kilomentor

Introduction

Industrially important chemical transformation are usually conducted in solution; however, these processes often lead to partial loss of the solvent into the atmosphere. The equipment used conventionally in batch chemical processing is typically not adequate to prevent troublesome emissions of the most volatile solvent vapours. Additionally, the contaminated waste solvents are commonly sent for destruction rather than being recycled, increasing the likelihood of cumulatively damaging emissions. Chemicals in the atmosphere are sometimes serious pollutants and there is a need to reduce these leakages. Today many of the most common volatile solvents used in chemical process development are under a cloud. It has been proposed that solvents be more efficiently recovered and recycled but this is often discouragingly expensive. One suggestion has been to use dissolution media with much higher boiling points than the most popular solvents, because their vapour pressures are lower, but distillation of such solvents consumes more energy. Another suggestion has been to use special designed substances with solvent-like dissolution properties that can be reversibly chemically dissociated into more volatile fragmented products while they are removed from a reactor and which then can be recombined to regenerate the solvent-like substance. An example is the adduct between sulfur dioxide and perylene (1,3-penadiene) which is a liquid. Another example is the combination of sulfur dioxide, formaldehyde that together wit water produce hydroxymethylsulfonic acid. Often the recommendation is made that the industrial process be reengineered to use a more environmentally friendly solvent even if the relative volatility of the solvent is not reduced. What has not been recommended up until now is some means to use more volatile, lower-boiling solvents which can be easily disltilled with a low energy requirement so that the increased risk of pollution is avoided.

Kilomentor [Dr. Clarke Slemon] has filed a US patent application US61/069,688 to address this problem. The key to this new technology is a means of reducing the vapour pressure of the volatile solvent when it is not in use as a reaction solvent. The central claim of the application is the combination of a recycled, constrained solvent with a substantially less volatile complexing agent in a closed storage vessel. When the volatile solvent material is complexed, its vapour pressure is conveniently low for easy storage. When it is needed as a reaction solvent, heating the complex dissociates it and the solvent can be distilled into the reactor. When the solvent is no longer needed in the reactor, it can be distilled back into the reservoir where it recombines with the complexing agent.

Solvents that form such useful complexes are called constrained solvents by Kilomentor. The combination of a constrained solvent with a complexing agent is not new. Solvates of ammonia, for example, calcium chloride mono ammoniate or zinc chloride diammoniate have been long known. An intelligent and experienced reader, once presented with the inventive combination of a low boiling readily gaseous solvent, a complexing agent and a confining element in the context of the problem to be solved might easily assemble the useful combinations. The invention is the combination to address the opportunity (problem).

Particular pairs of a constrained solvent and complexing agent are: dinitrogen tetroxide and 1,4-dioxane; dinitrogen tetroxide and dimethylsulfoxide; sulfur dioxide and potassium bromide; sulfur dioxide and sodium iodide, or ammonia and calcium nitrate.

There are advantages besides ecological ones to working with a solvent under conditions where it is a constrained solvent. Some solvents are too volatile, explosive with air, flammable, poisonous, smelly or irritating to be used in regular processes where significant leakage into the atmosphere might more likely occur. Carbon disulfide for example is an excellent solvent with a well known unique combination of properties, but because of it flammability and low flash point it is unacceptable for process chemistry. Carbon disulfide (B.P. 46 C) if it could be put in combination with an appropriate complexing agent might be useful.

A possible advantage of this technology might be that purification by distillation would be inexpensive because the heat of vaporization for such liquids is low and because the boiling point is above 0 C the first stage of cooling can be a brine chiller. Residual uncondensed gas might be delivered below the surface of the non-volatile storage solvent.

This solvent could be stored in pressure resistant tanks mixed with a low vapour pressure environmentally more benign liquid that has a rapidly increasing solubility for the low boiling solvent with increasing pressure and which had a negatively deviating Raoult’s law vapour pressure.

