Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Utility Patent
1999-06-10
2001-01-02
Padmanabhan, Sreeni (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C568S008000, C568S010000, C568S013000, C568S016000, C568S017000
Utility Patent
active
06169179
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for manufacturing (3S,4R)-4-[(R)-1′-formylethyl]azetidin-2-one derivatives—which are useful as intermediates for synthesis of carbapenem antibiotics—through asymmetric hydroformylation by use of both an optically active diphosphine compound and a rhodium complex as catalysts.
2. Description of the Related Art
In recent years, a number of metal complexes have been used in practice as catalysts for organic synthesis. Since noble metal complexes are stable and easy to handle, there have been conducted numerous synthesis studies have been conducted using such complexes as catalysts, regardless of their high prices. Thus, noble metal complexes have facilitated organic synthesis reactions which were believed to be impossible to carry out by conventional methods.
In particular, complexes of a transition metal such as rhodium or ruthenium and having an optically active diphosphine ligand are known as excellent catalysts for asymmetric synthesis, and a variety of phosphine compounds having a characteristic structure have been developed (edited by The Chemical Society of Japan,
Kagaku Sosetsu
32 “Chemistry of Organometallics,” pp. 237-238, 1982).
Asymmetric hydroformylation using a transition metal-optically active phosphine complex is one class of such reactions; e.g., reaction by use of a rhodium complex having an optically active 2,3-o-diisopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)-butane (hereinafter referred to as “DIOP”) ligand (Journal of Organic Chemistry, vol. 46, page 4422 (1981)); reaction by use of a rhodium complex having an optically active diphosphine (e.g., DIOP) ligand (Bulletin of Chemical Society of Japan, vol. 52, page 2605 (1976)); and a catalytic asymmetric hydroformylation of methyl acetamideacrylate by use of a rhodium complex containing DIOP, etc. as a ligand (Tetrahedron Asymmetry, vol. 10, page 693 (1990)).
As a catalyst formed of a complex having an optically active tertiary phosphate ligand, Tetrahedron Asymmetry, vol. 3, page 583 (1992) describes bis(triaryl phosphite) having an optically active binaphthyl skeleton, as well as asymmetric hydroformylation of vinyl acetate making use of a rhodium complex containing the phosphate as a ligand.
Recently, it has also been reported that a ligand called BINAPHOS having an asymmetric structure, i.e., having a binaphthyl skeleton and no C2 symmetry, is useful for the asymmetric hydroformylation of olefins (J. Am. Chem. Soc., 115, 7033 (1993)).
Thus, a variety of catalysts for asymmetric synthesis are known. Nevertheless, there is still demand for development of a catalyst that meets requirements of high selectivity called for by some target compounds.
High selectivity is particularly needed in the field of pharmaceuticals. For example, there has been reported a method for manufacturing (3S,4R)-4-[(R)-1′-formylethyl]azetidin-2-one derivatives serving as important intermediates for carbapenem antibiotics which have been actively developed in recent years, through asymmetric hydroformylation of 4-vinylazetidin-2-one by use of an optically active phosphine-phosphite compound and a metal compound containing Rh, etc. as catalysts (Japanese Patent Application Laid-Open (kokai) No. 6-316,560).
A method has also been reported in which asymmetric hydroformylation of 4-vinylazetidin-2-one is performed by use of an optically active phosphine-phosphinite compound and a metal compound containing Rh, etc. as catalysts (Japanese Patent Application Laid-Open (kokai) No. 9-40,684).
PROBLEMS TO BE SOLVED BY THE INVENTION
In all the above-described methods, however, there is observed formation of a normal species (n-form:2′-formylethyl form) which is a by-product attributed to regioselectivity to a formyl group-bonding and simultaneous formation of an S-species (i.e., &agr;-form) affecting the enantioselectivity in addition to an (R)-species (i.e., &bgr;-form), which is a target compound, attributed to configuration of a formyl group-bonding. Therefore, there has been demand for satisfying both regioselectivity and enantioselectivity, as well as the demand for obtaining a target compound in high yield.
