Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/73—Unsubstituted amino or imino radicals

Definitions

• the present invention resides generally in the field of the preparation and use of aminopyridine compounds, and in one particular embodiment to novel prilled forms of aminopyridine compounds.
• aminopyridines are well known intermediates to a broad range of useful compounds including for example pharmaceuticals, for instance antihistamines, dyestuffs, and other compounds.
• 2-aminopyridine in particular is used on a large scale worldwide as an intermediate to pharmaceutical compounds.
• Aminopyridines such as 2-aminopyridine have heretofore been available in crystalline or flaked forms.
• product forms have exhibited tendencies to agglomerate and dust, thus complicating storage and transfer operations.
• new product forms of aminopyridines are needed that avoid or reduce these difficulties which have been encountered in the handling of crystalline or flaked aminopyridine forms.
• the present invention addresses this need.
• aminopyridines in molten form exhibit properties whereby advantageous granular aminopyridine product forms can be provided by a melt extrusion processes, especially a prilling process. Accordingly, one embodiment of the present invention provides a process for manufacturing an aminopyridine product in a unique form which has reduced tendency to dust and improved free-flowing properties as compared, for example, to known flaked forms.
• the preferred process for preparing an aminopyridine product, especially 2-aminopyridine includes a step of providing the aminopyridine as a molten flowable mass. This flowable mass is then extruded through an orifice into discrete liquid portions each corresponding to a granule to be formed.
• Suitable melt temperatures range from the melting point for the aminopyridine up to just below the decomposition temperature for the aminopyridine, with preferred melt temperatures ranging from about the melting point of the aminopyridine up to about 90° above that point, more preferably from the melting point up to about 20°C above the melting point.
• the extruding step is conducted using equipment optimally designed for forming the discreet portions.
• equipment optimally designed for forming the discreet portions may involve an extrusion apparatus equipped to deliver the flowable mass through an orifice for a predetermined period of time to provide drops of the appropriate size.
• This control can be achieved, for example, by providing first and second wall members movable relative to one another to periodically align one or more orifices in the first member with one or multiple orifices in the second member for the predetermined period of time.
• the flowable mass is pressurized against the first wall member such that when orifice (s) in the first wall member are each aligned with one or multiple orifice (s) in the second wall member, an amount of the flowable mass is extruded through the orifices in the second wall member, for example downwardly onto a conveyor belt.
• Most preferred devices for these purposes include as the first member, a first container filled and pressurized with the flowable mass, and as the second member a second container, e.g. a drum, encasing the first container.
• the containers are movable (e.g. rotatable) with respect to one another, preferably provided by a static inner container and a movable (rotating) outer container.
• Movement of the second container results in periodic alignment of the orifice (s) in the first container with orifice (s) of the second container for the predetermined time, during which the drops of aminopyridine product material are extruded through the aligned orifices and downwardly onto a passing conveyer belt.
• Such processes provide preferred, smooth- surfaced aminopyridine product granules of uniform size and shape, for example generally hemispherical in shape .
• Another preferred embodiment of the invention provides a composition comprising a granulated aminopyridine, especially a granulated 2-aminopyridine product.
• Preferred such products have an average particle diameter of about 1 mm to about 10 mm, with most preferred product forms having smooth granules of substantially uniform size and/or shape.
• the invention provides improved aminopyridine products that overcome handling and processing difficulties previously encountered with aminopyridine products. Additional objects, features and advantages of the invention will be apparent from the description that follows.
• one preferred embodiment of the present invention provides novel forms of aminopyridine products.
• the novel forms in accordance with the invention are granular, and are preparable by melt extrusion processes which yield discreet liquid portions which upon solidification form smooth granules or prills.
• 2-aminopyridine exhibits properties under melt which render it advantageous in such melt extrusion processes.
• these properties include relatively rapid crystallization upon cooling, and the absence of substantial supercooling that would frustrate the ability to yield a three-dimensional particle in a melt extrusion process such as prilling.
• the structurally similar compounds, 3-aminopyridine and 4-aminopyridine will similarly exhibit such properties.
• Preferred melt extrusion processes of the invention involve the extrusion of molten 2-, 3- or 4- aminopyridine products.
• Preferred products for use in the invention thus include those of the formula:
• aminopyridine for melt extrusion processing in accordance with the invention is 2-aminopyridine:
• the aminopyridine is extruded, while molten, through an orifice in a fashion which provides granules of the desired size.
• Processes of the invention can, for example, be conducted in an extrusion apparatus as described in U.S. Patent No. 4,279,579, which is hereby incorporated herein by reference in its entirety.
• Such an apparatus includes a first container having a plurality of orifices and a second container disposed within the first container.
• Means are provided for admitting the flowable molten mass of product into the second container, and means are also provided for producing relative rotation between the containers to periodically align the orifices of the first container with a fluid passage (s) of the second container, so as to deposit drops of the flowable mass through the orifices of the first container downwardly onto a conveyor belt also provided in the apparatus.
