WO2004046105A2 - Synthesis of 3,5-dihydroxy-7-pyrrol-1-yl heptanoic acids - Google Patents

Abstract

Atorvastatin and related 3,5-dihydroxy-7-pyrrol-1-yl heptanoic acids can be made by oxidation of a 3,5-dihydroxy-7-pyrrol-1-yl heptanol precursor from novel but readily accessible starting materials. Silylether-protected 7-amino-3,5-dihydroxy heptanoic acid esters undergo Paal Knorr reaction with 1,4-diketones to give valuable silylether-diprotected 3,5-dihydroxy-7-pyrrol-1-yl heptanoic acid ester intermediates for preparing atorvastatin. The Paal Knorr reaction of ketal-proctected 7-amino-3R, 5R-dihydroxy heptanoic acid esters with 4-fluoro-α-(2-methyl-1-oxopropyl-Ϝ-oxo-N,β-diphenylbenzenebutanamide occurs in high yield with few side products when it is conducted in a low boiling point ether.

Description

SYNTHESIS OF 3,5-DIHYDROXY-7-PYRROL-l-YL HEPTANOIC ACIDS

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. provisional application No. 60/426,342, filed on November 15, 2002; provisional application No. 60/466,114, filed April 29, 2003; provisional application No. 60/480,440, filed June 23, 2003; and provisional application No. 60/483,381, filed June 27, 2003, the disclosures of which are entirely incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to processes for preparing 3,5-dihydroxy-7-pyrrol-l-yl heptanoic acids of a class that is effective at inhibiting the biosynthesis of cholesterol in humans, and more particularly to improved synthetic methods for preparing them from 7-amino-3,5- dihydroxy heptanoic acid and 1,4-diketo starting materials.

BACKGROUND OF THE INVENTION

It is known that certain 3,5-dihydroxy heptanoic acid derivatives are competitive inhibitors of the 3-hyώOxy-3-methyl-glutaryl-coenzyme A ("HMG-CoA"). HMG-CoA is a key enzyme in the biosynthesis of cholesterol in humans. Its inhibition leads to a reduction in the rate of biosynthesis of cholesterol. The first HMG-CoA inhibitor to be described is compactin ([lS-lXR^*), 7β, 8β(2S^*, 4S^*),8aβ]]-l,2,3,7,8,8a-hexahydro-7-methyl-8-[2-(tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-l-naphthalenyl 2-methylbutanoate), which was isolated from cultures oϊPenicillium in 1976. In 1987, lovastatin ([lS-flα^^α, 7β, 8β(2S^*, 4S^*),8aβ]]-l,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H- pyran-2-yl)ethyl]-l-naphthalenyl 2-methylbutanoiate) became the first ΗMG-CoA reductase inhibitor approved by the Food and Drug Administration (FDA) for treatment of hypercholesterolemia. Both compactin and lovastatin are derived from bacterial cultures. Two other naturally-derived HMG-CoA reductase inhibitors, simvastatin and pravastatin are structurally related to compactin and lovastatin.

In 1987, it was reported in U.S. Patent No. 4,681,893 that compounds within a certain class of 3,5-dihydroxy-7-pyιτol-l-yl hepanoic acid (and the conesponding lactones) also were effective at inhibiting the HMG-CoA reductase reductase enzyme. One such compound is [R

(R^*, R^*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-( 1 -methylethyl)-3-phenyl-4-

[(phenylamino)carbonyl]- 1 H-pynole- 1 -heptanoic acid ("atorvastatin"), which was said to provide surprising inhibition in U.S. Patent No. 5,273,995. Atorvastatin later received FDA approval as an adjunct to a low cholesterol diet to reduce elevated levels of total cholesterol, low density lipoprotein cholesterol, apo B and triglycerides and to increase levels of high density lipoprotein cholesterol in patients with hyperlipidemia.

In contrast to compactin, lovastatin, simvastatin and pravastatin, there is no known fermentation culture that produces atorvastatin. It, and other 3,5-dihydroxy-7-pynol-l-yl hepanoic acids, must be synthesized by traditional synthetic methods. The '893 patent describes a synthesis of racemic atorvastatin by a nine-step process that included building up of the heptanoic acid side chain by acetoacetic acid synthesis. The final product was a racemate containing 50% of the S,S stereoisomer.

The '995 patent describes a synthesis of the R,R stereoisomer of atorvastatin. The '995 patent used an iterative stepwise process to elaborate the 3,5-dihydiOxy heptanoic acid side chain. The C-5 stereocenter was set by stereoselective aldol-type condensation. Then, the chain was extended by another two carbon atoms and the C-3 stereocenter was set by Claisen condensation with tert-butyl acetate.

U.S. Patent No. 5,298,627 discloses a process for preparing atorvastatin in which the

3,5-heptanoic acid side chain is incorporated in a single convergent step rather than being elaborated from a propanal side chain as in the '893 and '995 patent processes. A precursor of the side chain of atorvastatin was made by Claisen condensation of NN-diphenyl acetamide and 4-cyano-3-hydroxy-butanoic acid ethyl ester. The resulting 6-cy-uιo-3,5-dihydroxy hexanoic acid amide was protected with 2,2-dimethoxypropane. The nitrile was reduced with

Raney-nickel and the resulting amine was reacted with 1,4-diketone 9 (structure shown in Example 3) in 2: 1 : 1 heptane: THF:toluene in the presence of pivalic acid as a catalyst. The reaction of the -tmine with the 1,4-ketone is known as the Paal-Knon pyrolle synthesis (hereafter "Paal Knon reaction"). It involves addition of a primary amine to both keto groups of the 1,4-ketone and elimination of two moles of water to achieve aromaticity. The product was an acetonide-protected 3,5-dihydroxy-7-pynol-l-yl hepantoic acid amide. After cleaving of the acetonide, the amide group was hydrolyzed to the carboxylic acid with sodium hydroxide to give atorvastatin as the sodium salt.

U.S. Patent No. 5,216,174 teaches generally that the Paal Knon reaction can be performed on an acetonide-protected 7-amino-3,5-dihydroxy heptanoic acid tert-butyl ester in an inert solvent or solvents such as, for example, hexane, toluene and the like for about 24 hours at about the reflux temperature of the solvent or solvents and that the product is not isolated but is treated directly with acid to remove the acetonide protecting group.

Baumann, K.L. et al. Tet. Lett. 1992, 33, 2283-84 describes a process for preparing atorvastatin, which involves preparing a pyrrole intermediate, in 75% yield from (4R-cis)-\,l- dimethylethyl-6-aminomethyl-2,2-dimethyl-l,3-dioxane-4-acetate tert-butyl ester. The Paal

Knon reaction is carried out in a temiary solvent mixture of toluene-heptane-tetrahydrofuran (THF) (1:4: 1) in the presence of a pivalic acid catalyst. Another similar condensation between a diketone and amine is described in U.S. Patent No. 5,397,792 where the condensation is carried out in a 6: 10:5 toluene eptane/tetrahydrofuran solvent mixture in the presence of pivalic acid as catalyst.

U.S. Patents 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 pynol-1-yl ethylmevalonolactones with variable substituents on the pyrrole ring.

Notwithstanding other efforts directed toward improvement of methods of synthesizing 3,5-dihydroxy-7-pynOl-l-yl heptanoic acids having HMG-CoA inhibitory activity, there remains a need for further advances in the methodology used to produce these compounds. SUMMARY OF THE INVENTION

Accordingly, the present invention provides processes for preparing 3,5-dihydroxy-7- pynol-1-yl heptanoic acids.

In one aspect of the present invention, a 3,5-dihydiOxy-7-pvnol-l-yl heptanoic acid is made by oxidizing a 3,5-dihydroxy-7-pynol-l-yl heptanol precursor compound. The oxidation can be done directly or with isolation of the intermediate aldehyde. The heptanol starting materials are a novel class of compounds. They can be made by reacting a ketal-protected 7- ammo-3,5-dihydroxy-l -heptanol with certain 1,4-diketones under acid catalyst conditions, preferably at elevated temperature and with removal of water. The 7-amino-3,5~dihydroxy~l- heptanols also are novel compounds.

In a second aspect of the invention, valuable intermediates for preparing HMG-CoA inhibitory compounds are prepared by reaction of silylether-diprotected 7-amino-3,5-dihydroxy heptanoic acid esters with certain 1,4-diketones. One route to the heptanoic acid starting material involves subjecting a ketal-protected 7-amino-3,5-dihydiOxy heptanoic acid ester to ketal cleaving conditions followed by silylation of the deprotected hydroxy groups. Although deprotection and reprotection ordinarily add two steps to a synthesis, in this process only one additional step is added because the silylethers are readily removed under the same conditions as those that are typically employed to hydrolyzed an ester. Hydrolysis of an ester is a nsubsequent transformation to obtain atorvastatin from intermediate compounds of this invention. Accordingly, converting from a ketal to a silylether protecting group does not require second separate deprotecting step.

In a third aspect of the invention, a known synthetic pathway for making atorvastatin is improved by conducting the Paal Knon reaction step in a low boiling point ether rather than in the solvent systems used in the past. In a low boiling point ether, the reaction goes in high yield and produces few side products.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a prefened reaction sequence of the present invention. When M is an alkali metal, i is 1. When M is an alkaline earth metal, is 2. FIG. 2 depicts a second prefened reaction sequence of the present invention. When M is an alkali metal, z is 1. When M is an alkaline earth metal, z is 2. FIG. 3 depicts a third prefened reaction sequence of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The chemical nomenclature used in this disclosure follows the system for naming compounds of the International Union of Pure and Applied Chemistry (IUPAC). The IUPAC system assigns a number to every atom in a compound. This disclosure also uses relative numbering where it is the clearest way to describe the invention to those skilled in the art. The absolute numbering assigned by the IUPAC system is to be distinguished from relative numbering commonly used to express bonding relationships between functional groups. Thus, it will be appreciated that the hydroxy groups of 3,5-dihydroxy heptanoic acid are in a 1,3 relationship to each other, because they are separated by three carbon atoms including those to which they are attached. Likewise, it will be appreciated that the keto groups of a 1,4-diketone of a particular compound will not necessarily be numbered 1 and 4 under the IUPAC system.

Whether atom numbering is absolute or relative will be clear to one skilled in the art from the context in which it is used.

As used herein, unless otherwise indicated, the term "alkyl," includes straight chained and branched alkyl groups containing from 1 to 6 atoms, the term "lower alkyl," includes straight chained and branched alkyl groups containing from 1 to 4 carbon atoms, and the term

"substituted phenyl," includes phenyl substituted with 1-3 groups of alkyls or halogens or alkoxides.

