Kilomentor
has already written educational blog articles treating the preparation of some
particular pharmaceutical salt types as well as making pharmaceutical salts in
general. Besides a general blog article, The Complete Blog for the
Preparation of Pharmaceutical Salts. Other Kilomentor blogs have appeared
for hydrochlorides, sulfates, and phosphates.
All of these are strong acids, which can be considered for making salts
with both weak and strong bases. Herein,
I have provided selected examples from patent applications that teach
experimental details for making benzenesulfonic acid salts also called
besylates. With the assistance of these
citations nothing more than ordinary laboratory skill should be needed to
prepare a besylate of most bases. Whether that salt will be crystalline is a
matter for empirical, but routine, experimentation. To quickly and easily see
the actual structure of the free base substance look to the original patent
document. The goal here is to lay out the reagents and experimental conditions.
WO1998054186A1
New
trans-5-chloro-tetrahydro-2-methyl-1H-dibenzoxepino-pyrrole - in aromatic
sulphonic acid salt form, useful in depot compositions for treatment of e.g.
central nervous system disorders.
EXAMPLE
I
A solution of 940 mg of benzenesulphonic acid in 15 ml of ethanol was added to
a solution of 1.7 g of trans- 5 -chloro-2,3,3a, 12b-tetrahydro- 2-methyl- I
H-dibenz[2,3:6,7] - oxepino[4,-c]pyrrole. Crystallization occurred, and the
crystals obtained were collected and recrystallized from 75 ml of boiling
ethanol. After cooling to 20°C the crystals were collected and dried in vacuo over calcium chloride and
potassium hydroxide. Yield: 1.9 g (72%) of trans-5- chloro-2,3,3a,12b-tetrahydro-2-methyl-IH-dibenz[2,3:6,7]oxepino[4,5c]
pyrrole benzenesulphonate (besylate). This salt was found to have a melting
point of 227.8°C and a solubility in water measured at 20°C of <<1 mg/ml.
WO2000032607A1
New
non-hygroscopic, thermally stable, crystalline salts of known carbapenem
antibiotic
wherein
R- is selected from Tosylate, Benzenesulfonate/Besylate, Naphthalenesulfonate, Napsylate,
Saccharate, Alizarate Each of these salt
forming anions are well known in the art and known to be non-toxic and
pharmaceutically acceptable.
A
process for the preparation of the salts of this invention comprises treating a
solution of Compound I with an alkali metal salt of formula M+ R-, wherein M+
is an alkali metal cation. A group of alkali metal cations includes sodium
(Na+), potassium (K+) and cesium (Cs+). A sub-group includes Na+ and K+, and
exemplary of this sub-group is Na+.
The counter ion associated with Compound I forming the starting material for
the process of this invention includes any counter ion, X- that will provide a
water soluble salt thereof. A group of such counter ions includes chloride,
triflate, hemisulfate, mopsylate (4-morpholinepropanesulfonate), bromide,
acetate and mesylate. A sub-group includes chloride and triflate; exemplary of
this sub-group is triflate.
The temperature at which the reaction is conducted is not critical. However,
because of the limited stability of the Compound I starting material, the
reaction temperature should be maintained at about 5 to about 25°C, and room
temperature (about 15 to about 25°C) is convenient. In one embodiment
of the process of this invention, a solution of Compound I suitable for
treatment with the alkali metal salt MR is obtained in the last step in the
synthesis of Compound I which involves the hydrogenolysis of an activated ester
of Compound I such as the p- nitrotolyl , benzyl, allyloxy, or p- methoxybenzyl
ester.
EXAMPLE
Hydrogenation of penultimate bis triflate and crystallization of the
benzenesulfonate
A
buffered solution of 4- morpholinepropanesulfonate was prepared by dissolving
2941 g in 58mL of water followed by addition of approximately I. 5N NaOH,
resulting in a final solution pH of 7.2. This solution was then added to 5000g
of penultimate bis triflate, and then 58L isopropanol was added. The resulting
pH of the slurry was 6. 9 The mixture was degassed and then 1250g 5% Pd/C added
and the system placed under hydrogen (40psi) until the reaction was done. The
resulting pH of the solution after reaction was 6.3.
The catalyst was filtered off and the cake slurry washed with 25L water. The
filtrate was immediately cooled to 5°C to improve the stability of the
Compound I cation.
The filtrate was washed with toluene (25L) and the layers separated.
The separation was done at 5-10°C, gave a clean cut, but required a 15
minute age to settle.
The washed filtrate was added to a solution of sodium benzenesulfonate (12.5kg)
in 37.5L water at 20°C.
The filtrate and aqueous sodium benzenesulfonate were added via a syringe
equipped with a 0.45 µm syringe filter to
remove nefloss. The pH of the aq. sodium benzenesulfonate solution was checked
before adding the washed filtrate and adjusted to 6.3 with an appropriate
amount of 0.002M TfOH solution. The resulting slurry was cooled to 5°C and filtered,
slurry washed with 1: 1 IPA:water and then water.
The solid was dried under nitrogen at ambient temperature.
Employing
the procedure substantially as described in the above EXAMPLE, but substituting
for the sodium benzenesulfonate used therein, an equimolar amount of an alkali
metal salt of an anion, R-, wherein R- is selected from tosylate, napsylate,
saccharate and alizarate, there was produced the corresponding salt of Compound
1.
WO2003043635A1
New
crystalline hydrate, anhydrate and amorphous forms of amlodipine besylate
useful for the treatment or prevention of e.g. hypertension, angina pectoris
Example
1 - Dihydrates 10
1
(a). 2 g of amlodipine besylate salt was dissolved in 50 ml of water at reflux.
The solution was allowed to cool to room temperature. After standing for 1
night at room temperature, the solid was filtered off and washed with 2 ml of
water. The solid was dried in a vacuum oven at about 25°C for 2 days. The
material gives an IR spectrum as shown in figure 1.
l
(b). 735.1 mg of the product of example l (a) was dried in a vacuum oven at
40°C for 65 hours. The weight loss was 0.043 g or 5.85%, which corresponds to
1.9 moles of water per mole of amlodipine. This anhydrate of the corresponding
dihydrate form gives an IR as shown in figure 2.
1.(c).
