PROCESS FOR THE PREPARATION OF VALSARTAN AND
INTERMEDIATES THEREOF
Priority
This application claims the benefit of U.S. provisional application Serial No. 60/473,640,
filed May 28, 2003; U.S. patent application Serial No. 107 , filed March 17, 2004;
PCT International Application No. PCT/04/ , filed March 17,2004; U.S.
provisional application Serial No. 607 , filed March 30,2004; U.S. provisional
application Serial No. 60/512,557, filed October 16, 2003; U.S. provisional application
Serial No. 60/471,871, filed May 20, 2003; and U.S. provisional application Serial No.
60/464,197, filed April 21, 2003, the contents of all of which are incorporated herein.
Field of the Invention
The present invention relates to a process for preparing valsartan and precursors
thereof.
Background
Valsartan, also known as (S)-N-(l-Carboxy-2-methyl-prop-1 -yl)-N-pentanoyl-N-
[2'-(lH-tetrazol-5-yl)bi phenyl-4-ylmethyl]-amine, has the following structure:
Formula CjgNsC
Molecular Mass 435.52
Exact Mass 435.227040
Composition c 66.19% H 6.71 % N 16.08% O 11.02
Melting Range 105-110°C
and is marketed as the free acid under the name DIOVAN. DIOVAN is prescribed as
oral tablets in dosages of 40 mg, 80 mg, 160 mg and 320 mg of valsartan.
Valsartan and/or its intermediates are disclosed in various references, including:
U.S. Pat. Nos. 5,399,578, 5,965,592, 5,260,325, 6,271,375, WO 02/006253, WO
01/082858, WO 99/67231, WO 97/30036, Peter Biihlmayer, et. al., Bioorgan. & Med.
Chem. Let., 4(1) 29-34 (1994), Th. Moenius, et. al., J. Labelled Cpd. Radiopharm., 43(13)
1245 - 1252 (2000), and Qingzhong Jia, et. al., Zhongguo Yiyao Gongye Zazhi, 32(9)
385-387(2001).
Valsartan is an orally active specific angiotensin II antagonist acting on the ATI
receptor subtype. Valsartan is prescribed for the treatment of hypertension. U.S. Pat. No.
6,395,728 is directed to use of valsartan for treatment of diabetes related hypertension.
U.S. Pat. Nos. 6,465,502 and 6,485,745 are directed to treatment of lung cancer with
valsartan. U.S. Pat. No. 6,294,197 is directed to solid oral dosage forms of valsartan.
The synthesis of valsartan is discussed, inter alia, in United States Patent No.
5,399,578. In the synthesis disclosed therein, the final synthetic step (exclusive of workup
and purification) involves the reaction of a cyano group on the biphenyl ring with an
azide, for example, tributyl tin azide. The reaction scheme of the '578 patent is as
follows:
CHO
(Figure Removed)
The starting compound in the '578 patent is made as follows:
NaOH
Peter Buhlmayer, et. al, Bioorgan. & Med. Chem. Let., 4(1) 29-34 (1994)
In Moenius, et. al., J. Labelled Cpd. Radiopharm., 43(13) 1245 - 1252 (2000),
various schemes for synthesis of valsartan are provided, with one being:
(Figure Removed)
Another paper, Qingzhong Jia, et. al., Zhongguo Yiyao Gongye Zazhi, 32(9) 385-
387 (2001), discloses a synthesis scheme for valsartan as follows:
CH3
(Figure Removed)
There is a need in the art for an improved synthetic process for the preparation of
valsartan and precursors of valsartan.
Objects and Summary of the Invention
In one aspect, the present invention provides a process for preparing valsartan
containing less than about 5000 ppm residual solvent, comprising the steps of:
a) providing valsartan containing less than about 10% organic solvent by weight; and
b) triturating the valsartan in water.
In one aspect, the present invention provides a process for preparing valsartan
containing less than about 5000 ppm residual solvent, comprising the steps of:
a) providing valsartan containing less than about 10% organic solvent by weight; and
b) contacting with humid air in a fluidized bed drier.
In one aspect, the present invention provides a process for preparing valsartan
containing less than about 5000 ppm residual solvent, comprising the steps of:
a) providing valsartan containing less than about 10% organic solvent by weight; and
b) maintaining the valsartan at a temperature of from about 5 to about 60°C under
pressure of less than 30mmHg for a period of from about 1 to 5 days.
In one aspect, the present invention provides a process for preparing compound G3:
G3
wherein A is a Cl to C4 alkyl ester and X is a trityl group, comprising the steps of:
a) reacting compound G2:
G2
wherein L is a leaving group, with a derivative of L-valine in an organic solvent;
b) heating the reaction mixture;
c) cooling; and
d) recovering the compound G3.
In one aspect, the present invention provides a process for preparing compound G4
(shown below), comprising the steps of:
a) reacting compound G3 :
wherein A is a Cl to C4 alkyl ester and X is a trityl group, with an acylating agent
in an organic solvent;
b) agitating the reaction mixture; and
c) recovering the compound G4.
In another aspect, the present invention provides a process for preparing compound
(Figure Removed)
wherein A is a Cl to C4 alkyl ester and X is a trityl group, comprising the steps of:
a) reacting compound G2:
G2
wherein X is a trityl group and L is a leaving group, with a derivative of L-valine
in an organic solvent in the presence of a phase transfer catalyst;
b) heating the reaction mixture;
c) cooling;
e) adding an acylating agent;
f) agitating the reaction mixture; and
g) recovering the compound G4.
In one aspect, the present invention provides a process for preparing valsartan
comprising the steps of:
a) reacting compound G2:
G2
with a derivative of L-valine in a first organic solvent to obtain a compound G3:
b) reacting compound G3 with an acylating agent in a second organic solvent to
obtain a compound G4;
OA
and G4
c) hydrolyzing compound G4 to obtain valsartan,
wherein A is a Cl to C4 alkyl ester, X is a trityl group and L is a leaving group.
In one aspect, the present invention provides a process for preparing L-valsartan
comprising the steps of:
a) heating trityl valsartan in methanol in the absence of an acid to hydrolyze the trityl
group in solution;
b) cooling the solution to precipitate the trityl group; and
c) recovering the L-valsartan.
In one aspect, the present invention provides a process for preparing L-valsartan from
trityl valsartan comprising the steps of:
a) stirring a heterogeneous mixture of valsartan in water and acetone;
b) basifying the mixture
b) removing the acetone;
c) filtering the water to remove the trityl group;
d) extracting the water at acidic pH with ethyl acetate; and
e) removing the iso-butyl acetate.
In one aspect, the present invention provides a process for preparing valsartan
comprising the steps of:
a) reacting compound G2:
G2
wherein X is a trityl group and L is a leaving group, with a derivative of L-valine
in an organic solvent;
b) heating the reaction mixture;
c) cooling;
d) recovering the compound G3:
G3
wherein A is a Cl to C4 alkyl ester; and
e) converting the product of step (d) to valsartan.
In one aspect, the present invention provides a process for preparing valsartan
comprising the steps of:
a) reacting compound G3:
C
N=N
G3
wherein A is a Cl to C4 alkyl ester and X is a trityl group, with an acylating agent
in an organic solvent;
b) agitating the reaction mixture;
c) recovering the compound G4:
OA
and
d) converting the product of step (c) to valsartan.
Detailed description of the invention
As used herein, the term agitation refers to causing motion in a liquid through
application of a force, such as by stirring.
As used herein, the terms 'triturating', 'slurrying1 and 'suspending1 are
interchangeable, and all refer to a process carried out in a heterogeneous mixture where
complete dissolution does not occur.
The present invention provides a process for synthesis of valsartan. In the
present invention, valsartan is prepared by reacting a compound of formula G2, wherein
G2
X is a trityl protecting group with a C\1to C4 ester of L-valine, followed by reaction with
valeroyl halide, and hydrolysis of the resulting product to obtain valsartan.
The reaction is carried out in an organic solvent. Examples of preferred organic
solvents include, but are not limited to, N,N dimethyl formamide (DMF), dimethyl
acetamide (DMA), toluene, hexane, 1,2-dimethoxyethane (DME), diethoxymethane,
tetrahydrofuran (THF), acetonitrile (ACN), benzene, m-xylene, ethyl acetate, o-xylene,
tetralins, formals, glyrnes and mixtures thereof. Other hydrocarbons useful in the practice
of the present invention will be apparent to the skilled artisan.
The synthesis of valsartan, of the present invention, includes the step of reacting
a 5-(4'bromomethylbiphenyl-2-yl)-lH-tetrazole with an L-valine Ci to Co, derivative. A
preferred 5-(4'bromomethylbiphenyl-2-yl)-lH-tetrazole is 5-(4'bromomethylbiphenyl-
yl)-l -trityl-lH-tetrazole (VLS-02). A preferred L-valine ester is L-valine methyl ester
(VLS-07) or t-butyl ester. The use of an alkyl ester allows for removal under relatively
mild conditions, and with hydrolysis. The step is carried out in an organic solvent
reaction system. To the organic solvent is added an amount of a basic material. The
basic material may be a carbonate salt of an alkali metal or an organic base. Preferred
salts of alkali metals include sodium carbonate and potassium carbonate. Carbonates are
suitable for a process on an industrial scale since they are cheaper than organic bases such
as DIEA. Preferred organic bases include triethanolamine, diethanolamine, triethylamine,
di-iso propyl methylamine and diethylamine. Ethyl amine is also cheaper than DIEA. As
described above the organic solvent is preferably selected from DMF, DMA, acetonitrile
(ACN), toluene, hexane, DME, diethoxymethane, THF, benzene, m-xylene, o-xylene,
ethyl acetate, tetralins, formals, glymes and mixtures thereof. A most preferred organic
solvent is acetonitrile. The reaction may optionally be carried out in the presence of a
catalyst. Preferred solvents for use with a phase transfer catalyst are toluene and ethyl
acetate. VLS-07 is added to the solvent/base mixture. VLS-02 is added (preferentially in
three separate portions) to the reaction mixture, and the resulting reaction mixture is
heated with agitation for a reaction time of between 1 to 6 hours.
After the reaction time, the reaction system is cooled, and the solvent is removed
to yield the crude residue of N-valine methyl ester 5-(4'methylbiphenyl-2-yl)-l-trityl-
IH-tetrazole reaction product (VLS-04). Typically the solvent is removed by evaporation
under reduced pressure.
In addition to bromine in VLS-02, other leaving groups may be utilized,
including other halogens such as chlorine, or sulfonates. The acylating agent used may
also include other leaving groups.
In a second step of the synthetic method of the present invention, the N-valine
methyl ester 5-(4'methylbiphenyl-2-yl)-l-trityl-lH-tetrazole reaction product (VLS-04) is
reacted with an acylating agent to form a valsartan precursor such as (S)-N-(lcarboxymethoxy-
2-methyl-prop-1 -yl)-N-pentanoyl-N-[2'-( 1 -trityl-1 H-tetrazol-5-yl)bi
phenyl-4-yl methylj-amine (VLS-05). Crude residue produced in the synthetic step
