Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-24
2003-03-04
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06528661
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds that suppress cholesterol biosynthesis in humans by competitively inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and, more particularly, to processes for preparing pharmaceutically appropriate salts for oral administration of such compounds.
BACKGROUND OF THE INVENTION
[R(R*,R*)]-2-(4-fluorophenyl)-&bgr;,&dgr;-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid (“atorvastatin”) is an inhibitor of cholesterol biosynthesis in humans. It is one of a class of drugs called statins. Statins suppress cholesterol biosynthesis by competitively inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (“HMG-CoA reductase”). HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is the rate determining step in the biosynthesis of cholesterol. Goodman and Gilman,
The Pharmacological Basis of Therapeutics
841 (MacMillan Publ. Co.: New York 7th ed. 1985). Decreased production of cholesterol stimulates LDL receptor activity and consequently reduces the concentration of LDL particles in the bloodstream. Reducing LDL concentration in the bloodstream decreases the risk of coronary artery disease
J.A.M.A.
1984, 251, 351-74.
Racemic trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydro-4-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-carboxamide (“the racemic atorvastatin lactone”) was reported to be a useful inhibitor of cholesterol biosynthesis in U.S. Pat. No. 4,681,893, in 1987. The racemic lactone was synthesized according to the chemical process summarized in Scheme 1.
Example 2 of the '893 patent describes the preparation of the sodium salt of (R*,R*) -2-(4-fluorophenyl)-&bgr;,&dgr;-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid (“racemic atorvastatin sodium”) by treating the racemic lactone with sodium hydroxide in THF:water, as shown in Scheme 2.
U.S. Pat. No. 5,273,995 discloses atorvastatin, the pure [R(R*,R*)] enantiomer of 2-(4-fluorophenyl)-&bgr;,&dgr;-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid. The '995 patent describes a stereoselective preparation (Scheme 3) of atorvastatin wherein the absolute configuration of the side chain hydroxy group closest to the pyrrole ring is set by a stereoselective aldol condensation. After chain extension with tert-butyl acetate, reduction of the &bgr; ketone proceeds under substrate stereocontrol to orient the &bgr; hydroxy group cis to the &dgr; hydroxy group.
The '995 patent describes a preparation of atorvastatin hemi-calcium, which is the salt form of the drug that has been approved by the U.S. Food and Drug Administration for oral administration to human patients. To prepare atorvastatin hemi-calcium, the '995 patent teaches that the sodium salt is prepared first by dissolving the lactone in methanol and water and adding a little less than one equivalent of sodium hydroxide to the solution until the lactone has been opened as determined by high performance liquid chromatography (HPLC). The '995 patent then teaches that the hemi-calcium salt may be prepared from the sodium salt by treating it with one equivalent or a slight excess of calcium chloride dihydrate (CaCl
2
.2H
2
O) (steps d and e of Scheme 3). To an atorvastatin sodium salt solution whose exact concentration has been determined by HPLC is slowly added an equivalent or slight excess of CaCl
2
.2H
2
O at elevated temperature while agitating the solution. After completing the addition, atorvastatin hemi-calcium is obtained as a precipitate by cooling the solution. The '995 patent also describes how the pure R,R stereoisomer may be obtained from a mixture of R,R and S,S stereoisomers obtained from the '893 patent process.
U.S. Pat. No. 5,298,627 discloses an improved, more convergent, process for preparing atorvastatin in which the side chain bearing the &bgr;,&dgr;-dihydroxy carboxylic acid—which is essential for biological activity—is incorporated in a single step (Scheme 4) rather than being elaborated from a propanal side chain as disclosed in the '893 and '995 patents.
The convergent step of the process is a Paal Knorr reaction (step e). After the convergent step, the acetonide protecting group on the &bgr; and &dgr; hydroxyls is cleaved with acid (step f). The '627 patent teaches that the sodium salt may be prepared from the N,N-diphenyl amide without intermediate isolation of the lactone by treating it with sodium hydroxide in a mixture of methanol and water (step g). The hemi-calcium salt is then prepared by dissolving the sodium salt in a solution of calcium acetate (Ca(OAc)
2
) at room temperature and crystallizing the hemi-calcium salt from the solution by cooling. The '627 patent also describes preparations in which other N,N-disubstituted acetamides are used in the first step in otherwise similar processes. The '627 process is said to be well adapted for large scale production of atorvastatin.
Brower, P. L. et al.
Tet. Lett.
1992, 33, 2279-82 states that (4R-cis)-1,1-dimethylethyl-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate is an ideal intermediate for preparing atorvastatin because it is highly crystalline and readily obtainable by recrystallization in high purity. After extensive optimization of the Paal-Knorr reaction, atorvastatin hemi-calcium was prepared from the highly crystalline intermediate in 60% yield following a procedure generally similar to steps (d) through (h) of Scheme 4. Baumann, K. L. et al.
Tet. Lett.
1992, 33, 2283-2284. Conversion of the Paal Knorr reaction product to atorvastatin hemi-calcium was carried out without isolation of intermediate products by deprotection of the acetonide with aqueous HCl/methanol, dilute base hydrolysis of the tert-butyl ester (anchimeric assistance) and treatment of the derived sodium salt with Ca(OAc)
2
as shown in Scheme 5. As in the process of the '627 patent previously described, the carboxyl protecting group was cleaved with sodium hydroxide and atorvastatin hemi-calcium was prepared by treating the sodium salt with calcium acetate.
U.S. Pat. Nos. 5,003,080; 5,097,045; 5,124,482; 5,149,837; 5,216,174; 5,245,047 and 5,280,126 disclose methods of making atorvastatin free acid and lactone and/or stereoisomers thereof. Roth, B. D. et al.
J. Med. Chem.
1991, 34, 357-66 discloses preparations of atorvastatin lactone and other pyrrol-1-yl ethylmevalonolactones with variable substituents on the pyrrole ring.
Kearney, A. S. et al. “The Interconversion Kinetics, Equilibrium, and Solubilities of the Lactone and Hydroxyacid Forms of the HMG-CoA Reductase Inhibitor, CI-981
” Pharm. Res.
1993, 10, 1461-65 reports that the carboxylic acid group of atorvastatin has a PK
a
of 4.46. The acidic proton of the carboxylic acid group of intermediate compounds used to prepare atorvastatin by the '893 and '995 patent processes must be masked during the chain elaboration steps. The carboxyl group is also protected during the Paal Knorr reaction in the '627 patent and Baumann et al. processes. Forming an ester is a well known way of protecting a carboxylic acid group and masking its acidic proton. Green, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis
3rd. ed., chapter 5 (John Wiley & Sons: New York 1999) (“Greene & Wuts”). It is also known, generally, that carboxylic acids that have been protected as esters may be deprotected by hydrolyzing the ester with a strong base. Id. at 377-78.
Sodium hydroxide is a strong base with a dissociation constant of 6.37 (pK
b
=−0.80),
Handbook of Chemistry and Physics
81st ed. 8-45 (CRC Press: Boca Raton 2000−01), and its use as a reagent for deprotecting ester-protected carboxylic acids is taught in the art. Green & Wuts, p. 377. Calcium hydroxide (Ca(OH)
2
), with a first dissociation constant of 3.74×10
−3
(pK
b
=2.43) and second dissociation
Ishai Eti
Lidor-Hadas Ramy
Lifshitz Revital
Niddam Valerie
Anderson Rebecca
McKane Joseph K.
Teva Pharmaceutical Industries Ltd.
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