A sample of the anhydrate formed in example 1 (b) was exposed to air and the
weight gain recorded as follows: Weight at start: 103.1 mg Weight after 30 min
105.7 mg Weight after 1 hour 107.3 mg
Weight after 3.5 hour 109.3 mg Weight after 21 hour 109.3 mg Total weight gain
of 6.2 mg or 6.0 %, which corresponds to two moles of water taken up for one
mole of amlodipine. This re-formed dihydrate has an IR spectrum as shown in 5
figure 3.
l(d).
A sample from example l(a) was annealed for 10 minutes at 90°C while another
sample of the same product was annealed for 30 minutes at 145°C. In both cases
the dihydrate was converted to the known anhydrate form as shown by IR. The IR
for the sample annealed for 10 minutes is as shown in figure 4 and the IR for
the sample to annealed for 30 minutes is as shown in figure 5.
l(e)
149.12 mg amlodipine besylate anhydrate was suspended in 3 ml water and was
shaken at 37 °C at 60 RPM for 48 hours. The suspension was allowed to cool to
room temperature and the solid was isolated by filtration and dried under
vacuum for three hours. This leads to amlodipine besylate dihydrate. The
material gives an IR spectrum 15 similar to figure 1.
Example
2 - Monohydrates
2(a).
4 g of amlodipine besylate salt was added to 200 ml of water, which was heated
to 90°C. A solution was obtained, which was allowed to cool to room
temperature. At 20°C, 2 ml of the clear solution was taken out and put in a
test-tube. The test- tube was placed in a water bath at 20 °C and amlodipine
besylate readily crystallized. 1 drop of the suspension from the test-tube was
added to the remaining amlodipine besylate solution (at 58°C). Crystallization
started at 55 °C. After the suspension was cooled down to 20 °C, the solid was
isolated by filtration and washed with 2 x 2 ml of water and dried in a vacuum
oven at 40°C for 16 hours to form a substantial or complete anhydrate of the
monohydrate crystal. The yield was 3.18 g of an amlodipine besylate having a
melting point on DSC at 92. 1-103.9 °C; solidifies at 119.1-130.0 °C; melting
and degradation at 196.0-202.4 °C. (rate 5 °C/min). The material has an IR as
shown in figure 6.
2.(b).
A sample of the dried amlodipine besylate from example 2(a) was exposed to air
and the weight gain recorded as follows: Weight at start: 318.6 mg 10 Weight
after 30 min 320.3 mg Weight after 1 hour 323.9 mg Weight after 3.5 hour 328.2
mg Weight after 21 hour 328.2 mg Total weight gain was 6.2 mg or 3.0 wt %,
which corresponds to one mole of water being taken up for one mole of amlodipine.
Thus, the material is a monohydrate and has an IR as shown in figure 7.
2.(c).
1.9 g of benzenesulfonic acid XH2O was dissolved in water. The solution was
heated to 40°C. At 40°C, while stirring, 4.0 g of amlodipine free base was
added portionwise in 10 minutes. The resulting suspension was stirred at 40°C
for I hour and allowed to cool to room temperature (without stirring) and set
aside at room temperature for 16 hours. The solid was filtered off and washed
with 5.0 ml of water. The solid was dried in a vacuum oven at 40°C for 16
hours. The yield was 5.4 g of an amlodipine besylate monohydrate salt having an
IR as shown in figure 8.
Example
3 - Powder X-ray diffraction Sample of amlodipine dihydrate from example l(a)
and amlodipine monohydrate from example 2(a) (having been sufficiently exposed
to air) were subjected to x-ray powder diffraction (powder-XRD). For
comparison, an amlodipine besylate anhydrate corresponding to the known form
was also subjected to powder- XRD. The results are shown in figures 9A-9C
wherein 9A is the known anhydrate form, 9B is the dihydrate form and 9C is the
monohydrate form. Both hydrate forms have a peak around 33-34 degrees and a
peak at about 37 degrees while the known anhydrate has neither. Indeed, the
dihydrate and monohydrate crystalline forms of the present invention can be
distinguished from each other and the known anhydrate form based on these, and
other, peaks in the powder XRD. A preferred embodiment of the present invention
is a crystalline amlodipine besylate having an X-ray diffraction peak in at
least one of the 33-34 degree range or about 37 degrees. Such a crystal may
contain bound water or not. In some embodiments, such a crystal preferably may
add or lose bound water without significantly changing the crystal lattice and
most preferably may add or lose bound water reversibly the same amount; i.e.,
the monohydrate based crystal takes up about one equivalent of water into the
lattice but not 2 equivalents.
Example
4
150 ml of water was heated to reflux whereupon 35 g of amlodipine besylate was
added and l 5 ml of water was used to wash the powder funnel. A clear solution
was obtained. The solution was set aside at 60°C. After 4 hours standing at
60°C, the solution was inoculated (seeded) with dihydrate salt from example
l(a) and set again at 60.C. After 1 night at 60°C the formed solid was filtered
off and washed with 2 x 20 ml of water and dried in a vacuum oven at 40°C. The
yield was 30.5 g of the known amlodipine besylate anhydrate having an IR as
shown in figure 10.
Example
5
200.mg of amlodipine besylate was dissolved in water at reflux. The hot
solution was cooled in a dry-ice-acetone bath. The frozen solution was
freeze-dried resulting in an amorphous amlodipine besylate salt form having an
IR as shown in figure 11.
Example
6
Crystallization of amlodipine besylate hydrates from ethanol/water 6(a) 8. 57 g
of amlodipine besylate was added to 25 ml of ethanol/water (50/1 v/v) in a 100 ml round-bottomed flask. The
flask was heated on a water- bath at 40°C until the solid was dissolved. The
solution was filtered through a 0.45 Micron filter and the filtrate was set in
a water- bath, which was heated to 40°C every three hours for a period of one
hour. The solution was allowed to evaporate partly during this heating and
cooling. After 1 night, a small crystal was formed. The flask was removed from
the water-bath and was allowed to cool to room temperature. After three days,
the flask was filled with big, square flat crystals. The crystals were analyzed
to confirm the dihydrate form and were used to measure single crystal X-ray
diffraction pattern.