By proper choice of reagents, co-reactants and catalysts, the very volatile solvent can be set up so that it can be distilled away from all the other components of the reaction mixture in such a state of purity that it would be usable, if not as a replacement for commercial grade solvent in every use, at least for a subsequent batch of the same product.

When the stored volatile solvent was needed in a repeat of the process step, it could be distilled out of its reservoir and condensed into the sealed preloaded reactor. The same cooling that is required to reach the reaction temperature is used to condense and retain the solvent. What is sacrificed is the ability to run reactions at 50 C and above. For these reactions the ecologically benign choice would have to be made from other alternatives.

Reactions that substantially proceed at ambient temperature but using the present technology are driven to completion by raising the temperature, could be driven to completion by concentrating the reaction mixture by starting the removal of the highly volatile solvent. This would dramatically increase the rate for reactions with a molecularity of two or higher. This includes most reactions that use a particular chemical reagent but does not include intramolecular rearrangements, hydrolyses or solvolyses.

The table shows solvents that might be used if a satisfactory complexing agent could be found.

Low boiling liquids that are already frequently used solvents are marked in bold in the table. The four highest boiling liquids are common organic solvents the first, second and third of which are typically avoided in process chemistry. Fluorine containing choices desirably handled in this confined manner because they may be ozone depleting substances: dibromodifluoromethane, dichlorofluoromethane, dibromodifluoromethane.

Two of these possibilities are not new to consideration as solvents, dinitrogen tetroxide and sulfur dioxide are two volatile dipolar aprotic solvents. In fact, I have on my book shelf a thin volume called Chemistry in Non-Aqueous Solvents, by Harry H. Sisler, Reinhold Publishing Company, 1961. In the pertinent chapters there is no discussion of possibility that these solvents could be easily recycled. This is the aspect, which provides the new perspective.

Dintrogen Tetroxide

Dinitrogen tetroxide melts at –12.C and its normal boiling point is 21.3 C thus its liquid range is convenient for its use as a solvent. The liquid may be readily supercooled and has been cooled as low as –110 C without it crystallizing. Its critical temperature is 158.2 C and its critical pressure is 100.0 atm. The density of dinitrogen tetroxide is 1.49 g/cc. at 0 C. The electrical conductance of liquid ditrogen tetroxide is very low. The specific conductance at 17 C is 2.36 X10-13. There is an equilibrium between ditrogen tetroxide and two molecules of the paramagnetic nitrogen dioxide. Although there is very little of the monomeric triatomic compound in the liquid at the boiling point there is about 16% in the gas phase.

A possible key to how dinitrogen tetroxide could be recycled is that it forms several fairly stable solvates with higher boiling liquids which comprise a large percentage of dinitrogen tetroxide. With p-dioxane dinitrogen tetroxide forms a 1:1 salt of melting point +45.2 C and a less stable one with 1,3-dioxane of mp 2 C. These complexes contain 60.7% dinitrogen tetroxide by weight. Thus to generate 100 ml of solvent it would only be necessary to decompose 250 gm of complex. The solid complex is heated to melting and the solvent distilled away from the dioxane residue. When the reaction in which it was mediating is complete the dinitrogen tetroxide can be distilled and condensed back into the dioxane solution where it reacts and returns to the solid state. The flask of solid is secure in the refrigerator in a stoppered flask. To se it as a solvent it needs to be appreciated that primary alcohols, amines, alkenes, and amides all react with dinitrogen tetroxide.

Sulfur Dioxide

Sulfor dioxide is widely used in the petrochemical industry as a solvent because of its ability to discriminate between function group classes, dissolving alkenes and aromatic hydrocarbons while having little solubility for saturated hydrocarbons. Means for recovering sulfur dioxide on scale are therefore most likely well developed by our engineering colleagues.