described above is dissolved in a suitable organic solvent. The organic solvent preferably
contains an amount of an organic basic material. Preferred organic basic materials
include triethylamine, di-iso propyl methylamine and tributylamine. Preferred organic
solvents include toluene, DMA, DMF, hexane and acetonitrile. A most preferred organic
solvent is dry toluene. To the resulting solution is added an acylating agent. The
acylating agent is valeroyl chloride in this case. The resulting mixture is agitated at room
temperature for a period of from about 12 to about 24 hours. Preferably the reaction
mixture is agitated for a period of about 20 hours. The time of the acylation reaction can
be conveniently monitored using thin layer chromatography. Following completion of
the reaction, the reaction mixture is neutralized with a molar excess of base, preferably
aqueous NaHCOs, and the resulting two-phase reaction system is separated. The organic
phase is washed and dried, and the reaction product, (S)-N-(l-carboxymethoxy-2-methylprop-
l-yl)-N-pentanoyl-N-[2'-(l-trityl-lH-tetrazol-5-yl)biphenyl-4-yl methyl]-amine,
(VLS-05), separated out. The separation may be carried out by any known method, but is
typically carried out by evaporation under reduced pressure. The reaction product may be
purified by, for example, chromatographic means, prior to further use in the synthesis.
The crude material may be used in the next step.
In a third step of the synthetic method of the present invention the protecting
groups, e.g., the trityl group attached to the tetrazole ring and the L-valine substituent
(such as the methyl ester group of L-valine methyl ester (VLS-07)), are cleaved by
hydrolysis to produce valsartan (VLS-00). Crude residue produced in the synthetic step
described above is dissolved in a suitable water-miscible solvent. A solvent is water
miscible if it is rniscible with water at least in any proportion from 80:20 to 20:80 (weight
basis). Preferred water-miscible solvents include acetone, methyl ethyl ketone (MEK),
acetonitrile, tetrahydrofuran (THF), dioxane and C] to €4 alcohols. Acetone is a most
preferred water-miscible solvent. The resulting solution is acidified and agitated at a
temperature of from about 0°C to about 40°C. Most preferably the temperature is about
room temperature. The time of the cleavage reaction can be conveniently monitored
using thin layer chromatography. An aqueous solution of a basic material is added.
Suitable basic materials include potassium hydroxide, potassium carbonate and sodium
hydroxide. The trityl alcohol formed is separated and the liquid phase is acidified by
addition of a suitable acid to a pH of about 3. Preferred acids include mineral acids,
hydrogen sulfate, trifluoroacetic acid, formic acid, hydrobromic acid and acetic acid. A
most preferred acid is hydrochloric acid or hydrogen sulfate. The resulting suspension is
extracted with ethyl acetate and the crude product, for example, (S)-N-(lcarboxymethoxy-
2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-( 1 H-tetrazol-5-yl) biphenyl-4-yl
methyl]-amine, (VLS-06), recovered by, for example, evaporation under reduced
pressure. The resulting product is dissolved in an organic solvent. Preferred organic
solvents include organic alcohols, acetone and acetonitrile. A most preferred solvent is
methanol. The resulting solution is cooled to a temperature of between about -10°C and
about 45°C. Preferably the resulting solution is cooled to a temperature of between about
0°C and about 4°C, The acid is neutralized with a molar excess of base, preferably
aqueous KOH, and the water-miscible solvent is evaporated, preferably at reduced
pressure. The time of the cleavage reaction can be conveniently monitored using thin
layer chromatography or HPLC monitoring. The solution is extracted with ethyl acetate
and acidified by addition of a suitable acid to a pH of about 3. Preferred acids include
mineral acids, hydrogen sulfate, trifluoroacetic acid, formic acid, hydrobromic acid and
acetic acid. A most preferred acid is hydrochloric acid or hydrogen sulfate. The resulting
suspension is cooled and the product recovered by, for example, extraction. If desired,
the isolated product can be washed with water, and dried, preferably at reduced pressure.
The use of hydrolysis to remove the trityl group allows for a process on an
industrial scale, since the trityl group precipitates as tri-phenyl carbinol, and may be
recycled to prepare compound G2. If the trityl group is removed by hydrogenation, the
protecting group that comes off would lack a hydroxide group that allows for
derivatization into a halide and reaction with the amine of the tetrazole group to obtain
compound G2.
Some of the steps of the present invention may be carried out in one pot, as
illustrated in the examples.
The valsartan synthesized may be obtained as various polymorphic forms in the
solid state. Such forms are disclosed in Appl. No. 60/455,286, Filed on March 17,2003,
entitled "Polymorphs of Valsartan and Processes for their Preparation", which is
incorporated herein by reference.
Crude valsartan may be crystallized from organic solvents such as
dichloromethane, diethyl ether, ethyl acetate, t-butyl acetate, acetone, methyl ethyl ketone
and isopropyl methyl ketone. In a preferred embodiment, valsartan is crystallized from
such €3 to C? ketone and esters, with ethyl acetate being particularly preferred.
When crude material is crystallized out of ethyl acetate, the wet material contains
about 17% ethyl acetate. It is believed that crystallization from other organic solvents
may also result in similar amounts of the solvent.
The present invention provides for removing residual organic solvent such as
ethyl acetate from the crude material. The wet valsartan, if having a high solvent content,
is first dried, for example with a fluid bed dryer or a vacuum dryer, to obtain valsartan
with less than about 10% organic solvent by weight. Preferably, after drying, in case of
ethyl acetate, the ethyl acetate contains about 2.7% ethyl acetate by weight.
The present invention provides three different ways of removing residual organic
solvent from valsartan which may not be removed by conventional drying means.
In the first embodiment, the crude valsartan containing less than about 10%
residual solvent is triturated in water, in order to remove the residual solvent to acceptable
levels (according to the ICH guidelines the level is limited to less than about 5000 ppm).
In one embodiment, after trituration in water, the level of the residual solvent is less than
about 4000, more preferably about 3600 ppm. Preferably the trituration is performed
from about 4 to about 50°C, more preferably from about 25 to about 40°C. Preferably,
the trituration is carried out for about 5 hours to about 48 hours, more preferably from
about 3 to about 20 hours. Preferably, the volume of water is about 4 to about 20 liters
per kilogram of valsartan.
Another manner to remove residual solvent, particularly ethyl acetate, is by
performing a solvent exchange by contacting the solvate with humid gas in a fluidized
bed apparatus. Preferably, the temperature is of about 25 °C to about 50°C, more
preferably about 30°C to about 40°C. The contacting may be carried out for preferably
about 6 hours to about 2 days. As used herein, the term "humid" refers to a relative
humidity of at least 30%, more preferably at least about 50% and most preferably at least
about 80%. A suitable fluidized bed apparatus is Retsch TG-100.
Another manner to remove the residual solvent is by harsh drying which is
carried out by maintaining the valsartan at a temperature of about 5 to about 60°C under
pressure of less than about 30mmHg for a period of about 1 to about 5 days. Preferably,
the pressure is less than about lOmmHg, more preferably less than about ImmHg.
The above embodiments for solvent removal often result in a powder, which is
highly amorphous in nature, but may have a low level of crystallinity.
The final material obtained in the present invention is of particular high purity.
The valsartan obtained is substantially free of its D-isomer. The tablet level of the Disomer
managed to obtain a sample with a level of <0.1% by HPLC according to USP, more
preferably about 0.07% of the D-isomer.
This reduction in the level of the D-isomer was carried out without use of any
special cleaning reagents. Examples 8 and 9 illustrate such cleaning effect. Without
being bound by any theory, when the cleaning effect appears during the synthesis, such
effect might be due to use of acetone/water. A preferred ratio of acetone to water is about
4 to about 0.5-1 (vol/vol). In examples 8 and 9, the ratio between acetone and water is
2/1, and the ratio of .the acetone/water solution to trityl valsartan is 9 ml of the mixture per
1 gram of trityl valsartan; In example 11 the ratio between acetone and water 3.5/1, and
the ratio of the acetone/water solution to trityl valsartan is 5ml of the mixture per 1 gram
of trityl valsartan. Cleaning with a mixture such as that of acetone and water is carried
out under heterogeneous conditions, rather than a clear solution: due to a difference of
solubility between the racemate valsartan and the valsartan (L-isomer), or trityl valsartan,
or L-trityl valsartan. The preferred ratios of the acetone to water, and the water/acetone
solution to the TVLS, are the ratios that give heterogeneous mixture, rather than a clear
solution.
The cleaning effect may also happen when hydrolyzing the protecting groups in
methanol in the absence of an acid. Simply, heating trityl valsartan, to reflux temperature
in methanol followed by cooling may result in cleaning.
The cleaning effect may also occur when triturating crystals obtained from ethyl
acetate in water to remove residual solvent.
Although the cleaning effect in the present invention is illustrated with trityl
valsartan as a starting material, one of skill in the art would appreciate that the cleaning
effect may be used in the same manner when having valsartan as a starting material. The
valsartan can for example be a sample recovered after hydrolysis of the methyl ester and
the trityl group, though preferably the ester is hydrolyzed first, and then the resulting trityl
valsartan is "cleaned" according to processes of the present invention.
Pharmaceutical formulations of the present invention contain crystalline or
amorphous valsartan, optionally in mixture with other form(s) of valsartan. The valsartan
prepared by the processes of the present invention are ideal for pharmaceutical
formulation. In addition to the active ingredient(s), the pharmaceutical compositions of
the present invention may contain one or more excipients. Excipients are added to the
composition for a variety of purposes.
Diluents increase the bulk of a solid pharmaceutical composition, and may make a
pharmaceutical dosage form containing the composition easier for the patient and care
giver to handle. Diluents for solid compositions include, for example, microcrystalline
cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelatinized starch,
calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium
phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate,
magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium
chloride, powdered cellulose, sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions that are compacted into a dosage form, such as
a tablet, may include excipients whose functions include helping to bind the active
ingredient and other excipients together after compression. Binders for solid
pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol),
carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated
vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®),
hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum
silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon ,
Plasdone®), pregelatinized starch, sodium alginate and starch.
The dissolution rate of a compacted solid pharmaceutical composition in the
patient's stomach may be increased by the addition of a disintegrant to the composition.
Disintegrants include alginic acid, carboxymethylcellulose calcium,
carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide,
croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,
magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin
potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch
glycolate (e.g. Explotab®) and starch.
Glidants can be added to improve the flowability of a non-compacted solid
composition and to improve the accuracy of dosing. Excipients that may function as
glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose,
starch, talc and tribasic calcium phosphate.
When a dosage form such as a tablet is made by the compaction of a powdered
composition, the composition is subjected to pressure from a punch and dye. Some
excipients and active ingredients have a tendency to adhere to the surfaces of the punch
and dye, which can cause the product to have pitting and other surface irregularities.
lubricant can be added to the composition to reduce adhesion and ease the release of the
product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl
monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable
oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium
stearyl fumarate, stearic acid, talc and zinc stearate.
Flavoring agents and flavor enhancers make the dosage form more palatable to the
patient. Common flavoring agents and flavor enhancers for pharmaceutical products that
may be included in the composition of the present invention include maltol, vanillin, ethyl
vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
Solid and liquid compositions may also be dyed using any pharmaceutically
acceptable colorant to improve their appearance and/or facilitate patient identification of
the product and unit dosage level.
In liquid pharmaceutical compositions of the present invention, valsartan and any
other solid excipients are dissolved or suspended in a liquid carrier such as water,
vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
Liquid pharmaceutical compositions may contain emulsifying agents to disperse
uniformly throughout the composition an active ingredient or other excipient that is not
soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions
of the present invention include, for example, gelatin, egg yolk, casein, cholesterol,
acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and
cetyl alcohol.
Liquid pharmaceutical compositions of the present invention may also contain a
viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining
of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer,
carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose,
ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene
carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch
tragacanth and xanthan gum.
Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose,
aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
18
Preservatives and chelating agents such as alcohol, sodium benzoate, butylated
hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be
added at levels safe for ingestion to improve storage stability.
According to the present invention, a liquid composition may also contain a buffer
such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium
lactate, sodium citrate or sodium acetate. Selection of excipients and the amounts used
may be readily determined by the formulation scientist based upon experience and
consideration of standard procedures and reference works in the field.
The solid compositions of the present invention include powders, granulates,
aggregates and compacted compositions. The dosages include dosages suitable for oral,
buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous),
inhalant and ophthalmic administration. Although the most suitable administration in any
given case will depend on the nature and severity of the condition being treated, the most
preferred route of the present invention is oral. The dosages may be conveniently
presented in unit dosage form and prepared by any of the methods well-known in the
pharmaceutical arts.
Dosage forms include solid dosage forms like tablets, powders, capsules,
suppositories, sachets, troches and losenges, as well as liquid syrups, suspensions and
elixirs.
The dosage form of the present invention may be a capsule containing the
composition, preferably a powdered or granulated solid composition of the invention,
within either a hard or soft shell. The shell may be made from gelatin and optionally
contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
The active ingredient and excipients may be formulated into compositions and
dosage forms according to methods known in the art.
A composition for tableting or capsule filling may be prepared by wet granulation.
In wet granulation, some or all of the active ingredients and excipients in powder form are
blended and then further mixed in the presence of a liquid, typically water, that causes the
powders to clump into granules. The granulate is screened and/or milled, dried and then
screened and/or milled to the desired particle size. The granulate may then be tableted, or
other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
A tableting composition may be prepared conventionally by dry blending. For
example, the blended composition of the actives and excipients may be compacted into a
slug or a sheet and then comminuted into compacted granules. The compacted granules
may subsequently be compressed into a tablet.
As an alternative to dry granulation, a blended composition may be compressed
directly into a compacted dosage form using direct compression techniques. Direct
compression produces a more uniform tablet without granules. Excipients that are
particularly well suited for direct compression tableting include microcrystalline
cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The
proper use of these and other excipients in direct compression tableting is known to those
in the art with experience and skill in particular formulation challenges of direct
compression tableting.
A capsule filling of the present invention may comprise any of the aforementioned
blends and granulates that were described with reference to tableting, however, they are
not subjected to a final tableting step.
The solid compositions of the present invention include powders, granulates,
aggregates and compacted compositions. The dosages include dosages suitable for oral,
buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous),
inhalant and ophthalmic administration. Although the most suitable route in any given
case will depend on the nature and severity of the condition being treated, the most
preferred route of the present invention is oral. The dosages can be conveniently
presented in unit dosage form and prepared by any of the methods well-known in the
pharmaceutical arts.
The solid compositions of the present invention may be a plurality of valsartan
particles wherein the mean particle size (dO.5) is about 2 im to about 7 um, and about 10
volume percent or less of the plurality of particles have a particle diameter equal to or
greater than about 10 um.
The active ingredient and excipients may be formulated into compositions and
dosage forms according to methods known in the art. The solid oral dosage forms
disclosed in U.S. Pat. Nos. 6,485,745 and 6,395,728 may be used as a guidance. The
dosages and formulation of DIOVAN may also be used for guidance. The dosage is
preferably from about lOmg to about i280mg, more preferably from about 20mg to about
640mg, and most preferably from about 40mg to about 320mg.
The present invention can be illustrated in one of its embodiments by the
following non-limiting examples.
Example 1: Preparation of VLS-Q4
(Figure Removed)
To a suspension of L-valine methyl ester (free base, VLS-07, 4.8 g, 36.3 mmol)
and K2CO3 (10.0 g, 72.6 mmol, 2 eq) in anhydrous acetonitrile (100 mL) was added VLS-
02 (18.2 g, 32.7 mmol, 0.9 eq) in three portions. The reaction was stirred for 3.5 hours at
70°C under argon (TLC monitoring; hexane/ethyl acetate 4:1), cooled to 0°C and filtered.
The filtrate was evaporated under reduced pressure to give 23.0 g of crude VLS-04 as a
sticky yellow oil, having a purity of 75-80%, as determined by HPLC.
Example 2: Preparation of VLS-05
..OMe OMe
Toluene, BuCOCl, Et,N
To solution of VLS-04 (prepared in Example 1, used without further purification;
75% purity, 23.0 g, 28.4 mmol) and triethylamine (5.2 g, 7.2 mL, 51.12 mmol, 1.8 eq) in
dry toluene (200 mL) was slowly added valeroyl chloride (4.8 g, 4.7 mL, 39.8 mmol, 1.4
eq) under Argon. The resulting mixture was stirred for 20 hours at room temperature
(TLC monitoring; hexane/ethyl acetate 4:1) and subsequently quenched with a 10%
aqueous solution of NaHCOs (100 mL). The reaction mixture was stirred for an
additional 30 min at room temperature, after which the two-phase mixture was separated.
The organic phase was washed with brine, dried over Na2SCO4, filtered and evaporated
under reduced pressure to give 25.0 g of crude VLS-05 (about 75 % purity by HPLC) as a
yellow semisolid. The crude VLS-05 product was purified on a short silica gel column
(hexane/ethyl acetate 8:1) to give 15.8 g (80 % yield based on VLS-02; 95 % purity by
HPLC) of VLS-05 as a yellow foam.
Example 3: Preparation of Valsartan (VLS-00)
OMe OH
"CPh,
1) acetone, aq HC1
2) MeOH, aq. NaOH
VLS-05 VLS-00
VLS-05 (15.0 g, 21.7 mmol), produced in Example 2, was dissolved in acetone
(90 mL) and 3N HC1 (22 mL, approx. 3 eq), and stirred for 5 hours at room temperature
(with TLC or HPLC monitoring). A solution of KOH (85 %, 5.8 g, 86.8 mmol, 4 eq) in
50 mL of water was slowly added, and the acetone was evaporated under reduced
pressure. Trityl alcohol precipitate was filtered and washed with water (20 mL), and the
combined aqueous filtrate washed with 50 mL of ethyl acetate and slowly acidified to pH
