Posted on 04 Jan, 2015 04:58

 As part of the increased popularity of ‘green chemistry’, many persons have considered doing organic chemical synthesis using water as solvent. This may be a good idea or it may be simplistic. Using water avoids organic solvents, but even when there are only small amounts of dissolved or entrained organics, cleaning up waste water so that it can be sent to sewage is neither simple nor green. Destroying water by combustion is expensive. Whatever the outcome of this controversy, detergents, emulsifiers or surfactants, whatever you choose to call them, can make homogeneous, bulk water containing substantial amounts of lipophilic materials. Chemicals can react in such media, sometimes with rate accelerations. It is not clear whether these accelerations are caused principally by miscelle formation or phase transfer catalysis or some combination of the two.  

Generally the presence of these amphiphilic substances makes isolation procedures more difficult, because chemical separation at the molecular level is achieved by phase separation at the macroscopic level and an emulsifying agent makes the two most common immiscible liquid phases oil and water, more miscible; therefore, it seems necessary that the surfactant should be destructible so that it loses its ability to emulsify once the reaction is complete and before the separation phase of the process is begun. 

An article by F.M. Menger, J.U. Rhee and H.K. Rhee published [J. Org.Chem., 40, 3803 (1975)] is one of the early preliminary explorations. In one experiment, they compared the oxidation of piperonal, mp 36° C, using potassium permanganate in water at 55°C, with and without 0.01M cetyltrimethylammonium bromide.  The authors observed about 33-37% yield without surfactant and 64-74% yield with surfactant.  Surprisingly, the yield appeared to be independent of the reaction time; whether 70, 100 and 150 minutes was used.  This was not further explored even though the authors were aware that in Organic Synthesis Coll. Vol. II this same reaction had been done without emulsifier at 80°C but with vigorous agitation of the water and molten piperonal phases giving a 97% yield. It may have been that the permanganate was degrading as the reaction proceeded and the oxidizing capacity was over after 70 minutes or less. Another complicating possibility is that at the reaction temperature the permanganate also attacks the bromide in the cetyltrimethyl ammonium salt.  The permanganate could oxidize bromide to bromine and this could in turn brominate the piperonal leading to brominated by-products. This latter suggestion is supported by the fact that in one of two runs of 70 minutes duration, where the emulsifier was mixed with the room temperature potassium permanganate and water and added dropwise to the warm piperonal solution, a yield of 74% was achieved compared to 66% when the emulsifier was all placed completely in the hot water and piperonal mixture before starting to add oxidant. These authors noted that the time saved from the increased reaction rate with emulsifier present was spent in the extended time needed to get phase separation in the extractive isolation. The experimental portion of thearticle states that when surfactant was present, 2 hours was allowed for phase separation. 

In another trial, a,a,a-trichlorotoluene was hydrolyzed by 20% aqueous sodium hydroxide at 80°C.  Using 0.01M cetyltrimethyl ammonium bromide the reaction gave a 98% yield in 1.5 hours while without catalyst there was zero yield.  In this reaction, the non ionic block polymer emulsifier  Brij 35 [C12H35(OCH2CH2)23OH ] reduced the time to 11 hours for a 97% yield. No detergent such as sodium lauryl sulphate was tried in these reactions.

 

David Jaeger worked on this possibility in the 1980s

Jaeger, D.A.; and Frey, M.R., J. Org. Chem. 47, 311 (1982).

Jaeger, D.A. and Ward, M.D. J. Org. Chem. 47, 2221 (1982).

Jaeger, D.A. and, Martin, C.A. and Golich, T.G. ????

Craig, A. Timothy G. Golich and David A Jaeger, J. of Colloid and Interfacial Science, 99, 561 (1984).

 

In reaction using a cleavable surfactant, the type of surfactant and the reagent and conditions for cleavage need to be selected in advance so that the product is inert. 

It is still necessary to be able to cleanly separate the cleaved lipophilic portion of the surfactant from the hydrophobic portion. 

If the hydrophilic portion is a di-quarternary ammonium salt it is a possibility that it can be precipitated as the embonate salt. This might be converted cleanly back into a more soluble quarternary ammonium species. 

It is also possible, if the lipophilic portion is a straight chain alcohol, it might be separated as a urea complex by crystallizing the complex out from a mixture of urea and methanol. 

This problem has been approached in a different aspect by persons who were asking how long chain quarternary ammonium salts could be metabolized.  In these cases the long chain amphiphile was interrupted by an ester which under physiological conditions could be hydrolyzed.

NOTE: This blog article was started at least ten years ago so there is a lot of literature not taken into consideration.  It is probably pertinent whether any degradable emulsifiers are now commercial.

