Process for preparing...

Details Process for preparing... Process for preparing...

2003-08-06

2004-08-17

Chang, Ceila (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06777560

ABSTRACT:

FIELD OF THE INVENTION
A method for preparing 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide, a key intermediate in the synthesis of atorvastatin calcium, is described.
BACKGROUND OF THE INVENTION
5-(4-Fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide (I) is a key intermediate in the synthesis of atorvastatin calcium (Lipitor®), known also by the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-&bgr;,&dgr;-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate. Atorvastatin calcium inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and thus is useful as a hypolipidemic and/or hypocholesterolemic agent.
A number of patents have issued disclosing atorvastatin, as well as processes and key intermediates for preparing atorvastatin. These include: U.S. Pat. Nos. 4,681,893, 5,273,995, 5,003,080; 5,097,045, 5,103,024, 5,124,482, 5,149,837, 5,155,251, 5,216,174, 5,245,047, 5,248,793, 5,280,126, 5,397,792, 5,342,952, 5,298,627, 5,446,054, 5,470,981, 5,489,690, 5,489,691, 5,510,488, 5,998,633, 6,087,511, 5,969,156, 6,121,461, 5,273,995 6,476,235, 5,969,156, and 6,121,461.
Existing approaches to the preparation of key intermediate (I) presented some shortcomings. For example, one approach relied on the use of a costly chiral raw material ((R)-4-cyano-3-hydroxy-butyric acid ethyl ester), and a low temperature diastereoselective borane reduction.
Scheme 1 summarizes an alternative approach disclosed in U.S. Pat. No. 6,476,235. Hydrogenation of &bgr;,&dgr; diketoacid 2 in the presence of a chiral ruthenium catalyst under acidic conditions proceeded to give diol 3 in moderate to good yields and 1:1 syn:anti diastereoselectivity with respect to the C-3 and C-5 chiral centers. A number of additional transformations are then necessary to reset the stereochemistry of the C-3 center in diol 3 to provide key intermediate (I). These steps include: (a) intramolecular cyclization of 3 to provide lactone 4; (b) elimination of water from lactone 4 to provide &agr;,&bgr; unsaturated lactone 5; (c) facial selective Michael addition of allyl or benzyl alcohol to &agr;,&bgr; unsaturated lactone 5 to provide saturated lactone 6; and removal of the allyl or benzyl moiety in lactone 6 via hydrogenolysis provided key intermediate (I).
As a preliminary matter, the asymmetric hydrogenation of ketones is a known transformation in organic synthesis. However, the complexity of the reaction increases in the case of 1,3,5-tricarbonyl systems, and poor yields and poor stereoselectivities often result. In fact, investigations by Saburi (
Tetrahedron
, 1997, 1993;49) and Carpentier (
Eur. J. Org. Chem
. 1999;3421) have independently demonstrated low to moderate diastereo- and/or enantio-selectivities for diketoester asymmetric hydrogenations.
Furthermore, the fact that the processes disclosed in the literature require high pressure hydrogenation and extended reaction times makes the procedures generally impractical and not amenable to large-scale manufacturing processes where safety, efficiency, and cost are critical considerations.
As a result, a need remains for an approach to the preparation of key intermediate (I) that is efficient, inexpensive, proceeds in a minimum of transformations, and occurs in good yield and high levels of diastereoselectivity.
SUMMARY OF THE INVENTION
These and other needs are met by the present invention which is directed to a process for the preparation of a compound of formula (I)
comprising:
(a) contacting in a solvent a compound of formula (II) with a transition metal catalyst, a hydrogen source, and a base to give a compound of formula (III):
wherein
R
1
is defined as —XR, wherein X is O, S, or Se, or
 wherein R
2
and R
3
are independently alkyl,
cycloalkyl,
arylalkyl, or
aryl, or
R
2
and R
3
taken together are —(CH
2
)
4
—,
—(CH
2
)
5
—,
—(CH(R
4
)—CH
2
)
3
—,
—(CH(R
4
)—CH
2
)
4
—,
—(CH(R
4
)—(CH
2
)
2
—CH(R
4
))—,
—(CH(R
4
)—(CH
2
)
3
—CH(R
4
))—,
—CH
2
—CH
2
-A-CH
2
—CH
2
—,
—CH(R
4
)—CH
2
-A-CH
2
CH
2
—,
—CH(R
4
)—CH
2
-A-CH
2
—CH(R
4
)—, wherein R
4
is alkyl of from one to four carbon atoms, A is O, S, or NH or NR wherein R is defined as alkyl, aryl, arylalkyl, or heteroaryl;
(b) conversion of the compound of formula (III) wherein R
1
is as defined above to a compound of formula (IV) using base;
and
(c) contacting in a solvent the compound of formula (IV) with an acid to afford a compound of Formula (I).
The invention also provides a process for the preparation of a compound of formula (I)
comprising:
(a) contacting in a solvent compound of formula (V) with a transition metal catalyst, a hydrogen source, and a base to give a compound of formula (VI):
wherein
R″ is defined as Me, Et, or t-Bu;
(b) conversion of the compound of formula (VI) wherein R″ is as defined above to a compound of formula (IV) using base;
and
(c) contacting in a solvent the compound of formula (IV) with an acid to afford a compound of Formula (I).
As disclosed herein, we surprisingly and unexpectedly found that the diol esters of the present invention, (R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid esters, can be obtained directly from the corresponding 1,3,5-tricarbonyl precursors in a highly stereoselective manner via a mild and efficient ruthenium-catalyzed asymmetric transfer hydrogenation reaction utilizing transition metal catalysts with chiral non-racemic ligands. The reaction proceeds in good yields at ambient temperature and atmospheric pressure. The invention process is thus safer and more efficient in large scale than earlier approaches, because it avoids the need for specialized high pressure equipment and the use of hydrogen gas. Because the transfer hydrogenation reaction occurs with high levels of syn diastereoselectivity, additional transformations are not necessary to correct the stereochemistry of the C-3 center, as in previous approaches, and the overall number of steps needed to convert the compound of formula (II) to key intermediate (I) is minimized. Moreover, the invention process avoids the use of a costly, chiral raw material ((R)-4-cyano-3-hydroxy-butyric acid ethyl ester), and a low temperature diastereoselective borane reduction, as was necessary in earlier approaches to the preparation of key intermediate (I).
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The term “alkyl” means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
The term “cycloalkyl” means a saturated hydrocarbon ring having 3 to 8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
“Alkoxy” and “thioalkoxy” are O-alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for “alkyl”.
The term “aryl” means an aromatic radical which is a phenyl group, a phenylalkyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, halogen, trifluoromethyl, dialkylamino as defined above for alkyl, nitro, cyano,
as defined above for alkyl, —(CH
2
)
n
2
—N(alkyl)
2
wherein n
2
is an integer of from 1 to 5 and alkyl is as defined above and
as defined above for alkyl and n
2
.
The term “heteroaryl” means a 5- and 6-membered heteroaromatic radical which may optionally be fused to a benzene ring containing 1 to 3 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl, 1

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