In particular, there has been demand for a method for effectively manufacturing (3S,4R)-4-[(R)-1′-formylethyl]azetidin-2-one derivatives having a methyl group at the &bgr;-position, which are of great value for use as important intermediates for carbapenem antibiotics, with high regioselectivity and enantioselectivity.
SUMMARY OF THE INVENTION
The present inventors have conducted earnest studies to solve the above problems, and found that (3S,4R)-4-[(R)-1′-formylethyl]azetidin-2-one derivatives having a methyl group at the &bgr;-position of the present invention are effectively manufactured through asymmetric hydroformylation by use of both an inexpensive and easily available optically active diphosphine compound and a rhodium complex as catalysts. The present invention was accomplished based on this finding.
Accordingly, the present invention provides a method for manufacturing (3S,4R)-4-[(R)-1′-formylethyl]azetidin-2-one derivatives represented by formula (3):
wherein R
1
represents a hydrogen atom or a protective group for a hydroxyl group; through asymmetric hydroformylation of 4-vinylazetidin-2-one represented by formula (1):
wherein R
1
has the same meaning as described above; in the presence of a rhodium complex and a (2S,4S)-diphosphine compound represented by formula (2):
wherein R
2
represents a phenyl group which may be substituted with 1-5 substituent(s) selected from a lower alkyl group, a lower alkoxy group, and a halogen atom.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Hereafter, the present invention will be described in detail.
The 4-vinylazetidin-2-one (formula (1)) used as starting materials in the present invention are conventionally known compounds, which may be synthesized through, for example, a method described in Liebig Ann. Chem., 539-560 (1974).
Specifically, a 4-acetoxyazetidinon-2-one derivative (formula (4)) is subjected to reaction with sodium benzenesulfinate, sodium p-toluenesulfinate, or the corresponding potassium salt or lithium salt in a soluble solvent such as acetone-water, methanol, or water-methanol to thereby derive to a compound represented by formula (5). Subsequently, this compound is reacted with an organic vinyl compound—for example, a vinylating agent such as vinyl magnesium chloride, vinyl magnesium bromide, vinyl magnesium iodide, divinyl magnesium, vinyl lithium, vinyl zinc chloride, or divinyl zinc—to thereby obtain 4-vinylazetidin-2-one (formula (1)):
wherein R
1
has the same meaning as described above; Ac represents an acetyl group; and Ar represents a phenyl group which may be substituted with a halogen atom, a lower alkyl group, etc.
The substituent R
1
in 4-vinylazetidin-2-one (formula (1)) represents a hydrogen atom or a protective group for a hydroxyl group, and as the protective group for a hydroxyl group there may be used typical protective groups, i.e., a protective group which may be converted to a hydroxyl group through hydrolysis or hydrogenation used. Examples include organic silyl groups, an acyl group, and aralkyl groups. Specific examples include tri-lower alkylsilyl groups, diphenyl-lower alkylsilyl groups, a triphenylsilyl group, lower alkylcarbonyl groups, a benzyl group, and a benzoyl group. Preferred examples include tri-lower alkylsilyl groups and diphenyl-lower alkylsilyl groups.
Of these protective groups for a hydroxyl group, there is preferred a group substituted with a linear or branched alkyl group having 1-6 carbon atom(s) as the lower alkyl substituent. Examples of the tri-lower alkylsilyl groups include a tert-butyldimethylsilyl group, a dimethyltexylsilyl group, a triethylsilyl group, a truisopropylsilyl group, and a trimethylsilyl group, with a tert-butyldimethylsilyl group being particularly preferred. A tert-butyldiphenylsilyl group is preferre
Alper Howard
Miura Takashi
Saito Takao
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Padmanabhan Sreeni
Takasago International Corporation
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