6.(b)
1.5
g amlodipine besylate monohydrate was suspended in 4.0 ml ethanol and 6.0 ml
water. The mixture was heated to 70°C. A clear solution was obtained. The
solution was placed in a water-bath at 35°C and the water-bath was allowed to
slowly cool to room temperature. After 16 hours, the temperature was 25.8 °C,
no crystals were formed. The solution was seeded with a few crystals of the
monohydrate. Crystallization started. After 2 days, a few crystals were taken
out of the flask and dried on air for 1 hour. I.R. spectrum was measured.
(monohydrate). The flask containing the crystals was used to measure single
crystal X-ray diffraction pattern.
Example
7 Amlodipine besylate monohydrate 7(a)
35 g benzenesulfonic acid was dissolved in 600
ml water and heated to 70°C. 10 g of
amlodipine base was added and the resulting suspension was heated to 85°C. It
became a clear solution. The solution was stirred for 30 minutes at 85°C and
allowed to cool to room temperature while stirring. At 50°C the solution was
seeded with a few crystals of amlodipine besylate monohydrate. Crystallization
started very quick and very small particles were obtained. After cooling the
suspension to room temperature it was stirred for 2 hours at room temperature.
The solid was isolated by filtration and washed with 2xlSO ml water. Dried in a
vacuum oven at 40°C. Yield: 120 g very fine white powder. Water content
(K.Fischer titration): 3.09% (1 equivalent). Particle size <20 m.
7(b)
180 g amlodipine was- suspended in 1000 ml water and heated to 60 °C. 70 g
benzenesulfonic acid was dissolved in 200 ml water and added to the suspension.
The resulting mixture was heated to 85°C and stirred for 30 minutes. It became
a clear solution. The stirred solution was allowed to cool to 65 °C and was
seeded with 100.mg of amlodipine besylate monohydrate. Crystallization started
and the suspension was allowed to cool slowly to room temperature. After
cooling to room temperature, the suspension was set aside for 16 hours. The
solid was isolated by filtration and washed with 2 x 200 ml water. Dried in a
vacuum oven at 40°C for 2 days, the solid was exposed to air for 1 day. Yield:
249 g. Water content ( K.Fischer titration): 3.09 % (1 equivalent).
Particlesize:<250 m.
7.(c)
900 g amlodipine was suspended in 5 I water and heated to 60°C. 350 g
benzenesulfonic acid was dissolved in water and added to the suspension. The
resulting mixture: was heated to 85°C and stirred for 30 minutes. It became a
clear solution. The stirred solution was allowed to cool to 65°C and was seeded
with 200 mg amlodipine besylate monohydrate crystals. Crystallization started
and the suspension was allowed to cool slowly (16 hours) to room temperature.
After cooling to room temperature the solid was isolated by filtration and
washed with 2 x 1 I water. Dried in a vacuum oven at 40°C for 2 days. The solid
was then exposed to air for 1 day. Yield: 1.25 kg Amlodipine besylate 15
monohydrate.;
7(d)
Improvement of colouration ' 7(d)(1) 2.5 g of amlodipine besylate monohydrate
from the above experiment 7(c): was dissolved in 15 ml water at 85°C and 250 mg
charcoal was added. The resulting suspension was stirred for 10 minutes at
85°C. The hot suspension was filtered over a 20 hot filter with Celite. The
filtrate was allowed to cool to room temperature. The solid that was formed was
isolated by filtration and dried in a vacuum oven at 40°C for 1 night. A white
crystalline powder was obtained. IR spectrum revealed the structure of I
amlodipine besylate monohydrate.
7.(d)(2)
200 mg of amlodipine besylate monohydrate from the above experiment 7(c) was
suspended in 1 ml tert-butylmethylether. The suspension was set aside for 2 hours.
The solid was isolated by filtration and dried in a vacuum oven at 40°C for 1
night. A white crystalline powder was obtained. IR spectrum revealed the
structure of amlodipine besylate monohydrate.
7.(d)(3)
250 mg of amlodipine besylate monohydrate from the above experiment (7c) was
suspended in 2 ml of ethyl acetate/n-hexane 1:1 (v/v) mixture saturated with
water. After 5 minutes, the solid was isolated by filtration and dried at air
for 2 hours.
A white crystalline powder was obtained. Yield: 240 mg. IR spectrum revealed
the structure of amlodipine besylate monohydrate.
Example
8 (Reference)
Crystals
of the known prior art anhydrous amlodipine besylate suitable for X-ray
diffraction studies were prepared. A single crystal was mounted in air on a glass
fiber.
WO2003082293A1
New
benzenesulfonate salt of a morpholine urea derivatives having CCR-3 antagonist
activity useful for treating inflammatory conditions e.g. asthma and rhinitis
In
a further aspect of the invention, there is provided a process for the
preparation of a compound of formula (I), which process comprises the reaction
of a compound of formula (Ial) with a source of the besylate anion and a
suitable C-6 alkanol and water.
Suitable sources of the besylate anion are benzenesulphonic acid and besyiate
salts such as ammonium besylate. A preferred source of the besylate anion is
benzenesulphonic acid.
Typically, the compound of formula (IA) is suspended in a suitable C1-6
alkanol, suitably ethanol or isopropyl alcohol, and water at elevated
temperature, suitably a temperature in the range 35 - 45°C. A solution of the
source of besylate anion, preferably benzenesulfonic acid, in water is added. A
suitable anti solvent, suitably isopropyl acetate, is optionally added to the
solution and the mixture is cooled to 0- 25°C. A suitable non-polar solvent
such as an aliphatic hydrocarbon, e.g cyclohexane may optionally be added. The
mixture may optionally be seeded with crystals of the compound of formula
(I)..The mixture is maintained at a reduced temperature for a suitable period
of time to allow crystallization of the product, and isolated by filtration.
Suitable seed crystals of the compound of formula (I) may be prepared by
spontaneous crystallization of a mixture of compound of formula (IA) and
benzenesulphonic acid from aqueous C1-6 alkanol mixtures at reduced
temperature, suitably 0 to 25°C.