The boiling point of sulfur dioxide is –10.02 C and its freezing point is –75.46 C. Its density at –10 C is 1.46 g/cc. Sulfur dioxide displays some useful solvent properties for metathesis reactions and is a good solvent for Friedel Craft reactions in part because AlCl₃ dissolves readily in it.

The characteristic with which we are particularly focussed here however is the possibility that the sulfur dioxide could be trapped as a reversible adduct for storage. Looking at the data available in the Sisler book one can see that the potassium bromide solvate might be a good choice. The solvate combines 4 equivalents of sulfur dioxide with one formula weight of potassium bromide working out to a sulfur dioxide content of about 68%. Thus to prepare 100 ml of liquid sulfur dioxide would require 215 gm of the solvate. At –1 C the vapour pressure over this solid is already 1 atmosphere so it would need to be refrigerated strongly to keep it confined as the complex. More stable compounds however contain a smaller weight percent of sulfur dioxide. Aluminum chloride forms a disolvate with sulfur dioxide. As with the dinitrogen tetroxide case, the gas can be distilled away from the reservoir solid and condensed as liquid in the reactor and then distilled back into mixture r in the reservoir when the solvent was no longer needed.

The sulfate salt is the second most common pharmaceutical salt behind the hydrochloride. Bisulfate salts are quite acidic so the base from which one is made needs to be acid stable.

Sulfuric acid is a diprotic acid. It can form two different stoichiometric salt types: the 1:1 bisulfate salt and the 2:1 sulfate salts in which two moles of amine are protonated by each of the two protons of H₂SO₄. The pKas of sulphuric acid are –3 and 1.92 with almost five orders of magnitude difference between the acidity of the first and second hydrogen. Most pharmaceutical salts are of the 1:1 bisulfate type. Sulfates are most often made by the addition of an, at least partially aqueous, solution of acid because neat acid is not soluble in apolar solvents and it has some dehydrating capability which can lead to by-products when sufuric acid is in excess. Typical organic solvents used in making sulfates are methanol, ethanol, 1-propanol, 2-propanol, acetone and mixtures thereof. Acetone however is not recommended because an excess of acid causes the oligomerization of acetone creating color in the solution.

Kilomentor anticipates that by providing some examples of pharmaceutical sulfate salt preparations with some commentary to draw attention to important aspects of the methods a skilled experimentalist should have no difficulty making others.

US7230016 PREPARATION OF PIOGLITAZONE SULFATE

24.g of sulfuric acid was added slowly, at room temperature, to 250 ml of methanol followed by addition of 80 g of pioglitazone base with stirring. The mixture turned into a clear solution. 250 ml of ether was slowly added followed by 500 ml of heptane. A solid precipitated, and the suspension was stirred for 3 hours. The solid (98.4 g, yield was 96.5%) was collected by filtering and washed once with ether. The solid had a mp: 1113.5-116.5° C. (recrystallized from methanol).

This example illustrates the addition of the base to the organic solution of sulphuric acid in methanol. Although a small amount of methyl hydrogen sulphate might form this not a problem because MeOSO2OH is a pharmaceutically acceptable counterion. Note also that in the procedure the chemistry provided three opportunities to obtain crystals. Pioglitazone hydrogen sulfate might have precipitated from the methanol solution itself after partial dissolution. The salt might have crystallized when the methanol was diluted 50:50 with diethyl ether. The final opportunity occurred when the solution was diluted 1:1 with heptane and this was successful. Notice that the methanol could not be diluted with heptane directly. Two phases would have resulted. This is an example of a well designed approach to getting crystalline solid. If crystals still had not formed the solution would have been concentrated.

WO06040728A1: Preparation of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

Example 1
1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea

(1 equivalent) is dissolved in ethanol at a concentration of 25% w/w and the mixture is heated at 50°C. Aqueous sulfuric acid (1M, 1.1 equivalents) is added. Optionally, the crystallization is initiated by a wet seed of Example 1 (0.5%). The suspension is cooled to 0°C with a cooling rate of 15 C°/h and maintained at this temperature at least 1 hour before filtration and washing with aqueous ethanol (50 % W/V). The solid is dried at 30°C under a wet stream of nitrogen (50% RH) to provide the title compound with a purity of 97.7% with a yield of approximately 90%.

