degree. C. to 35.degree. C. under
reduced pressure (10 mbar), and the residue was mixed with water
(20 ml) and ethyl acetate (30 ml). The water layer was separated
and extracted with ethyl acetate (20 ml.times.2). The combined
organic layers were washed with brine (10 ml.times.2), dried over
sodium sulfate, and evaporated to give cilexetil trityl candesartan
crude, as a semi-solid, 94.38% pure by HPLC.
[0033] The crude product was triturated with hexane (30 ml) at
25.degree. C. to 27.degree. C. for about 3 h. Thereafter, the
solids were filtered off, washed on the filter with hexane (5
g.times.2) and dried at 25.degree. C. to 27.degree. C. under
reduced pressure (10 mbar) to give cilexetil trityl candesartan (12
g, 84.8%) 94.64% pure by HPLC.
Example 2
Method of Making Cilexetil Trityl Candesartan with a PTC
[0034] A suspension of trityl candesartan (2.0 g, 2.93 mmol),
cilexetil chloride (1.21 g, 5.86 mmol), potassium carbonate (1.22
g, 8.83 mmol), and tetrabutylammoniumhydrogensulfate (0.2 g) in
toluene (20 ml) was stirred at 50.degree. C. to 55.degree. C. for
about 8.5 h. The reaction progress was monitored by TLC. The
mixture was poured into water (100 ml) and neutralized with citric
acid (solid). The organic layer was separated, washed with water,
and extracted with ethyl acetate (20 ml.times.3). The combined
organic layers were washed with brine (10 ml), dried over sodium
sulfate, and evaporated. The residue was triturated with hexane (20
ml) at 20-25.degree. C. for about 30 min, filtered and dried at
40.degree. C. and at less than about 30 mbar to give white powder
(1.68 gr, 67.2%), with 97.90% purity by HPLC.
Example 3
Method of Deprotection using Methanesulfonic Acid
[0035] A solution of cilexetil trityl candesartan (0.50 g, 0.59
mmol), methanesulfonic acid (0.09 g, 0.88 mmol), dichloromethane
(10 ml) and methanol (1 ml) was stirred at 25.degree. C. to
27.degree. C. for about 4 h. The reaction was monitored using thin
layer chromatography (TLC monitoring). The reaction mixture was
neutralized with a saturated solution of sodium bicarbonate and the
dichloromethane was removed under reduced pressure. The residue was
diluted with water (10 ml) and extracted with ethyl acetate (20
ml.times.2). The combined organic layers were washed with brine (10
ml.times.2), dried over sodium sulfate, and evaporated to give
Candesartan cilexetil crude.
Example 4
Method of Deprotection using p-Toluene Sulphonic Acid
[0036] A solution of cilexetil trityl candesartan (0.50 g, 0.59
mmol), PPTS (pyridine para-toluene sulphonic acid, 0.22 g, 0.88
mmol), dichloromethane (10 ml) and methanol (1 ml) was stirred at
25.degree. C. to 27.degree. C. for about 20 h. The reaction
progress was monitored using thin layer chromatography (TLC
monitoring). The reaction mixture was neutralized with a saturated
solution of sodium bicarbonate. The dichloromethane was removed
under reduced pressure, the residue was diluted with water (10 ml)
and extracted with ethyl acetate (20 ml.times.2). The combined
organic layers were washed with brine (10 ml.times.2), dried over
sodium sulfate, and evaporated to give Candesartan cilexetil
crude.
Example 5
Method of Deprotection using Formic Acid
[0037] A solution of cilexetil trityl candesartan (2.0 g, 2.35
mmol), formic acid (2.16 g, 46.9 mmol), dichloromethane (8 ml) and
methanol (4 ml) was stirred at 25.degree. C. to 27.degree. C. for
about 5 h (TLC monitoring). The reaction mixture was neutralized
with a saturated solution of sodium bicarbonate. The
dichloromethane was removed under reduced pressure, the residue was
diluted with water (10 ml) and extracted with ethyl acetate (20
ml.times.2). The combined organic layer was washed with brine (10
ml.times.2), dried over sodium sulfate and evaporated to give an
oil (2.05 g) which was crystallized from tert-butyl methyl ether
(TBME) (2.7 g) to give Candesartan cilexetil (0.95 g, 66.4%).