Unless otherwise indicated, compounds used in or obtained by practice of the present invention include any salts, solvates or crystalline forms of the compounds. However, when a salt or solvate is specifically indicated, only that salt or solvate (in any crystalline or amorphous form) is meant.

The compounds depicted in formulae in this disclosure include all stereoisomers except where indicated in a formula by solid or hatched wedge-shaped bonds or by the description in the accompanying text. The present invention provides processes for synthesizing 3,5-dihydiOxy-7-pynol-l-yl heptanoic acids of Formula (I)

wherein: Ri is selected from the group consisting of: 1-naphthyl, 2-naphthyl, cyclohexyl, cyclohexylmefhyl, norbomenyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms, benzyl,

3 , or 4-pyridinyl, and 2-, 3-, or 4-pyridinyl-N-oxide; R₂ or R₃ are independently selected from the group consisting of: hydrogen, alkyl of from one to six carbon atoms, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, or alkoxy of from one to four carbon atoms, cyano, trifluoromethyl, or

— CONR₅ Rs where R₅ and Rg are independently hydrogen, alkyl of from one to six carbon atoms, phenyl, phenyl substituted with fluorine, chlorine, bromine, cyano, or trifluoromethyl;

R₄ is selected from the group consisting of: alkyl of from one to six carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and trifluoromethyl.

In prefened 3,5-dihydroxy-7-pynol-l-yl heptanoic acids of the present invention, the 3- and 5- carbon atoms have an R configuration. In more prefened 3,5-dihydroxy-7-pynol-l- yl heptanoic acids, Ri is 4-fluorophenyl and R₃ is a radical of formula -CONR₅R_<5. Yet more prefened 3,5-dihydroxy-7-pynol-l-yl heptanoic acids are those wherein R, is 4-fluorophenyl, R₃ is a radical of formula -CONR₅R-₅ and _j is alkyl or trifluoromethyl, with isopropyl being especially prefened. Yet even more prefened 3 , 5-dihydroxy-7-pynol- 1 -yl heptanoic acids are those having the prefened R_l3 R₃ and R₄ substitutents wherein R₂ is phenyl. An especially prefened specific 3,5-dihydroxy-7-pynol-l-yl heptanoic acid is atorvastatin.

It will be understood by those skilled in the art that the 1,5-relationship between the carboxylic acid group and a hydroxyl group on the heptanoic side chain of these compounds causes them to be capable of adopting a lactone form. Both the free acid and lactone fonns are intended unless indicated otherwise even though a formula being refened to may depict only the free acid form. The free acid form of these compounds can form metal salts. It will be appreciated that a salt formed by contacting a compound of Formula (I) with a metal contains the free acid as one of its components.

In accordance with one aspect of the present invention, the 3,5-dihydroxy-7-pynol-l- yl heptanoic acid of Formula (I) is synthesized by oxidizing a ketal-protected 3,5-dihydroxy-7- pynol-l-yl-1 -heptanol of Formula (II)

to a ketal-protected 3,5-dihydroxy-7-pynol-l-yl-l-heptanoic acid of Formula (III):

and then cleaving the ketal protecting group (R₇-C-R₈). Substitutents R₇ and R₈ are each independently selected from the group consisting of hydrogen, alkyl, substituted or unsubstituted phenyl, or R₇ and R₈ together with the carbon to which they are attached form a C₅-C₇ carbo cycle, except that R₇ and R₈ are not both hydrogen. Prefened alkyl groups are methyl and tert-butyl. Prefened substituted phenyl groups are /?-C₆H₄OCH₃, j?-C₆H₃(OCH₃)₂, o,t)-C₆H₃(OCH₃)₂, /?-C₆IL,NO₂ and -C₆H₄NO₂ Especially prefened R₇-C-R₈ carbenyl fragments are isopropylidene, ethylidene, tert-butylmethylidene, 1-tert-butylethylidene, 1- phenylethylidene, l-(4-methoxyphenyl) ethylidene, cyclopenylidene, cyclohexylidene, cycloheptylidene, 4-methoxybenzylidene, 2,4-dimethyxybenzylidene, 3,4- dimethoxybenzylidene, 2-nitrobenzylidene, 4-nitrobenzylidene, mesitylene and diphenylmethylene.

Compounds of Formula (II) have not been prepared before and constitute an aspect of the invention. An especially prefened compound of Formula (II) is (4R-cώ)-6-[2-[2-(4-

Fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)cai'bonyl]pynol-l-yl]ethyl]-4-(2- hydroxyethyl)-2,2-dimethyl-l,3-dioxane 1, whose preparation and characterization is set forth in Examples 1-3, below.

The primary alcohol of the Formula (II) compound can be oxidized directly to the acid (without intermediate isolation of the aldehyde) using known strong oxidizers such as MnO₂,

KMnO₄, RuO₄, NaClO₂ and K₂Cr₂O₇. For example, the oxidation can be performed following the methodology of Lehel, Sz. et al. J. of Labelled Cpd, And Radiopharm. 2000, 43, 807-815; Takano, S. et al. Heterocycles 1988, 27, 2413-2415; Singh, A. et al. Tet. lett. 1992, 33, 2307-2310 or Sano, H. et al. Tetrahedron 1995, 51, 1387-1394, which are hereby incorporated by reference in their entirety and in particular for their teachings related to the oxidation of primary alcohols to carboxylic acids in the presence of ketal-protected 1,3-diols. Alternatively, oxidation of the primary alcohol of compounds of Formula (II) can be conducted in two steps with isolation of the intermediate aldehyde, a 4-(2-oxoethyι)-6-(2- (pyιτol-l-yl)ethyl)-l,3-dioxane of Formula (IN)

Mild oxidizing conditions must be used in order to be able to isolate the aldehyde. Suitably mild oxidizing agents include (COCl)₂/DMSO (Swern) (Org Syn Coll. Vol. 7, 1990, 258), pyridinium dichromate, pyridinium chlorochromate, ΝaOCl/TEMPO and pentavalent iodine reagents such as Dess-Martin periodinane (J. Org. Chem., 1983, 48, 4155). Dess-Martin periodinane is a prefened mild oxidizing agent because of its selectvity.

The isolated aldehyde of Formula (IV) is then oxidized to the carboxylic acid using suitable oxidizing agent such as ΝaClO₂ or AgNO₃, with NaClO₂ being prefened.

In the last step of the process, the ketal protecting group is cleaved by conventional techniques employing acidic conditions which are well known in the art.

The ketal protecting group can be hydrolyzed with an acid catalyst in an alcohol, ether or hydrocarbon solvent.

The acid catalyst may be a mineral acid, a sulfonic acid or a carboxylic acid.

Exemplary acid catalysts include, but are not limited to hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, methanesulfonic acid, perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, toluenesulfonic acid and the like. A prefened acid catalyst is hydrochloric acid (HC1).

The ketal can be cleaved in an alcohol solvent including but not limited to Cι-C₆ alcohols including methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl- 2-propanol, pentanol, hexanol, cyclohexanol, ethylene glycol and diethylene glycol. A prefened alcoholic solvent is ethanol. Ethereal solvents that can be used include but are not limited to dioxane, THF and DME. A prefened ethereal solvent is THF. The ketal can be cleaved in an hydrocarbon solvent such as toluene, hexane, and heptane.

Deprotection yields the 3,5-dihydroxy-7-pynol-l-yl heptanoic acid of Formula (I), which may then be converted, if so desired, to a metal salt by contacting it with a source of the metal cation. Pharmaceutically acceptable metal salts, which are prefened, include sodium, potassium, calcium, magnesium, aluminum, iron and zinc salts. To prepare a metal salt of the 3,5-dihydroxy-7-pynol-l-yl heptanoic acid of Formula (I), the heptanoic acid and a source of the metal cation are dissolved in a solvent. Then, the desired metal salt of the Formula (I) compound is precipitated from the solution. The source of the metal cation contains the metal ion and a counterion. The solvent is selected with the consideration that the protonated counterion be highly soluble in the solvent so that the source of metal ion does not precipitate from the solution in competition with the desired salt. Thus, for example, water and ethanol are good solvents when the source of the metal cation is NaOH, Ca(OH)₂ or Ca(OAc)₂.

The heptanol of Formula (II) used in the process can be prepared from readily available and/or commercially available starting material. According to one prefened synthetic route to the heptanol of Formula (II) shown in FIG. 1, a ketal-protected 6-cyano-3,5-dihydroxyl hexanoic acid ester of Formula (V)

is double reduced with a strong reducing agent that is able to reduce nitrile groups to primary amines and carboxylic acid esters to primary alcohols. Substituent R₉ is a substituted or unsubstituted Ci- lower alkyl radical, preferably tert-butyl. An especially prefened compound of Formula (V) is (¥R-cώ)-6-cyanomethyl-2,2-dimethyl-l,3-dioxane-4-acetic acid tert-butyl ester 2 . Compound 2 is readily available in high yield by known processes. Brower, P.L. et al. Tet Lett. 1992, 33, 2279-82, teaches three routes to prepare (4R-cis)-6- cyanomethyl-2,2-dimethyl-l,3-dioxane-4-acetic acid tert-butyl ester. Two routes start with 4- bromo-3-hydroxybutyric acid esters prepared according to the method of Sletzinger, M. et al. Tet. Lett, 1985, 26, 2951 and U.S. Patent No. 4, 611, 067. The third route starts with (4R- ct5^,)-6-hydroxymethyl-2,2-dimethyl-l,3-dioxane-4-acetate tert-butyl ester which is commercially available. All publications cited in this paragraph are incorporated herein by reference in their entirety and in particular for their teachings concerning preparation of compound 2. Exemplary reducing agents for reducing the nitrile and ester groups of the compound of

Formula (V) include alkali metal and alkaline earth metal borohydrides, borane, dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides, or dialkyl aluminum hydrides (such as di- isobutylalurninum hydride). The prefened reducing agent is lithium aluminum hydride. The reduced product is a 6-(2-aminoethyl)-4-(2-hydroxyethyl)- 1 ,3-dioxane of Formula

(VI)

Compounds of Formula (VI), which also have not been prepared before, constitute an aspect of the invention. An especially prefened compound of Formula (VI) is (4R-cώ)-6-(2-

Arn oethyl)-4-(2-hydroxyethyl)-2,2-dimethyl-l,3-dioxane 3, whose preparation and characterization is set forth in Example 1, below.

