US10125152
Formation of the acid chloride (Va) involves treatment of (IV) with a chlorinating agent such as thionyl chloride, phosphorous pentachloride or oxalyl chloride, in a solvent such as dichloromethane, in the presence of a catalyst such as DMF, at around room temperature. In certain cases, DMF is also used as a co-solvent. Formation of the anhydride (Vb) (Z is C═O) involves treatment of (IV) with a sterically hindered acid chloride or chloroformate, such as trimethylacetyl chloride or isopropylchloroformate, in an inert solvent such as dichloromethane, in the presence of a non-nucleophilic base, such as triethyl amine or diisopropylamine at room temperature or below. Formation of the activated ester (Vc) involves treatment of (IV) with an activating reagent system such as EDCI, DCC/HOBt, HATU, BOP reagents or TBTU, in a solvent such as DMF, DMA, NMP or dichloromethane at room temperature or below(*室温またはそれ以下で)(International Journal of Pharmaceutical Sciences Review and Research (2011), 8(1), 108-119).
Alternatively, the 1,2 diamino-ethyl substructure can be prepared from a suitable aryl-alkyl ketone such as (XX) (SCHEME 5). For example, treatment of (XX) with trimethylsilyl-triflate, in ether, at about 0° C., in the presence of triethylamine provides silyl-enol ether (XXI). Treatment of (XXI) with a halogenating reagent, such as bromine, NCS, or pyridinium tribromide in an inert solvent such as dichloromethane or cyclohexane, at a temperature between −78° C. and room temperature furnishes the α-halo-ketone (XXII). (XXII) is condensed with an amine (NHR4R5) in an inert solvent such as toluene, THF, acetonitrile or DMA, at room temperature or above(*室温またはそれ以上で), to yield the α-amino-ketone (XXIII). Reductive amination of (XXIII) as described above, yields the diamino-ethyl derivative (XXIV) which is further processed (benzyl ether removal and oxidation) to provide the requisite acid (IV) as described above.
US8541484
According to another aspect, the dehydrated hydrogel is placed in i) water, saline solution, Ringer's solution, saline solution, buffer solution, etc., or combinations thereof, ii) a humidity chamber, or iii) room temperature or elevated temperature. By being rehydrated.
According to another aspect, the dehydration is carried out by leaving the hydrogel in air, by placing the hydrogel in a vacuum at room temperature or at an elevated temperature, for example, at 40° C., above about 40° C., about 80° C., above 80° C., about 90° C., about 100° C., above 100° C., about 150° C., about 160° C., above 160° C., about 180° C., about 200° C., or above 200° C.
Cold irradiation is described in detail in U.S. Pat. No. 6,641,617, U.S. Pat. No. 6,852,772, and WO 97/29793. In the cold irradiation process, a polymer is provided at room temperature or below room temperature. Preferably, the temperature of the polymer is about 20° C. Then, the polymer is irradiated. In one embodiment of cold irradiation, the polymer may be irradiated at a high enough total dose and/or at a fast enough dose rate to generate enough heat in the polymer to result in at least a partial melting of the crystals of the polymer.
PVA-PAA gels or PVA-PAA-PEG gels can be built up in a layer-by-layer fashion by sequentially molding different concentration solution in the mold to achieve gradient properties. The gradient is thus disposed in a direction perpendicular to the direction of deposit. A hot (for example, about 90° C.) PVA-PAA-PEG mixture solution is poured into a container up to a certain thickness to form the first layer. The solution in the mold is gelled by cooling down to the room temperature or lower temperature. Upon gelling, the first layer in the container is heated to a temperature below the melting temperature with no disruption of the formed layer. Another layer of solution is added from a hot PVA-PAA-PEG mixture to the first layer to ensure adhesion of the two layers. The second layer can be formed from same or different composition of the polymer solution, or a new component can be added in the mixture. The container is again cooled down to form a layered gel structure. This procedure can be repeated to the desired number of layers or thickness. Such layer-by-layer gel formation can be applied to PVA-PEG gels or PVA cryogel as well, followed by PAA diffusion.
In another embodiment, PEG containing PVA hydrogel is prepared by starting with an aqueous PVA solution (at least about 10% (wt) PVA, above about 15% (wt) PVA, about 20% (wt) PVA, about 25% (wt) PVA, about 27% (wt) PVA, about 30% (wt) PVA, about 35% (wt) PVA, about 40% (wt) PVA, about 45% (wt) PVA, about above 50% (wt) PVA) and mixing it with a low molecular weight PEG solution at an elevated temperature (above room temperature or above 50° C.). Upon cooling down to room temperature, the mixture forms a PVA-PAA-hydrogel containing water and the non-solvent PEG. In another embodiment, the hot PVA-PAA/PEG mixture is not cooled to room temperature but instead is subjected to freeze-thaw cycles.
6). In another embodiment of a PAA-incorporated PVA cooling gel and subsequent PEG doping , a hot water-containing poly (vinyl alcohol) (PVA) solution at room temperature or higher was cast (optionally preheated) to form a PVA cooling gel. ), Cooled to 0 ° C. or lower, and melted at a temperature of 0 ° C. or higher. The total PVA content in the gel is about 10%, 15%, 20%, 25%, 27%, 30%, 35%, 40%, 45%, or their degree, any value between them, or It can be more than that. The PVA cooling gel is immersed in an aqueous solution of PAA that diffuses the PAA into the gel. Use vigorous stirring and / or high temperature to increase diffusivity. The diffusivity can also be increased by immersing the gel in a supercritical fluid. The gel can then be immersed in the PEG to extract the PEG into the gel while extracting some or all of the water.
US8420629
In some embodiments, the methods further comprise reacting the compound of Formula I with phosphoric acid to form the phosphate salt. The phosphoric acid salt of the compound of Formula I may be produced by treating a solution of the corresponding free base in an organic solvent, such as ethanol (EtOH), with a solution of phosphoric acid in an organic solvent, such as ethanol, at room temperature or at an elevated temperature (e.g., from about 60 to about 70° C.). The produced crude phosphate salt may then be further purified by recrystallization or re-slurry in an organic solvent or a mixed organic solvent system.