Example 6
Method of Deprotection using Formic Acid
[0038] A solution of cilexetil trityl candesartan (1.0 g, 1.18
mmol) was dissolved in toluene (10 ml) at 50.degree. C. to
55.degree. C. followed by addition of formic acid (1.1 g, 23.88
mmol), and methanol (6 ml). The solution was heated to 50.degree.
C. to 55.degree. C. for about 7 h. The reaction mixture was cooled
to 20.degree. C. to 25.degree. C., pH adjusted to pH of 6.4 with 1
N NaOH, and extracted with ethyl acetate (20 ml.times.3). The
combined organic layers were washed with brine (10 ml.times.2),
dried over sodium sulfate and evaporated to give a semi-solid mass
(0.79 g).
Example 7
Method of Deprotection using Formic Acid
[0039] A solution of trityl candesartan cilexetil (30 g, 0.035 mol)
in toluene (180 ml), methanol (180 ml), and formic acid (1.6 g,
0.035 mol) was refluxed for about 10 h. The reaction was monitored
using HPLC. Thereafter, the solution volume was reduced by
evaporation under reduced pressure (30 mbar) at a temperature of
about 55.degree. C. to 60.degree. C. to obtain viscous oil (36.5
g). The oil was dissolved in a mixture of toluene:methanol (65.7
g:7.3 g), stirred at about 0.degree. C. to 5.degree. C. until
crystallization started, and kept at 2.degree. C. to 8.degree. C.
for about 20 hours. The solids were collected by filtration, washed
on the filter with a mixture toluene/methanol (90:10 w/v, 15 g),
and dried under reduced pressure (10-50 mm Hg) at a temperature of
about 50.degree. C. to 55.degree. C. to yield candesartan cilexetil
(16.88 g, 78.6%) as a white powder.
Example 8
Method of Deprotection using Trifluoroacetic Acid
[0040] The protecting group (trityl) was removed using strong
organic acids. Trifluoroacetic acid (0.1 ml, 1.3 eq.) was added at
20.degree. C. to 25.degree. C. to a stirred suspension of cilexetil
trityl candesartan (1 g) in methanol (6 ml) and toluene (6 ml).
After 50 min of stirring at 20.degree. C. to 25.degree. C. a
solution formed. The solution was stirred at 20.degree. C. to
25.degree. C. for about an additional 6 h. Thereafter, the pH of
the solution was adjusted to 6.4 with a saturated aqueous solution
of sodium bicarbonate, the solution was diluted with brine (20 ml),
and extracted with ethyl acetate (20 ml.times.2). The combined
organic layers were washed with brine (10 ml), dried over sodium
sulfate, filtered, and the volume reduced by evaporation to give a
semi-solid mass crude candesartan cilexetil.
[0041] Alternatively, trichloroacetic acid may be used with this
process.
Example 9
Method of Deprotection using Trifluoroacetic Acid
[0042] Trifluoroacetic acid (0.17 g, 0.65 eq.) was added dropwise
at a temperature of about 20.degree. C. to about 25.degree. C. to a
stirred suspension of cilexetil trityl candesartan (2 g, 2.34 mmol)
in toluene (12 ml) and methanol (12 ml). A solution formed after
1.5 h of stirring and the solution was stirred for about 20 h at a
temperature of about 20.degree. C. to about 25.degree. C.
Thereafter, the pH of the solution was adjusted to a pH 6.5 with a
saturated solution of sodium bicarbonate, diluted with water (30
ml), and extracted with ethyl acetate (20 ml.times.4). The organic
layers were collected and dried over sodium sulfate, filtered, and
the solvent was removed by evaporation to yield semi-solid
candesartan cilexetil.
Example 10
Deprotection without Acid
[0043] Cilexetil trityl candesartan (5.0 g, 5.86 mmol) was
dissolved at 60.degree. C. in toluene (30 ml). Methanol (30 ml) was
added and the solution was heated in an oil bath to 70.degree. C.
for about 19 h. The volume of the solution was reduced at
50.degree. C. to 60.degree. C. under reduced pressure to a weight
of about 16 g and then cooled to -10.degree. C. for about 48 h. The
precipitated solids were collected by filtration, washed with cold
methanol (MeOH at about 0.degree. C. to 5.degree. C.; 2
ml.times.2), dried on the filter for about 1 h to give crude
candesartan cilexetil (3.1 g, 88.5%). The crude candesartan
cilexetil was dissolved at reflux in methanol (23 ml), the solution
was filtered under reduced pressure, and cooled under stirring in
an ice bath for about 3 h. White solids were collected by
filtration, washed with methanol (2.5 ml.times.3), and dried in the
open air overnight to give candesartan cilexetil as a white solid
(2.3 g, 74%) with 99.28% purity by HPLC.