The 6-(2-aminoethyl)-4-(2-hydroxyethyl)-l,3-dioxane is then condensed with a 1,4- diketone of Formula (VII)

to produce the ketal-protected 3, 5-dihydroxy-7-pynol-l-yl-l -heptanol of Formula (II).

The reaction of 1,4-dicarbonyl compounds with ammonia or primary ∑imines giving substituted pynoles is known as the Paal-Knon reaction. The reaction was discovered late in the nineteenth century. C. Paal, Rer. 1885, 18, 367, L. Knon, Rer. 1885, 18, 299. It has general applicability and is promoted by heating, removal of water and acidic conditions. The unprotected terminal alcohol group on compound 3 used in Example 3 did not interfere with the reaction.

In accordance with this aspect of the invention, the Paal-Knon reaction of a Formula (VI) compound with a Formula (VII) compound is carried out in a solvent, with an acid catalyst under reflux and with evaporative removal of water, for example, by using a Dean-Stark trap.

Suitable solvents include any that do not inhibit the reaction or decompose or otherwise divert the starting material from the desired product. Non-limiting examples of such solvents are pentane, n-hexane, n-heptane, cyclohexane, benzene, isopropyl benzene, chlorobenzene, dichlorobenzene, dichloromethane, dichloroethane, chloroform, tetrachloroform, tetrachloromethane, toluene, xylene, mesitylene, MTBE, THF, dioxane and the like. Prefened solvents are mixtures of heptane and THF and toluene, with toluene being especially prefened. Suitable acid catalysts include, but are not limited to, carboxylic acids such as acetic acid, butyric acid, pivalic acid, benzoic acid and trichloro acetic acid, phenols and cresols.

When the Paal-Knon reaction is performed under prefened conditions, the reaction takes about twenty hours to go to completion. If a water-immiscible solvent is used, the reaction mixture can then be washed with water and after phase separation the 3,5-dihydroxy- 7-pynOl-l-yl-l -heptanol of Formula (II) is obtained in the organic phase. Otherwise, the reaction mixture can be concentrated, taken up in a water-immiscible solvent, washed with water, after which the Formula (II) compound is obtained in the organic phase. An especially prefened technique for conducting the Paal-Knon reaction using amines of Formula (VI) has been developed. According to the prefened technique, the amine of Formula (VI) is brought into contact with the 1,4-diketone (VII) as an acid addition salt with pivalic acid. This technique therefore delivers one molar equivalent of an acid catalyst to the Paal-Knon reaction mixture simultaneously with the amine of Formula (VI). The pivalic acid salt of an amine of Formula (VI) can be generated by dissolving the amine in a suitable solvent and adding pivalic acid to the solution. Suitable solvents are preferably aprotic, moderately polar organic liquids like lower alkyl ethers and lower alkyl ketones that are sufficiently polar to dissolve the amine, but are sufficiently non-polar that the salt, once formed, is poorly soluble and precipitates in good yield. Methyl tert-butyl ether ("MTBE") has been found to be a suitable solvent for compound 3.

After the Paal-Knon reaction, the ketal-protected 3,5-dihyώOxy-7-pynol-l-yl-l- heptanol (II) is oxidized to the conesponding carboxylic acid as previously described. In a second aspect, the present invention provides a process for preparing compounds of Formula (I) by application of the Paul-Knon reaction to a silylether-diprotected 7-arnino- 3,5-dihydroxy heptanoic acid ester and a 1,4-diketone of Formula (VII) followed by deprotection of the hydroxy groups and hydrolysis of the ester.

The silylether-diprotected 7-am o-3,5-dihydroxy heptanoic acid esters useful in the process are those having the molecular Formula (VIII) or (IX)

wherein R₉ is as previously defined and R₁₀, R_π, R₁₂, R₁₃ and R₁₄ are independently selected from the group consisting of C C₆ linear, branched and cyclic, substituted and unsubstituted hydrocarbyl radicals and phenyl.

Compounds of Formula (IX) have not been prepared before and constitute an aspect of the invention. An especially prefened compound of Formula (IX) is 6-(2-aminoethyl)-2,2- diisopropyl-l,3-dioxa-2-silacyclohexane-4-acetic acid tert-butyl ester 4, whose preparation is set forth in Example 11, below. Compounds of Formulae (VIII) and (IX) can be prepared by either of two other processes described below or any other way. Referring now to FIG. 2, compounds of Formulae (VIII) and (IX) can be prepared from compounds of Formula (V), such as compound 2.

In a first alternative process, the ketal protecting group of a Formula (V) compound is cleaved under acidic conditions to yield a 6-cyano-3,5-dihydroxy hexanoic acid ester of

Formula (X).

The hydiOxy groups of the product are then reprotected as silylethers and the silylated product is subjected to nitrile reduction to yield the desired starting material for the Paal-Knon reaction. The 3- and 5-hydroxy groups of the 7-amino-3,5-dihydroxy hexanoic acid ester of

Formula (X) are protected as silylethers using any reagent known to those skilled in the art to be useful for silylating secondary hydroxy groups. Exemplary monofunctional silylating agents include, but are not limited to, those that introduce: a trimethyl silyl group, such as, chlorotrimethylsilane, bromotrimethylsilane, trimethylsilyl trichloroacetate, 3- trimethylsilyloxazolidinone, trimethylsilyltrifluoromethanesulfonate, N-methyl-N-

(trimethylsilyl)acetamide, N-methyl-N(trimethylsilyl)trifluoroacetamide, N,O-bis- (trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)acetamide, N,O-bis-

(trimethylsilyl)trifluoiOacetamide, N-trimethylsilyldiethylamine, and N-trimethylsilylimidazole and hexamethyldisilazane; a triethyl silyl group, such as chlorotriethylsilane, N-methyl-N- triethylsilyltrMuoroacetamide, allyltriethylsilane, N-triethylsilylacetamide, triethylsilyldiethylamine,

1 -methoxy- 1 -triethylsiloxypropene, 1 -methoxy-2-methyl- 1 -triethylsiloxypropene and triethylsilyl triflate; a triisopropylsilyl group such as, trisopropylsilane and triisopropylsilyltrifluoromethylsulfonate; a dimethyl-zso-propylsilyl group, such as c loxo-iso- propyldimethylsilane and di(z^'5^, -propyldimethylsilyl)-ιnώιe; a diethyl-wo-propylsilyl group such as chlorodiethyl-wo-propylsilane, and diethyl-wo-propylsilyl triflate; a dimethylthexyl group such as chlorodimethylthexylsilane and dimtheylthexylsilyl triflate; a tert-butyldimethylsilyl group such as chloro-tert-butyldimethylsilane, tert-butyldimethylsilyl trfluoromethane sulfonate, allyl-tert- butyldimethylsilane, 4-tert-butyldimethylsiloxy-3-penten-2-one, 1 -(tert- butyldimethylsiyl)imidazole, N-tert-butyldimethylsilyl-N-methyltrffluoroacetamide, 1 -(tert- butyldimethylsiloxy)-l-methoxyethene, tert-butyldimethylsilyl triflate; a tert-butyldiphenylsilyl group such as chloro-tert-butyldiphenylsilane and tertbutyldiphenylsilyl triflate; a triphenylsilyl group, such as chlorotriphenylsilane and bromotriphenylsilane; a diphenylmethylsilyl group, such as chloromethyldiphenylsilane; or a di-tert-butylmethylsilyl group such as di-tert- butylmethylsilyl triflate, to name but a few.

In addition, difunctional silylating reagents can be used to protect the 1,3-diol of the 7- anrno-3,5-dihydiOxy heptanoic acid ester. Such difunctional silylating reagents include those that introduce a di-tert-butylsilyl group, such as di-tert-butyldichlorosilane and di-tert- butyldi(trifluoroacetyl)silane; a di-ώo-propylsilyl group, such as di-fso-propyldichlorosilane and di-wo-propyldi(trifluoroacetyl)silane; a dimethylsilyl group, such as dimethyldichlorosilane; a diethylsilyl group, such as diethyldichlorosilane; and a diphenylsilyl group, such a dichlorodiphenylsilane and diphenyldi(trifluoroacetyl)silane. Difunction silylating reagents are prefened because they tend to be more stable to a subsequent hydrogenation step. Especially prefened silylating agents are dichlorodi-wo- propylsilane, dichlorodiphenylsilane and di-tert-butyldichlorosilane.

Silylation using many of the silylating agents produces an acid byproduct, e.g. HC1 or triflic acid, that will hinder the reaction if it is allowed to accumulate in the reaction mixture. Accordingly, an acid scavenger should be added to the reaction mixture. Acid scavengers are well-known and include but are not limited, to non-nucleophilic amine bases such as N,N- diisopropylethylamine, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-lutidine, triethylamine, 2-, 3-, or 4- picoline, N-methyl morpholine, imidazole, pyridine and pyrimidine. A prefened acid scavenger is triethylamine. With a particular silylating agent, it also may be beneficial to add an activator such as

N-hydroxybenzotriazole ("HOBT"), imidazole or DMAP to the reaction mixture to accelerate the reaction.

According to a specific prefened procedure, the silylating agent is dichlorodi-wo- propylsilane, the acid scavenger is triethyl amine, the solvent is THF, CH₂C1₂ or toluene, and the silylether-diprotected product is isolated by filtering off Et₃N»HCl, the filtrate is washed with water, and the solvent is evaporated.

Silylation of the 6-cyano-3,5-dihydroxy hexanoic acid ester of Formula (X) yields a silylether-diprotected 6-cyano-3,5-dihydroxy hexanoic acid ester of Formula (XI) or (X3I).

In addition, silylation may yield some silyl monoprotected products:

The monoprotected products can be carried forward in mixture with the diprotected products in the Paal-Knon reaction. Compounds of Formula (XII) have not been prepared before and constitute an aspect of the invention. An especially prefened compound of Formula (XII) is 6-cyanomethyl-2,2- diisopropyl-l,3-dioxa-2-silacyclohexane-4-acetic acid tert-butyl ester 5, whose preparation is set forth in Example 10, below.