Comments
Posted on 01 Jan, 2015 07:28

 Substances that differ very little in structure can be anticipated to be those most difficult to separate whether on a laboratory or plant scale. Compounds that only differ in the location or orientation of a double bond fall in this group. Indeed, because a double bond does not substantially change the polarity of molecules in which it is present, such related olefin mixtures may be among the most difficult to separate. Kilomentor has already made mention of hexachlorocyclopentadiene as a potential reagent for separation of alkene isomers by competitive Diels-Alder reaction, particularly noting that compound’s ability to react even with electron rich alkenes; however, there would be environmental and hence regulatory concerns using this reagent at scale.

The powerful  enophile N-sulfinyl benzenesulfonamide (I) is another agent that might separate isomeric olefins by competitive reaction. Such use has not been reported as far as I know but I haven’t searched the electronic literature in the past five years. It is reported to react with a wide variety of olefins. The compound is inexpensively prepared from the commercial substances benzenesulfonamide and thionyl chloride [G. Kreske and W. Wucherpfennig.  Newer Methods of Preparative Organic Chemistry., W. Foerst Ed., Vol. V (1968) pp. 109.] Reaction of (I) with a number of different substrates is published [Gérard Deleris, Josef Kowalski, Jacques Dunogues and Raymond Calas, Tet. Lett. 1977 (48) pp 4211-4214.].

Such adducts would contain a hydrogen on nitrogen α both to a sulfoxide and to a sulfone function that would make the hydrogen on nitrogen acidic. Thus, such product should be extractable into dilute aqueous base. If the starting mixture of alkenes to be separated is not acidic to begin with, the reaction would make the treated mixture separable by simple extraction.

The amount of purification must be a function of the relative rates of reaction and the starting relative concentrations.  It would seem that terminal alkenes impurities would be removed preferentially in the presence of a predominant internal double bond.

The adducts between (I) and olefins can be reduced by lithium aluminum hydride to produce allylic thiols. These in turn are probably subjects for desulfurization.

Comments
Posted on 31 Dec, 2014 23:18

 Crystallization in the laboratory is rarely performed completely under an inert atmosphere. Most commonly crystal filtration is done in the open air on a Buchner filter followed by washing with ice-cold wash liquid and then partial drying by the passage of air drawn through the filter cake by water aspirator vacuum. Because it is conducted in this fashion the final crystallization temperature and the temperature of the wash liquid is rarely taken below zero degrees Centigrade because this would cause moisture from the air to contaminate the solvents used and/or to condense on the porcelain or glass filter funnel.  But conversely, if the Buchner filter is not sufficiently cold, it becomes more difficult to draw off the mother liquors and the wash solvent without partially redissolving the filtrand. Thus laboratory filtration in the air is more problematic. These are not problems in the kilolab, pilot plant or plant. For safety and to avoid contamination all operations are done in a closed system that is easily kept dry and inert. As a result, cooling to a lower temperature, such as -20° C,  is simple during all the operations of crystal formation, collection and washing.

Sometimes efforts to find a suitable solvent system for recrystallization of a compound, which is crystalline within the typical ambient temperature range, can be replaced with a low temperature recrystallization from hexane, pentane, or other hydrocarbon liquid. The large temperature range between the liquid’s boiling point and -20°C diminishes the need for a dramatic difference in solubility between the refluxing hot solvent and that same solvent at 0°C. What is needed to explore such an approach is rather a methodology for checking out low temperature recrystallization at a laboratory scale. Roger Giese described such an apparatus and its mode of use in Journal of Chemical Education, 45, 610 (1968). Step by step instructions are provided. The apparatus is sufficiently simple that it can be put together by modifying a chromatography column that has a fritted glass disc as the plug. Because it operates with its own jury-rigged cold bath made from a plastic bottle, it does not need to fit in a Dewar for cooling, unlike the apparatus described by C. Frank Shaw, III and A. L. Alfred in Journal of Chemical Education, 47, 165 (1970).

Comments
Posted on 14 Dec, 2014 03:46

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 <<I 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

 

Materials

 Amt. Mole MW Penultimate Bis Triflate 5000g

 4.73 1058 % Pd/C

1250g Isopropanol ,58L 4-Morpholinepropanesulfonic acid 2971g 14.2 209.26 5N NaOH 1.42L 7.1 Toluene 30L Water 126L Sodium Benzenesulfonate 12.5kg

A buffered solution of 4- morpholinepropanesulfonic acid was prepared by dissolving 2941 g in 5 8L 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 um 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. 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.

  1.  

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.

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(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.

  1. 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.

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Posted on 27 Nov, 2014 20:00

 Kilomentor has already published a panel of 30 questions that would test whether a chemist has the learning or experience to do process development.Search good industrial chemist in the search box of this blog. 

Here are thirty more  such questions.

1.            You have a weakly acidic organic compound dissolved in aqueous alkali. Upon acidification by adding mineral acid drop by drop, aiming to reach a weakly basic condition, the neutralized compound precipitates, but the drop by drop addition into the solution caused insoluble lumps from the local excess of strong acid. How would you achieve very gradual acidification to the weakly basic condition? Give as many different answers as you know.

