1. Field of the Invention
The present invention relates to a new polyether derivative and a process for producing the same. More specifically, the invention relates to a polyether derivative which is useful for chemical modification of microcapsules or physiologically active protein, chemical modification in a drug delivery system, and for other purposes, and a profitable process for producing the derivative.
2. Description of the Related Art
About the so-called diazo type heat-sensitive recording materials (see, for example, Kohji Satoh et al., “Journal of the Institute of Image Electronics Engineers of Japan”, vol. 11, No. 4, pp. 290–296 (1982)), a method of microencapsulating a diazonium salt compound, thereby isolating the compound from a coupler, water and a basic compound is suggested (see Tomomasa Usami et al., “Journal of the Society of Electrophotography of Japan” vol. 26, No. 2, pp.115–125 (1987)). As such microcapsules, microcapsules having a polyurethane or polyurea wall are well known (see, for example, Asaji Kondoh, “Microcapsules”, published by the Nikkan Kogyo Shimbun, Ltd. in 1970, and Tamotsu Kondoh et al., “Microcapsules”, published by Sankyo Shuppan Co., Ltd. in 1977).
As a polyhydric isocyanate compound which is a material for constituting the above-mentioned microcapsules having a polyurethane or polyurea wall, for example, an adduct of 2,4-tolylene diisocyanate and trimethylolpropane or an adduct of xylylene diisocyanate and trimethylolpropane is mainly used (see, for example, Japanese Patent Application Laid-Open (JP-A) Nos. 62-212190 and 4-261893). Also known is an adduct of a polymer having, at one terminal thereof, an active hydrogen (such as polyether, polyester, polyamide, polyurea, polyurethane, polysiloxane or a polymer from a vinyl monomer), and a polyfunctional isocyanate having two or more isocyanate groups therein (see, for example, JP-A No. 10-114153). The usefulness of polyether derivatives each having, at one terminal thereof, active hydrogen is described therein.
In recent years, attention has been paid to polyether compounds each having a modified terminal as important carriers for drug delivery systems or combinatorial synthesis, and compounds wherein an amino group is introduced into a polyether compound have been actively researched. As polyether derivatives having an alkyl-modified amino terminal, the following are known: a derivative obtained by tosylating a terminal hydroxyl group of polyethylene glycol, converting the tosylated group to phthalimide by Gabriel's method and further converting the phthalimide to an aminoethyl group by deprotection (see, for example, J. Org. Chem. <45> 5364 (1980)); a derivative obtained by causing a Michael reaction between acrylonitrile and the terminal hydroxyl group of methoxypolyethylene glycol, and then converting the resultant terminal group to an aminopropyl group by reduction (see, for example, JP-A No. 11-263834); a derivative obtained by causing the terminal hydroxyl group of methoxypolyethylene glycol to react with one isocyanate group of alkane diisocyanate, causing the remaining isocyanate group to react with t-butylalcohol to be converted to urethane, and further generating an aminoalkyl group by deprotection (see, for example, Eur. Poly. J. <19>, 341 (1983)); and a derivative obtained by causing the terminal hydroxyl group of methoxypolyethylene glycol to react with Boc-glycine in the presence of DCC (dicyclohexylcarbodiimide) and subsequently converting the resultant to a glycine ester by the deprotection of the Boc group with TFA (trifluoroacetic acid) (see, for example, J. Am. Chem. Soc. <118>, 10150 (1996)); and other derivatives.
However, the synthesis of these polyether derivatives each having a terminal amino group causes a number of problems: the purification thereof for example becomes difficult because of byproducts such as tosylate salt, phthalhydrazide, and dicyclohexylurea; it is also not possible to avoid using an excessive amount of acetonitrile; and in addition a side reaction is caused at the time of deprotection.
As a polyether having an aryl-modified amino terminal, a 3-amino-4-alkylaminobenzoic acid ester of methoxypolyethylene glycol is synthesized (see, for example, Tetrahedron Letters, <43>, 1529 (2002)). However, no other substitution styles have been known. Moreover, it is difficult to remove dicyclohexylurea, which is produced by a side reaction, since DCC is used to synthesize a nitrobenzoic acid ester derivative of methoxypolyethylene glycol, the ester being a precursor.
USPTO Backgrounds
USPTO Backgrounds