Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
  • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
  • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
  • C07D279/18—[b, e]-condensed with two six-membered rings
  • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom

Definitions

• the present invention relates to new spherical agglomerates of 10-phenothiazinylpropanoic acid.
• the invention also relates to the process for obtaining said agglomerates.
• 10-Phenothiazinylpropanoic acid is an organic product, used as a synthesis intermediate.
• a method of preparing said product is described by Nathan L. SMITH J. Org. Chem. 15, pp. 1125 (1950).
• the product obtained is in the form of a precipitate which presents difficulties in separation, by filtration which necessarily involves a recrystallization step in an organic solvent, generally an alcohol.
• the product must have good flow properties and not clot in temporary storage facilities, of the hopper type or when used in subsequent processing processes, or during prolonged storage in usual packaging .
• the present invention provides a new presentation of 10-phenothiazinylpropanoic acid as well as a process for obtaining it which makes it possible to solve the filtration problem.
• the present invention relates to spherical agglomerates of 10-phenothiazinylpropanoic acid.
• 10-phenothiazinylpropanoic acid is understood to mean 3- (10-phenothiazinyl) propanoic acid than similar products, that is to say products in which the benzene rings of the phenothiazinyl radical may have substituents insofar as they do not modify the surface properties.
• spherical agglomerates is understood to mean solid particles with high sphericity.
• the characteristic of the process of the invention is to stir a suspension of 10-phenothiazinylpropanoic acid in water, in the presence of a binder liquid immiscible with water chosen from esters of aliphatic or cycloaliphatic acids, aliphatic or cycloaliphatic alcohols, aliphatic or cycloaliphatic ketones.
• the agglomerates obtained according to the invention have specific physicochemical characteristics. They have a particle size essentially in spherical form, having a diameter which can vary over a wide range. Note that the sizes are determined by image analysis. Generally, the particle size expressed by the median diameter
• Another characteristic of the agglomerates of the invention is that the level of fines (particles less than 100 ⁇ m) is low, preferably less than 0.5%, and even more preferably less than 0.1%.
• spherical agglomerates of 10-phenothiazinylpropanoic acid are prepared by stirring a suspension of 10-phenothiazinylpropanoic acid in water in the presence of a water-immiscible binder liquid such as cited above.
• a water-immiscible binder liquid such as cited above.
• the binding liquid use is made of an organic solvent in which 10-phenothiazinylpropanoic acid is very slightly soluble, that is to say that it has a solubility of less than 5%, and preferably less than 1%.
• the binding liquid chosen from esters of aliphatic or cycloaliphatic acids, aliphatic or cycloaliphatic alcohols, aliphatic or cycloaliphatic ketones, generally meets this requirement when its carbon condensation is at least 5. There is no upper limit on the number of carbon atoms except that this binder must remain liquid during granulation.
• another variant of the process of the invention consists in starting from a liquid which can be solid at room temperature (most often between 15 ° C and
• esters of aliphatic acids used are in particular the acetates of n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl.
• aliphatic alcohols mention may in particular be made of isopentanol and octanol.
• ketones mention will be made more particularly of cyclohexanone.
• n-propyl acetate or isopropyl acetate is preferably chosen.
• the starting 10-phenothiazinylpropanoic acid can be crystallized or ground product.
• the particle size expressed by the median diameter (d5fj) varies widely, for example from 1 ⁇ m to 100 ⁇ m.
• the amount of water relative to 10-phenothiazinylpropanoic acid is not critical; however, it is preferred to use suspensions corresponding to about 400 to 2000 cm 3 of water, preferably from 800 to 1000 cm 3 per 100 g of 10-phenothiazinylpropanoic acid.
• the mixture is kept under stirring.
• the type of agitation is not critical, however, it is preferred to use a shear agitation of the Rushton® turbine type, for example.
• the mixing speed of the mixture must be sufficient to obtain a homogeneous suspension of 10-phenothiazinylpropanoic acid in water and a homogeneous dispersion of the binder liquid.
• a speed of 500 to 800 rpm is generally used when operating in a 1 liter reactor.
• the amount of binding liquid relative to 10-phenothiazinylpropanoic acid is critical. Below a minimum quantity of binding liquid, agglomeration does not occur; on the other hand, if we use a too much binding liquid, the solid particles are dispersed in the binding liquid and they deform easily.
• the determination of the proportions between which the spherical agglomerates form and remain stable can be carried out in the following manner.
• the binder liquid is added dropwise. Aliquots of the suspension are taken during the addition, the examination of which makes it possible to determine the minimum quantity of binder liquid necessary for the formation of spherical agglomerates. The addition of the binder liquid is continued to determine from what quantity of said liquid the spherical agglomerates start to disintegrate.
• the quantity to be used advantageously varies between 0.4 and 0.7 g per g of 10-phenothiazinylpropanoic acid.
• the binder liquid it is not necessary to gradually add the binder liquid; the amount of this necessary for the formation of spherical agglomerates can be added all at once to the stirred aqueous suspension of 10-phenothiazinylpropanoic acid.
• spherical agglomerates occurs a few minutes after the addition of the binder liquid.