Example
1:
4-([;,r((2S)-4-(3,4-
dichlorobenzyl)morpholin-2-ylmethyll amino)carbonyllaminolmethyl) benzamide
benzenesulfonate dihydrate
4-({[;({[;(2S)-4-(3,4-
dichlorobenzyl)morpholin-2-y,];methyl} amino)carbonyl];amino} -methyl)benzemide
(15g) was suspended in ethanol (60ml) and water (7.5ml) at 40°C. A solution of
benzenesulfonic acid (6.0g) in water (7. 5ml) was added, followed by addition
of further water (1 5ml). Isopropyl acetate (300ml) was added at 40°C, followed
by addition of ethanol (40ml). The mixture was cooled 20 to 0°C, diluted with
cyclohexane (10 ml) and seeded with authentic
4-({[;({[;(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl];methyl}amino)carbonyl];
amino}methyl) benzamide benzenesulfonate hydrate. The mixture was chilled at 0
°C over 1 h, cyclohexane (100ml) added over 15min and the mixture aged at 0°C.
The product was isolated by vacuum filtration, washed with isopropyl acetate (2
x 25-30ml) and dried in vacuo about 25°C to give the title compound as a white
solid (16.44g).
Example2:
4-(n(T,r(25)-4-(3.4-dichlorobenzyl)morpholin-2-
yllmethyl: amino)carbonyl1aminolmethvi)benzamide benzenesulfonate dihydrate
The
slurry of Description 9 was cooled to 50 plus or minus 3C° and isopropanol
(30ml) added, followed by an aqueous solution of benzenesulfonic acid (32% w/v,
10ml). The mixture was cooled to 22 plus or minus 3°C over ca 1 h, seeded with
authentic 4- ({[;({[;(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl];methyl} amino)
carbonyl];amino}methyl) benzemide hydrate and aged at 22°C for 72 h. The
mixture was cooled to 0 over 1h and filtered. The filter cake was washed with a
4:1:0.1 mixture of isopropyl acetate/isopropyl alcohol/water (2.5ml) and dried
in vacuo at 25°C to give the title compound as a white solid (6.9g).
Example
3:
4-(((2S)-4-(3,4-dichlorobenzvl)morpholin-2-yl1methyll
amino) carbonyllaminolmethvl)benzamide benzenesulfonate dihvdrate
A
solution of 1-[;(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]; methylamine (60g)
in tetrahydrofuran (120ml) was added to a suspension of carbonyl diimidazole
(38.8g) in tetrahydrofuran (600ml) over 25min at O - 5°C. The mixture was
warmed to 10-15°C, and held for 15min. Isopropanol (30ml) was added over 10
min, and the mixture was stirred for a further 45 min at 10-15°C. 4 Aminomethyl
benzamide (35.9g) was added, and the mixture was heated to 55-60°C, and held
for 90min. Tetrahydrofuran (240ml) was removed by distillation, and the mixture
was cooled to 20-25°C. The mixture was treated with isopropyl acetate (480ml)
and 5% aqueous potassium dihydrogen phosphate (480ml), and the aqueous phase
was removed. The organic phase was washed with further 5% aqueous potassium
dihydrogen phosphate (2 x 480ml), and finally water (480ml). The organic phase
was concentrated to 250ml by distillation, diluted with isopropanol (850ml),
and reconcentrated to a final volume of 420 ml. The mixture was cooled to
20-25°C, treated with a solution of benzenesulfonic acid (38.5g) in water
(110ml) and warmed to 35°C. Isopropyl acetate (720ml) was added, the mixture
was cooled to 20-25°C, and seeded with authentic 4 ({[; ({[;(2S)-4-
(3,4-dichlorobenzyl)morpholin-2-yl];methyl}amino) carbonyl];amino} methyl)
benzamide benzenesulfonate dihydrate. The mixture was stirred for 3h at this
temperature, treated with further isopropyl acetate (180ml), stirred for 30min
and cooled to 0-5°C
. The product was isolated by vacuum filtration, washed with isopropyl
acetate:isopropanol:water (6:1:0.1, 350ml) and dried n vacuo at 35 plus or
minus 5C° to give the title compound as a white solid (115.6g).
WO2004007485A1:
BESYLATE SALTS
New
crystalline forms of
6-fluoro-8-(4-methylpiperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(4-(4-propionyl-piperazin-1-yl)-phenyl)-amide besylate salts
Example
6.
Compound I Besylate Form V
A
mixture of Compound I besylate (Form II) (100mg) and acetonitrile (I ml) was
stirred overnight at room temperature. The solid was collected by filtration
and washed with acetonitrile (0.5 ml). The yield of Compound I besylate was 92
ma.
The crystals were analysed by XRPD.
Example
3. Compound I Besylate Form II.
A
mixture of Compound I free base (378 mg), 90% benzenesulphonic acid acid (123
mg), dimethylsulfoxide (2 ml) and ethanol (10 ml) was heated at 80°C to give a
clear solution.
The solution was cooled to room temperature, diluted with more ethanol (5 ml)
and the solvent allowed to evaporate over 3 days. The residual gum was stirred
with ethanol (6 ml) for two days at room temperature. The solid was filtered
off, washed with ethanol (2 ml) then dried overnight to a constant weight. The
yield of Compound I besylate was 351 mg.
Example
2. Compound I Besylate Form I
A
mixture of Compound I free base (378 mg), 90% benzenesulphonic acid (122 mg),
tetrahydrofuran (30 ml) and water (2 ml) was heated at 70°C to give a clear
solution. The solution was cooled to 23°C and stirred overnight. The solid was
filtered off, washed with tetrahydrofuran (2 ml; and dried overnight in vacuo
at 65°C. The yield of Compound I besylate was 378 mg.
The crystals were analysed by XRPD.
Example
4. Compound I Besylate Form III.
A
mixture of Compound I free base (378 mg), 90% benzenesulphonic acid (122 mg)
and methanol (5 ml) was heated at 50 °C to give a clear solution. The solution
was cooled and stirred overnight at room temperature. The solid was filtered
off, washed with methanol (2 ml) and dried overnight in vacuo at 65°C. The
yield of Compound I besylate was 260 mg.
The crystals were analysed by XRPD.
Example
5. Compound I Besylate Form IV.
A
mixture of Compound I besylate (Form III) (100mg) and acetonitrile (I ml) was
stirred overnight at room temperature. The solid was collected by filtration
and washed with acetonitrile (0. 5ml). The yield of Compound I besylate was 94
mg.