3 with 3N aqueous HC1. The resulting suspension was extracted twice with ethyl acetate,
and the organic layers combined, washed with brine, and evaporated under reduced
pressure to give 8.8 g (approx.90 % yield) of crude VLS-06.
The residue was redissolved in methanol (80 mL), cooled to 0-4 °C and treated
with a 5% aqueous solution of KOH (65 mL, 49.0 rnmol, -2.5 eq). The resulting mixture
was stirred for 5 hours at room temperature (with TLC and HPLC monitoring), and most
of the methanol evaporated under reduced pressure. The aqueous solution was extracted
with ethyl acetate (2 x 30 mL), and slowly acidified to pH 3 with 3N aqueous HC1. The
resulting suspension was cooled down to 0-4 °C, stirred for 30 min and filtered. The filter
cake was washed with several portions of water, and dried under reduced pressure at 40-
50 °C to give 7.6 g (81 % based on VLS-05; 96-98 % purity by HPLC) of VLS-00 as a
white solid.
Example 4- Preparation of VLS-04
O OMe
H2N
VLS-07
OMe
3 Solvent, K2CO3
VLS-02 VLS-04
1) Toluene as a solvent (liquid-solid phase transfer procedure):
VLS-07 (free base, 2.00 g, 15.3 mmol, 1.5 eq), Bii4NHSO4 (Phase transfer, 1.56
g, 4.6 mmol, 0.3 eq) and K2CO3 (8.5 g, 61.2 mmol, 6 eq) were heated to 85-90°C in dry
Toluene (25 mL) under Argon and solution of VLS-02 (5.66 g, 10.2 mmol) in dry
Toluene (30 mL) was added during 1.5 h period. The resulted suspension was vigorously
stirred at 85-90°C for 4 h (TLC monitoring, Hex/EtOAc 4:1) and then cooled to 0-4°C.
The precipitate was filtered and the filtrate was evaporated under reduced pressure to give
7.0 g (near quant.) of crude VLS-04 (85 % purity about HPLC) as yellow viscous oil.
The crude was used in the next step without any purification (The crude VLS-04 was also
purified on a silica gel column to give 75 % yield of VLS-04 with 95 % purity by HPLC).
2) Acetonitrile as a solvent:
VLS-07 (free base, 2.00 g, 15.3 mmol, 1.5 eq) and K2CO3 (7.05 g, 51.0 mmol, 5
eq) were heated to 70°C in dry acetonitrile (25 mL) under Argon and VLS-02 (5.66 g,
10.2 mmol) was added in one portion. The resulted suspension was vigorously stirred at
70°C for 2.5 h (TLC monitoring, Hex/EtOAc 4:1) and then cooled to 0-4°C. The
precipitate was filtered and the filtrate was evaporated under reduced pressure to give
7.0g (near quant.) of crude VLS-04 (85% purity about HPLC) as yellow viscous oil. The
crude was used in the next step without any purification (The crude VLS-04 was also
purified on a silica gel column to give 75% yield of VLS-04 with 95% purity by HPLC).
Second step:
The crude VLS-04 from the previous step (7.0 g, -10 mmol) and Et3N (3.04 g,
4.18 mL, 30.1 mmol, 3 eq) were dissolved in dry Toluene (50 mL) under Argon and
Valeroyl chloride (2.77 g, 2.72 mL, 23.0 mmol, 2.3 eq) was added dropwise at room
temperature. The resulted suspension was stirred 5-6 h (TLC monitoring, Hex/EtOAc 4:1)
at room temperature and quenched with 10% aqueous NaHCOs (60 mL). The two-phase
mixture was vigorously stirred for 30 min, the phase were separated and organic one
washed with brine, dried over Na2SO4, filtered and evaporated to give about 8.0 g of
crude VLS-05 (-80 % purity by HPLC).
One-Pot Procedure:
VLS-07 (free base, 2.00 g, 15.3 mmol, 1.5 eq), Bi^NHSCv (Phase transfer, 1.56 g,
4.6 mmol, 0.3 eq) and K2CO3 (8.5 g, 61.2 mmol, 6 eq) were heated to 85-90°C in dry
Toluene (25 mL) under Argon and solution of VLS-02 (5.66 g, 10.2 mmol) in dry
Toluene (30 mL) was added during 1.5 h period. The resulted suspension was vigorously
stirred at 85-90°C for 4 h (TLC monitoring, Hex/EtOAc 4:1) and then cooled to 0-4°C.
The precipitate was filtered, the filtrate was mixed with Et3N (3.04 g, 4.18 mL, 30.1
mmol, 3 eq) under Argon and Valeroyl chloride (2.77 g, 2.72 mL, 23.0 mmol, 2.3 eq) was
added dropwise at room temperature. The resulted suspension was stirred 5-6 h (TLC
monitoring, Hex/EtOAc 4:1) at room temperature and quenched with 10 % aqueous
NaHCO3 (60 mL). The two-phase mixture was vigorously stirred for 30 min, the phase
were separated and organic one washed with brine, dried over Na2SO4, filtered and
evaporated to give about 8.0 g of crude VLS-05 (-70-75 % purity by HPLC).
Example 5- Preparation of VLS-00 from VLS-05
(Figure Removed)
1. Two step procedure via VLS-06:
VLS-05 was converted to VLS-00 as follows: VLS-05 (15.0 g, 21.7 mmol) was
dissolved in acetone (90 mL) and 3N HC1 (22 mL, ~3 eq) and stirred for 5h at room
temperature (TLC or HPLC monitoring). A solution of KOH (85 %, 5.8 g, 86.8 mmol, 4
eq) in 50 mL of water was slowly added and acetone was evaporated under reduced
pressure. The precipitate (Trityl alcohol) was filtered and washed with water (20 mL);
the combined aqueous filtrate washed with 50 mL of EtOAc and slowly acidified to pH 3
with 3N aqueous HC1. The resulted suspension was extracted twice with EtOAc, the
combined organics were washed with brine and evaporated under reduced pressure to
give 8.8 g (-90 % yield) of crude VLS-06. The residue was re-dissolved in MeOH (80
mL), cooled to 0-4°C and treated with 5% aqueous solution of KOH (65 mL, 49.0 mmol,
-2.5 eq). The resulted mixture was stirred for 5 h at room temperature (TLC and HPLC
monitoring) and most of the MeOH was evaporated under reduced pressure. The aqueous
solution was extracted with EtOAc (2 x 30 mL) and slowly acidified to pH 3 with 3N
aqueous HC1. The resulted suspension was cooled down to 0-4C, stirred for 30 min and
filtered. The cake was washed several times with water and dried under reduced pressure
at 40-50C and crystallized from Hex/EtOAc 1:2 afforded 7.1 g (75 % based on VLS-05,
96-98 % chemical purity by HPLC) of VLS-00 as a white solid.
2. One-pot procedure:
VLS-05 (15.0 g, 21.7 mmol) was dissolved in acetone (90 mL) and 3N HC1 (22
mL, ~3 eq) and stirred for 5 h at room temperature (TLC or HPLC monitoring). A
solution of KOH (85 %, 6.1 g, 108.5 mmol, 5 eq) and Bu4NHSO4 (0.75 g, 2.2 mmol, 0.1
eq) in 60 mL of water was slowly added, the resulted suspension was stirred for 24 h at
room temperature and Acetone was evaporated under reduced pressure. The precipitate
(Trityl alcohol) was filtered and washed with water (20 mL); the combined aqueous
filtrate washed with 50 mL of EtOAc and slowly acidified to pH 2 with 6 N aqueous HCI.
The resulted suspension was extracted twice with EtOAc (total 120 mL), the combined
organics were washed with brine and concentrated to 50 mL volume under reduced
pressure. This solution was cooled down to 0-4C, stirred for 5 h and filtered to give 7.2 g
(75 % based on VLS-05, 97 % chemical purity by HPLC) of VLS-00 as a white solid.
Example 6- Preparation of Valsartan using EtOAc as a solvent
(Figure Removed)
To a suspension of L-valine methyl ester (free base, VLS-07, 5.0 g, 36.5 mmol, 1.5 eq)
and K2CO3 (28 g, 203 mmol, 8 eq) in dry EtOAc (150 mL), VLS-02 (14.2 g, 25.5 mmol)
was added in one portion. The reaction was stirred for 20-24 h at reflux temperature
under argon (TLC monitoring; Hex/EtOAc 4:1), cooled to 0°C, followed by addition of
valeroyl chloride (7.3 g, 7.2 mL, 61.0 mmol, 2.4 eq). The resulting suspension was
stirred for 2 hours at room temperature (TLC monitoring; Hex/EtOAc 4:1) and quenched
with Water (200 mL). After stirring of 1 h at room temperature, the two-phase mixture
was separated, the organic phase washed with water and evaporated under reduced
pressure to give 20.5 g of crude VLS-05 (about 90-95 % purity by HPLC) as yellow
foam. VLS-05 (20.5 g, -25.5 mmol) was dissolved in acetone (100 mL) and 3N HCI (25
mL, ~3 eq), and stirred for 5 hours at room temperature.
A solution of NaOH (6.1 g, 152.5 mmol, 6 eq) in 15 mL of water was slowly
added and the resulting yellow solution was stirred for 10 h at room temperature and 4
hours at 50°C. Water (70 mL) was added, acetone was evaporated under reduced
pressure and the precipitate (trityl alcohol) was filtered and washed with water (2 x 30
mL); the combined aqueous filtrate washed with EtOAc (2 x 30 mL) and slowly acidified
to pH 2.5-3.5 with concentrated HCI. The resulting suspension was extracted twice with
EtOAc (total 200 mL), the combined organics were washed with brine dried over
4, filtered and evaporated under reduced pressure to 60 mL volume. Hexane (20
26
mL) was added and the resulting solution was vigorously stirred at 0-5°C for 2-3 hours.
The suspension was filtered, the solid washed with cold mixture Hexane/EtOAc (1:1, 2 x
20 mL) and dried under reduced pressure at 50°C until constant weight to give 7.7 g (-70
% yield for 4 steps) of crude VLS-00 as white powder.
Example 7: Trituration of Valsartan
Valsartan (5 grams, contained 2.7 % of EtOAc) was suspended in 50 mL of water and
stirred for 12 hours at 40°C. The suspension was filtered, washed with water and the
solid was dried for 3 hours at 35°C under reduced pressure to give 4.9g of valsartan as a
white powder.
Example 8: Hydrolysis and Cleaning of Trityl valsartan
A solution of 98 % sulfuric acid (1.45 g, 14.75 mmol) in water (30 mL) was added at
27 °C to a suspension of triryl valsartan, containing 7.97 % of D-trityl valsartan, (10 g,
14.75 mmol) in acetone (60 mL). The obtained suspension was stirred at 23-27°C for
about 24 h. The suspension was basified with 3 N solution of sodium hydroxide to pH
11.7- 11.9. Acetone was then distilled off and the precipitated solids so-formed were
filtered off and washed with water (6 mL x 2). The combined water layers were extracted
with ethyl acetate (18 mL x 2), the water solution was acidified with 3 N solution of
sulfuric acid to pH 2.5 - 2.7, extracted with ethyl acetate (36 mL x 3), dried over sodium
sulfate, filtered and evaporated to give a semi-solid residue (3.9 g) of VLS, containing
0.40% of D-VLS.
Example 9: Cleaning D-isomer during the reaction
A solution of 98 % Sulfuric acid (1.45 g, 14.75 mmol) in Water (30 mL) was added to a
solution of TVLS, containing about 4 % of D-TVLS, (10 g, 14.75 mmol) in Acetone (60
mL), and the suspension formed was stirred at 15 - 25 °C for about 24 h. After this, the
suspension was basified with 3 N solution of Sodium Hydroxide to pH 11.7-11.9,
Acetone was removed under reduced pressure at 30 °C, Triphenylcarbinol was filtered off
and washed with Water (6 mL x 2), the basic aqueous solution was extracted with Ethyl
Acetate (18 mL x 2), acidified with 3 N Solution of Sulfuric acid to pH 2.6 - 2 8,
extracted with Ethyl Acetate (36 mL x 3), the Ethyl Acetate solution was washed with
brine (20 mL), dried over Sodium sulfate and evaporated to give a solid residue of VLS
(3.92 g, 61 %) containing 0.59 % of D-VLS.
27
Example 10: Hydrolysis and Cleaning of Trityl valsartan
Trityl valsartan (5.0 g) was mixed with methanol (50 mL) and the suspension was heated
to reflux to give a solution which was refluxed for about 1 h (TLC monitoring,
DCM/Methanol 7:1). The solution was heated at this temperature for an additional 1.5 h.
The solution was then cooled to 20-25°C and stirred for about 1 h at this temperature.
Thee precipitated solids were filtered off and the filtrate was kept overnight at 4-8°C and
