Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-13
2002-04-16
Chang, Ceila (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S326000
Reexamination Certificate
active
06372911
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to processes for preparing &bgr;-hydroxy carbamates and oxazolidinones. More particularly, the invention is directed to the aminohydroxylation of olefins by reacting the olefins with a carbamate in aqueous solvent in the presence of a base, an osmium catalyst, a co-oxidant selected from a halohydantoin and a haloisocyanuric acid or its alkali metal salt, and optionally an asymmetric ligand. The invention is further directed to conversion of &bgr;-hydroxy carbamates to oxazolidinones which are useful as chiral auxiliary agents and as intermediates for the formation of pharmaceutically active substances such as alpha 1 a adrenergic receptor antagonists. The invention is also directed to a process for preparing nitrogen-functionalized derivatives of the oxazolidinones.
References are made in this application to various publications, the disclosures of which are hereby incorporated by reference in their entireties, in order to more fully describe the state of the art to which this invention pertains.
BACKGROUND OF THE INVENTION
Olefins have been converted to &bgr;-hydroxy carbamates by reaction with carbamates using t-butyl hypochlorite as a co-oxidant. WO 97/46516, for example, discloses the conversion of olefins to asymmetric &bgr;-hydroxy carbamate products by the asymmetric addition of a carbamoyl radical and a hydroxyl radical to the double bond, wherein the olefin is reacted with a carbamate in a reaction solution containing an osmium catalyst, NaOH, t-butyl hypochlorite, a chiral ligand, and a solvent having an organic component and an aqueous component. The use of t-butyl hypochlorite in aminohydroxylations is problematic, because it is relatively expensive, can explode at room temperature, and is light sensitive resulting in a relatively short shelf life. To minimize safety hazards, t-butyl hypochlorite is generally used in solution form (typically an aqueous solution), which can present handling problems in large scale operations.
Methods for preparing 2-oxazolidinones are described in M. E. Dyen et al., Chem. Rev., 67, 197 (1967) and L. Ager et al., Chem. Rev., 96, 835 (1996). The compounds can be prepared, for example, by reaction of &bgr;-aminoalcohols with phosgene. As another example, asymmetric 2-oxazolidinones have been prepared from commercially available amino acids (e.g., phenylalanine, valine, phenylglycine, norephedine and t-leucine) by reducing the acids to their corresponding aminoalcohols using reducing agents such as sodium borohydride-sulfuric acid, NaBH
4
, LiAlH
4
and the like, and then reacting the aminoalcohols with phosgene or with a dialkylcarbonate. Thus, L-phenylalanine can be reduced with borane, followed by reaction with diethylcarbonate to produce an enantiomerically pure 4-benzyl-2-oxazolidinone.
SUMMARY OF THE INVENTION
The present invention is an aminohydroxylation process in which an olefin compound is reacted with a carbamate in the presence of a co-oxidant selected from a halohydantoin (e.g., 1,3-dichloro-5,5-dimethylhydantoin), a haloisocyanuric acid, and an alkali metal salt of a haloisocyanuric acid (e.g., sodium dichloroisocyanurate). These co-oxidants are highly effective, with the process typically characterized by higher enantioselectivity, better yields and/or shorter reaction times than analogous hypochlorite processes. The use of a hydantoin provides other significant benefits over known hypochlorite-based aminohydroxylation processes in that the hydantoins (i) are typically stable solids which present essentially no explosion hazards, (ii) can be safely handled in solid form which permits easy scale-up of the reaction, and (iii) are comparatively inexpensive.