After silylation, the nitrile group of the silylether-diprotected 6-cyano-3,5-dihydroxy hexanoic acid ester is selectively reduced to give the silylether-diprotected 7-arnino-3,5- dihydroxy heptanoic acid ester of Formula (NIII) or (IX). The selective reduction can be performed with Raney-nickel in an alcohol solution with ΝH₃ under 4.0-4.5 atm hydrogen pressure. The crude product can then be used in the Paal-Knon reaction with or without purification or it can be purified and converted to its pivalate salt by the technique previously described for generating the pivalate salt of compounds of Formula (VI). Prefened solvents in which to generate the pivalate salt of the silylether-diprotected 7--ιrnino-β-δ-dihydroxy heptanoic acid ester are heptane, THF and toluene. Referring again to FIG. 2, a second alternative process for preparing silylether- diprotected 7-amino-3,5-dihydiOxy heptanoic acid esters of Formulae (VIII) and (IX) begins with compounds of Formula (XIII)

Compounds of Formula (XIII) can be prepared by selective nitrile reduction of compounds of Formula (V) with a molybdenum doped Raney nickel catalyst in a mixture of ammonia and methanol under 50 psig H₂ at room temperature as described in Baumann, K.L. et al. Tet. Lett. 1992, 33, 2283-2284. The compounds of Formula (XIII) are converted to compounds of Formulae (VIII) and

(IX) by cleaving the ketal to form a 7~-uτmo-3,5-dihydroxy heptanoic acid ester of Formula (XIV):

and reprotecting the deprotected hydroxy groups as silylethers. The ketal protecting group of compounds of Formula (XIII) can be cleaved under acidic conditions like those previously described for deprotecting compounds of Formula (III). Preferably, the ketal is cleaved in a solution containing approximately one molar equivalent of HCl with respect to the compound of Formula (XIII), the 7-amino-3,5-dihydroxy heptanoic acid ester is isolated as its hydrochloride salt (XTV)

and the salt is carried forward in the next step. One exemplary and prefened reaction mixture for ketal deprotection is prepared by dissolving the compound of Formula (XIII) in an alcohol or ether, preferably ethanol or THF, and slowly adding one equivalent of aqueous hydrochloric acid to the solution. When the solvent is ethanol, dropwise addition of a 5.7% solution of HCl in ethanol is especially prefened while, when the solvent is THF, dropwise addition of 37% HCl in water is prefened.

Hydrolysis should go substantially to completion after about three hours at ambient temperature (the temperature of the solution increases by about 5°C to about 10°C due to exothermicity of the reaction).

After the deprotection is complete, the solvent is evaporated leaving the hydrochloride salt as a residue. Care should be taken to evaporate the solvent without excessive heating because the salt starts to decompose above about 60 °C. The salt also is hygroscopic. When aqueous acid is used as the acid catalyst, rotary evaporation at mild temperatures will not remove all of the water. It is desirable to further dry the salt before silylating the hydroxy groups in the next reaction. To further dry the salt, it can be taken up in THF and stirred over 4A molecular sieves. Drying over molecular sieves was found to reduce the water content of the salt from about 2% to about 0.8% (Karl Fischer). Although alternative drying agents like MgSO₄ and CaCl₂ can be used, they were found to be less effective at drying the hydrochloride salt. The dried salt can be used conveniently as the starting material in the silylation step that follows. The 7-ammo-3,5-dihydroxy heptanoic acid ester can be silylated under the same conditions as the 6-cyano-3,5-dihydroxy heptanoic acid esters of Formula (X). However, when silylating compounds of Formula (XTV) which are functionalized with a nucleophilic amine group, it is preferable to use a monofunctional silylating agent. The silylating agent will bond to the amine as well as the hydroxyl groups. Thus, it is preferable to use an excess of the monofunctional silylating agent and acid scavenger, yet more preferably from about three to about five molar equivalents of a monofunctional silylating agent with respect to the compound of Formula (XTV) and from about four to about six molar equivalents of the acid scavenger. It is acceptable that some monofunctional silyating agent react with the amine to form tri-silylated compounds of Formula (NUT):

because the silyl group detaches from the amine during aqueous workup. However, it has been observed that when difunctional silylating agents are used, polymerization tends to occur and reduce the yield of the desired silyl diprotected compound of Formula (IX). For that reason, a monofunctional silylating agent is prefened for silylating compounds of Formula (XΪN)

In addition, some monosilylated products (VIII") and (VIII'") may also be produced

(VIII") (VIII'")

which can be canied forward in the Paal-Knon reaction.

In a particular embodiment, wherein chloro-tert-butyldimethylsilane is used as the silylating agent, the acid scavenger is triethyl -irnine, and the solvent is THF or toluene, then the product can be isolated by filtering off Et₃N^»HCl and evaporating the solvent. The crude product can then be canied forward without intermediate purification. The silylether-diprotected 7-amino-3,5-dihydroxy heptanoic acid ester in either free base or pivalate salt form can be used as starting material for the Paal-Knon synthesis of silylether-diprotected 3,5-dihydroxy-7-pynol-l-yl heptanoic acid esters of Formulae (XV) and (XVI)

enroute to the 7-pynol-yl-3,5-dihydroy-l -heptanoic acids of Formula (I). Compounds of Formula (XV) have not been prepared before and constitute an aspect of the invention. Especially prefened compounds of Formula (XV) are (4R-cώ)-6-[2-[2-(4- Fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl] pynol-l-yl]ethyl]-2,2- diisopropyl-l,3-dioxa-2-silacyclohexane-4-acetic acid tert-butyl ester 6, whose preparation is set forth in Example 13, below, and (4R-cf ')-6-[2-[2-(4-Fluorophenyl)-5-(l-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]pynol-l-yl]ethyl]-2,2-diisopropyl-l,3-dioxa-2- silacyclohexane-4-acetic acid tert-butyl ester 8, which can be made by a method analogous to Examples 10-14, but substituting dichlorodiphenylsilane for dichlorodiisopropylsilane in Example 11. The Paal-Knon reaction is preferably carried out at elevated temperature, with an added acid catalyst if the amine starting material is not a pivalate salt, and with evaporative removal of water employing generally the conditions previously described for reacting compounds of Formulae (VI) and (VII).

After the Paal-Knon reaction, the product is desilylated, hydrolyzed to the free acid (or lactone) and optionally salifϊed.

The silyl protecting group(s) can be removed conventionally using reagents that generate fluoride anion, such as tetrabutylammonium fluoride ("TBAF"), HF/pyridine, HF/Et₃N, BF₃'H₂O and LiBF₄.

In addition, we have found that the silyl protecting group of compounds of Formulae (XV) and (XVI) can be removed concurrently with hydrolysis of the ester group using an alkali metal hydroxide, alkoxide or carbonate such as sodium hydroxide, potassium hydroxide, and potassium carbonate. It will be appreciated that changing a protecting group ordinarily introduces two additional steps to a synthesis: deprotection of the original protecting group and addition of the new group. However, replacement of the ketal protecting group of compounds of Formulae (V) and (XIII) with silyl protecting groups introduces only one additional step to the synthesis of compounds of Formula (I) because the silyl group is removed under the same conditions employed in hydrolyzing the ester.

Silyl groups with aryl substituents like SiPh₂ are more susceptible to removal by a strong base. Suitable solvents for base-induced desilylation include but are not limited to the alcohol solvents listed above in the acetonide deprotecting step. According to a prefened technique, the Formula (XV) or (XVI) compound is concunently desilylated and hydrolyzed with sodium hydroxide in methanol and the compound of Formula (I) is recovered as its sodium salt.

In a third aspect, the present invention provides a process for preparing atorvastatin by contacting a ketal-protected 7-amino-3R,5R-dihydroxy heptanoic acid ester of Formula (Xffl')

with 4-fluoro-α-(2-methyl-l-oxopropyl-γ-oxo-N,β-diphenylbenzenebutanarnide 9 (structure shown in Example 3) under acidic conditions at elevated temperature and in a solvent system comprising tetr-mydiOfuran in an amount of five to about twenty five liters per kilogram of the ketal-protected 7-amino-3,5-dihydroxy heptanoic acid ester of Formula (XLTT) to form a ketal- protected 3,5-dihydroxy-7-pynol-l-yl heptanoic acid ester of Formula (XVIP)

Forming the pynole ring in THF solvent reduces the amount of side products in the final product. One undesired side product of the Paal-Knon reaction is a compound of Formula (XVIII):

(XVIII)

which forms by amination of the ester group of the starting material (XIII') or product (XVLT) with unreacted starting material.

Another impurity that is found in the product mixture is the desfluoro compound of Formula (XTV), which may be derived from unfluorinated diketo starting material.

The compounds are carried forward when the acetonide and ester groups are removed to form the conesponding tetrahydroxy compound 10 and desfluoiOatorvastatin 11

These impurities can be separated from atorvastatin by high performance liquid chromatography ("HPLC"). It was discovered that the proportion of compounds 10 and 11 in the final product were substantially reduced by conducting the Paal-Knon reaction in a low boiling point ether, such as, for example, THF. Another advantage of using a low boiling point ether in lieu of the solvent systems used in the past is that the solvent can be conveniently recycled because it contains only one component.

In a prefened embodiment, the Paal-Knon reaction is carried out in a single component solvent system of a low boiling point ether that is at least of technical grade purity and with pivalic acid as the acid catalyst. Preferably, the solvent is tetrahydrofuran. The pivalic acid may be added to the reaction mixture either separately or as a pivalate salt of the ketal-protected 7- amino-3R,5R-dihydroxy heptanoic acid ester. After dissolving the reactants and acid catalyst in the low boiling point ether, the solution is heated to reflux. Under these conditions, the reaction goes to completion in from about 24 to about 72 hours. After the reaction is complete, the reaction mixture is concentrated, either on a rotary evaporator or by distillation. According to a prefened technique for isolating the 3,5-dihydroxy-7-pvnol-l-yl heptanoic acid ester of Formula (XNLT), the residue of evaporation is dissolved in a lower alkyl alcohol such as methanol, ethanol, or isopropanol and then heated until it dissolves. Water is then added. The mixture is cooled and stirred at ambient temperature for 1 to 24 hours to precipitate the product, which is then separated from the reaction mixture, e.g. by filtering or decanting. The 3,5-dihydroxy-7-pynol-l-yl heptanoic acid ester of Formula (XVLT) can be converted to atorvastatin by contacting it with an acid like aqueous HCl to remove the acetonide protecting group followed by contacting with Ca(OH)₂ to hydrolyze the ester and form the calcium salt as taught in commonly-assigned U.S. Patent No. 6,528,661, which is hereby incorporated by reference in its entirety. Alternatively, the ketal of the Formula (XVII') compound may be cleaved with an acid and the ester group hydrolyzed with an alkali metal hydroxide, alkoxide or carbonate, such as sodium hydroxide, resulting in an alkali metal salt of atorvastatin. The alkali metal salt may then be transposed, if so desired, with calcium chloride to atorvastatin hemi-calcium as described in Example 10 of U.S. Patent No. 5,273,995, with calcium acetate as described in U.S. Patent No. 5,298,627 or by other means known to one of skill in the art. Compounds of Formula (I) are known to be useful in plasma cholesterol reduction therapy. Accordingly, the products of the present inventive processes, including their pharmaceutially acceptable salts, find use in treatment of hypercholesterolemia and hyperlipidemia.