The crystals were analysed by XRPD.
WO2004106344A2
New
amorphous salts of clopidogrel including clopidogrel mesylate, clopidogrel
besylate and clopidogrel tosylate, and crystalline salt of clopidogrel,
clopidogrel besylate useful for treating e.g. atherosclerosis
Experiment
5 Preparation of Clopidogrel besylate amorphous form
Clopidogrel
base was dissolved in acetone to obtain a clear solution. Then benzenesulfonic
acid was added to the solution at 20 C. The reaction mixture was heated to
reflux temperature for 2 to 10 hours. The solvent was evaporated to dryness
under reduced pressure to obtain the title salt as a powder m. p: 86-95 C
(soften) XRD: Amorphous DSC: No melting peaks s % water: 0. 5-4% by weight.
(obtained in different batches).
Example
6
Preparation of Clopidogrel besylate amorphous form
Clopidogrel
base was dissolved in methanol to obtain a clear solution. Benzenesulfonic acid
was added to the solution at 20°C. The reaction mixture was heated to reflux
temperature for 2 to 10 hours. The solvent was evaporated to dryness under
reduced pressure to obtain the title compound m. p.: 84-93 C (soften) XRD:
Amorphous lo DSC: No melting peak % water: 0. 5-4% by weight (obtained in
different batches).
Similarly, the same salt was prepared in THF, acetonitrile and other similar
solvents either alone or as a mixture of two or more solvents described
elsewhere in the specification.
Example
7
Preparation of Clopidogrel besylate amorphous form
Clopidogrel
base was dissolved in methanol. Benzenesulphonic acid was added to the solution
at 20°C. The reaction
mixture was heated to reflux temperature for 2 hours. The solution was cooled
to room temperature and was added drop-wise to diethyl ether. The suspension
was stirred at RT. The solid was filtered and dried in a vacuum oven to give
Clopidogrel besylate, similar to that obtained above.
Similarly, the same salt was prepared using acetone, acetonitrile and other
similar solvents either alone or as a mixture of two or more solvents described
elsewhere in the specification.
Example
8
Preparation of Clopidogrel besylate amorphous form
Clopidogrel
base was dissolved in methanol. Benzenesulphonic acid was added to the solution
at 20°C. The reaction
mixture was heated to reflux temperature for 2 hours. The solution was cooled
to room temperature and the methanolic solution was added drop-wise to the
boiling toluene. The resulting solution was refluxed for an additional 20
minutes. The solution was cooled to room temperature and was stirred at this
temperature for extended hours. The solvent was evaporated under reduced
pressure to dryness to obtain Clopidogrel besylate, similar to that obtained
above.
Similarly, the same salt was prepared using acetone, acetonitrile and other
similar solvents either alone or as a mixture of two or more solvents described
elsewhere in the specification.
Example
9
Preparation of Clopidogrel besylate crystalline form
Clopidogrel
besylate amorphous was stirred in diethyl ether at 20°C . The obtained
white solid was collected by filtration, washed with diethyl ether and dried.
in a vacuum oven to obtain Clopidogrel besylate in crystalline form. m.p.:
126-130°C(range obtained
from different batches).
XRD: Crystalline DSC: 127.5 - 132.9 C % water: 0.1-0.3 % by weight (range
obtained from different batches) The above process for preparing Clopidogrel
besylate crystalline form, is carried out using different ethers wherein each
alkyl radical of the ether is independently selected from the group consisting
of methyl, ethyl, propyl, isopropyl, butyl, 1- butyl, 2-butyl and t-butyl or
mixtures thereof.
Example
10
Preparation
of Clopidogrel besylate crystalline form
Clopidogrel besylate amorphous was stirred in
n-heptane at 20 C. The obtained white solid was collected by filtration, washed
with n-heptane, and dried in a vacuum oven to obtain Clopidogrel besylate in
crystalline form. m. p: 125-130 C (range obtained from different batches).
XRD: Crystalline DSC: 125.5 - 130.9 C % water: 0.1-0.3 % by weight (range
obtained from different batches).
Similarly, Clopidogrel besylate crystalline form was prepared in hexane,
n-heptane, cyclohexane, petroleum ether as solvents as well as their mixtures.
Example
11
Preparation
of Clopidogrel besylate crystalline form;
Clopidogrel
base was dissolved in diethyl ether at 20-25 C. To this was added benzene
sulphonic acid dissolved in diethyl ether. The reaction mixture was stirred at
25-30 C for 24-30 furs. The white solid was collected by filtration, washed
with diethyl ether, and dried at 50-60 C in a vacuum oven to obtain Clopidogrel
besylate crystalline form m.p.: 124-130 C (range obtained from
differentbatches).
XRD: Crystalline DSC: 128.9- 132.7 C % water: 0.2 % The above process for
preparing Clopidogrel besylate crystalline form, is carried out using different
ethers wherein each aLkyl radical of the ether is independently selected from
the group consisting of methyl, ethyl, propyl, isopropyl, butyl, 1-butyl,
2-butyl and t-butyl or mixtures thereof.
WO2005075454A2
New
acid addition salt of
4-((4-methyl-1-piperazinyl)methyl)-N-(4-methyl-3-((4-(3-pyridinyl)-2-pyrimidinyl)amino)phenyl-benzamide
e.g. succinate or benzoate useful in the treatment of tumor disease
Example
9
pyrimidinyl];amino];phenyl];-
benzamide, benzenesulphonate 4-[;(4-Methyl-1 - piperazinyl)
methyl];-N-[;4-methyl-3-[;[;4-(3-pyridinyl)-2- pyrimidinyl];amino];
phenyl];-benzemide (4.94 g,10 mmol) is added to a solution of benzenesulphonic
acid (Fluke, Buchs, Switzerland; 1.61 g,10 mmol) in hot toluene (40 mL).