then at -13 °C for about 1 h. The precipitated solids were filtered off; the filtrate was
evaporated to give a semisolid residue (2.25 g, 70 %). The level of the D-isomer was
0.4%
Example 11: Hydrolysis and Cleaning of Tritvl valsartan
To clear yellow solution of Valsartan Trityl (400 g, -80 % assay, -0.50 mol) containing
4% of D-trityl valsartan in Acetone (1600 mL, 5 volumes), H2SO4 (98 %, 73.5 g, 40.0
mL, 0.75 mol) dissolved in H2O (450 mL, 1.5 volumes) was slowly added keeping
reaction temperature in range 35-40°C. The resulted suspension (the suspension
disappeared after 1-1.5 h of stirring) was stirred for 3h at 35-40°C (TLC monitoring;
Hex/EtOAc 1:1), cooled to room temperature and slowly basified to pH 12.0 - 12.5 with
NaOH (-4.5 eq, 90.0 g, 2.25 mol) dissolved in H2O (600 mL). Acetone was evaporated
under reduced pressure at 30°C and the resulted precipitate (triphenyl carbinol) was
filtered and washed with H2O (200 mL). The combined aqueous phase was extracted with
EtOAc (500 mL) and acidified to pH 2 - 3 with 3M Na2SO4 (~300mL). The acidic
aqueous suspension was extracted with EtOAc (2200 mL), the organic phase was dried
over Na2SO4 (200 g) and evaporated under reduced pressure. The sticky semisolid residue
(-400 g) containing 3.8% D-trityl valsartan was crystallized from EtOAc (1500 mL,
solution at 60°C, start of precipitation at 23°C, then 15h at 20-21°C and Ih at 0-4°C). The
precipitate was filtered, washed with cold (-5°C) EtOAc (200 mL) and dried under
reduced pressure at 50°C for Ih to give 193 g of crude Valsartan as white solid containing
0.38% D-trityl valsartan. The crude was recrystallized from EtOAc (1500 mL, solution at
63°C, start of precipitation at 27°C, then 15h at 20-2FC and Ih at 0-4°C) to give -150 g
of Valsartan crystals as white powder. Valsartan crystals were triturated with H2O (1500
mL) for 24 h at 30°C, filtered, washed with H2O (2 x 200 mL) and dried on the filter for 1
h (Valsartan after trituration contains ~25 % (w/w) of H2O). Then, Valsartan was dried
28
under reduced pressure (10-13 mmHg) at 50°C for 5 h (KF -0.9 %) to give 142 g (71-72
% yield) of the desired product (VLS-303-07, assay 99.8 % by titration) as white powder.
The D isomer detected in the final product (USP forum 2003 method) is 0.07%.
The isoleucine impurity was detected by HPLC at a level of 0.01% area.
Example 12: Hydrolysis and Cleaning of Trityl valsartan
A solution of 98% Sulfuric acid (1.45 g, 14.75 mmol) in Water (30 mL) was added to a
solution of TVLS, containing about 4 % of D-TVLS, (10 g, 14.75 mmol) in Acetone (60
mL), and the suspension formed was stirred at 15 - 25 °C for about 24 h. After this, the
suspension was basified with 3 N solution of Sodium Hydroxide to pH 11.7 — 11.9,
Acetone was removed under reduced pressure at 30°C, Triphenylcarbinol was filtered off
and washed with Water (6 mL x 2), the basic aqueous solution was extracted with Ethyl
Acetate (18 mL x 2), acidified with 3 N Solution of Sulfuric acid to pH 2.6-2 8, extracted
with Ethyl Acetate (36 mL x 3), the Ethyl Acetate solution was washed with brine (20
mL), dried over Sodium sulfate and evaporated to give a solid residue of VLS (3.92 g,
61%) containing 0.59% of D-VLS.
Example 13: Process for the preparation of Valsartan, starting from tritvl valsartan
TVLS (10.0 g, 14.75 mmol) was dissolved at reflux in Methanol (100 mL) and the
solution was refluxed for about 3 h (TLC control). The solution was cooled to 20 -25 °C
and basified with 3 N aqueous solution of Sodium hydroxide to pH 11.8. Methanol was
removed under reduced pressure at 30 °C, the precipitate was filtered off and washed on
the filter with Water (6 mL x 2). The aqueous filtrate was extracted with ethyl acetate (14
mL x 2) and acidified with 3 N solution of Sulfuric acid to pH 2.7. The precipitated
viscous oil was extracted with Ethyl Acetate (18 mL x 3), the combined extracts were
washed with brine (20 mL), dried over Sodium sulfate and evaporated to give a solid
residue of VLS, (4.81 g, 74.9 %). The level of the D-isomer was 3.85%.
Example 14: Hydrolysis and Cleaning of Tritvl valsartan
TVLS (5.0 g) was dissolved in Methanol (50 mL) at reflux and the solution was refluxed
for about 1 h (TLC control). Methanol was removed under reduced pressure to obtain a
residue (10 g). The residue was kept overnight at 4-7°C, the precipitate was filtered off,
the filtrate evaporated to give the solid residue of VLS (2.89 g, 89.5 %). The level of the
D~isomer was 4.4%.
Example 15: Hydrolysis and Cleaning of Tritvl valsartan
A 10 liter reactor equipped with mechanical stirrer, condenser and thermometer, was
charged at ambient temperature with trityl valsartan (1 Kg), acetone (4 L) and an aqueous
mixture of H2SO4 98% (H2SO4:H2O 100 mL: 1125 mL). The slurry was then heated to
36°C and stirred at a rate of 400 rpm for 5 hours until the end of the reaction (monitoring
by TLC).
The slurry was then cooled to 22-24°C and was basified with a mixture of NaOH flakes
(243 g) and water (1620 cc) while maintaining the temperature below 28°C. At the end
of the addition the temperature was 23 °C and the pH was 12.5. The reactor jacket was
then heated to 40°C, and the acetone of the reaction mixture was distilling off under
vacuum (40-200 mm Hg). The distillation lasted 4 hours and the jacket was then cooled
to 30°C. The triphenyl carbinol that precipitated during the distillation was filtered and
washed with water (500 mL). The mother liquor so obtained (3930 g) was returned to the
reactor and EtOAc (1250 mL) was added and stirred for 30 minutes, then the stirring was
stopped for 30 minutes and the separation of the two phases was performed. The aqueous
phase (4083 g) was returned to the reactor and was acidified with an aqueous mixture of
H2SC>4 98% (H2SC>4: water 150 g : 417 mL) while maintaining the temperature below
25°C. At the end of the addition the temperature was 25°C and the pH was 2.5. EtOAc
(5500 mL) was then added and stirred for 30 minutes, then the stirring was stopped for 30
minutes and a phase separation was performed. To the organic phase (~6600 g), sodium
sulfate (Na2SO4 450 g) was added, stirred in the reactor for 20 minutes and then the
reactor content was filtered under vacuum. The organic phase was returned to the reactor
and a distillation was performed under vacuum (10-200 mm Hg) at 40°C. The distillation
lasted 6.5 hours leading to a solid residue in the reactor. Then the vacuum was stopped
and EtOAc (3750 mL) was added while the reactor was heated to 50°C until getting a
clear solution. The heating was continued for 0.5 hours. Then the clear solution was
cooled to 32-34°C and seeded with 0.5 g of Valsartan. At the end of the addition the
stirring was maintained for 0.5 hours at 32-34°C, then cooled during 2 hours until 22-
24°C and maintained while stirring for 0.5 hours at this temperature. The slurry was then
cooled during 2 hours until 0-2°C and maintained while stirring for 0.5 hours at this
temperature. The suspension was then filtered, washed with EtOAc (500 mL) to obtain
630.3 g of wet material.
Example 16
Preparation of Valsartan Crystals
A 10 liter reactor equipped with mechanical stirrer, condenser and thermometer, was
charged with Valsartan crude wet (630 g) and EtOAc (3700 mL). The jacket was then
heated to 45°C and stirred at a rate of 400 rpm until getting a clear solution. The heating
was continued for 0.5 hours. Then the clear solution was cooled to 34-36°C and seeded
with 0.1 g of VLS. At the end of the addition the stirring was maintained for 0.5 hours at
34-36°C, then cooled during 2 hours until 24-26°C and maintained while stirring for 0.5
hours at this temperature. The slurry was then cooled during 2.5 hours until 0°C (±5°C)
and maintained while stirring for 0.5 hours at this temperature. The slurry was then
filtered and washed with EtOAc (400 mL) to obtain 549.3 g of wet material.
Example 17: Drying the wet valsartan with vacuum dryer while stirring
600 g of Valsartan prepared according to example 38 were put in the drying apparatus
while heating to 45°C under vacuum (less than 60 mm Hg). The solid was maintained for
2 hours without stirring, and then the stirrer was put on (15-20 rpm) for about 7 hours
until the loss on drying reach not more than 2%. The XRD pattern showed that the
material is essentially amorphous, and the DSC showed an endotherm with enthalpy
J/g.
Example 18: Drying the wet valsartan with vacuum dryer while stirring then
humidification with humid nitrogen
600 g of Valsartan prepared according to example 38 were put in the drying apparatus
while heating to 45 °C under vacuum (less than 60 mm Hg). The solid was maintained
for 2 hours without stirring, and then the stirrer was put on (15-20 rpm) for about 4 hours
until the loss on drying reach 6.5%. 60 g of the so obtained solid was put in a 0.5 L
reactor at 50°C under stirring (20 rpm). To this solid was flowed humidified nitrogen
during 2 hours. Then the nitrogen was stopped and the solid was put under vacuum (less
31
than 30 mm Hg) for 3 hours. The vacuum was stopped and humidified nitrogen was
flowed inside the reactor for 2 hours (humidification of the nitrogen was done by
bubbling nitrogen through a vessel of water). Then the nitrogen was stopped again and
the solid was put again under vacuum (less than 30 mm Hg) for 5 hours.
The XRD pattern showed that the material is essentially amorphous, and the DSC showed
an endotherm with enthalpy 29 J/g
Example 19: Drying the wet Valsartan with vacuum dryer while stirring then
humidification with fluidized bed.
85 g of the material obtained in example 39 (after drying with stirring and LOD=2%) was
put in the fluidized bed at 30-40°C during 13 hours. The XRD pattern showed that the
material is essentially amorphous, and the DSC showed an endotherm with enthalpy 29
Example 20: Harsh Drying.
10 g of Valsartan with loss on drying less than 10% are dried under vacuum oven (1 mm
Hg) at 60°C for 24 hours to get a compound with loss on drying less than 0.5%.
Example 21 : Harsh Drying.
10 g of Valsartan with loss on drying less than 10% are dried under vacuum oven (50 mm
Hg) at 30°C for 5 days to get a compound with loss on drying less than 0.5%.
Example 22: Harsh Drying.
10 g of Valsartan with loss on drying less than 10% are dried under vacuum oven (40 mm
Hg) at 20 °C for 5 days to get a compound with loss on drying less than 0.5%.
Having thus described the invention with reference to particular preferred
embodiments and illustrative examples, those in the art can appreciate modifications to
the invention as described and illustrated that do not depart from the spirit and scope of
the invention as disclosed in the specification. The Examples are set forth to aid in
understanding the invention but are not intended to, and should not be construed to, limit
its scope in any way. The examples do not include detailed descriptions of conventional
methods. Such methods are well known to those of ordinary skill in the art and are
described in numerous publications.

