Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-30
2003-01-21
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C558S289000, C564S455000, C568S881000
Reexamination Certificate
active
06509472
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to novel 4-cyclohexyl substituted 1,3,2-oxazaborolidine chiral accessories of (R) and (S) configurations and processes for producing and using them. More particularly, the present invention relates to a process for an enantioselective reduction of prochiral ketones to chiral secondary alcohols using the novel chiral accesories.
2. Description of Related Art
Chiral accessories of formula A, which are useful for catalyzing an enantioselective reduction of ketones by borane, are well known in the art. See e.g., Tetrahedron: Asymmetry, Vol. 5, No. 2, pp. 165-168 (1994); Tetrahedron: Asymmetry, Vol. 5, No. 3, pp. 465-472 (1994); Tetrahedron: Asymmetry, Vol. 9, No. 7, pp. 1091-1095 (1998); Tetrahedron: Asymmetry Report Number 13, Vol 3, No. 12, pp. 1475-1504 (1992); Tetrahedron: Asymmetry, Vol. 7, No. 11, pp. 3147-3152 (1996); and SynLett, pp. 273-274 (March, 1997).
where,
R
1
is an alkyl or aryl group,
R
2
is an alkyl or aryl group,
R
3
is a hydrogen atom or an alkyl, aryl, aralkyl or alkoxy group.
These chiral accessories are generally prepared from enantiomerically pure amino acids. Consequently, only compounds having absolute (S) configurations can generally be prepared inexpensively, since only (S)-amino acids are typically found in nature. In contrast, (R)-amino acids are usually relatively expensive, because they are generally not found in nature and must be prepared either de novo, which entails separation from racemic mixtures, or by expensive enantioselective routes.
Many useful pharmaceutical agents require for their manufacture, chiral secondary alcohol intermediates having an absolute configuration which is introduced by means of the chiral accessories of type A having the (R) absolute configuration. It is obviously a disadvantage that expensive (R)-amino acids are required for the manufacture of many useful pharmaceutical agents. One of the few inexpensive (R)-amino acids is (R)-phenylglycine (formula 1), which is a precursor to (R)-4-phenyl-5,5-disubstituted oxazaborolidines of formula B. (R)-phenylglycine is relatively cheap because it is manufactured on a multi-ton scale as an intermediate in the synthesis of penicillin G. However, (R)-4-phenyl-5,5-disubstituted oxazaborolidines of formula B that are derived
from (R)-phenylglycine are often not especially efficient chiral accessories, as they can lead to lower enantiomeric ratios in the borane reduction products of prochiral ketones.
Common compounds of formulas A and A′ have the R
1
substituent equal to an isopropyl or —(CH
2
)
3
— group, with the terminal methylene moeity connected to the adjacent nitrogen atom on the ring (replacing a hydrogen atom) forming a five-membered ring. Unfortunately, the known compounds in the (R) configuration with R
1
equal to, respectively, the isopropyl or —CH
2
)
3
— group, are not inexpensive since they are derived from, respectively, (R)-valine and (R)-proline, which are relatively expensive synthetic amino acids. Prior attempts to produce quality, inexpensive chiral accessories of formula A with (R) or (S) configurations have only met with minimal success.
A goal achieved by this invention was to overcome these and other prior art problems. Accordingly, this invention, which includes novel, quality, inexpensive chiral accessories of the (R) or (S) absolute configurations, provides a superior benefit over the current art.
It is an object of this invention to provide inexpensive, novel chiral accessories of the (R) and (S) absolute configurations.
It is a further object of this invention to provide a process for producing inexpensive, novel chiral accessories of the (R) and (S) absolute configurations.
It is yet another object of this invention to reduce prochiral ketones enantioselectively to chiral secondary alcohols with inexpensive, novel chiral accessories of the (R) and (S) absolute configurations.
These and other objects of the present invention will become apparent after reading the following description and claims.