The
solution is evaporated to dryness under reduced pressure and the resulting
residue is re-crystallized from ethanol - ethylacetate. The product is
filtered-off and dried to afford 4-[;(4-methyl-1 - piperazinyl)
methyl];-N-[;4-methyl-3-[;[;4-(3-pyridinyl)- 2-pyrimidinyl];amino];phenyl];-
benzemide, benzenesulphonate as a pale-yellow crystalline solid, having the
following analytical properties: Analysis found: C, 64.19; H. 5.68; N. 14.93;
S. 4.87%; H2O, 0. 34%.
Calculated
for C35H37N7O4S - 0.12 H2O: C, 64.28; H. 5.74; N. 14.99; S. 4. 90%; H2O, 0.33%.
WO2005051394A1
New
benzenesulfonate salt of
4-(bis(2-methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4-
methoxyphenyl)-(1,5-alpha)-pyrazolo-1,3,5-triazine is corticotropin releasing
factor receptor antagonist useful to treat e.g. anxiety and depression
Example
7: Preparation of Polymorph H-1 [;00451 Polymorph H-1 was prepared by
recrystallization of the crude material from Example 5 with three volumes of
isopropyl acetate at 60°C and cooled slowly to 10°C where the product was
collected by filtration.
WO2006019668A2
New
(1S,5S)-3-(5,6- dichloropyridin-3-yl) -3,6-diazabicyclo- (3.2.0)heptane
benzenesulfonate useful to treat pain and to ameliorate or prevent disorders
affected by nicotinic acetylcholine receptors e.g. Alzheimer's disease.
To
prepare (lS,5S)-3-(5,6-dichloropyridin-3-yl)-3,6- diazabicyclo[;3.2.0]; heptane
benzenesulfonate,
(1
S,SS)-3-(5,6- dichloropyridin-3-yl)-3,6- diazabicyclo[3.2.0];heptane can be
dissolved in a solvent, preferably at about room temperature, which for the
purpose of this application is 25 °C. Preferably, the solvent is an alcohol,
for example methanol, ethanol, 1- propanol, or isopropanol. The solvent can be
used alone or as a mixture of suitable solvents, and can, but need not, contain
up to 50% water. One example of a preferred solvent mixture is 95% ethanol/5%
methanol. ! Benzenesulfonic acid dissolved in a solvent is reacted with
(lS,5S)-3-(5,6- dichloropyridin-3-yl)-3,6- diazabicyclo[3.2.0];heptane to
prepare the (IS,5S)-3-(5,6- dichloropyridin-3-yl)-3,6-diazabicyclo[3.2.
0]heptane benzenesulfonate salt. Generally, from about 0.7 to about 1.5 moles
of benzenesulfonic acid are reacted with one mole of (1 S,5S)-3- (5, 6-
dichloropyridin-3-yl)-3,6-diazabicyclo[;3.2.0];heptane. Preferably about 1.1
moles of benzenesulfonic acid are used. The benzenesulfonic acid can be
dissolved in any solvent suitable for dissolving (lS,SS)-3-(5,6-
dichloropyridin-3-yl)-3,6-diazabicyclo[;3. 2.0];heptane.
The
solvent can be the same or different from the solvent used to dissolve the
(lS,5S)-3-(5,6- dichloropyridin-3-yl)-3,6-diazabicyclo[ 3.2.0]; heptane, but
preferably the solvent systems are miscible.
Seed
crystals of (1 S,5S)-3-(5,6-dichloropyridin-3-yl)-3,6- [bennzenesulfonate can
be added to the reaction mixture or slurried with the benezenesulfonic acid
solution to facilitate preparation of the
(IS,5S)-3-(5,6-dichloropyridin-3-yl)-3,6- diazabicyclo[3.2.0];heptane
benzenesulfonate salt. Preferably, the benzenesulfonic acid solution, with or
without seed crystals of (lS, 5S)-3- (5,6-dichloropyridin-3-yl)-3,6-
diazabicyclo[;3.2.0]; heptane benzenesulfonate is added to the
(lS,5S)-3-(5,6-dichloropyridin 3- yl)-3,6- diazabicyclo[;3.2.0];heptane slowly
to allow for the crystallization. I The process for preparing the
(lS,5S)-3-(5,6- dichloropyridin-3-yl)-3,6- diazabicyclot[3 2 1];heptane
benzenesulfonate salt can be better understood in connection with the following
Examples, which are intended as a illustration of the compounds and methods of
the invention and are not intended to limit the scope of the invention, which
is defined by the appended claims
Example
1
(1 S,5S)-3-(5,6-dichloropyridin-3-yl)-3,6-diazabicyclo[;3.2. 0];heptane
benzenesulfonate (lS,5S)-3-(5,6-Dichloropyridin-3-yl)-3,6- diazabicyclo[3. 2.0
];heptane (500 ma) in 1 propanol (10 mL) was filtered through a 0.2- micron
syringe filter, stirred at room! temperature, and treated with a solution of benzenesulfonic
acid (324 ma) in 1-propanol (2 mL). After approximately 1 minute, solids
started to precipitate. The resulting slurry was - 12 stirred at room
temperature for 30 minutes and filtered. The wet cake was washed with 1
propanol (1 rnL) and dried overnight in a vacuum oven at 50 °C to provide the
title! compound as a white solid (622 mg).
Example
2
(1 S,5S)-3-(5,6-dichloropyridin-3-yl)-3,6-diazabicyclo[;3.2. 0] heptane
benzenesulfonate Tert-butyl (lR,5S)-3-(5,6-dichloropyridin- 3-yl)-3,6- diazabicyclo[;3.2.0];heptane-6-
carboxylate (642 ma) in 1 -propanol (8 mL) was treated with benzenesulfonic
acid (516 ma) and heated at 75 °C with stirring for 2 hours. The reaction
mixture was cooled to room temperature, filtered, and the wet cake was dried in
a vacuum oven at 50 °C to provide 292 mg of the title compound.
Example
3
(lS,5S)-3-(5,6-dichloropyridin-3-yl)-3,6-diazabicyclo[;3.2. 0;heptane
benzenesulfonate (Amorphous) (1 S,5S)-3-(5,6- Dichloropyridin-3-yl)-3,6-
diazabicyclo[;3.2.0];heptane benzenesulfonate (3.0 g) was dissolved in water
(200 mL) and 30 mL of this solution was filtered through a 0.45- micron syringe
filter. The filtrate was lyophilized to provide the title compound as a white
solid (450 rug). No birefringence was observed under a microscope.