Having thus described the present invention with reference to certain prefened embodiments, the processes for producing the 3,5-dihydroxy-7-pynol-lyl heptanoic acids of the present invention are further illustrated by the examples which follow. These examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way. EXAMPLES

General

(4R-ct5^,)-6-(2-cyanomethyl)-4-(2-hydroxyethyl)-2,2-dimethyl- 1 ,3-dioxane was prepared as described in Brower, P.L. et al. Tet Lett. 1992, 33, 2279-82. 4-Fluoro-α-(2- methyl-l-oxopropyl-γ-oxo-N,β-diphenylbenzenebutanamide was prepared according to the method described in U.S. Patent No. 5,124,482. Unless otherwise indicated, all solvents were reagent grade. Diethyl ether was dried over sodium. All other solvents and reagents were used as received except where indicated otherwise.

Abbreviations that appear in this disclosure are commonly used in organic chemistry and include:

Ac Acetyl

DMAP 4-Dimethylamino pyridine;

DME 1,2-Dimethoxy ethane

DMF N,N-Dimethylformamide;

DMSO Dimethylsulfoxide;

Et₃Ν Triethyl amine

LAH Lithium aluminum hydride

MTBE Methyl-tert-butyl ether t-BuOH tert-Butanol

Ra-Ni Raney nickel

THF Tetrahydrofuran

HOBT N-Hydroxybenzotriazole

TBDMS tert-Butyldimethylsilyl

Triflate Trifluoromethanesulfonate Method A: Synthesis by Oxidation of A Ketal-Protected 3.5-Dihvdroχy-7-Pvnol-l-yl-l- Heptanol to A Ketal-Protected 3,5-Dihvdroxy-7-Pvnol-l-yl Heptanoic Acid

Example 1

(4R-c^)-6-(2-Ammoethyπ-4-(2-hvdroxyethyl)-2.2-dimethyl- 1 ,3-dioxane 3

To a 500 ml round bottom flask was added (4R-czV)-6-(2-cyanomethyl)-4-(2- hydroxyethyl)-2,2-dimethyl-l,3-dioxane-4-acetic acid tert-butyl ester 2 (10 g, 37.1 mmol) and dry ether (180 ml) . LAH was dissolved in diethyl ether that had been dried over sodium to give a 1M solution. The LAH solution (63 ml, 63 mmol) was added dropwise to the stirred solution at 0°C. The resulting bright yellow suspension was stirred at 0°C for 15 minutes and then allowed to warm to room temperature and stirred overnight. The next morning, the reaction was quenched by cooling the mixture in an ice bath and adding a 1 : 1 solution of methanol: water (10 ml) . The mixture was stirred for 10 minutes and then filtered through a

Buchner funnel. The solids were stirred with ethyl acetate and then filtered and washed with ethyl acetate. The combined organic solvents were evaporated leaving a residue of the title compound (6.95 g, 92.1%). Η NMR (300 MHz, CDC1₃) δ 4.2 (m, 2H), 3.7 (t, 2H), 2.7 (t, 2H), 1.7 (m, 5H), 1.5 (s, 3H), 1.4 (s, 3H), 1.25 (m, 1H) ppm; ¹³C NMR (75 MHz, CDCL) δ 100.6, 68.7, 67.6, 58.2, 38.4, 38.2, 37.3, 36.1, 29.4, 19.9 ppm.

Example 2

(4R-c^)-6- 2-AnιmoethylV4- 2-hvdroxyethyl)-2,2-dimethyl-l,3-dioxane pivalate salt 12 To a round bottom flask containing compound 3 (0.62 g, 30.5 mmol) prepared as described in Example 1 was added MTBE (7ml). The mixture was stirred until it claiified and then pivalic acid (0.31 g, 30.0 mmol) was added. The mixture was heated to reflux for 1 hour and then cooled to room temperature and further cooled in an ice bath to precipitate the pivalate salt. The white salt was collected on a filter and washed with MTBE to give 0.08 g of the title compound (8.7%). Η NMR (300 MHz, CDC1₃) δ 5.4 (br.s, 4H), 4.1 (dddd, 1H), 4.0 (dtd, 1H), 3.8 (m, 2H), 2.9 (t, 2H), 1.7 (m, 4H), 1.5 (dt, 1H) 1.5 (s, 3H), 1.4 (s, 3H), 1.3 (dt, 1H) 1.2 (S, 9H) ppm; ¹³C MR (75 MHz, CDC1₃) 184.6, 98.8, 69.0, 67.9, 60.6, 39.0, 38.1, 37.5, 36.5, 30.2, 19.9, 27.8 ppm.

Example 3

(4R-g^)-6-[2-[2-(4-Fluorophenyl)-5-π-methylethyl)-3-phenyl-4-[(phenyl-mιino)caι-bonyl] pynol-l-yl]ethyl]-4-(2-hydroxyethyl)-2.2-dimethyl-l,3-dioxane 1

To a 50 ml three necked flask was added pivalate salt 3 (0.67 g, 2.2 mmol) prepared as described in Example 2, 4-fluoro-α-(2-methyl-l-oxopropyl-γ-oxo-N,β- diphenylbenzenebutana ide 9 (0.76 g, 1.83 mmole) and toluene (10 ml). The stirred mixture was refluxed for 27 hours and washed twice with water (15 ml)(ethyl acetate and NaCl were added to assist in the separation). The organic phase was dried over MgSO and evaporated, leaving a residue ofthe title compound (0.86 g, 80.1%). ¹H NMR (300 MHz, CDC1₃) δ 7.1 (m, 14H), 6.9 (br.s, 1H), 4.1 (ddd, 1H), 4.0 (m, 1H), 3.8 (ddd, 1H), 3.73 (m, 3H), 3.67 (m, 1H), 3.6 (heptet, 1H), 1.7 (m, 4H), 1.5 (d, 6H), 1.4 (s, 3H), 1.3 (s, 3H), 1.2 (dt, 1H), 1.1 (dt, lH) ppm; ¹³C NMR (75 MHz, CDC₁₃) δ 164.8, 163.9, 160.6, 141.5, 138.3, 137.8, 134.6, 133.2, 133.1, 130.5, 129.0, 128.7, 128.6, 128.3, 128.2, 126.5, 125.3, 123.5, 121.8, 119.5, 115.5, 115.3, 115.2, 98.6, 68.8, 66.5, 60.6, 40.8, 38.0, 36.1, 30.0, 26.1, 21.7, 21.6, 19.8 ppm. MS (FAB): m/z 585.2 (M+H⁺).

Example 4

(4R-c^)-6-[2-[2-(4-Fluorophenv -5- i-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl] pynol-1-yl] ethyl] -4-(2-oxoethyl)-2.2-dimethyl-l ,3-dioxane 13 A 3 -necked round bottom flask was purged with nitrogen. To the flask were added compound 1 (2.0 g, 34.2 mmol) prepared as described in Example 3 and dry dichloromethane (15 ml). The stirred mixture was cooled in an ice bath and 2.18 g of Dess-Martin periodinane reagent was added. After 5 hr, the reaction was quenched with water. The phases were separated and the aqueous layer was washed with chloroform. The combined organic phases were extracted with saturated solution of Na^Os, 5% NaHCO₃ and brine. The organic phase was dried over MgSO₄ and stripped of solvent on a rotary evaporator leaving a residue of the title compound (1.87 g, 93.8%). Η NMR (300 MHz, CDC1₃) δ 9.7 (t, 1H), 7.1 (m, 14H), 6.9 (br.s, 1H), 4.3 (m, 1H), 4.1 (ddd, 1H), 3.8 (ddd, 1H), 3.7 (m, 1H), 3.6 (heptet, 1H), 2.6 (ddd, 1H), 2.4 (ddd, 1H), 1.7 (m, 2H), 1.5 (d, 6H), 1.4 (s, 3H), 1.3 (s, 3H), 1.1 (m, 2H) ppm; ¹³C NMR (75 MHz, CDC1₃) δ 200.6, 138.4, 134.6, 133.2, 133.1, 130.5, 128.7,

128.3, 127.6, 126.6, 123.5, 119.5, 115.5, 115.2, 98.8, 66.3, 64.3, 49.7, 40.8, 38.0, 36.1, 29.8, 26.1, 21.7, 21.6, 19.6 ppm. Example 5

NaCIO_j, NaH₂P0₄-H₂0

(4R-c^V6-[2-[2-(4-FluorophenylV5-(l-methylethyl)-3-phenyl-4-[(phenyl-ιmino)carbonyl] pynol-l-yl]ethyl]-2,2-dimethyl-l,3-dioxane-4-acetic acid 14

To a stirring solution of compound 13 (1.22 g, 2.09 mmole) prepared as described in

Example 5 and 2-methyl-2-butene (0.21 ml, 4.18 mmole) in t-BuOH (12 ml) was added a solution of NaClO₂ (0.57 g, 6.27 mmole) and NaH₂PO₄ ^«H₂O (0.57 g, 4.18 mmole) in water (7.5 ml) at room temperature. The solution was stined at room temperature for 4 h. Saturated

Na₂SO₃ (5 ml) was added and the resulting mixture was stined and added to diluted HCl (30 ml) and extracted with CH₂C1₂ (3x50 ml). The combined extracts were washed with brine (2x20 ml), dried (MgSO₄) and evaporated to give 0.42 g (33.5%) of crude product. The product residue can then be converted to atorvastatin hemi-calcium with Ca(OH)₂ following generally the procedure of U.S. Patent No. 6,528,661.

Method B: Synthesis Involving Condensation of A Silylether-Diprotected 7-Amino-3,5- Dihvdroxyl Heptanoic Acid Ester with A 1.4-Diketone

Example 6

7-Amino-3(R),5(R)-dihydroxy heptanoic acid tert-butyl ester hydrochloride salt 15

To a 1 L reactor equipped with a mechanical stiner, a thermometer and a condenser, 5 was added THF (384 g) and (4R-cw)-6-(2-annnoethyl)-2,2-dimethyl-l,3-dioxane-4-acetic acid tert-butyl ester 16 (109 g, 0.4 mol). A solution of 37% aq. HCl (38 g) was added dropwise over about 30 mins at room temperature. Addition of the acid lowered the pH from 10 to 3. The acidic solution was stined at room temperature for 3 hours.

