Process for the manufacture of organic compounds

Details Process for the manufacture of organic compounds Process for the manufacture of organic compounds

2003-01-24

2004-12-28

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06835838

ABSTRACT:

In one embodiment, the invention provides an enantioselective method for preparing compounds having Formula (S
1
), (S
2
), or (S
3
) as follows:
wherein
R
1
is independently an unsubstituted or substituted alkyl, cycloalkyl or aralkyl; and
R
2
, R
3
, R
4
, R
5
, R
6
and R
7
are, independently, hydrogen, halogen, hydroxy, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaralkyl, optionally substituted alkoxy, aryloxy, aralkoxy, heterocyclooxy or heteroaralkoxy.
Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification unless they are otherwise limited in specific instances either individually or as part of a larger group.
The term “optionally substituted alkyl” refers to unsubstituted or substituted straight or branched chain hydrocarbon groups having 1-20 carbon atoms, preferably 1-7 carbon atoms. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like. Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more of the following groups: halo, hydroxy, cycloalkyl, alkoxy, alkenyl, alkynyl, alkylthio, alkylthiono, sulfonyl, nitro, cyano, alkoxycarbonyl, aryl, aralkoxy, heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and the like.
The term “lower alkyl” refers to those alkyl groups as described above having 1-7 carbon atoms, preferably 1-4 carbon atoms.
The term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.
The term “alkenyl” refers to any of the above alkyl groups having at least two carbon atoms and further containing at least one carbon to carbon double bond at the attachment point. Groups having 2-4 carbon atoms are preferred.
The term “alkynyl” refers to any of the above alkyl groups having at least two carbon atoms and further containing at least one carbon to carbon triple bond at the attachment point. Groups having 2-4 carbon atoms are preferred.
The term “cycloalkyl” refers to optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, each of which may be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, alkylthio, nitro, cyano, alkoxycarbonyl, sulfonyl, heterocyclyl and the like.
Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like.
Exemplary bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the like.
Exemplary tricyclic hydrocarbon groups include adamantyl and the like.
The term “alkoxy” refers to alkyl-O—.
The term “alkylthio” refers to alkyl-S—.
The term “alkylthiono” refers to alkyl-S(O)—.
The term “trialkylsilyl” refers to (alkyl)
3
Si—.
The term “trialkylsilyloxy” refers to (alkyl)
3
SiO—.
The term “alkylsulfonyl” refers to alkyl-S(O)
2
—.
The term “sulfonyl” refers to alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.
The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6-12 carbon atoms in the ring portion, such as phenyl, naphthyl, tetrahydronaphthyl, biphenyl and diphenyl groups, each of which may optionally be substituted by 1-4 substituents, such as alkyl, halo, hydroxy, alkoxy, acyl, thiol, alkylthio, nitro, cyano, sulfonyl, heterocyclyl and the like.
The term “monocyclic aryl” refers to optionally substituted phenyl as described under aryl.
The term “aralkyl” refers to an aryl group bonded directly through an alkyl group, such as benzyl.
The term “aralkylthio” refers to aralkyl-S—.
The term “aralkoxy” refers to an aryl group bonded directly through an alkoxy group.
The term “arylsulfonyl” refers to aryl-S(O)
2
—.
The term “arylthio” refers to aryl-S—.
The term “heterocyclyl” or “heterocyclo” refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The heterocyclic group may be attached at a heteroatom or a carbon atom.
The term “heteroaryl” refers to an aromatic heterocycle, e.g., monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl and the like, optionally substituted by, e.g., lower alkyl, lower alkoxy or halo.
The term “heteroarylsulfonyl” refers to heteroaryl-S(O)
2
—.
The term “heteroaralkyl” refers to a heteroaryl group bonded through an alkyl group.
Accordingly, compounds having Formula (S
1
), (S
2
), or (S
3
) may be prepared by first condensing a disilyloxydiene having Formula (II)
wherein
R
1
is independently an unsubstituted or substituted alkyl, cycloalkyl or aralkyl; and
R and R′ represent lower alkyl, preferably ethyl or methyl, and R and R′ may be identical or different,
with an aldehyde having Formula (Q
1
), (Q
2
), or (Q
3
) as follows:
wherein R
2
, R
3
, R
4
, R
5
, R
6
and R
7
have meanings as defined for Formula (S
1
), (S
2
), or (S
3
) in the presence of a titanium (IV) catalyst having Formula (IV)
wherein R
8
is a lower alkyl, and the binaphthyl moiety is in the S-configuration, in an inert solvent to obtain compounds having Formula (S
1
), (S
2
), or (S
3
) in high chemical yield and enantiomeric purity.
In the aldol condensation above the molar ratio of a disilyloxydiene of Formula (II) to an aldehyde having Formula (Q
1
), (Q
2
), or (Q
3
) initially present in the reaction mixture ranges from 1:1 to 6:1, preferably from 1:1 to 4:1, and more preferably from 1.5:1 to 3:1.
The disilyloxydiene of Formula (II) may be prepared by reacting an acetoacetate of Formula (VI)
wherein R
1
is independently an unsubstituted or substituted alkyl, cycloalkyl or aralkyl; with a silylating agent, such as tri(lower alkyl)silyl chloride or tri(lower alkyl)silyl trifluoromethanesulfonate, preferably trimethylsilyl chloride or triethylsilyl chloride, in the presence of a base, such as triethylamine, diisopropylethylamine or N-methylmorpholine, preferably triethylamine, in an organic solvent, such as pentane, hexane, heptane, tetrahydrofuran, diethyl ether or dichloromethane, preferably hexane, at a temperature ranging from about −25° C. to about 30° C. to form a silylenolether of Formula (VII)
wherein
R
1
is independently an unsubstituted or substituted alkyl, cycloalkyl or aralkyl; and
R is a lower alkyl.
The silylenolether of Formula (VII) may then be treated with a base, such as lithium diisopropylamide or lithium, sodium or potassium bis(trimethylsilyl)amide, preferably lithium diisopropylamide, followed by addition of a silylating agent, such as tri(lower alkyl)silyl chloride or tri(lower alkyl)silyl trifluoromethanesulfonate, preferably trimethylsilyl chloride or triethylsilyl chloride, in an inert solvent, such as diethylether or tetrahydrofuran, preferably tetrahydrofuran, at a temperature ranging from about −40° C. to about −100° C. to form the disilyloxydiene of Formula (II).
Lithium diisopropylamide may be generated in situ from diisopropylamin

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