2.            You have planned to crystallize a tertiary amine as its hydrobromide salt from water  but too much solid is still being lost dissolved in the filtrate. What can you do to increase the recovery without dilution by organic antisolvent?

  • 3.           You have a tertiary amine of molecular weight about 500 that you wish to crystallize as a crystalline salt. The common salts either do not crystallize or have other problems. You want to prepare the perchlorate but do not want to add reagent perchloric acid. How would you achieve this experimentally?

  • 4.            What inexpensive carboxylic acid forms salts soluble in organic solvents with most metal cations?

    5.            Name a carboxylicacid that leads to pharmaceutically acceptable salts that, with many amines, have a high propensity to give poorly water soluble salts?

    6.            Which of the following solvents is questionable for use at scale in a plant setting? After each one that is questionable name the risk:  pentane, heptane, carbon disulfide, diethyl ether, methyl- t-butyl ether, diisopropyl ether, benzene, N,N-dimethylaniline, carbon tetrachloride, toluene, chloroform, isopropyl acetate, 2-methoxyethanol, HMPA, ethylene glycol.

    7.            How could you simply and cleanly separate a mixture of alpha p-methoxyphenethylamine and N-ethyl-p-methoxyaniline dissolved in either ethyl acetate or toluene?

    8.            What is a ”Wolf and Lamb” reaction?

    9,          Chemically speaking, what is a ‘chaser’?

    10.          Chemically speaking, what is ‘phase switching’? Why is it important for developing separation strategies?

    11.          If you have equal volumes of pyridine and water mixed together, describe a simple way to separate them into two phases and recover the pyridine?

    12.         One way to separate alcohols from non-alcohols is to prepare an alcohol derivative in situ that can be extracted into an aqueous phase and then, in a subsequent operation, reform the alcohol and back extract into organic solvent. List reagents that separate alcohols from non-alcohols this way.

    13.          How is the easiest way you can think of to separate a neat mixture of 4-phenyl-3-buten-1-ol and biphenyl by simple liquid-liquid extraction?

    14.          How would you separate n-pentylamine (bp 104 C) and piperidine (bp 106 C) making use of the fact that one is a primary amine and the other secondary but without losing either in a reaction that is hard to reverse? (Hint: distillation is used at one point but not fractional distillation).

    15.          Finely divided anhydrous calcium chloride when stirred in a hexane slurry, which includes a drop of ethanol, will form complex precipitates with many compounds containing what functional group?

    16.          What is the Hinsberg test? Sub-classes of what functional group does it distinguish among? Which sub-classes undergo a phase switch?

    17.          If the compound that you wish to purify has too high a boiling point to be conveniently distilled, what common derivative class should you start considering?



18.          The reagent (solvent) t-butanol is stable to oxidation; however, it freezes at room temperature. What reagent (solvent) is most frequently used to replace t-butanol in a reaction sequence that will experience low temperatures?

19.          What is a 'pseudopolymorph'?

20.          What is ‘digestion’ in the organic chemistry context?

21.          The glyme solvents are high boiling water soluble polyethers. After doing a solvent switch, residues of glymes can be removed by complexation with either of two different substances. What are they? (Hint: p-dioxane forms one complex but not the other)

22.          At scale, is recrystallization at -20 C relatively simple compared to working in the lab? If yes, why?; if no, why not?

23.          In aq. sodium hydroxide, into which a small amount of Adogen 336 has been added, the substrates phenylacetonitrile and 1,3-dibromobutane react together. What is going on?

24.         What is the main reason that, in the plant, a solvent change is more complicated than one at lab scale?

25.          What is a thermotrophic solvent system?

26.          In process validation, how does a critical parameter relate to a reduction in yield?

27.          Why are genotoxic impurities of such great concern in designing a process to make a pharmaceutical?

28.          What is swish chromatography?  Suppose your company thinks that its patented process is being used to make a product competing with its own.  How does swish chromatography help you?

29.          Butyl lithium is less frequently used in reactions at scale than in the lab. What is used more often as a replacement for it in the plant and why is this replacement usually done?

30.          Name some solvents that are substantially immiscible with water, but which, with only a few extractions, can extract from an aqueous solution  organic compounds that have significant water solubility, to give solutions in that organic solvent that can be further dried by azeotropic distillation?

 

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Who is the Kilomentor?

Dr Clarke Slemon is the Kilomentor. With a PhD in Chemistry from Harvard University and over 40 years of experience, he is an end-to-end chemical synthesis & pharmaceutical mentor with extensive experience in API process development, drug product formulation, stability studies, bioequivalence studies, ANDAs and patent/legal reviewing.

His specialities are in chemical process development, organic synthesis, separation, purification, scale-up and impurity identification.

He now writes the Kilomentor Blog that teaches chemical process development worldwide for free.

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