The solvent was stripped on a rotary evaporator at 20 mm Hg vacuum at 50°C. The 10 residue (112 g, quant.) was dissolved in THF (335 g) and dried over molecular sieves (33 g).

Drying over molecular seives lowered the amount of water from~2% to 0.8%.

Example 7

7-Am o-3 R),5(R)-di(tert-butyldimethylsiloxy) heptanoic acid tert-butyl ester 17

To a 1 L reactor equipped with a mechanical stiner, a thermometer and a condenser, was added THF (360 g) and a 31 wt. % solution of hydrochloride salt 15 in THF (174 g, 0.2 mol) prepared as described in Example 6. Then, a solution of Et₃N (108 g) and TBDMSC1 0 (108 g) in THF (120 g) was added dropwise over an hour. The temperature in the reactor remained between 24 and 28°C during the addition of the silylating reagent. The resulting slurry was stirred overnight for about 19 h and then filtered through a Buchner funnel. The collected solid was washed with THF (250 g). The filtrate and washings were combined and evaporated on a rotary evaporator to constant weight to give the title compound (104 g, quant.). Example 8

[R (R R^*)]-2-(4-fluorophenyl)-β,δ-di(tert-butyldimethylsiloxy)-5-fl-methylethv -3-phenyl-4- [(phenyla ino) carbonyl] -lH-pyrrole-1 -heptanoic acid tert-butyl ester 18

The product residue of Example 7 was dissolved in toluene (300 g). To a 3 -necked, round-bottom flask equipped with a mechanical stiner, a thermometer and a Dean-Stark apparatus was added toluene (20 g), a portion of the toluenic solution of compound 17 (47 g solution, 9.2 g, 20 mmol), 1,4-diketone 9 (3 g, 7 mmol) and pivalic acid (0.5 g, 5 mmol). The mixture was heated to reflux and allowed to reflux through the Dean Stark apparatus for 17 h.

The reaction mixture was washed with water (50 g) to give a toluene solution (60 g) contain crude compound 18.

Example 9

\R (R^*. R^* ]-2-f 4-fluorophenyl_>-β,δ-dmvdroxy-5-( 1 -methylethylV3-phenyl-4-

[(phenylamino)carbonyl]-lH-pynole-l -heptanoic acid sodium salt 19

To a 3 -necked, round-bottom flask equipped with a condenser, was added the crude compound 18 (~1 mmol) prepared as described in Example 8, methanol (7 g) and 5% aq. NaOH (4.3 g). Progress of the reaction was monitored by HPLC. The mixture was refluxed for 6 h, diluted with methanol (3 g) and water (5 g) and washed with MTBE (2x7 g). The aqueous phase was diluted with water to 25 ml prior to HPLC analysis. The yield of Atorvastatin sodium was -20% from compound 16.

Method C: Alternative Synthesis Involving Condensation of A Silylether-Diprotected 7- Amino-3.5-Dihydroxyl Heptanoic Acid Ester with A 1.4-Diketone

Example 10

6-Cvanomethyl-2,2-diisopropyl-l,3-dioxa-2-silacyclohexane-4-acetic acid tert-butyl ester 5

Into a 250 ml 3-necked round-bottom flask were added 6-cyano-3,5-dihydroxy heptanoic acid tert-butyl ester (11.19 g, 48.8 mmol), dichloromethane (60 ml), HOBT (0.75 g) and Et₃N (21 ml). A solution of dichlorodiisopropylsilane (10 ml) in dichloromethane (35 ml) was added dropwise to the flask over 25 min. while the temperature was monitored so as to not exceed 30°C. The mixture was stirred at reflux for 4 h and then cooled to room temperature.

The solids were filtered and the brown filtrate was extracted with water (30 ml) and dilute HCl (30 ml)(pH~4.5), dried over MgSO₄ and evaporated leaving a residue of the title compound

(14.13 g, 84.8%). Η NMR (300 MHz, CDC1₃) 4.5 (dddd, 1H), δ 4.3 (dtd, 1H), 2.6 (dd,

1H), 2.52 (dd, 1H), 2.48 (dd, 1H), 2.4 (dd, 1H), 1.9 (dt, 1H), 1.6 (dt, 1H), 1.5 (s, 9H), 1.04

(m, 8H), 1.01 (d, 3H), 1.00 (d, 3H) ppm; ¹³C NMR (75 MHz, CDC1₃) δ 170.0, 116.9, 80.6,

69.9, 68.9, 44.7, 40.7, 28.0, 27.0, 16.8, 16.3, 13.4, 11.9 ppm. Example 11

6-(2-Arninoethyl)-2.2-diisopropyl-l,3-dioxa-2-silacvclohexane-4-acetic acid tert-butyl ester 4

A solution of compound 5 (7.82 g, 22.9 mmol) prepared as described in Example 10 was dissolved in a solution of 12% NH₃ in methanol (100 ml) and added to a Pan shaker containing Raney nickel that had been washed with absolute ethanol before use. The solution was shaken under 65-73 psi. hydrogen pressure for 7.75 hr. The Raney nickel was removed by filtering through a pad of celite under nitrogen stream to avoid ignition of the Raney nickel and washed with methanol. The filtrate was concentrated at reduced pressure to yield 7.14 g (90.2%) of the title compound as a green oil. Η NMR (300 MHz, CDC1₃) 4.4 (dddd, 1H), 4.1 (dtd, 1H), 2.9 (m, 2H), 2.7 (m, 3H), 2.6 (dd, 1H), 2.4 (dd, 1H), 2.3 (dd, 1H), 1.7 (dt, 1H), 1.6 (td, 1H), 1.5 (s, 9H), 1 (m,14) ppm; ¹³C NMR (75 MHz, CDC1₃) δ 170.5, 80.4, 72.0, 70.6, 45.1, 42.2, 41.8, 38.7, 28.1, 17.0, 16.6, 16.4, 13.4, 13.1, 12.7, 11.9 ppm.

Example 12

6-(2-Aminoethyl)-2,2-diisopropyl-l,3-dioxa-2-silacvclohexane-4-acetic acid tert-butyl ester pivalate salt 20

Compound 4 (1.91 g, 5.5 mmol) prepared as described in Example 11 was dissolved in a 4: 1 : 1 mixture of heptane:toluene:THF (10 ml). A solution of pivalic acid (0.56 g, 5.5 mmol) in

4: 1 : 1 heptane:toluene:THF (3ml) was added. The mixture was refluxed for 1 h. The hot yellow solution was filtered and transfened to a sub-zero freezer. After standing overnight, a few white grains appeared. The solution was then left in a fume hood in an open flask for the night and transfened back to the freezer for another two days. A pale yellow precipitate that formed was filtered and washed with a cooled solution of 4: 1 heptane:toluene and under vacuum at 25 °C to give the title compound (0.563 g, 22.8%). Η NMR (300 MHz, CDC1₃) 7.0 (m, 3H), 4.4 (dt, 1H), 4.1 (m, 1H), 3.0 (m, 2H), 2.4 (dd, 1H), 2.3 (dd, 1H), 1.75 (br.s, 2H), 1.7 (br.d, 1H), 1.5 (s+m, 10H), 1.0 (m, 7H), 0.99 (d, 1H), 0.97 (d, 1H), 0.86 (heptet, 1H) ppm; ¹³C NMR (75 MHz, CDC1₃) δ 170.3, 80.5, 72.1, 70.5, 45.0, 42.0, 28.2, 28.1, 17.0, 16.5, 16.4, 13.4, 11.9 ppm

Example 13

(4R-c^V6-[2-[2-(4-Fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl] pynol-l-yl]ethyl]-2.2-diisopropyl-l,3-dioxa-2-silacyclohexane-4-acetic acid tert-butyl ester 6

To a 50 ml 3 necked round bottom flask equipped with thermometer and condenser were added compound 20 (0.53 g, 1.2 mmol) prepared as described in Example 12, 1,4- diketone 9 (0.36 g, 0.86 mmol) and a 2:2:1 mixture of heptane:toluene:THF (10 ml). The mixture was refluxed for 25 hr. The solvent was evaporated and the residue was dissolved in chloroform, washed with saturated NaHCO₃ and concentrated. The title compound (0.35 g,

55.8%) was isolated by gradient flash chromatography (ether/hex.). H NMR (300 MHz, CDC1₃) δ 7.1(m, 14H), 6.9 (br.s, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 3.9 ( , 2H), 3.6 (heptet, 1H), 2.4 (dd, 1H), 2.3 (dd, 1H), 1.6 (m, 4H), 1.54 (d, 3H), 1.5 (d+m, 4H), 1.4 (s, 9H), 1.3 (dt, 1H), 1.0 (m, 7H), 0.92 (d, 1H), 0.90 (d+m, 2H) ppm; ¹³C NMR (75 MHz, CDC1₃) δ 170.3, 160.6, 141.5, 138.4, 134.7, 133.2, 133.0, 130.5, 128.6, 128.3, 126.5, 123.4, 121.7, 119.5, 115.5, 115.2, 80.5, 71.0, 70.3, 44.8, 41.7, 41.2, 40.2, 28.1, 26.0, 21.6, 16.9, 16.4, 13.4, 11.8 ppm. MS (FAB): m/z 726.4(ivr).

Example 14

[R (R R^*)]-2-(4-fluorophenyl β.δ-dihydro y-5-(l-methylethyl)-3-phenyl-4- [(phenylamino) carbonyl] -lH-pynole-1 -heptanoic acid hemi-calcium 21

(4R-cw)-6-[2-[2-(4-Fluorophenyl)-5-(l-methylethyl)-3-phenyl-4- [(phenylan-vino)carbonyl]pvnOl-l-yl]ethyl]-2,2-diisopropyl-l,3-dioxa-2-silacyclohexane-4- acetic acid tert-butyl ester 8 (2.12 g, 2.7 mmol) prepared analogously to the method described in Examples 10 through 13 was dissolved in ethanol (21.8 ml). Water (4.2ml) and Ca(OH)₂

(0.294 g) were added and the suspension was heated to 70°C for 5.5 hours. Hot water (21 ml) was added to the solution at 65°C. The solution was then cooled slowly to room temperature. The white precipitate that formed on cooling was filtered and dried at 60°C for 24 hours to give atorvastatin hemi-calcium (0.4 g, 26%).