We claim:
1. A process for preparing compound G3:
(Formula Removed)

wherein A is a C1 to C4 alkyl ester and X is a trityl group, comprising the steps of: a) reacting compound G2:
(Formula Removed)

wherein L is a leaving group, with a derivative of L-valine in an organic solvent;
b) heating the reaction mixture;
c) cooling; and
d) recovering the compound G3.
2. The process as claimed in claim 1, wherein A is a methyl group.
3. The process as claimed in claim 1, wherein A is a t-butyl group.
4. The process as claimed in claim 1, wherein the organic solvent in step (a) is selected from the group consisting of acetonitrile, toluene, acetone, ethyl acetate, dimethyl acetamide, DMF, hexane and mixtures thereof.
5. The process as claimed in claim 4, wherein said organic solvent is acetonitrile.
6. The process as claimed in claim 1, wherein step (a) is carried out in the presence of an alkali metal carbonate or organic base.
7. The process as claimed in claim 6, wherein said alkali metal carbonate is potassium carbonate.
8. The process as claimed in claim 1, wherein the mixture of step (b) is heated for a period of time of about 1 and about 6 hours.
9. The process as claimed in claim 1, wherein the process is performed in the presence of a phase transfer catalyst.
10. A process for preparing compound G4:

(Formula Removed)

