Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-10
2004-07-20
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S521000, C548S230000, C560S160000
Reexamination Certificate
active
06765100
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for producing and purifying N-carbamate-protected &bgr;-aminoepoxide with a specific steric configuration {(2R, 3S) or (2S, 3R)} and a method for producing the crystal. The invention also relates to a method for producing and purifying N-carbamate-protected &bgr;-aminoalcohol with a specific steric configuration {(2R, 3S) or (2S, 3R)}.
BACKGROUND OF THE INVENTION
The N-carbamate-protected &bgr;-aminoepoxide represented by the general formula (2) is a useful compound as a pharmaceutical intermediate:
{in the formula, R represents a lower alkyl group, benzyl group or fluorenylmethyl group; A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing a hetero atom in these carbon backbones; * represents asymmetric carbon atom; the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R)}.
It is known for example that (2R, 3S)-N-carbamate-protected &bgr;-aminoepoxide is useful as an intermediate of HIV protease inhibitors and renin inhibitors (see for example Raddatz et al., Journal of Medicinal Chemistry, 1991, 34, 11,3269 or T. Archibald et al., Scientific Update Conference Manual, Chiral USA 99, Full Scale Chiral Separations Using SMB, May 4, 1999, San Francisco, Scientific Update).
It has been known that N-carbamate-protected &bgr;-aminoepoxide represented by the general formula (2) can be synthesized according to the following pathway.
{in the formula, R and A represent the same meanings described above; X represents halogen atom}.
When (3S)-N-carbamate-protected &agr;-halomethylketone as the compound represented by the general formula (4) is used as a starting material, for example, the starting material is reduced to afford (2R, 3S)-N-carbamate-protected &bgr;-aminoalcohol, followed by treatment with a base, to afford (2R, 3S)-N-carbamate-protected &bgr;-aminoepoxide.
Similarly, when (3R)-N-carbamate-protected &agr;-halomethylketone is used as a starting material, the starting material is reduced to afford (2S, 3R)-N-carbamate-protected &bgr;-aminoalcohol, followed by treatment with a base, to afford (2S, 3R)-N-carbamate-protected aminoepoxide.
Herein, the reduction of N-carbamate-protected &agr;-halomethylketone with an appropriate reducing agent involves the generation of the diastereomer as a byproduct.
For example, the reduction of (3S)-N-carbamate-protected &agr;-halomethylketone represented by the general formula (13) involves the generation of the diastereomer (2S, 3S)-N-carbamate-protected &bgr;-aminoalcohol (7) as a byproduct.
Upon treatment with a base, the byproduct is converted to as (2S, 3S)-N-carbamate-protected &bgr;-aminoepoxide (11) as the diastereomer of the objective compound (see the following scheme).
{in the formulas, R, A, X represent the same meanings as described above.}
More specifically, for example, it is reported that the reduction of, e.g., (3S)-3-tert-butoxycarbonylamino-1-halo-4-phenyl-2-butane in ether with lithium aluminum tri-tert-butoxyhydride involves the generation of the diastereomer (2S, 3S)-3-tert-butoxycarbonylamino-1-halo-2-hydroxy-4phenylbutane at a ratio of about 1 mol equivalent to 5 to 8 mol equivalents of the objective (2R, 3S) compound (see P. Raddatz et al., J. Med. Chem., 1991, 34, 11, 3269 or T. Archibald et al., Scientific Update Conference Manual, Chiral USA 99, Full Scale Chiral Separations Using SMB, May 4, 1999, San Francisco, Scientific Update). (2R, 3S)-3-tert-butoxycarbonylamino 1,2-epoxy-4-phenylbutane afforded by an additional treatment with a base also contains the diastereomer at about the same ratio.
The above references disclose methods for separating (2R, 3S)-N-carbamate-protected &bgr;-aminoalcohol or (2R, 3S)-N-carbamate-protected &bgr;-aminoepoxide by silica gel chromatography or high-performance liquid chromatography, but the methods require the use of vast amounts of expensive carriers and solvents and take a long time due to the complex procedures. Accordingly, these methods are not industrially appropriate.