Example 11
Deprotection without Acid
[0044] Cilexetil trityl candesartan (20 g, 23 mmol) was dissolved
at 60.degree. C. in toluene (120 ml). Methanol (120 ml) was added
and the solution was heated in an oil bath at about 75.degree. C.
to 80.degree. C. for about 13 hours. The solution was reduced in
volume by evaporation at 50.degree. C. to 60.degree. C. under
reduced pressure to give a viscous residue (about 27 g) which was
dissolved in methanol (60 ml) and the solvent removed by
evaporation to dryness to give a foam (about 23 g). The foam was
dissolved in methanol (about 40 g) at reflux temperature. The
solution was then filtered under reduced pressure, cooled to
4.degree. C. to obtain a solid and kept at this temperature for 12
to 15 hours.
[0045] The precipitated solids were collected by filtration, washed
with the cold methanol at about 0.degree. C. to 5.degree. C. (20
ml.times.2) and dried at 50.degree. C. under vacuum to give
candesartan cilexetil (15.5 g). Trituration of candesartan
cilexetil (1 g) with toluene (5 ml) at 25.degree. C. to 27.degree.
C. during 1 h gave candesartan cilexetil (about 0.65 g).
Example 12
Deprotection without Acid
[0046] A mixture of trityl candesartan cilexetil (20 g, 23.45
mmol), toluene (60 ml), methanol (60 ml), and water (1 ml) was
gently refluxed for about 12 h. The reaction was monitored by HPLC.
The solution volume was reduced by evaporation under reduced
pressure (30 mbar) at a temperature of about 55.degree. C.
60.degree. C. to obtain viscous oil of candesartan cilexetil as a
residue (36.5 g).
Example 13
Deprotection without Acid
[0047] A mixture of trityl candesartan cilexetil (20 g, 23.45
mmol), toluene (60 ml), methanol (120 ml), and water (1 ml) was
gently refluxed for about 5 h. The reaction progress was monitored
by HPLC. The solution volume was reduced by evaporation under
reduced pressure (30 mbar) at a temperature of about 55.degree. C.
to 60.degree. C. to obtain viscous oil of candesartan cilexetil as
a residue (36.5 g).
Example 14
Deprotection without Acid
[0048] A mixture of trityl candesartan cilexetil (20 g, 23.45
mmol), methanol (200 ml), and water (1 ml) was gently refluxed for
about 16-17 h. The reaction progress was monitored by HPLC. The
solution volume was reduced by evaporation under reduced pressure
(30 mbar) at a temperature of 55.degree. C. to 60.degree. C. to
obtain viscous oil of candesartan cilexetil as a residue.
Example 15
Deprotection without Acid
[0049] A solution of trityl candesartan c (TCS, 350 g, 410.3 mmol),
toluene (1050 mL), methanol (2100 mL) and water (17.0 mL) was
refluxed for about 2-4 h (HPLC control), the solvents were
evaporated at 40-50.degree. C./P<100 mbar to give a residue as a
viscous oil, the residue was dissolved at 45-55.degree. C. in a
mixture of Toluene/Methanol (1041 g, 95:5, w/w) to give a clear
solution.
[0050] The solution was cooled to (-5)-(20).degree. C. the solution
was kept at this temperature for about 8-12 hr, the precipitated
solids were filtered off, washed on the filter with cold Toluene
(350 mL) to give a wet solid (295.8 g, 83.0%) 110 g of the wet
solid were dried at 50.degree. C./10 mbar for 2-6 hr to give a wet
white solid (94 g (LOD=15-25%)). The wet white solid (43.75 g) was
dissolved at 40-60.degree. C. in Ethanol Absolute (215-363 mL
6-10V), the solution was filtered and returned to the reactor, then
the solution was cooled to (-15)-(5).degree. C. and was kept at
this temperature for about 2-24 hr. The precipitated solids were
filtered off, washed with cold Ethanol Absolute (23-35 mL) to give
wet solid which was dried at 50.degree. C./10 mbar to constant
weight to give cilexetil candesartan (21.5 g, 67%).