• Such processes in which discreet drops or portions are caused to solidify to form flowable granules are generally referred to as prilling processes, and the resulting granules are referred to as prills.
• the conveyor belt is a cooled stainless steel belt, which hastens the solidification of the flowable mass drops as they exit the passage provided by the aligned orifices.
• Suitable devices for the conduct of such processes are commercially available from Sandvic Process Systems, Inc. of Totowa, New Jersey, U.S.A. Further information regarding such devices is available from Sandvic 's trade literature, including that entitled Sandvik Rotoform® Process, Premium Pastilles at high production rates, low production costs (1993); A World of Chemical Experience in Chemical Processing: Sandvik Process Systems.
• the aminopyridine compound is provided in a molten state for extrusion processing.
• Preferred melt processing temperatures will range from about the melting point of the product up to the decomposition temperature of the compound. More preferred temperatures will be at about the melting point up to about 90°C above the melting point of the compound in hand.
• 2- aminopyridine a generally suitable temperature range is about 56°C to about 150°C, and a more preferred temperature range is about 60°C to about 80°C.
• 3- aminopyridne a suitable temperature range is about
• a suitable temperature range is about 158°C to about 250°C, more preferably about 158°C to about 180°C.
• the temperature utilized will be selected in light of the conditions at hand, and will be optimized to provide the desired viscosity of the flowable product mass for extrusion processing in accordance with the invention.
• Granulated products in accordance with the invention will preferably have smooth granules with an average particle diameter of about 1 to about 10 mm, more preferably about 1 to about 5 mm.
• preferred products will have granules of substantially uniform shape and size.
• granulated products of the invention will have a substantially 3- dimensional shape (i.e. the deposited drops will solidify prior to their spreading to form a substantially 2-dimensional flake) , which provides improved flow properties for the solid product in accordance with the invention.
• Preferred granules so prepared will generally also have a non-uniform thickness, with a relatively flat or planar surface on a first side (from contact with the conveyor belt) , and a generally arcuate surface on a second side opposite the first side.
• Preferred granulated products of the invention also exhibit desirable dissolution properties in aqueous medium, meaning that while provided in a readily handled and manipulated granulated form in the dry state, once placed in aqueous media, the product granules break up and dissolve into solution with relative ease and quickness, generally within about a few minutes with agitation.
• preferred granulated products of the invention will have a low level of fines having a particle diameter of less than 600 microns, more preferably less than 5% by weight fines. Particle integrity of preferred products will also minimize the generation of fines under conditions of abrasion and impact.
• the preferred granulated products of the invention are free-flowing, and exhibit a reduced tendency to aggregate as compared to corresponding flaked product forms. These products thus overcome difficulties which have been encountered with prior flaked aminopyridine forms, and are advantageously handled in manufacturing, storage and use operations.
• products of the invention demonstrate advantages making them well suited for transport operations including gravity flow or vacuum, (e.g. as in gravity flow addition or vacuum addition to reactors) , and can optionally be packaged in containers adapted to facilitate such operations.
• granulated products of the invention can be packaged in containers that are adapted for connection to reactor ports and that incorporate product release mechanisms that are activatable upon or after such connection.
• Such containers may also be adapted for efficient gravity flow of the granular product out of an opening of the container, and in this regard may have a shape adapted to release all of the granular product upon activation of the product release mechanism.
• the container may include one or more wall members inclined downwardly toward the opening of the container adapted for connection to the reactor port. In this manner, safe, efficient and convenient use of granular products of the invention is facilitated.
• the bore size on the rotating shell of the rotoformer was 1.5 mil.
• 2-aminopyridine was maintained as a melt at about 60°C-70°C for feed to the rotoformer.
• molten 2- aminopyridine was extruded through the bores onto the cooled belt of the rotoformer, providing 2- aminopyridine prills having diameters of about 2-3 mm.
• the prills were removed at the end of the belt by a micarta laminated plastic blade, at which point the prills exhibited a temperature of about 27-28°C.
• the prills were found to be substantially uniform in shape and to exhibit excellent hardness and integrity. The prills also exhibited little or no tendency to cake.
• Example 1 The procedure of Example 1 is repeated, except using 3- aminopyridine to make a prilled 3-aminopyridine product. In addition, the 3-aminopyridine is maintained as a melt at 65°C to 75°C for feed to the rotoformer.
• Example 1 The procedure of Example 1 is repeated, except using 4-aminopyridine to make a prilled 4-aminopyridine product. In addition, the 4-aminopyridine is maintained as a melt at 160°C to 170°C for feed to the rotoformer.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pyridine Compounds (AREA)
• Medicinal Preparation (AREA)
• Glanulating (AREA)

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• 2000
  • 2000-01-21 CN CN 00805133 patent/CN1344253A/zh active Pending
  • 2000-01-21 WO PCT/US2000/001513 patent/WO2000043363A1/en not_active Application Discontinuation
  • 2000-01-21 JP JP2000594779A patent/JP2002535309A/ja active Pending
  • 2000-01-21 EP EP00905694A patent/EP1144379A4/en not_active Withdrawn
  • 2000-01-21 AU AU27339/00A patent/AU2733900A/en not_active Abandoned

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