Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2002-07-18
2003-04-08
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C548S517000, C548S561000
Reexamination Certificate
active
06545153
ABSTRACT:
An improved synthesis for the preparation of 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 is described where methyl cyanoacetate is converted in eight operations or fewer to the desired product, as well as other valuable intermediates used in the process.
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 is a valuable intermediate in the synthesis of Lipitor® (atorvastatin calcium) known 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. The aforementioned compound is useful as an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and is thus useful as a hypolipidemic and/or hypocholesterolemic agent.
U.S. Pat. No. 4,681,893, which is herein incorporated by reference, discloses certain trans-6-[2-(3- or 4-carboxamido-substituted-pyrrol-1-yl)alkyl]-4-hydroxy-pyran-2-ones including trans (±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N, 4-diphenyl-1-](2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.
U.S. Pat. No. 5,273,995, which is herein incorporated by reference, discloses the enantiomer having the (R,R) form of the ring-opened acid of trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N, 4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, i.e., [R-(R*,R*)]-2-(4-fluorophenyl)-&bgr;,&dgr;-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid.
U.S. Pat. Nos. 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; and 6,087,511, which are herein incorporated by reference, disclose various processes and key intermediates for preparing atorvastatin.
Crystalline forms of atorvastatin calcium are disclosed in U.S. Pat. Nos. 5,969,156 and 6,121,461 which are herein incorporated by reference.
A synthetic procedure for the preparation of 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 is disclosed in U.S. Pat. No. 5,273,995.
The asymmetric reduction of &bgr;-ketoesters, as well as &bgr;-diketones, is a well-established transformation in organic synthesis. However, the complexity of these reactions 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 in the prior art require high pressure hydrogenation and extended reaction times makes these procedures impractical and not amenable to large-scale manufacturing processes.
However, we have 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 hydrogenation reaction utilizing chiral non-racemic diphosphine ligands in the presence of secondary activating agents such as protic acids.
The object of the present invention is a short and efficient process for the preparation of 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. The present 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. Furthermore, a key Paal-Knorr condensation step, common to the present and prior art processes, has been improved through a significant decrease in reaction time.
Thus, the present process has significant advantages over the prior art processes and is amenable to large-scale synthesis.
SUMMARY OF THE INVENTION
Accordingly, the first aspect of the present invention is an improved process for the preparation of a compound of Formula (13)
which comprises:
Step (a) reacting a compound of Formula (1)
wherein R is alkyl, aryl, arylalkyl, or heteroaryl in a solvent with a compound of Formula (2)
R
1
—H (2)
wherein R
1
is —XR wherein
X is O,
S, or
Se, or R
1
is
wherein R
2
or R
3
is independently
alkyl,
cycloalkyl,
arylalkyl, or
aryl, or
R
2
and R
3
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 N and R is as defined above to afford a compound of Formula (3)
wherein R
1
is as defined above;
Step (b) reacting a compound of Formula (3) with hydrogen in the presence of a catalyst and a strong acid in a solvent to afford a compound of Formula (4)
wherein Y is Cl, Br, TsO, MsO, or HSO
4
, and R
1
is as defined above;
Step (c) reacting a compound of Formula (4) with a base in a solvent followed by the addition of a compound of Formula (5)
R—CO
2
H (5)
wherein R is as defined above in a solvent to afford a compound of Formula (6)
wherein R and R
1
are as defined above;
Step (d) reacting a compound of Formula (6) with Compound (7)
in a solvent with removal of water to afford a compound of Formula (8)
wherein R
1
is as defined above;
Step (e) reacting a compound of Formula (8) with a compound of Formula (9)
wherein M is sodium, lithium, potassium, zinc, magnesium, copper, calcium, or aluminum and R
1
is as defined above, in a solvent in the presence of a strong base to afford a compound of Formula (10)
wherein R
1
is as defined above;
Step (f) reacting a compound of Formula (10) with hydrogen in the presence of a catalyst in a solvent in the presence of an acid to afford a compound of Formula (11)
wherein R
1
is as defined above or a compound of Formula (11a)
Step (g) reacting a compound of Formula (11b)
wherein R
1a
is OH, —XR wherein
X is O,
S, or
Se, or R
1a
is
wherein R
2
or R
3
is independently
alkyl,
cycloalkyl,
arylalkyl, or
aryl, or
R
2
and R
3
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 N, and R is as defined above in a solvent in the presence of an acid, followed by reaction with a base, an acylating agent, and an acylation catalyst in a solvent to afford a compound of Formula (12)
Step (h) reacting a compound of Formula (12) with HO—M in an alcohol of Formula (17) or (17b)
HOCH
2
-Aryl (17)
or HO-Allyl (17b)
wherein M is sodium, lithium, potassium, zinc, magnesium, copper, calcium, or aluminum; or with a compound of Formula (16) or (16b)
M
⊕⊖
OCH
2
-Aryl (16)
or M
⊕⊖
O-Allyl (16b)
wherein M is as defined above in an alcohol of Formula (17) or (17b) wherein aryl or allyl in a compound of Formula (16) or (16b) and (17) or (17b) is the same, in a solvent followed by the addition of hydrogen in the presence of a catalyst and an
Butler Donald Eugene
Dejong Randall Lee
Nelson Jade Douglas
Pamment Michael Gerard
Stuk Timothy Lee
McKane Joseph K.
Saeed Kamal
Tinney Francis J.
Warner-Lambert & Company
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