DEFINITIONS AND USAGE OF TERMS
The term “enantioselective catalyst,” as used herein, means a compound which together with a borane reagent reduces a prochiral ketone to an optically active alcohol.
The term “chiral accessory,” as used herein, is synomous with the term “enantioselective catalyst.”
The term “prochiral ketone,” as used herein, means a ketone which on reduction can produce an optically active alcohol. Furthermore, a prochiral ketone will have structurally different moieties attached to its carbonyl group.
The term “alkyl,” as used herein, means an unsubstituted or substituted, straight or branched, hydrocarbon chain. “Lower alkyl” has from 1 to 8 carbon atoms, preferably, from 1 to 4 carbon atoms.
The term “cycloalkyl,” as used herein, means an unsubstituted or substituted, saturated carbocyclic ring. “Lower cycloalkyl” has from 3 to 8 carbons.
The term “aryl,” as used herein, means a substituted or unsubstituted aromatic carbocyclic ring. Preferred aryl groups include phenyl, tolyl, xylyl, cumenyl and napthyl.
The term “aralkyl,” as used herein, means an alkyl moiety substituted with an aryl group. Preferred aralkyls include benzyl, phenylethyl, and 1- and 2-naphthylmethyl.
The term “alkoxy,” as used herein, means a straight or branched, hydrocarbon chain attached to an oxygen atom which is bonded to another atom of a compound. “Lower alkoxy” has from 1 to 8 carbon atoms, preferably, from 1 to 4 carbon atoms.
The terms “secondary chiral alcohol” and “optically active alcohol,” as used herein, each mean an alcohol compound having a hydroxyl group attached to a carbon atom bearing a hydrogen atom and two other non-identical groups.
The term “substantially non-reactive substituent,” as used herein, means a substituent that is not materially affected by either the reagents or solvents used during a chiral borane reduction of a ketone. That is, no significant side reactions occur involving the substituents, which would materially impair the optical and chemical efficacies of the compounds or processes at issue.
The term “enantiomeric excess” (ee), as used herein, means the excess amount of one enantiomer over the other enantiomer in a mixture of enantiomers, expressed in terms of percent, for example, a 9:1 ratio of R:S is equal to an 80% enantiomeric excess (ee) of (R).
The term “borane reagent,” as used herein, means a reagent that is a source of borane or supplies borane in a reaction. Typical reagents which are sources of borane include diborane gas (H
3
B—BH
3
), borane-THF complex (in THF solution), borane dimethylsulfide complex and borane 1,4-oxathiane complex.
It is understood by those skilled in the art that the chiral accessories described herein exist in both the (R) and (S) absolute configurations. A (S) configuration refers to a counterclockwise arrangement of high to low priority substituents about an asymmetric carbon atom. A (R) configuration refers to a clockwise arrangement of high to low priority substituents about an asymmetric carbon atom. Compounds having (R) absolute configurations are specifically described herein. However, it is known to those skilled in the art that (S) configurations can also be produced from appropriately configured starting materials. The compounds described and claimed herein include their enantiomers, and solvates and salts thereof.
It is also known to a skilled artisan that the substituents defined in the compounds of the invention may themselves be substituted with a variety of groups, such as alkyl, cycloalkyl, aryl, aralkyl, hydroxy and alkoxy groups, or a variety of atoms, such as halogen atoms. These groups and atoms are substantially non-reactive substituents.
SUMMARY OF THE INVENTION
The invention relates to a compound having the formula I:
where, the two R
2
groups are identical and=substituted or unsubstituted, aryl, alkyl, cycloalkyl or aralkyl, and R
3
=H or substituted or unsubstituted, aryl, alkyl, aralkyl or alkoxy, for example, an alkoxy group, OR
5
, where R
5
is a substituted or u
Kalyanaraman Palaiyur S.
Kutzenco Allan N.
Lambkin Deborah C.
Schering Corporation
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