The example illustrates the addition of the acid to an excess of base. The addition is performed warm. An aqueous sulphuric acid reagent is used and it is added to a water miscible solvent in this case ethanol. Using seeds of the salt product is optional here. The example prescribes a cooling rate that will lower the temperature to the final filtration temperature over somewhat more than 3 hours. This is followed by a hold time to ensure that all the material that can crystallize has come out before the filtration. The wash solution is a mixture of solvents similar to that from which the solid is crystallized. Often a slightly less polar wash solution is used than the mixture from which the crystals are produced. This gives some assurance that the wash will not redissolve the solid. Although it is not reported the wash solvent is usually cooled to the temperature of the slurry that was filtered originally. On scale, this is done simply by loading the wash solvent mixture into the crystallizer. Because the solvent is a mixture with water, there is no danger of condensing damaging moisture into the wash solution. The example illustrates using a moist gas stream to dry the solid without dehydrating it.

Example 2
1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate trihvdrate.

To a suspension of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (21.36 kg) in CH₃OH (178 L) is added aqueous H2SO4 (6 L, 9.91%) during 10 min. The clear solution is filtered and further aqueous H2SO4 (33.8 L, 1.07 M) is added during 45 min. The solution is cooled to -2°C during 1.5 h and stirred at -5 to -9°C for 1 h. The formed precipitate is filtered, washed with cooled CH30H (- 5°C, 54 L) and dried under a stream of nitrogen provide 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate of formula l as a non-defined hydrate. A slurry of the so obtained salt in H2O (16.2% w/w) is stirred for 3 days at 25°C. Filtration and drying at 30°C under a wet stream of nitrogen (50% RH) provides the title compound.

This example replaces the ethanol with methanol and is in most particulars very much the same. Here unhydrated gas was used in the drying ad there apparently was some dehydration. Stirring a slurry in water for an extended period recreates the hydrate illustrating a method of preparing a pseudopolymorph hydrate. Drying to the trihydrate was successful when the relative humidity was controlled at 50%.

Example 4
1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate

1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (15.4 kg, 1 equivalent) is dissolved in ethanol (78 L) and the mixture is heated at 50°C. Aqueous sulfuric acid (1M, 1.1 equivalents) is added during minutes. The crystallization is initiated by a wet seed of Example 1 (1%) as described below. The suspension is cooled to 1°C with a cooling rate of 14C°/h and maintained at this temperature at least 11 hours before filtration and washing with aqueous ethanol (50 % W/W, 50 L). The solid is dried at 30°C under a wet stream of nitrogen (33-40% RH) to provide the title compound with a purity of 99.4% with a yield of approximately 79%.
The wet seed used in the above procedure is prepared by mixing - 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate (Example 1,) with a saturated solution (421 9) of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate (Example 1, 73.9 9) in aqueous ethanol (50 % W/W, 810 9).

Example 5

1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulphate dihvdrate

1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (1.01 kg, 1 equivalent) is dissolved in ethanol (3.05 kg) under stirring (200±20 rpm) and the mixture is heated at 50°C. Aqueous sulfuric acid (1 M, 1.1 equivalents) is added during 20 minutes. The crystallization is initiated by a wet seed of Example 1 (1 %) as described below. The obtained mixture is maintained at 50°C for about 15 minutes, then it is cooled to 0°C with a cooling rate of 15°C/h and maintained at this temperature for least 1 hour before filtration and washing with aqueous ethanol (50 % W/W, 3 kg). The solid is dried in a conductive agitated dryer at a temperature of 35± 3°C under a wet stream of nitrogen (45±5% RH), optionally under stirring (max. rpm) in case the cake humidity is below 25%, to provide the title compound with a purity of 99.8% with a yield of approximately 94%.