More particularly, the invention is a process for preparing a &bgr;-hydroxy carbamate product which comprises reacting an olefin compound containing at least one carbon-carbon double bond with a carbamate in an aqueous solvent and in the presence of a base, an osmium catalyst, a co-oxidant, and optionally an asymmetric ligand, to form a reaction mixture containing the &bgr;-hydroxy carbamate product; wherein the co-oxidant is
(1) a hydantoin is of Formula (Ia):
wherein X and X′ are each independently H, Cl, or Br, and at least one of X and X′ is Cl or Br; R
1
and R
2
are each independently selected from H, C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, C
4
-C
20
alkylcycloalkyl, and C
4
-C
20
cycloalkyl-alkyl; or
(2) an isocyanuric acid of Formula (Ib):
or an alkali metal salt thereof; wherein Y, Y′ and Y″ are each independently H, Cl, or Br, and at least one of Y, Y′ and Y″ is Cl or Br.
One embodiment of the invention is the process as set forth in the preceding paragraph, wherein the starting olefin compound is characterized by the absence of a C
2
axis of symmetry parallel to the double bond, the reaction mixture includes the asymmetric ligand, and the product is an asymmetric &bgr;-hydroxy carbamate.
Another embodiment of the invention is the process as set forth in either of the two preceding paragraphs, farther comprising treating the reaction mixture with additional base to form at least one oxazolidinone; and optionally further comprising recovering the oxazolidinone from the reaction mixture. In an aspect of this embodiment, the additional base used to form the oxazolidinone is an alkali metal carbonate, and the oxazolidinone is recovered by acidifying the reaction mixture containing the oxazolidinone, neutralizing the acidified mixture with base, and extracting the oxazolidinone with organic solvent.
Still another embodiment of the invention is a process for reacting an amine with the oxazoldinone prepared and recovered as described above to obtain a coupled amine product.
These and other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is a process for preparing a &bgr;-hydroxy carbamate product which comprises reacting an olefin compound containing at least one carbon-carbon double bond with a carbamate in an aqueous solvent and in the presence, of a base, an osmium catalyst, a co-oxidant selected from a halohydantoin, a haloisocyanuric acid, and an alkali metal salt of a haloisocyanuric acid, and optionally an asymmetric ligand to form a reaction mixture containing the &bgr;-hydroxy carbamate product.
The hydantoin employed in the process of the invention is a halohydantoin of Formula (Ia):
wherein X and X′ are each independently H, Cl, or Br, and at least one of X and X′ is Cl or Br; R
1
and R
2
are each independently selected from H, C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, C
4
-C
20
alkylcycloalkyl, and C
4
-C
20
cycloalkyl-alkyl. In one embodiment, R
1
and R
2
are each independently selected from H and C
1
-C
6
alkyl (e.g., H and C
1
-C
4
alkyl), and X and X′ are as heretofore defined. In a second embodiment, X and X′ are both Cl, and R
1
and R
2
are as heretofore defined. In an aspect of the second embodiment, X and X′ are both Cl and R
1
and R
2
are each independently selected from C
1
-C
4
alkyl. In a third embodiment, one of X and X′ is Cl, the other of X and X′ is Br, and R
1
and R
2
are as heretofore defined. A suitable hydantoin is, for example, 1,3-dichloro-5,5-dimethylhydantoin; i.e., X and X′ are both Cl, and R
1
and R
2
are both methyl. Other suitable hydantoins include, but are not limited to, 1,3-dibromo-5,5-dimethylhydantoin, 1-bromo-3-chloro-5,5-dimethylhydantoin, 3-bromo-1-chloro-5,5-dimethylhydantoin, and 1,3-dichloro-5-methyl-5-isopropylhydantoin.
The isocyanuric acid employed in the process of the invention is a haloisocyanuric acid of Formula (Ib):
or an alkali metal salt thereof; wherein Y, Y′ and Y″ are each independently H, Cl, or Br, and at least one of Y, Y′ and Y″ is Cl or Br. In one embodiment, no more than one of Y, Y′ and Y″ is H, and, in an aspect of this
Barta Nancy
Larsen Robert D.
Sidler Daniel R.
Weissman Steven A.
Brown Baerbel R.
Chang Ceila
Fitch Catherine D.
Merck & Co. , Inc.
Walton Kenneth R.
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