Of the references above, the latter reference discloses on page 3 that because (2R, 3S)-N-carbamate-protected &bgr;-aminoalcohol or (2R, 3S)N-carbamate-protected &bgr;-aminoepoxide is at a lower melting point and a higher solubility than those of the diastereomer, the ratio of the diastereomer to the objective compound can be reduced to 94:6, at most, by purification with crystallization and that no more purification thereof by recrystallization is possible.
Further, the technique for removing other impurities is not necessarily satisfactory. Hence, the development of an industrial method for producing highly pure (2R, 3S)- or (2S, 3R)-N-carbamate-protected &bgr;-aminoepoxide has been desired.
BRIEF SUMMARY OF THE INVENTION
It is an object of the present invention to provide an industrial method for producing (2R, 3S)- or (2S, 3R)-N-carbamate-protected &bgr;-aminoepoxide (including the crystal) and N-carbamate-protected &bgr;-aminoalcohol.
The present inventors have made investigations so as to solve the problem. The following findings have been found.
1) By dissolving (2R, 3S)-N-carbamate-protected &bgr;-aminoalcohol containing at least the diastereomer as an impurity or an optical isomer thereof in a solvent including at least one or more selected from aromatic hydrocarbon solvent, aryl halide solvent, saturated hydrocarbon solvent, aqueous mixture solvent, acetone and 2-propanol, thereby removing insoluble matters, the diastereomer as an impurity is highly separated and removed.
2) By treating (2R, 3S)-N-carbamate-protected &bgr;-aminoepoxide containing at least the diastereomer as an impurity or an optical isomer thereof with an acid, thereby converting the diastereomer as an impurity to oxazolidin-2-one derivative, and separating and removing the resulting derivative in water or an aqueous mixture solvent, the diastereomer as an impurity is highly separated and removed.
3) By crystallizing (2R, 3S)-N-carbamate-protected &bgr;-aminoepoxide or an optical isomer thereof in an aqueous mixture solvent, a more highly pure crystal of the epoxide can be obtained.
Accordingly, the object of the present invention, and others, may be accomplished with a method for producing N-carbamate-protected &bgr;-aminoepoxide crystal including:
(a) dissolving N-carbamate-protected &bgr;-aminoalcohol containing at least the diastereomer as an impurity and being represented by the general formula (1), in a solvent including at least one or more selected from aromatic hydrocarbon solvent, saturated hydrocarbon solvent, aqueous mixture solvent, acetone and 2-propanol, to remove insoluble matters:
{in the formula, R represents a lower alkyl group, benzyl group or fluorenylmethyl group; A represents an unsubstituted or substituted alkyl group with 1 to 10 carbon atoms, an unsubstituted or substituted aryl group with 6 to 15 carbon atoms or an unsubstituted or substituted aralkyl group with 7 to 20 carbon atoms, or a group containing one or more hetero atoms in these carbon backbones; X represents halogen atom; * represents asymmetric carbon atom; the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R)};
(b) treating the N-carbamate-protected &bgr;-aminoalcohol represented by the general formula (1) with a base, thereby converting the N-carbamate-protected &bgr;-aminoalcohol to N-carbamate-protected &bgr;-aminoepoxide represented by the general formula (2):
{in the formula, R, A and * represent the same meanings as described above; the steric configuration at 2- and 3-positions is (2R, 3S) or (2S, 3R)};
(c) treating the N-carbamate-protected &bgr;-aminoepoxide containing at least the diastereomer as an impurity and being represented by the general formula (2) with an acid, thereby converting the diastereomer as an impurity to oxazolidin-2-one derivative represented by the g
Hirose Naoko
Honda Yutaka
Izawa Kunisuke
Nakano Takashi
Nakazawa Masakazu
Ajinomoto Co. Inc.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Richter Johann
Zucker Paul A.
LandOfFree
Method for producing epoxide crystal does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for producing epoxide crystal, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for producing epoxide crystal will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3194194