The wet seed used in the above procedure is added in two shots and is prepared by mixing 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate (Example 1, 6.5 9) with a saturated solution (13.9 9 for the first shot, plus 15.6 9 for subsequent rinsing and second shot) of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-quinolin-4-yl)-urea sulfate dihvdrate (Example 1, 7.0 9) in aqueous ethanol (50 % W/W, 50.0 9) for about 2 minutes. The first shot of wet seed is prepared at least 5 minutes before use to ensure that the seed is correctly wetted.

Example 5 illustrates that in a process description of crystallization the mixing times, cooling rates and stirring need to be precisely controlled. The need to properly moisten the seed crystals with the solvent is also illustrated. If the seeds’ surface does not wet properly they cannot catalyze crystal growth properly.

US20060194833A1: Crystalline 1H-imidazo[4,5-b]pyridin-5-amine, 7-[5-[(cyclohexylmethylamino)-methyl]-1H-indol-2-yl]-2-methyl, sulfate (1:1), trihydrate and its pharmaceutical uses

According to the method, ER807447 is first suspended in water to form an aqueous suspension. Sulfuric acid is added to the aqueous suspension to form a solution while keeping the internal temperature of the solution below 25° C. The solution typically has a yellow color. The solution may optionally be filtered to remove particulates from the solution. Other techniques for removing particulates known in the art, centrifuging, etc. may be used as the filtering step. The solution is then slowly warmed until E6070 crystallizes from solution. The solution may be warmed to about 100° C. Typically crystal formation occurs at temperatures of about 70° C. Preferred rates of warming typically range from about 30 minutes to 5 hours. Longer or shorter times may be used, particularly depending upon the batch size. E6070 may not crystallize as readily from highly dilute solutions.

To enhance crystallization, an anti-solvent may be used in the method of making the crystalline E6070 or to recrystallize crystalline E6070. The recrystallization procedure is described in Example 5. In the above method, the anti-solvent may be added to the aqueous suspension before sulfuric acid addition or to the solution after sulfuric acid addition and the optional filtration step. Useable anti-solvents and their use are known in the art. Typical anti-solvents include water-miscible anti-solvents such as, for example, methanol, ethanol, 1-propanol, 2-propanol, acetone and mixtures thereof. When an anti-solvent is used, the solution may become cloudy. It is generally not necessary to warm the solution to as high of temperatures as when just using an aqueous solution.

The procedure above illustrates forming a bisulfate from water. Filtration or other clarification of the formed solution is illustrated. Removing insolubles removes nuclei that can catalyze improper nucleation. The example illustrates that a bisulfate salt in water may actually be supersaturated but the rate of nucleation may be impracically slow. Heating the solution increases the rate of nucleation and causes the insoluble salt to come out. If the sulphate is a high molecular weight molecule that should give an insoluble sulphate in water, perhaps heating will enhance the rate of seed formation as here.

The use of an antisolvent is also illustrated. Note that water miscible organics are often antisolvents for sulphate salts because sulphate salts are so hydrophilic.

Tizanidine Monosulfate (5-chloro-4-f2-imidazolin-2-ylamino')-2,l,3-benzothiadiazole monosulfate )

In a second preparation, tizanidine monosulfate was prepared by the following method: to solid tizanidine (9.957 g; 39.24 mol) was added a solution of sulfuric acid (5.438 g; 55.45 mol) in acetonitrile (175 mL). The yellow solid rapidly converted to a white crystalline solid. The mixture was heated to 60°C and stirred for 90 minutes. The mixture was cooled to room temperature and the solid was subsequently filtered and washed with additional acetonitrile (50 mL). The solid was collected via filtration and air-dried.