Upon isolation of the material, it was kept in a dry environment.
Alternatively, dissolve approx 0.5 g of the besylate salt in approx 50 mL of
water. The mixture was stirred until completely dissolved. The solution was
filtered through a 0.2 lam filter. The solution was lyophilized and transferred
to a dry atmosphere immediately upon completion of the lyophilization.
Example
4N
(1 S,SS)-3-(5,6-dichloropyridin-3-yl)-3,6-diazabicyclo[;3.2. 0];heptane
benzenesulfonate
A
30-gallon reactor was charged with a solution of tert- butyl (lR,5S)-3-(5,6-
dichloropyridin-3-yl)-3,6- diazabicyclo[;3.2.0]; heptane-6-carboxylate (11.2
Kg) in toluene (77.1 Kg). The mixture was distilled to a volume of
approximately 12 L, treated with n-propanol (45 Kg), filtered into a tared
drum, and the reactor was rinsed with n- propanol (5 Kg). Deloxan_ THE resin (5
Kg) was charged to a filter pot and washed with n-propanol until water was
removed from the resin. The resin was charged to a pressure canister, followed
by the solution of tert-butyl (lR,5S)-3-(5,6-dichloropyridin-3- yl)-3,6- ;
diazabicyclo[;3.2.0]; heptane-6-carboxylate in n- propanol. After stirring for
at least 12 hours at room temperature, the resin was filtered off and the
residue was washed with n-propanol (10 Kg). The solution was charged to a
30-gallon reactor, warmed to 40 °C, and treated with a solution of
benzenesulfonic acid (6.12 Kg) in n-propanol (9.8 Kg) that was filtered into
the I reactor. The resulting solution was seeded with product seed crystals
(100 g), stirred at 40 °C for at least 12 hours, the temperature was increased
to 60 °C, and the mixture was stirred at °C for about 4 hours. The reaction
mixture was slowly cooled to room temperature, at a rate of 10 °Clhour. The
mixture was stirred at room temperature for 12 hours, filtered, and - 21 the
wetcake washed with n-propanol (20 Kg). The obtained solid was dried under
vacuum in a tumble dryer at 55 °C to provide 9.55 Kg (92%) of the title
compound.
WO2006038041A1
Besylate
salts of amino heterocycles are cyclooxygenase-2 inhibitors useful to treat or
prevent pain, cough, depression, gastrooesophageal reflux disease or another
disorder
In
general, the besylate salts can be prepared by adding benzene sulfonic acid to
a solution of the free base of compound I in a solvent, such as an aprotic
solvent, such as DMF, generally at a temperature of about 40°C. To enable
crystallization to occur a less polar solvent, such as isopropyl acetate, is
added, optionally with seeding with the desired crystalline product. The
solution is generally aged for about 30 minutes, with further addition of the
less polar solvent, followed by further ageing for one or two hours.
The
reaction mixture is generally cooled to 20-25°C, further aged for about two
hours and finally filtered, optionally washed and then dried to yield the
desired product generally in crystalline form. I
The
following Examples illustrate the present invention.
Example
1 7-(5-Methvl-6- 5-trifluoromethylpYridin-2-Y];amino jpyrimidin-4 yl)quinolinium
benzenesulfonate To a solution of the free base (see Example 41 in
WO-A-05047279) in DMF (40 ml) was added benzenesulfonic acid (1.05 eq., 4.3 g,
27.2 mmol) at 40°C. Isopropyl acetate (10 ml) was added into the solution,
which was then seeded with the product (10 mg). The solution was aged for 30
min. then more isopropyl acetate (70 ml) was added over 12 hours, keeping the
internal temperature at cat 40°C. After addition, the batch was cooled to
20-25C, aged for 2 hours, then filtered. The resulting cake was washed with
isopropyl acetate (10 mL), then dried to give the title compound (13.4 g, 95
%).
WO2007084194A1
DNT-BENZENESULFONATE
AND METHODS OF PREPARATION THEREOF
Preparation
of DNT-benzenesulfonate Example 1:
Benzenesulfonic
acid (2.4 g) was added to 4g of DNT in 30 ml of water, and the mixture was
stirred for an additional 1hour, filtrated, and washed with water. After drying
in a vacuum oven (10 mm Hg) at 5O0C for 16 hours, 1.5 g (67.5% yield), of
product were obtained. The product was analyzed by XRD, and found to be Form
BSulfl after the drying.
Preparation
of DNT Example 2:
A
2 liter reactor equipped with mechanical stirrer is charged with a mixture of
107 g DNT-benzenesulfonate, 600 ml water, 96 ml of a 22 percent solution of
ammonium hydroxide, and 1 liter of toluene. The mixture is stirred at 25 °C for
20 to 30 minutes, and the organic phase is separated and washed with water (3 x
300 ml).
The
toluene solution of DNT can be used to form duloxetine hydrochloride without
evaporation.
Example
3:
A
100 ml three necked flask, equipped with mechanical stirrer, thermometer, dean
stark, and condenser, was charged with 5 g of DNT and 25 ml of toluene. The
clear solution was heated, and an azeotropic distillation was performed for about
30 to about 60 minutes. After cooling to room temperature, 4.6 ml of ethyl
chloroformate were added during over a period of 1to 2 hours, and the reaction
mixture was stirred at room temperature over night.
; Diluted NH4OH was added to the reaction mixture, which was stirred for an
additional 30 minutes. After phase separation, the organic phase was washed
with water (3 x 20 ml), dried over Na2SO4, filtered, and concentrated to
dryness to give 5.2 g of a brownish oil. (88% chemical yield).
WO2007109434A1
BESYLATE
SALT FORM OF 1- (5-TERT-BUTYL-2-P-T0LYL-2H-PYRAZ0L-3-YL) -3- (4- (6-
(MORPHOLIN-4-YL-METHYL) -PYRID IN- 3 -YL) -NAPHTHALEN- 1-YL) -UREA AND
POLYMORPHS THEREOF
Preparation
of Compound I BF Type F and Type F dried.