Example 16
Deprotection without Acid
[0051] A suspension of cilexetil trityl candesartan (50.0 g, 58.62
mmol), water (2.64 g, 2.5 eq), and methanol (500 ml, 10 eq. by
volume) was refluxed for about 16.5 h to obtain a clear solution.
The solvents were removed by evaporation at 30 mbar and 40.degree.
C. to obtain a solid residue (51.7 g). The residue was dissolved at
60.degree. C. in a mixture of toluene/methanol (95:5 w/w, 125 g),
cooled to 20-23.degree. C. and stirred for about 15 h. A
precipitate appeared and was collected by filtration, washed with a
cold (4.degree. C.) mixture of toluene/methanol (95:5 w/w, 25 g),
and dried for 2 h at 50.degree. C. and 30 mbar to give a crude
solid candesartan cilexetil (32.41 g, 90.5%), with 99.32% purity by
HPLC.
Example 17
Deprotection without Acid
[0052] A solution of Trityl Candesartan Cilexetil (100.0 g, 0.117
mol), Water (5.3 g), Toluene (600 mL) and Methanol (600 mL) was
refluxed for about 10 h (HPLC in process control) and the solvents
were evaporated at 60.degree. C./30 mbar to obtain an oily residue.
A part from the residue (6.84 g) was dissolved at 50.degree. C. in
a mixture of Toluene/Methanol 95:5 (w/w), (11.2 g). A solution was
stirred for about 6 h at 2-8.degree. C., the solids were filtered
off, washed with a cold mixture of Toluene/Methanol 95:5 (w/w),
(3.4 g) and dried at 60.degree. C./30 mbar to the constant weight
to give white solid (3.47 g, 86.8%), 99.15% pure by HPLC.
Example 18
Recrystallization in Methanol
[0053] The compound of Example 8 (5 g) was dissolved in methanol
(25.0 g) at a temperature of about 18.degree. C. to 23.degree. C.
to obtain a clear solution and upon which the solid precipitated to
form a suspension. The suspension was stirred at 18.degree. C. to
23.degree. C. for about 60 h, the resulting solid was collected by
filtration, washed with methanol (2.5 g), and dried under reduced
pressure (10 mbar) at a temperature of about 50.degree. C. to
55.degree. C. until the solid had a constant weight to obtain
candesartan cilexetil (4.2 g, 84%) as a white powder.
Example 19
Recrystallization in Methanol
[0054] The compound of Example 8 (2 g) was dissolved in methanol
(6.0 g) at 50.degree. C. to obtain a clear solution. The solution
was cooled to about 18.degree. C. to 23.degree. C. until a
precipitate began to form. Thereafter, the suspension was stirred
at 18.degree. C. to 23.degree. C. for about 60 h, the solid was
collected by filtration, washed with methanol (1.0 g), and dried
under reduced pressure (10 mbar) at a temperature of 50.degree. C.
to 55.degree. C. until the solid had a constant weight to obtain
candesartan cilexetil (1.74 g, 87.0%) as a white powder.
Example 20
Recrystallization in Ethanol
[0055] The compound of Example 8 (5 g) was dissolved in ethanol
(25.0 g) at 50.degree. C. to obtain a clear solution. The solution
was cooled to about 18.degree. C. to 23.degree. C., until a
precipitate began to form. The suspension was stirred at 18.degree.
C. to 23.degree. C. for about 60 h, the solid collected by
filtration, washed with ethanol (2.5 g), and dried under reduced
pressure (10 mbar) at a temperature of 50.degree. C. to 55.degree.
C. until the solid had a constant weight to obtain candesartan
cilexetil (4.17 g, 83.4%) as a white powder.
Example 21
Recrystallization in Ethanol
[0056] The compound of Example 1 (2 g) was dissolved in ethanol
(25.0 g) at 60.degree. C. to obtain a clear solution. The solution
was cooled to about 18.degree. C. to 23.degree. C., until a
precipitate began to form. The suspension was stirred at 18.degree.
C. to 23.degree. C. for about 60 h, the solid was collected by
filtration, washed with ethanol (1.0 g), and dried under reduced
pressure (10 mbar) at a temperature of 50.degree. C. to 55.degree.
C. until the solid had a constant weight to obtain candesartan
cilexetil (1.68 g, 84.0%) as a white powder.
* * * * *