Tizanidine monosulfate comprises a 1:1 ratio of ionized tizanidine to sulfate counterion. In this example sulfuric acid in acetonitrile is used

Rosiglitazone Sulfate

Example 1:

5-[4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy]benzyl] thiazolidine-2,4-dione sulfate

5-[4-[2- (N-Methyl-N-(2-pyridyl)amino) ethoxy]benzyl]thiazolidine-2,4- dione (20.0 g) in glacial acetic acid (50 ml) was stirred and heated to 75°C until a clear solution 5 was observed. Concentrated sulfuric acid (1. 5 ml) was added and the stirred solution cooled to 21 °C. After evaporation of solvent under reduced pressure, methanol (100 ml) was added and the mixture stirred at 21°C for 48 hours. The solid was collected by filtration, washed with methanol (50 ml) and dried under vacuum to give 5-[4-[2-(N-
methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione sulfate (10.7 g) as a crystalline solid.

Melting point: 184 - 189°C.

DSC: Tosser = 184.4°C, Tpeak = 189.1 °C Elemental Analysis: 15 Found: C; 52.96 H; 4.94 N; 10.23 S; 11.78 Theory: (C36H40N6O,oS3) C; 53. 19 H; 4.96 N; 10.34 S; 11.83

In this example glacial acetic acid is used as solvent for the free base and heating is require to get a clear solution. The experimentalist apparently expected the sulfate to precipitate at about ambient but it did not. It is important that in this example the basic group was tertiary because the combination of acetic acid and sulfuric acid could cause acetylation with primary or secondary amines. Undeterred the experimentqalist removed some acetic acid under vacuum and replace it with the antisolvent methanol. This time cooling gave the desired solid derivative.

Example 2:

5-[4-l2-(N-methyl-N-(2- pyridyl)amino) ethexylbenzyl] thiazolidine-2,4 20 dione sulfate

5- [4-[2-(N-Methyl-N-(2- pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione (40.0 g) in glacial acetic acid (100 ml) was stirred and heated to 70°C until a clear solution was observed. Concentrated sulfuric acid (3.1 ml) was added and the mixture stirred for 10 minutes at 70°C, then cooled to 21°C with stirring. The solvent was evaporated under reduced pressure, followed by the addition of methanol (100 ml) and the mixture was stirred at 21 °C until crystallization was complete. The product was collected by filtration, washed with methanol (200 ml) and dried under vacuum over phosphorus pentoxide for 4 hours at 50°C to give 5-[4-[2-(N-methyl-N-(2 pyridyl)amino)ethoxy] benzyl]thiazolidine-2,4-dione sulfate (36.9 g) as an off white crystalline solid.

Example 3:

5-[4-[2-(N-methyl-N-(2-pyridyl)amino) ethexy]benzyl] thiazolidine-2,4 dione sulfate

Concentrated sulfuric acid (1.94 ml) was added to a stirred suspension of 5-[4- [2 35 (N-methyl-N-(2-pyridyl)amino) ethoxy]benzyl] thiazolidine-2,4-dione (25.0 g) in methanol (1000 ml) at 56°C. The reaction mixture was stirred at 60°C until a clear solution was observed, then cooled to 21 °C and stirred at this temperature for 16 hours.
The product was collected by filtration, washed with methanol (100 ml) and dried under vacuum at 21°C for 3 hours to afford 5-[4-[ 2-(N-methyl-N- (2 pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione sulfate (19.5 g) as a white crystalline solid.

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• Symmetrical Bis-N,N-(3-nitrophenyl)urea: A Super Co-crystal Former that might have applications in Product Purification.
• The Importance of the Molecular Weight of a Salt Former in choosing a Pharmaceutical Salt
• Reiterating the Objective of the Kilomentor Blog
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• Phosphate Pharmaceutical Salts : Chemical Process Development & Organic Synthesis
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• Kilomentor weighs in as “Pharmaceutical Manufacturing Goes Green”.
• Another Way to Separate Phenolics by Crystallizing of Co-crystals?
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