Organic compounds -- part of the class 532-570 series – Organic compounds – Heavy metal containing
Reexamination Certificate
2002-05-21
2004-10-19
Chang, Celia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heavy metal containing
C556S021000, C502S155000, C540S450000, C546S217000, C548S111000, C568S008000, C568S017000
Reexamination Certificate
active
06806378
ABSTRACT:
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable
REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK
Not Applicable
FIELD OF THE INVENTION
This invention relates generally to preparing nonracemic chiral alcohols. It more particularly relates to preparing nonracemic chiral alcohols by hydrogenation of ketones using transition metal catalysts comprising nonracemic chiral ligands. Nonracemic chiral alcohols are useful as pharmaceuticals and other bioactive products and as intermediates for the preparation of such products.
BACKGROUND OF THE INVENTION
Ketones can be converted to racemic chiral alcohols by hydrogenation using certain catalyst systems of ruthenium, a phosphine ligand, a 1,2-diamine, and an alkaline base. Aromatic and heteroaromatic ketones can be hydrogenated to nonracemic chiral alcohols by using certain catalyst systems of ruthenium, an appropriate enantiomeric diphosphine ligand, an enantiomeric 1,2-diamine, and an alkaline base.
Angew. Chem. Int. Ed
., vol. 40, (2001), 40-73 (a review with 211 references); U.S. Pat. No. 5,763,688
; J. Am. Chem. Soc
., vol. 117 (1995), 2675-2676
; J. Org. Chem
., vol. 64 (1999), 2127-2129. Others have noted that such ketones can be hydrogenated to nonracemic chiral alcohols using related catalyst systems formed with a racemic chiral 1,2-diamine. In their catalyst system, the active diastereomeric ruthenium catalyst is formed with the enantiomeric atropisomeric diphosphine ligand and the “matched” enantiomer of the racemic chiral 1,2-diamine. Interestingly, the diastereomeric ruthenium complex with the “unmatched” enantiomer of the racemic chiral 1,2-diamine, if it is formed, is relatively inactive.
Angew. Chem. Int. Ed
., vol. 40, (2001), 40-73; European Patent Application 901 997
; J. Am. Chem. Soc
., vol. 120 (1998), 1086-1087. A catalyst system of ruthenium, the atropisomeric diphosphine (S)-2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl (S-BINAP), achiral ethylene diamine, and potassium hydroxide in isopropanol is reported to hydrogenate 1′-acetonaphthone to (R)-1-(1-naphthyl)-ethanol in 57% enantiomeric excess. The corresponding catalyst system having enantiomeric (S,S)-1,2-diphenylethylenediamine instead of achiral ethylene diamine is reported to hydrogenate 1′-acetonaphthone under the same conditions to (R)-1-(1-naphthyl)ethanol in 97% enantiomeric excess.
Angew. Chem. Int. Ed
., vol. 40, (2001), 40-73
; J. Am. Chem. Soc
., vol. 117 (1995), 2675-2676.
An attempt to provide a catalyst system of ruthenium, the atropisomeric diphosphine S-BINAP, enantiomeric (S,S)-1,2-diphenylethylenediamine, and 1,8-diaza-bicyclo[5.4.0]undec-7-ene as the base (in the place of the alkali base used in the references discussed above) gave no catalytic activity for the hydrogenation of acetophenone. The addition of selected alkali salts of tetrakis[3,5-bis(trifluoromethyl)phenyl]borate to this attempted catalyst system provided catalytic activity for the hydrogenation of acetophenone to nonracemic 1-phenethanol. The investigators conclude that alkali metal cations are required for the activity of this catalyst system.
Angew. Chem. Int. Ed
., vol. 40, (2001), 3581-3585.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a catalyst system as well as a process for the preparation of a nonracemic chiral alcohol by hydrogenation of a ketone using the catalyst system. The catalyst system comprises ruthenium, a nonracemic chiral diphosphine ligand, an amino-thioether ligand, and a base. Surprisingly, and in contrast to teaching in the art, a chiral diamine ligand is not required to obtain highly enantioselective hydrogenation of a ketone to a nonracemic chiral alcohol when using a catalyst system comprising ruthenium, a nonracemic chiral diphosphine ligand, an amine ligand and a base. Accordingly, the present invention provides methods for the highly enantioselective hydrogenation of a ketone to a nonracemic chiral alcohol using an amino-thioether ligand, with a catalyst system also comprising ruthenium, a nonracemic chiral diphosphine ligand, and a base.
In one group of embodiments the base is selected from alkylamidines, alkylguanidines, aminophosphazenes, and proazaphosphatranes.
BRIEF DESCRIPTION OF THE DRAWINGS
Not applicable
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
As used herein, the term “treating”, “contacting” or “reacting” refers to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product. “Side-reaction” is a reaction that does not ultimately lead to a production of a desired product.
“Alkyl” means a linear saturated monovalent hydrocarbon radical or a branched saturated monovalent hydrocarbon radical or a cyclic saturated monovalent hydrocarbon radical, having the number of carbon atoms indicated in the prefix. For example, (C
1
-C
6
)alkyl is meant to include methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl and the like. For each of the definitions herein (e.g., alkyl, alkenyl, alkoxy, aralkyloxy), when a prefix is not included to indicate the number of main chain carbon atoms in an alkyl portion, the radical or portion thereof will have twelve or fewer main chain carbon atoms. A divalent alkyl radical refers to a linear saturated divalent hydrocarbon radical or a branched saturated divalent hydrocarbon radical having the number of carbon atoms indicated in the prefix. For example, a divalent (C
1
-C
6
)alkyl is meant to include methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
“Alkenyl” means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond. For example, (C
2
-C
6
)alkenyl is meant to include, ethenyl, propenyl, and the like.
“Alkynyl” means a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond and having the number of carbon atoms indicated in the prefix. For example, (C
2
-C
6
)alkynyl is meant to include ethynyl, propynyl, and the like.
“Alkoxy”, “aryloxy”, “aralkyloxy”, or “heteroaralkyloxy” means a radical —OR where R is an alkyl, aryl, aralkyl, or heteroaralkyl respectively, as defined herein, e.g., methoxy, phenoxy, benzyloxy, pyridin-2-ylmethyloxy, and the like.
“Aryl” means a monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms which is substituted independently with one to four substituents, preferably one, two, or three substituents selected from alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino and heteroalkyl. More specifically the term aryl includes, but is not limited to, phenyl, biphenyl, 1-naphthyl, and 2-naphthyl, and the substituted derivatives thereof.
“Aralkyl” refers to a radical wherein an aryl group is attached to an alkyl group, the combination being attached to the remainder of the molecule through the alkyl portion. Examples of aralkyl groups are benzyl, phenylethyl, and the like.
“Heteroalkyl” means an alkyl radical as defined herein with one, two or three substituents independently selected from cyano, alkoxy, amino, mono- or di-alkylamino, thioalkoxy, and the like, with the understanding that the point of attachment of the heteroalkyl radical to the remainder of the molecule is through a carbon atom of the heteroalkyl radical.
“Heteroaryl” means a monocyclic or bicyclic radical
Jiang Qiongzhong
Tucker Charles E.
Chang Celia
DSM N.V.
Townsend and Townsend / and Crew LLP
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