Oxirane derivative and process for the preparation thereof

Details Oxirane derivative and process for the preparation thereof Oxirane derivative and process for the preparation thereof

1999-08-19

2002-09-24

Buttner, David J. (Department: 1712)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Mixing of two or more solid polymers; mixing of solid...

C525S409000, C528S405000, C528S421000, C568S618000, C568S621000, C568S622000

Reexamination Certificate

active

06455639

ABSTRACT:

TECHNICAL FIELD
The present invention relates to an oxirane derivative and a process for the preparation thereof. More particularly, the present invention relates to a high molecular oxirane derivative having a narrow molecular weight distribution, little impurity content and a high purity useful as a starting material of terminal-modified oxirane derivative for medical purposes, particularly for chemical modification of physiologically active protein such as polypeptide and enzyme and chemical modification in drug delivery system for liposome, polymer micelle, etc., and a process for the preparation thereof.
BACKGROUND ART
In recent years, terminal-modified oxirane compounds have attracted attention as an important carrier for drug delivery system. Thus, compounds having amino group or carboxyl group incorporated in oxirane compound have been under extensive study. As such terminal-modified oxirane compounds there have been exemplified 2,4-bis(methoxypolyethylene glycol)-6-chloro-s-triazine containing triazine ring as inclusion (JP-A-3-72469 (The term “JP-A” as used herein means an “unexamined published Japanese patent application”)) , and compound obtained by converting terminal hydroxyl group in methoxypolyethylene glycol to carboxymethyl group, and then converting it to hydroxysuccinimide ester (E. Dellacherie et al., “Macromol. Chem. Suppl.”, 9, pp.43-46, 1985). Examples of publications carrying these terminal-modified oxirane compounds and their application include J. Milton Harris, “Laboratory Synthesis of Polyethylene Glycol Derivatives”, Macromol. Chem. Phys., C25 (3), pp.325-375, 1985, K. Takahashi, A. Ajima, et al, “Biochemical and Biophysical Research Commu.”, Vol. 125, No. 2, pp. 761-766, 1984, Y. Kamisaki, H. Wada, et al., “The Journal of Pharmacology and Experimental Therapeutics”,Vol. 216, No.2, pp.410-414, 1981,Y.Kamisaki, H. Wada, et al., “Gann”, Vol. 73, pp. 470-474, 1982; A. Matsushima, H. Nishimura, et al., “Chemistry Letters”, pp. 773-776, 1980, K. Ono, Y. Kai, H. Maeda et al., “J. Biomater. Sci. Polymer Edn.”,Vol. 2, No. 1, pp.61-65,1991, and T. Yoshimoto, H. Nishimura, Y. Saito, et al., “Jpn. J. Cancer Res. (Gann)”, Vol. 77, pp. 1,264-1,270, 1986. Such a terminal-modified oxirane compound can be prepared by subjecting as a starting material a high molecular compound obtained by adding oxirane or alkyloxirane to a compound containing active hydrogen to reaction on the terminal hydroxyl group so that it is converted to a compound having various functional groups. Known examples of the oxirane compound to be used as a starting material include a compound having one hydroxyl group obtained by adding oxirane or alkyloxirane to aliphatic or aromatic alcohol, and a compound having two or more hydroxyl groups obtained by adding alkyloxirane to polyhydric alcohol.
On the other hand, these terminal-modified high molecular oxirane compounds are mostly used for medical purposes and need to be high purity compounds. Thus, various proposals have been made for such high purity compounds and their preparation processes. For example, JP-A-3-72469 and JP-A-8-165343 refer to percent modification of terminal hydroxyl group in oxirane compound and propose a synthesis method little liable to production of by-products which comprises removing impurities produced as much as possible at the purification step to prepare a high purity terminal-modified oxirane compound. The preparation method proposed places emphasis of interest on the purification during the preparation of terminal-modified derivative from oxirane derivative but takes into little account impurities contained in the oxirane compound to be used as a starting material. As a result, terminal-modified compounds derived from oxirane similar compounds having different molecular weights or different numbers of functional groups can be hardly removed depending on their structure because their physical properties are very similar to that of the desired compound. Even if these terminal-modified compounds can be removed anyway, many steps are required. Further, yield drop or other problems occur.
For example, when it is attempted to synthesize a terminal-modified oxirane compound from as a starting material an oxirane compound having one hydroxyl group such as methoxypolyethylene glycol, a terminal-modified oxirane compound having a predetermined molecular weight which is modified for only one hydroxyl group is designed pharmaceutically. Thus, if the resulting compound contains a terminal-modified compound having two hydroxyl groups as an impurity or compounds having different molecular weights, no desired compound can be obtained, causing a great problem in the design of quality of drug. For example, if a large amount of by-products are produced, it is necessary to examine the by-products for toxicity, occasionally giving a necessity of effecting experiment and clinically study again.
In general, an oxirane compound having one hydroxyl group can be obtained by subjecting a monohydric alcohol having one hydroxyl group as a starting material to addition reaction with oxirane in the presence of an alkaline catalyst such as potassium hydroxide and sodium hydroxide or a Lewis acid catalyst such as boron trifluoride and tin tetrachloride. If water molecules contained in the catalyst or alcohol as a starting material are present in the reaction system, oxirane is added to the water molecules to produce a polyethylene glycol having two hydroxyl groups. The polyethylene glycol has two reaction points and thus has oxirane added thereto in an amount of about twice that of the desired compound having one reaction point and hence a molecular weight as much as about twice that of the desired compound.
If the alcohol to be used as a starting material has a large number of carbon atoms and hence a boiling point of remarkably higher than that of water, the removal of water content from the system by dehydration of the reaction system having the catalyst charged therein under reduced pressure makes it possible to reduce somewhat the produced amount of diol compound as a by-product. On the contrary, however, if the alcohol to be used as a starting material has a small number of carbon atoms and hence a boiling point close to or lower than that of water, water content cannot be removed from the reaction system by dehydration under reduced pressure. In most cases, however, as alcohol to be used as a starting material from which a terminal-modified high molecular oxirane compound to be used as a starting material of drug is prepared there are used C
1-4
aliphatic alcohol or C
6-7
aromatic alcohol which are used as a protective group for hydroxyl group.
It has been suggested that decomposition reaction can occur as well depending on the reaction temperature and amount of catalyst to produce a low molecular vinyl compound (Yoshihiko Oshima et al., “Coating Engineering”, Vol. 22, No. 9, pp. 397-403, 1987). Such a vinylether can be easily hydrolyzed under acidic conditions to produce a hydroxyl group. Thus, if a mineral acid or the like is used to remove the alkaline catalyst, such a vinylether becomes an oxirane derivative having a different molecular weight from that of the main component which then becomes a terminal-modified compound having a different molecular weight from the desired compound at the subsequent reaction. On the other hand, if no mineral acid is used to remove the catalyst, the vinylether remains to be a vinyl group which then is left unreacted at the step of introducing a functional group into the terminal of polyoxirane derivatives. Thus, the vinylether remains as an impurity. Further, it is known that the polymerization of cyclic monomers such as oxirane involves monomer addition reaction which is not accompanied by chain end and the resulting polymer has a Poisson distribution (P. J. Flowrie, “High Molecular Chemistry”, 2nd vol., pp. 314-315, translated by Shoten Oka, Maruzen, 1964). It is also known that the ratio of weight-average molecular weight Mw to number-average molecular weight Mn is represented by the following

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