Example 15

\R (R^*. R^*^-2-f 4-fluorophenylVβ,δ-dfovdroxy-5-f 1 -methylethylV3-phenyl-4- [(phenylamino carbonyl]-lH-pynole-l-heptanoic acid hemi-calcium salt 21 Compound 6 prepared as described in Example 13, was dissolved in ethanol (10 ml) and the mixture was heated to 30°C. Sodium hydroxide (2.61 g) was added and the mixture was heated to 55 °C. After 25 h, the mixture was cooled to ambient temperature. The solution was thent acidified to pH 2-2.5 with 8% HCl (aq) (1.7 ml). Calcium hydroxide (0.12 g) was then added and the resulting suspension was heated to 70 °C for 4 h then was filtered while hot. The filtrate was heated again to 72 °C and 15 ml of water was added. The mixture was then cooled to ambient temperature and held there until the product appeared to be completely precipitated. The product was collected on a filter and dried at 60 °C overnight to give atorvastatin hemi-calcium (0.26 g, 56.4%).

Method E: Improvements Pertaining to The Reaction of Ketal-Protected 7-Amino-3,5- Dihydroxy Heptanoic Acid Ester with 4-Fluoro-α-(2-Methyl-l-Oxopropyl-γ-Oxo-N,β~ Diphenylbenzenebutanamide

Pivalic acid

(4R-c^V6-[2-[2-r4-FluorophenylV5-ri-methylethylV3-phenyl-4-

[(phenylammo)carbonyl]pynol-l-yl]ethyl]-4-2.2-dimethyl-l ,3-dioxane-4-acetic acid tert-butyl ester 22

Example 16

To a 100 ml 3 necked round bottom flask equipped with thermometer, condenser and magnetic stiner, was added compound 16 (6.12 g, 22.4 mmol), pivalic acid (1.15 g, 11.25 mmol), 1,4-diketone 9 (6.99 g, 16.7 mmol) and THF (37 ml). The mixture was refluxed for 40 h. After cooling, the reaction mixture was concentrated on a rotary evaporator. The brown oily residue was dissolved in ethanol (45 ml) with heating. Then, water (18.5 ml) was added dropwise. The mixture was cooled slowly to room temperature and then stirred for another 3 h. The solid was filtered off and washed with a 5:2 mixture of ethanol and water, then dried at 55°C overnight to give the title compound as an off-white solid (8.66 g, 79.0%).

Example 17 To a 500 ml 3-necked round bottom flask equipped with thermometer, condenser and magnetic stiner, were added compound 16 (30 g, 0.109 mole), pivalic acid (5.17 g, 50 mmol), 1,4 diketone 9 (35.2 g, 85 mmol) and THF (180 ml). The mixture was refluxed for 72 h and cooled to 25 °C. The brown oil residue was dissolved in 260 ml ethanol by heating to 65 °C. Water (100 ml) was added dropwise over 45 min. The mixture was cooled slowly to room temperature and stirred overnight. The precipitated solid was filtered, washed with 5:2 ethanol: water and dried at 60 °C overnight to give the title compound as an off-white solid (41.5 g, 75.1% yield).

Example 18 (Comparative)

To a IL reactor equipped with thermometer, condenser and mechanic stiner, was added compound 16 (30.0 g, 0.109 mole), pivalic acid (5.17 g, 0.05 mole), 1,4 diketone 9 (35.2 g, 0.085 mole) and a 2:2:3 mixture of heptane: toluene:THF (180 ml). The mixture was refluxed for 48 hr and then cooled to 25 °C. The solvents were evaporated. The brown oil residue was dissolved in ethanol (240 ml) by heating to 63 °C. Then, water (96 ml) was added dropwise over 120 min. When the solution became turbid, it was cooled slowly to room temperature and stined over night. The precipitated solid was filtered, washed with 5:2 ethanol: water (180 ml) and dried at 60 °C for 22 hr, to give the title compound as on off-white solid (40.24 g, 72.3%).

Having thus described the invention with respect to certain prefened embodiments and further illustrated it with examples, those skilled in the art may come to appreciate substitutions and equivalents that albeit not expressly described are taught and inspired by this invention. Whereas such substitutions and equivalents do not depart from the spirit of the invention they are within its scope which is defined by the claims that follow.

Claims

What is claimed is:

1. A process comprising: a) providing a ketal-protected 3 , 5-dihydroxy-7-pyιτol- 1 -yl- 1 -heptanol of Formula (II):

and b) oxidizing the ketal-protected 3 , 5-dihydroxy-7-pynol- 1 -yl- 1 -heptanol of

Formula (II) to a ketal-protected 3, 5-dihydroxy-7-pynol-l-yl heptanoic acid of Formula (III)

wherein R, is selected from the group consisting of: 1-naphthyl, 2-naphthyl, cyclohexyl, cyclohexylmethyl, norbornenyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms, benzyl,

3 , or 4-pyridinyl, and 2-, 3-, or 4-pyridinyl-N-oxide; R₂ and R₃ are independently selected fi-om the group consisting of: hydrogen, alkyl of from one to six carbon atoms, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, or alkoxy of from one to four carbon atoms, cyano, trifluoromethyl, and — CONR₅R₆ where R₅ and Rg are independently hydrogen, alkyl of from one to six carbon atoms, phenyl, phenyl substituted with fluorine, chlorine, bromine, cyano, or trifluoromethyl; R₄ is selected from the group consisting of: alkyl of from one to six carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and trifluoromethyl R₇ and R₈ are each independently selected from the group consisting of hydrogen, alkyl, substituted or unsubstituted phenyl, or R₇ and R₈ together with the carbon to which they are attached form a C₅-Cj carbocycle, except that R₇ and R₈ are not both hydrogen.

2. The process of claim 1 wherein the 3- and 5- carbons of the heptanol chain of the compound of Formula (II) and the heptanoic acid chain of the compound of Formula (III) have an R configuration.

3. The process of claim 1 or claim 2 wherein R_x is 4-fluorophenyl, R is phenyl, R₃ is a radical formula -CONRjRg and R₄ is alkyl or trifluoromethyl.

4. The process of claim 3 wherein R_: is 4-fluorophenyl, R₂ is phenyl, R₃ is a radical formula -C(O)N-C₆H₅ and i is isopropyl.

5. The process of any preceeding claim further comprising deprotecting the 3- and 5- hydroxy groups of the 3,5-dihydiOxy-7-pynOl-l-yl heptanoic acid of Formula (III) to yield atorvastatin free acid, atorvastatin lactone or mixture thereof.

6. The process of claim 5 further comprising salifying the atorvastatin free acid, atorvastatin lactone or rnixture thereof to atorvastatin hemi-calcium or solvate thereof.

7. The process of claim 6 wherein the atorvastatin hemi-calcium or solvate thereof is atorvastatin hemi-calcium trihydrate.

8. The process of any preceding claim wherein R₇ is methyl and R₈ is methyl.

9. The process of any preceding claim wherein the ketal-protected 3,5-dihydroxy-7- pynol-l-yl-1 -heptanol is provided by: a) reducing a ketal-protected 6-cyano-3,5-dihydroxy hexanoic acid ester of Formula (N)

wherein R₉ is a substituted or unsubstituted C C₇ lower alkyl radical, to a ketal-protected 7-arnino-3,5-dihydroxy-l -heptanol of Foπnula (VI)

and b) converting the ketal-protected 7-arrύno-3,5-dihydroxy- 1 -heptanol to the ketal- protected 3 , 5-dihydroxy-7-pynOl- 1 -yl- 1 -heptanol.

10. The process of claim 9 wherein converting comprises: a) generating a pivalate salt of the ketal-protected 7-am o-3, 5-dihydroxy- 1- heptanol, and b) condensing the ketal-protected 7-amino-3 , 5-dihydroxy- 1 -heptanol with a diketone of Formula (Nil):

by contacting the pivalate salt with the diketone.

11. The process of any of claims 1 to 8 wherein providing a ketal-protected 3,5-dihydroxy- 7-pynol-l-yl-l -heptanol of Formula (II) comprises: i) reducing a ketal-protected 6-cyano-3, 5-dihydroxy hexanoic acid or lower alkyl ester thereof of Formula (N)

to a ketal-protected 7-amino-3, 5-dihydroxy- 1 -heptanol of Formula (VI)

ii) generating a pivalate salt of the ketal-protected 7-amino-3,5-dihydroxy-

1 -heptanol, and iii) condensing the ketal-protected 7-amino-3 , 5-dihydroxy- 1 -heptanol with a diketone of Formula (Nil):

by contacting the pivalate salt with the diketone, and the process further comprises deprotecting the 3- and 5-hydroxy groups of the 3,5- dihydroxy-7-pynol-l-yl heptanoic acid of Formula (III).

12. 7-amino-3, 5-dihydroxy- 1 -heptanol and its 1,3-dihydroxy protected derivatives.

13. The 3S,5R stereoisomers of the 7-amino-3,5-dihydroxy-l-heptanol and its 1,3- dihydroxy protected derivatives of claim 12.

14. The 1 ,3-dihydroxy protected derivative of claim 12 having the molecular Formula (NI):

wherein R₇ and R₈ are each independently selected from the group consisting of hydrogen, alkyl, substituted or unsubstituted phenyl, or R₇ and R₈ together with the carbon to which they are attached form a C₅-C₇ carbocycle, except that R₇ and R₈ are not both hydrogen.

15. The 1 ,3-dihydroxy protected derivative of claim 14 where the R₇-C-R₈ carbenyl fragment is selected from the group consisting of isopropylidene, ethylidene, tert- butylmethylidene, 1-tert-butylethylidene, 1-phenylethylidene, l-(4- methoxyphenyl) ethylidene, cyclopenylidene, cyclohexylidene, cycloheptylidene, 4- methoxybenzylidene, 2,4-dimethyxybenzylidene, 3,4-dimethoxybenzylidene, 2- nitrobenzylidene, 4-nitrobenzylidene, mesitylene and diphenylmethylene.

