Making Benzenesulfonate/Besylate Pharmaceutical Salts

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 &lt;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:&lt;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.