wherein A is a C1 to C4 alkyl ester and X is a trityl group, comprising the steps of:


a) reacting compound G3:

(Formula Removed)
wherein A is a C 1 to C4 alkyl ester and X is a trityl group, with an acylating agent in an organic solvent;
b) agitating the reaction mixture; and
c) recovering the compound G4.

11. The process as claimed in claim 10, wherein the acylating agent in step (a) is an acid chloride.
12. The process as claimed in claim 11, wherein said acylating agent is valeroyl chloride.
13. The process as claimed in claim 10, wherein the organic solvent in step (a) is selected from the group consisting of acetonitrile, toluene, acetone, ethyl acetate, dimethyl acetamide, DMF, hexane and mixtures thereof.
14. The process as claimed in claim 13, wherein said organic solvent is toluene.
15 The process as claimed in claim 10, wherein step (a) is carried out in the presence of an organic base.
16. The process as claimed in claim 15, wherein said organic base is selected from the group consisting of triethylamine, tributylamine and diisopropyl methyl amine.
17. The process as claimed in claim 10, wherein the mixture of step (b) is neutralized with an aqueous base.
18. The process as claimed in claim 17, wherein said aqueous base is NaHC03.
19. A process for preparing compound G4;

(Formula Removed)
wherein A is a C1 to C4 alkyl ester and X is a trityl group, comprising the steps of: a) reacting compound G2:
(Formula Removed)

wherein X is a trityl group and L is a leaving group, with a derivative of L- valine in an organic solvent in the presence of a phase transfer catalyst;
b) heating the reaction mixture;
c) cooling;
e) adding an acylating agent;
f) agitating the reaction mixture; and g) recovering the compound G4;
wherein steps 9a0 and (e) are carried out in the presence of an alkali metal carbonate or organic base.