16. An acid addition salt of the 1,3-dihydroxy protected derivative of claim 14.

17. The acid addition salt of claim 16 that is a pivalate salt.

18. A compound of Formula (II) :

wherein R₂ is selected from the group consisting of: 1-naphthyl, 2-naphthyl, cyclohexyl, cyclohexylmethyl, norbornenyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms, benzyl,

3 , or 4-pyridinyl, and 2-, 3-, or 4-pyridinyl-N-oxide; R₂ and R₃ are independently selected from the group consisting of: hydrogen, alkyl of from one to six carbon atoms, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, or alkoxy of from one to four carbon atoms, cyano, trifluoromethyl, and — CONR₅R_<5 where R₅ and Rg are independently hydrogen, alkyl of from one to six carbon atoms, phenyl, phenyl substituted with fluorine, chlorine, bromine, cyano, or trifluoromethyl; _t is selected from the group consisting of: alkyl of from one to six carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and trifluoromethyl R₇ and R₈ are each independently selected from the group consisting of hydrogen, alkyl, substituted or unsubstituted phenyl, or R₇ and R₈ together with the carbon to which they are attached form a C₅-Cj carbocycle, except that R₇ and R₈ are not both hydrogen.

19. The compound of claim 18 wherein the 3- and 5- carbons of the heptanol chain of the compound of Formula (II) have an R configuration.

20. A process comprising: a) providing a silylether-diprotected 7-amino-3, 5-dihydroxy heptanoic acid ester, and b) condensing the silylether-diprotected 7-amino-3,5-dihydroxyl heptanoic acid ester with a diketone of Foπnula (VII):

wherein Ri is selected from the group consisting of: 1-naphfhyl,

2-naphthyl, cyclohexyl, cyclohexylmethyl, norbornenyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms, benzyl,

3 , or 4-pvridinyl, or 2-, 3-, or 4-pyridinyl-N-oxide; R₂ and R₃ are independently selected from the group consisting of: hydrogen, alkyl of from one to six carbon atoms, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, or alkoxy of from one to four carbon atoms, cyano, trifluoromethyl, or

--CONR₅R₅ where R₅ and Rg are independently hydrogen, alkyl of from one to six carbon atoms, phenyl, phenyl substituted with fluorine, chlorine, bromine, cyano, or trifluoromethyl; R₄ is selected from the group consisting of: alkyl of from one to six carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and trifluoromethyl, to form a silylether-diprotected 3,5-dihydroxy-7-pvnol-l-yl heptanoic acid ester.

21. The process of claim 20 wherein the silylether-diprotected 7-amino-3,5-dihydroxyl heptanoic acid ester has the molecular Formula (IX): Rl3_\ /^R14

(-T O O (IX)

H,NT

wherein, R₉ is a substituted or unsubstituted C,-C₇ lower alkyl radical, and

R₁₃ and R₁₄ are independently selected from the group consisting of C C₆ linear, branched and cyclic, substituted and unsubstituted hydrocarbyl radicals and phenyl.

22. The process of claim 21 wherein the silylether-diprotected 7-am o-3,5-dihydroxyl heptanoic acid ester is provided by selective reduction of the nitrile group of a silylether- diprotected 6-cyano-3, 5-dihydroxy hexanoic acid ester.

23. The process of claim 22 wherein the silylether-diprotected 6-cyano-3, 5-dihydroxy hexanoic acid ester is provided by: a) deprotecting a ketal-protected 6-cyano-3, 5-dihydroxy hexanoic acid ester of Formula (V):

to form a 6-cyano-3, 5-dihydroxy hexanoic acid ester of Formula (X):

OH OH O

^NCNΛ Λ_CΓ ^R' ^(X)

wherein R₇ and R₈ are each independently selected from the group consisting of hydrogen, alkyl, substituted or unsubstituted phenyl, or R₇ and R₈ together with the carbon to which they are attached form a C₅-C₇ carbocycle, except that R₇ and R₈ are not both hydrogen, R₉ is a substituted or unsubstituted Ci-C₆ lower alkyl radical, and b) silylating the hydroxy groups of the 6-cyano-3, 5-dihydroxy hexanoic acid ester to form the silylether-diprotected 6-cyano-3,5-dihydiOxy hexanoic acid ester.

24. The process of claim 20 wherein the silylether-diprotected 7-ammo-3,5-dihydroxyl heptanoic acid ester has the molecular Formula (NIII):

wherein, R₉ is a substituted or unsubstituted -C₇ lower alkyl radical, and

R₁₀, R_n and R_12j are independently selected from the group consisting of C,-C₆ linear, branched and cyclic, substituted and unsubstituted hydrocarbyl radicals and phenyl.

25. The process of claim 24 wherein the silylether-diprotected 7-amino-3 , 5-dihydroxy heptanoic acid ester is provided by: a) providing a ketal-protected 7-amino-3, 5-dihydroxy heptanoic acid ester of Formula (Xlll):

b) deprotecting the ketal-protected 7-arnino-3, 5-dihydroxy heptanoic acid ester of Formula (XIII) to form a 7-amino-3,5-dihydiOxy heptanoic acid ester of Formula (XTV):

OH OH O

H₂N ^^ ^^ ^^ ^o^x

wherein R₇ and R₈ are each independently selected from the group consisting of hydrogen, alkyl, substituted or unsubstituted phenyl, or R₇ and R₈ together with the carbon to which they are attached form a C₅-C₇ carbocycle, except that R₇ and R₈ are not both hydrogen,

R₉ is a substituted or unsubstituted C C₇ lower alkyl radical, and c) silylating the hydroxy groups of the 7-arnino-3,5-dihydiOxy heptanoic acid ester to form the silylether-diprotected 7-amino-3, 5-dihydroxy heptanoic acid ester.

26. The process of claim 25 wherein the ketal-protected 7-amino-3, 5-dihydroxy heptanoic acid ester is provided by selective reduction of the nitrile group of a ketal-protected 7- amino-3, 5-dihydroxy heptanoic acid ester of Formula (V):

27. The process of any of claims 20 to 26 wherein R_x is 4-fluorophenyl, R₂ is phenyl, R₃ is a radical formula -C(O)N-C₆H₅ and ₄ is isopropyl.

28. The process of claim 27 further comprising converting the silylether-diprotected 3,5- dihydroxy-7-pynol-l-yl heptanoic acid ester to atorvastatin free acid, atorvastatin lactone or an atorvastatin metal salt.

29. The process of claim 28 wherein the silylether-diprotected 3,5-dihydroxy-7-pynol- 1 -yl heptanoic acid ester is converted to atorvastatin sodium by contacting with a source sodium ions.

30. The process of claim 29 further comprising transposing the atorvastatin sodium to atorvastatin hemi-calcium.

31. The process of claim 28 wherein converting comprises: a) desilylating the 3- and 5- hydroxy groups to form an atorvastatin ester with a desilylating reagent, and b) hydrolyzing the ester group of the atorvastatin ester with a hydrolyzing reagent different from the desilylating reagent.

32. The process of claim 31 wherein the desilylating agent generates fluoride anion.

33. The process of claim31 wherein the hydrolyzing reagent is calcium hydroxide.

34. A compound of Formula (IX):

(IX)

wherein, R₉ is a substituted or unsubstituted C₁-C₇ lower alkyl radical, and

R₁₃ and R₁₄ are independently selected from the group consisting of - linear, branched and cyclic, substituted and unsubstituted hydrocarbyl radicals and phenyl.

35. A pivalate salt of the compound of the compound of claim 34.

36. A compound of Formula (XII) :

^R13_{\ /} ^R14

wherein, R₉ is a substituted or unsubstituted C C₇ lower alkyl radical, and

R₁₃ and R₁₄ are independently selected from the group consisting of Cι-C₆ linear, branched and cyclic, substituted and unsubstituted hydrocarbyl radicals and phenyl.

7. A compound of Formula (XV)

wherein Ri is selected from the group consisting of: 1-naphthyl, 2-naphthyl, cyclohexyl, cyclohexylmethyl, norbornenyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms, benzyl,

3 , or 4-pvridinyl, and 2-, 3-, or 4-pyridinyl-N-oxide; R₂ and R₃ are independently selected from the group consisting of: hydrogen, alkyl of from one to six carbon atoms, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, or alkoxy of from one to four carbon atoms, cyano, trifluoromethyl, and

— CONR_{5 5} where R₅ and Rg are independently hydrogen, alkyl of from one to six carbon atoms, phenyl, phenyl substituted with fluorine, chlorine, bromine, cyano, or trifluoromethyl; R-ι is selected from the group consisting of: alkyl of from one to six carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and trifluoromethyl, Rc_> is a substituted or unsubstituted C C₇ lower alkyl radical, and R₁₃ and R₁ are independently selected from the group consisting of Cι-C₆ linear, branched and cyclic, substituted and unsubstituted hydrocarbyl radicals and phenyl.

38. The compound of claim 37 wherein Ri is 4-fluorophenyl, R₂ is phenyl, R₃ is a radical formula -C(O)N-C₆H₅ and R₄ is isopropyl.

39. A process comprising: a) providing a ketal-protected 7-amino-3, 5-dihydroxy heptanoic acid ester of Formula (XHT)

b) condensing the ketal-protected 7-amino-3,5-dihydroxy heptanoic acid ester with a 1,4-diketone of Formula (VIP):

in a solvent system comprising low boiling point ether in an amount of from about five to about twenty five liters per kilogram of the a ketal-protected 7-amino- 3, 5-dihydroxy heptanoic acid ester of Formula (XQT) to form a ketal-protected 3,5-dihydroxy-7-pynol-l-yl heptanoic acid ester of Formula (XVII'):

wherein R₇ and R₈ are each independently selected from the group consisting of hydrogen, alkyl, substituted or unsubstituted phenyl, or R₇ and R₈ together with the carbon to which they are attached form a C₅-C₇ carbocycle, except that R₇ and R_g are not both hydrogen, and R₉ is a substituted or unsubstituted C,-C₇ lower alkyl radical.

40. The solvent of claim 39, wherein the solvent system consists essentially of a low boiling point ether.

41. The solvent system of claim 40 wherein the solvent system consists essentially of tetrahydrofuran.

42. The solvent system of claim of any of claims 39 to 41 wherein the solvent system consists of tetrahydrofuran.

43. The process of claim 39 wherein the ketal-protected 7-arnino-3, 5-dihydroxy heptanoic acid ester is provided by selective reduction of a ketal-protected 6-cyano-3,5-hexanoic acid ester of Formula (V):

44. The process of any of claims 39 to 43 wherein the ketal-protected 6-cyano-3 ,5- hexanoic acid ester is selectively reduced with Raney-nickel.

45. The process of claim 39 further comprising converting the ketal-protected 3,5- dihydiOxy-7-pynol-l-yl heptanoic acid ester to atorvastatin free acid, atorvastatin lactone or a metal salt of atorvastatin.

46. The process of claim 45 wherein the ketal-protected 3,5-dihydroxy-7-pynol-l-yl heptanoic acid ester is converted to atorvastatin hemi-calcium trihydrate.