US2005124641A1PendingUtilityA1
Process for preparing chiral diol sulfones and dihydroxy acid HMG CoA reductase inhibitors
Priority: Jun 6, 2001Filed: Jan 20, 2005Published: Jun 9, 2005
Est. expiryJun 6, 2021(expired)· nominal 20-yr term from priority
A61P 3/06C07D 221/16A61P 43/00C07D 491/04C07D 405/06C07D 319/06C07D 417/12C07D 413/12C07D 405/12
41
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Claims
Abstract
A process is provided for preparing chiral diol sulfones of the structure where R 3 is preferably where R 4a is preferably aryl such as phenyl, and R 1a is preferably alkyl such as t-butyl, which are intermediates used in preparing HMG CoA reductase inhibitors.
Claims
exact text as granted — not AI-modified1 . A compound having the structure
(A) where X 1 is CF 3 SO 2 O—, CH 3 SO 2 O— or p-CH 3 —(C 6 H 5 )SO 2 O—; or R 3 —S— or R 3 SO 2 — where
R 3 is
R 4a (R 4a is alkyl, arylalkyl, aryl or cycloalkyl),
(R 5 is H, alkyl, arylalkyl, aryl, CF 3 , halo or NO 2 ),
(X a is O or S), or CF 3 ;
and R 1a is alkyl, cycloalkyl, arylalkyl, aryl or CbZ;
(B) a compound having the structure
where
represents a single bond or a double bond,
Y is alkyl, aryl, arylalkyl or CbZ, and
R 10a is
(C) a compound having the structure
where
X 1a is
wherein R 4a is aryl, alkyl, arylalkyl, or cycloalkyl; and Y is alkyl, aryl, arylalkyl or CbZ, and T f is trifluoromethanesulfonyl; or
(D) a compound having the structure
where R 10 is the residue of an HMG CoA reductase inhibitor or hydrophobic anchor.
2 . The compound as defined in claim 1 having the structure
wherein where R 10 is R 10a or
where
X is CH 2 , O, S or NR 7 ;
R 1 and R 2 are the same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or cycloheteroalkyl;
R 4 is H, halogen, CF 3 , hydroxy, alkyl, alkoxy, alkanoylamino, aroylamino, or cyano;
R 7 is H, alkyl, aryl, alkanoyl, aroyl, or alkoxycarbonyl;
or, the compound as defined in claim 1 having the structure
or
X 1 1a is
or
3 . A process for preparing a chiral sulfone as defined in claim 1 having the structure
wherein R 1a is alkyl, cycloalkyl, arylalkyl, aryl, or CbZ;
R 3 is
or CF 3 ;
where
R 4a is alkyl, aryl, arylalkyl, or cycloalkyl,
R 5 is H, alkyl, aryl, arylalkyl, CF 3 , halo or NO 2 and
X a is O or S;
which comprises treating a solution of sulfonate 2
where R 2a is SO 2 CF 3 , SO 2 CH 3 , or SO 2 (C 6 H 5 )-p-CH 3 , with a thiol of the structure 3
R 3 SH 3
to provide chiral sulfide 4
and treating the chiral sulfide with an oxidizing agent to provide the chiral sulfone, 1 where R 3 is
4 . A process for preparing a trans olefin as defined in claim 1 having the structure
where Y is alkyl, aryl arylalkyl or CbZ and R 10 is a residue of an HMG CoA reductase inhibitor or hydrophobic anchor
which comprises reacting an aldehyde of the structure
with a chiral sulfone of the structure
wherein R 1a is alkyl, cycloalkyl, arylalkyl, aryl or CbZ;
R 3 is
or CF 3 ,
where
R 4a is alkyl, aryl, arylalkyl, or cycloalkyl,
R 5 is H, alkyl, aryl, arylalkyl, CF 3 , halo or NO 2 and
X a is O or S;
in the presence of a base at a reduced temperature to form the trans olefin.
5 . The process as defined in claim 4 wherein R 10 is
where
X is CH 2 , O, S or NR 7 ;
R 1 and R 2 are the same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or cycloheteroalkyl;
R 4 is H, halogen, CF 3 , hydroxy, alkyl, alkoxy, alkanoylamino, aroylamino, or cyano;
R 7 is H, alkyl, aryl, alkanoyl, aroyl, or alkoxycarbonyl.
6 . The process as defined in claim 5 where in the trans olefin formed
R 10 is where X is CH 2 ; Y is alkyl; R 1 is aryl; R 2 is alkyl; R 4 is H.
7 . The process as defined in claim 6 where in the trans olefin formed, R 1 is p-F—C 6 H 5 and R 2 is i-C 3 H 7 .
8 - 10 . (canceled)
11 . A process for preparing a saturated dihydroxy acid of the structure
where R 10 is the residue of an HMG CoA reductase inhibitor or hydrophobic anchor,
(a) which comprises providing a trans olefin of the structure
where Y is alkyl, aryl, arylalkyl or CbZ, as defined in claim 1 ,
subjecting the trans olefin to hydrogenation to form the saturated acetonide
subjecting the acetonide to acidic conditions to form the saturated lactone
and optionally treating the saturated lactone with aqueous base to form the saturated dihydroxy acid ester salt
or (b) which comprises
treating a dihydroxy acid ester of the structure
with base to form the corresponding acid salt, treating the dihydroxy acid salt with acid to form the free acid of the structure
and subjecting the free acid to hydrogenation to form the corresponding saturated free acid of the structure
12 . The process as defined in claim 11 wherein R 10 is
X is CH 2 , O, S or NR 7 ;
R 1 and R 2 are the same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or cycloheteroalkyl;
R 4 is H, halogen, CF 3 , hydroxy, alkyl, alkoxy, alkanoylamino, aroylamino, or cyano;
R 7 is H, alkyl, aryl, alkanoyl, aroyl, or alkoxycarbonyl.
13 . The process as defined in claim 12 wherein the compound formed has the structure
14 . A process for preparing a chiral sulfone as defined in claim 1 of the structure
where Y is alkyl, aryl, arylalkyl or CbZ, which comprises treating a triflate of the structure
with a thiol of the structure
R 3 SH
where R 3 is
and R 4a is phenyl,
to form the chiral sulfide
and treating the chiral sulfide with an oxidizing agent to form the chiral sulfone.
15 . A process for preparing a sulfone as defined in claim 1 of the structure
where X 1 is CF 3 SO 2 O—, CH 3 SO 2 O— or p-CH 3 —C 6 H 5 —SO 2 O—,
which comprises treating a chiral alcohol of the structure
with an anhydride of the structure R 2a —O—R 2a (where R 2a is the same as X 1 , defined above) in the presence of an organic base to form the sulfonate.
16 . A process for preparing a trans olefin as defined in claim 1 having the structure
where
X is CH 2 , O, S or NR 7 ;
Y is alkyl, aryl, arylalkyl or CbZ;
R 1 and R 2 are the same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl or cycloheteroalkyl;
R 4 is H, halogen, CF 3 , hydroxy, alkyl, alkoxy, alkanoylamino, aroylamino, or cyano;
R 7 is H, alkyl, aryl, alkanoyl, aroyl, or alkoxycarbonyl;
which comprises reacting a pyridine carboxylaldehyde of the structure
with a chiral sulfone of the structure
where
X 1 is
where R 4a is aryl, alkyl, arylalkyl, or cycloalkyl, as defined in claim 1 , in the presence of a base to form the trans olefin.
17 - 20 . (canceled)Join the waitlist — get patent alerts
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