Compound I (955 g) and tetrahydrofuran (THF) (9.2 L) were added to a 22 L
reactor at 20-25 0C under nitrogen. The mixture was warmed to 35 0C with
stirring to obtain a complete solution. A stock solution of benzenesulfonic
acid was prepared by dissolving 270.9 g of solid anhydrous benzenesulfonic acid
in 5.17 L of THF. To the solution of compound I was added 443 g of the
benzenesulfonic acid stock solution. A seed slurry of compound I Type F (system
composition = 20 mg of I BF type F/mL THF) was added to the 22 L reactor to
yield a relatively thin slurry. The remaining benzenesulfonic acid stock
solution (3.95 kg) was added to the reactor at linear rate over 2 h while
maintaining the temperature at 35 0C. It was found preferable to add the
benzenesulfonic acid solution directly into the vortex of the stirring slurry
to prevent a yellow discoloration during the salt formation. The
benzenesulfonic acid solution addition vessel was rinsed with 482 mL of THF and
the rinse was added to the 22 L reactor. The resulting slurry was cooled to 20
0C linearly over 1 h and allowed to stir overnight. The solids were collected
by filtration and washed with about 3 L of THF to give I BF Type F (See Figure
9). The wet cake was dried under vacuum with a nitrogen flow at 80 0C for 24 h
to give 1.18 kg of I BF Type F dried (See Figure 10). At this point the THF
level was less than 1.0 weight %.
Preparation of Compound I BF Type B Compound I BF Type F dried (1.178 kg) and
n-butyl acetate (16.5 L) were added to a 22 L reactor. The stirred slurry was
heated to 90 0C over 30 min. The slurry was stirred and seeded with about 80 mL
of a slurry of I BF Type B in n-butyl acetate at a concentration of about 300
mg/mL. (The seed slurry may be independently prepared from I BF Type F in
-butyl acetate at 90 0C). The seeded slurry was stirred at 90 0C for 6 h. Over
this time period the I BF Type F dried converted to I BF Type B. The resulting
Type B slurry in n-butyl acetate was cooled at a linear rate to 20 0C over 4 h.
The
solids were collected by filtration and washed with about 3.6 L of n-butyl
acetate.
The
washed solids were dried at about 70 0C under vacuum with a nitrogen flow for
24 h to give 1.15 kg of I BF Type B (See Figure 12).
Preparation
of Compound I BF Type A 1.46 g of amorphous Compound I BF and 23 mL of
n-butanol was added to a 50 mL reactor. The contents were heated to about 68 0C
to dissolve the solids. The hot solution was seeded with Compound I BF
n-butanol solvate. The resulting slurry was cooled to ambient temperature and
allowed to stir overnight. The slurry was filtered and the resulting wet cake
was washed with n-heptane. The washed solids were dried under a nitrogen
atmosphere for 30 minutes at ambient temperature to produce 1.1 16g of Compound
I BF n-butanol solvate. A portion of the Compound I BF n-butanol solvate was
dried at 118 0C under vacuum with a nitrogen purge for 45 minutes to produce
0.71 g of Compound I BF Type A.
WO2007131759A1
A
PROCESS FOR THE PREPARATION OF AMLODIPINE BENZENESULFONATE
Said
slurry residue is recrystallized from a mixture of 200 mL of ethyl acetate and
10 mL of water. 35.72 g of wet precipitate of amlodipine benzenesulfonate is
obtained, which is dried at temperature up to 70°C and reduced pressure (400
mbar) for 24 hours. 23.52 g of dry amlodipine benzensulfonate is obtained,
which is suspended in 240 mL of demineralized water and 2 mL of ethyl acetate
and the obtained suspension is heated to 80 0C until the clear solution is
formed. Obtained clear solution is cooled slowly with stirring for 24 hours at
room temperature, whereat amlodipine benzenesulfonate monohydrate crystallize.
The obtained crystalline amlodipine benzenesulfonate monohydrate is filtered
off, washed with demineralized water and the obtained 39.02 g of wet
precipitate of crystalline amlodipine benzenesulfonate monohydrate is dried at
temperature up to 800C and reduced pressure (400 mbar) for 4 hours. After
drying 18.83 g of crystalline amlodipine benzensulfonate is obtained.
18.83 g of crystalline amlodipine benzenesulfonate is suspended in 175 mL of
demineralized water and the obtained suspension is heated to 83 0C until a
clear solution is formed. Ethyl acetate is evaporated in vacuo and suspension
cooled to room temperature. After 5 hours the suspension is filtered, washed
with demineralized water, resulting 32.93 g of wet precipitate of amlodipine
benzenesulfonate, which is dried at 5 O0C and reduced pressure (400 mbar).
After drying 17.09 g of dry amlodipine benezensulfonate is obtained.
17.09 g of amlodipine benzenesulfonate is recrystallized from methanol (25 mL).
Obtained suspension of amlodipine benzenesulfonate in methanol is heated to
800C to dissolve completely all of amlodipine benensulfonate. Resulting
solution is cooled slowly to the temperature of about 20 0C and then allowed
the product to crystallize for 18 hours. The resulting suspension is then
cooled slowly to about - 10°C for 2 hours. The resulting crystals of amlodipine
benzenesulfonate are filtered off and the precipitate washed with 5 mL of
methanol (mother liquors are kept for later isolation of additional quantity of
crystalline amlodipine benzenesulfonate to improve the overall yield). Obtained
17.23 g of methanol wet precipitate of amlodipine benzenesulfonate is dried at
temperature up to 80 °C and reduced pressure (under 400 mbar) for 1 hour. Thus,
16.57 g dry crystalls of amlodipine benzenesulfonate are obtained.
Obtained 16.57 g dry crystalline amlodipine benzenesulfonate is recrystallized
again from methanol (25 mL) Obtained suspension of amlodipine benzenesulfonate
in methanol is heated to 80 °C to dissolve completely all of amlodipine
benzenesulfonate. The resulting solution is cooled slowly at 20 0C for 18 hours
and the obtained solution is then cooled to - 100C for 2 hours. After
completing of the crystallization, the product is filtered off, washed with
methanol (5 mL), whereat 16.12 g of methanol wet precipitate of amlodipine
benzenesulfonate is dried at temperature up to 80°C and reduced pressure (under
400 mbar) for 1 hour. Thus, 15.12 g of dry white crystalls of amlodipine
benzenesulfonate of high purity, m.p.
201..0 0C, are obtained.