20. The process as claimed in claim 19, wherein the organic solvent in step (a) is selected from the group consisting of acetonitrile, toluene, acetone, ethyl acetate, dimethyl acetamide, DMF, hexane and mixtures thereof.
21. The process as claimed in claim 20, wherein said organic solvent is toluene.
22. A process for preparing valsartan comprising the steps of:
a) reacting compound G2:
(Formula Removed)

with a derivative of L-valine in a first organic solvent to obtain a compound G3:

(Formula Removed)
b) reacting compound G3 with an acylating agent in a second organic solvent to obtain a compound G4;

o(Formula Removed)

and
c) hydrolyzing compound G4 to obtain valsartan, wherein A is a CI to C4 alkyl ester, X is a trityl group and L is a leaving group.
23. The process as claimed in claim 22, wherein the hydrolyzing step comprises:
a) dissolving compound G4, wherein A is a C1 to C4 alkyl ester and X is a trityl group, in a water-miscible solvent;
b) acidifying the solution;
c) adding an aqueous basic solution and evaporating the water-miscible solvent to obtain a precipitated trityl group;
d) separating the precipitate and acidifying the remaining mixture;
e) extracting the mixture;
f) dissolving the extract in an organic solvent;
g) cooling the solution; h) evaporating the solvent; and
i) recovering valsartan.
24. The process as claimed in claim 23, wherein the water-miscible solvent is selected from the group consisting
of acetone, methyl ethyl ketone (MEK), acetonitrile, tetrahydrofuran (THF) and dioxane.
25. The process as claimed in claim 24, wherein said water-miscible solvent is acetone.

26. The process as claimed in claim 23, wherein the aqueous basic solution added in step (c) is selected from the group consisting of potassium hydroxide, potassium carbonate and sodium hydroxide.
27. The process as claimed in claim 23, wherein the mixture of step (d) is acidifying to a pH of about 3.
28. The process as claimed in claim 23, wherein the solution of step (d) is acidified using acids selected from the group consisting of mineral acids, hydrogen sulfate, trifluoroacetic acid, formic acid, hydrobromic acid and acetic acid.
29. The process as claimed in claim 23, wherein the mixture of step (d) is extracted with ethyl acetate.
30. The process as claimed in claim 23, wherein the organic solvent of step (f) is selected from the group consisting of C1-C4 alcohol, acetone and acetonitrile.
31. The process as claimed in claim 30, wherein said organic solvent is methanol.
32. The process as claimed in claim 23, wherein the solution of step (0 is cooled to a temperature of about-10 and about 15°C.
33. The process as claimed in claim 32, wherein the solution of step (f) is cooled to a temperature of about 0 and about 4°C.
34. The process as claimed in claim 23, further comprising neutralizing the mixture of step (g) with a base.
35. The process as claimed in claim 34, wherein said base is KOH.
36. The process as claimed in claim 22, wherein the hydolysis is performed in the presence of a phase transfer catalyst.
37. The process as claimed in claim 22, which is an industrial process.
38. The process as claimed in claim 22, further comprising the steps of: a) crystallizing the valsartan obtained in step (c) from an organic solvent; b) drying the valsartan to have less than about 10% by weight organic solvent; c) triturating the valsartan in water.
39. The process as claimed in claim 38, wherein the valsartan of step (f) is triturated in about 4 to about 30 volumes of water per 1 gr of valsartan, for a period of time of about 5 and about 48 hours.
40. The process as claimed in claim 38, wherein the valsartan prepared has less than about 0.10% of D-isomer.
41. The process as claimed in claim 40, wherein the D-isomer is present at about 0.07% as area percentage HPLC.
42. The process as claimed in claim 22, further comprising the steps of: a) crystallizing the valsartan obtained in step (c) from an organic solvent; b) drying the valsartan to have less than 10% by weight organic solvent; and c) contacting the valsartan with humid air in a fluidized bed drier.
43. The process as claimed in claim 42, wherein the atmosphere in the fluidized bed drier is at least 30% humidity.
44. The process as claimed in claim 22, further comprising the steps of: a) crystallizing the valsartan obtained in step (c) from an organic solvent; b) drying the valsartan to have less than about 10% by weight organic solvent; and c) maintaining the valsartan at a temperature of from about 5 to about 60°C under pressure of less than about 30mmHg for a period of from about 1 to 5 days.
45. The process as claimed in claim 44, wherein the valsartan of step (f) is maintained under pressure of less than about lOmmHg.
46. The process as claimed in claim 45 wherein the valsartan of step (f) is maintained under pressure of less than about ImmHg.

47. The process as claimed in claims 38,42 and 44 wherein the organic solvent is selected from the group consisting of ethyl acetate, butyl acetate, diisopropyl acetate, dichloromethane and acetone.
48. The process as claimed in claim 47, wherein the organic solvent is ethyl acetate.
49. The process as claimed in claims 38,42 and 44 wherein the valsartan of step (e) is dried at a temperature of from about 5 to about 60°C.
50. A process for preparing L-valsartan comprising the steps of: a) heating trityl valsartan in methanol in the absence of an acid to hydrolyze the trityl group in solution; b) cooling the solution to precipitate the trityl group; and c) recovering the L-valsartan.
51. The process as claimed in claim 50, wherein the heating is carried out to about reflux temperature.
52. The process as claimed in claim 50, wherein the valsartan is recovered by evaporation of the methanol.
53. The process as claimed in claim 50, wherein the cooling is carried out to a temperature of about 10 to about-20°C.
54. The process as claimed in claim 50, wherein the process results in a level of D-isomer of less than about 0.4% as area percentage HPLC.
55. A process for preparing L-valsartan from trityl valsartan comprising the steps of:

a) stirring a heterogeneous mixture of valsartan in water and acetone;
b) basifying the mixture
c) removing the acetone;
d) filtering the water to remove the trityl group;
e) extracting the water at acidic pH with ethyl acetate; and
f) removing the iso-butyl acetate.

56. The process as claimed in claim 55, wherein the removing is carried out with evaporation.
57. The process as claimed in claim 55, wherein the pH is of from about 2 to about 5.
58. The process as claimed in claim 55, wherein the process results in about 0.4% of D-isomer.
59. A process for preparing valsartan comprising the steps of:
a) reacting compound G2:
(Formula Removed)
wherein X is a trityl group and L is a leaving group, with a derivative of L- valine in an organic solvent;
b) heating the reaction mixture;
c) cooling;
d) recovering the compound G3:
(Formula Removed)

wherein A is a C1 to C4 alkyl ester; and

e) converting the product of step (d) to valsartan. 60. A process for preparing valsartan comprising the steps of: a) reacting compound G3:

(Formula Removed)

wherein A is a CI to C4 alkyl ester and X is a trityl group, with an acylating agent in an organic solvent;
b) agitating the reaction mixture;
c) recovering the compound G4:
(Formula Removed)
and
d) converting the product of step (c) to valsartan. 61. A process according to claim 60 wherein compound G4 is prepared by the process comprising the steps of:

a) reacting compound G2, wherein X is a trityl group and L is a leaving group, with a derivative of L-valine in an organic solvent selected from the group consisting of acetonitrile, toluene, acetone, ethyl acetate, dimethyl acetamide, DMF, hexane and mixtures thereof with an alkali metal carbonate or organic base;
b) heating the reaction mixture;
c) cooling;
d) recovering the compound G3, wherein A is a C1 to C4 alkyl ester and X is a trityl group;
e) reacting the product of step (d) with an acylating agent in an organic solvent selected from the group consisting of acetonitrile, toluene, acetone, ethyl acetate, dimethyl acetamide, DMF, hexane and mixtures thereof, and an organic base is selected from the group consisting of tnethylamine, tributylamine and diisopropyl methyl amine;
f) agitating the reaction mixture; and
g) recovering the compound G4.
62.Valsartan having less than 0.1% as area percentage HPLC of the corresponding D-isomer prepared by the process as claimed in any preceding claim.
63. The valsartan as claimed in claim 62 wherein the D-isomer is present in less than 0.07% prepared by the process as claimed in any preceding claim.