• the diameter of the agglomerates then increases approximately linearly with respect to the duration of the agitation and then remains practically constant. It is therefore possible to stop the growth of agglomerates when they have reached the desired size.
• the spherical agglomerates can be separated from the formation medium according to conventional solid / liquid separation techniques, preferably by filtration.
• the constituents (water and binding liquid) of the liquid phase can be separated, for example by azeotropic distillation, and recycled in subsequent operations.
• the size of the agglomerates can be increased by carrying out, after the agglomeration step and before the solid / liquid separation step, an additional addition of 10-phenothiazinylpropanoic acid in suspension in water or 10-phenothiazinylpropanoic acid powder in the stirred medium containing the agglomerates.
• the added solid 10-phenothiazinylpropanoic acid binds to the surface of the formed grains and thus coats them with a solid layer.
• the amount of 10-phenoth ⁇ az ⁇ nylpropano ⁇ que acid added may represent from 5 to 50% by weight of solid 10-phenoth ⁇ az ⁇ nylpropano ⁇ que acid initially agglomerated.
• the agglomerates obtained according to the process of the invention can then be dried according to the conventional techniques known to those skilled in the art.
• the drying is generally carried out under atmospheric pressure or under reduced pressure (for example between 50 and 100 mBar).
• the drying is most often carried out in air at a temperature which can range from ambient temperature, for example 20 ° C. to a temperature of 100 ° C., preferably between 50 ° C. and 90 ° C.
• the drying time is continued until a constant weight is obtained.
• the spherical agglomerates obtained according to the method of the invention, and which themselves constitute another object of the invention, have good mechanical strength, advantageous flowability properties and are easily handled. In addition, they are very easily filterable.
• 10-phenothiazinylpropanolque acid is suspended in aqueous suspension.
• the amount of water used to perform this operation depends on the particle size of the starting powder. It will be specified by way of indication that a quantity of water of 500 cm 3 to 2000 cm 3 is advantageously used per 100 g of 10-phenoth ⁇ az ⁇ nylpropanoic acid.
• the contacting of the water and the powder is preferably carried out with stirring for a period varying, for example, between 5 min and 20 min.
• the wet powder is separated by any suitable method, preferably by filtration, and then the powder thus obtained is subjected to an agglomeration step carried out according to the process of the invention.
• organic solvents suitable for this adsorption include aliphatic ethers, preferably isopropyl ether, aliphatic esters, preferably n-propyl or isopropyl acetate, aromatic hydrocarbons, halogenated or not, preferably toluene or monochlorobenzene.
• the amount of organic solvent (s) used is not critical and can be very variable. Thus, it can represent from 1 to 200% of the weight of 10-phenothiazinylpropanoic acid, preferably between 1 and 10%.
• the adsorption of these products is carried out by dispersing them in an aqueous suspension of 10-phenothiazinylpropanoic acid with vigorous stirring.
• the suspension is then subjected to a separation operation, preferably a filtration.
• the product obtained is then subjected to the agglomeration process according to the invention.
• agglomeration can be favored by increasing the pH of the suspension of 10-phenothiazinyipropanoic acid, preferably between 4 and 6.
• any suitable means can be used, and more particularly one or more washes with water of the starting product can be carried out.
• the agglomeration can be carried out in the presence of a mineral salt preferably having a high ionic strength.
• a mineral salt preferably having a high ionic strength.
• salts mention may be made, in particular of calcium salts, preferably, calcium carbonate, calcium sulfate and aluminum salts, preferably, aluminum sulfate. The addition of such a salt promotes agglomeration.
• the amount of salt used is advantageously chosen from a range going from 0.5 to 5% of the weight of 10-phenothiazinylpropanoic acid.
• the process of the invention leads to agglomerates, the agglomeration of which can be facilitated by prior wetting operations using an aqueous or organic liquid.
• Example 1 is a mixture of the following examples.
• the agglomeration of 10-phenothiazinylpropanoic acid is carried out in two successive stages.
• the operation is carried out at room temperature.
• the filter cake is used in the next step.
• the agglomerates formed are dried in an oven at 70 ° C under atmospheric pressure for 2 hours.
• the level of fines is not quantifiable.
• Agglomeration of 10-phenothiazinylpropanoic acid is carried out by prior adsorption of monochlorobenzene on 10-phenothiazinylpropanoic acid and by addition of calcium carbonate to promote agglomeration.
• the operation is carried out at room temperature.
• the particle size characteristics of the starting 10-phenothiazinylpropanoic acid are as follows:
• the system is agitated for 30 min.
• the contents of the reactor are then filtered.
• the filter cake is then washed with 1 liter of water.
• the system is agitated for 1 hour. 30 g of isopropyl acetate are then added to the reactor.
• the system is agitated for 1 hour. 0.2 g of calcium carbonate is then added to the reactor.
• Granules of size less than a millimeter are then formed after 1 h 30 min of stirring.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

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• 1996
  • 1996-03-07 FR FR9603114A patent/FR2745813B1/fr not_active Expired - Fee Related
• 1997
  • 1997-03-07 EP EP97914359A patent/EP0885203A1/de not_active Withdrawn
  • 1997-03-07 US US09/142,472 patent/US5994538A/en not_active Expired - Fee Related
  • 1997-03-07 JP JP9531533A patent/JP2000506159A/ja active Pending
  • 1997-03-07 WO PCT/FR1997/000405 patent/WO1997032864A1/fr not_active Ceased

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