WO2008075165A1

WO2008075165A1 - Novel process for the synthesis of [r-(r, r)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid or a pharmaceutically acceptable salt thereof

Info

Publication number: WO2008075165A1
Application number: PCT/IB2007/003902
Authority: WO
Inventors: Timothy Jay Chopra; Padraig Mary O'neill; Philippa Brenda Wilkes
Original assignee: Pfizer Products Inc
Current assignee: Pfizer Products Inc
Priority date: 2006-12-19
Filing date: 2007-12-03
Publication date: 2008-06-26
Anticipated expiration: 2009-06-19
Also published as: AR064421A1; TW200848406A; JP2008150376A

Abstract

An improved synthesis for the preparation of [R-(R*, R*)]-2-(4-fluorophenyl)- β, δ-dihydroxy-5-(1- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1-heptanoic acid or a pharmaceutically acceptable salt thereof, as well as other valuable intermediates used in the process, are described. The compounds prepared by a process of the invention are useful in treating hyperlipidemia, hypercholesterolemia, osteoporosis, benign prostatic hyperplasia, or Alzheimer's disease.

Description

NOVEL PROCESS FOR THE SYNTHESIS OF [R-(R*,R*)]-2-(4-FLUθROPHENYL)-β, δ-DIHYDROXY-5-

(1-METHYLETHYL)-S-PHENYL-^t(PHENYLAMINO)CARBONYL]-IH-PYRROLE-I-HEPTANOIC ACID

OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

FIELD OF THE INVENTION

An improved synthesis for the preparation of [R-(R*, R*)]-2-(4-fluorophenyl)- β, δ-dihydroxy-5-(1- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid or a pharmaceutically acceptable salt thereof, as well as other valuable intermediates used in the process, are described.

BACKGROUND OF THE INVENTION

The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG- CoA reductase. Statins inhibit HMG-CoA reductase from catalyzing this conversion. As such, statins are collectively potent lipid lowering agents.

Atorvastatin and pharmaceutically acceptable salts thereof are selective, competitive inhibitors of HMG-CoA reductase. Atorvastatin calcium is currently sold as LIPITOR® having the chemical name [R- (R*,R*)]-2-(4-fluorophenyl)- β, δ-dihydroxy-S^I-methylethyO-S-phenyM-^phenylaminoJcarbonyll-IH- pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate and the formula

As such, atorvastatin calcium is a potent lipid-lowering compound and is thus useful as a hypolipidemic and/or hypocholesterolemic agent. Atorvastatin calcium is also useful in the treatment of osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer's disease.

A number of patents and published International Patent Applications have issued describing atorvastatin, formulations of atorvastatin, as well as processes and key intermediates for preparing atorvastatin.

The object of the present invention is to provide an improved process for the preparation of [R- (R*,R*)]-2-(4-fluorophenyl)- β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H- pyrrole-1-heptanoic acid or a pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION

The invention provides a process for making atorvastatin or a pharmaceutically acceptable salt thereof comprising the steps of:

(i) reacting a compound of formula (I):

wherein R is an alkyl group; alternatively, R is a C₁-C₄ alkyl group; alternatively, R is isopropyl ortert- butyl; alternatively, R is isopropyl; or alternatively, R is tert-butyl; under suitable reaction conditions to form a compound of formula (II):

wherein R is as defined above and R₁ and R₂ taken together with the atoms to which they are attached form a cyclopentylidene or cyclohexylidene group;

(ii) reacting a compound of formula (II) under suitable reaction conditions to form a compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein R₁ R₁ and R₂ are each as defined above;

(Hi) reacting a compound of formula (III) under suitable reaction conditions to form a compound of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein R is H or as defined above, R-i and R₂ are each as defined above; and

(iv) reacting a compound of formula (IV) under suitable reaction conditions to form 2-(4 — fluorophenyl)- β, δ-dihydroxy-δ^i-methylethyO-S-phenyl-^fphenylaminoJcarbonyπ-IH-pyrrole-i- heptanoic acid (V):

or a pharmaceutically acceptable salt thereof, wherein R is H or as defined above, R₁ and R₂ are each as defined above. According to the process of the invention described above, the C-3 and C-5 chiral centers of compounds (I)-(V) can have the same or different R or S configuration or each process step can be performed with a racemic or other mixture.

The invention provides a process for the preparation of [R-(R*, R*)]-2-(4-fluorophenyl)- β, δ- dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid or a pharmaceutically acceptable salt thereof comprising the steps of: (i) reacting a compound of formula (Ia):

wherein R is as defined above for a compound of formula (I) under suitable reaction conditions to form a compound of formula (Ha):

wherein R is as defined above for a compound of formula (II) and R₁ and R₂ taken together with the atoms to which they are attached form a cyclopentylidene or cyclohexylidene group;

(ii) reacting a compound of formula (Ha) under suitable reaction conditions to form a compound of formula (Ilia):

or a pharmaceutically acceptable salt thereof, wherein R₁ Ri and R₂ are as defined above for a compound of formula (III); (iii) reacting a compound of formula (Ilia) under suitable reaction conditions to form a compound of formula (IVa):

or a pharmaceutically acceptable salt thereof, wherein R, R₁ and R₂ are as defined above for a compound of formula (IV); and

(iv) reacting a compound of formula (IVa) under suitable reaction conditions to form the [R- (R*,R*)]-2-(4-fluorophenyl)- β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H- pyrrole-1-heptanoic acid (Va):

or a pharmaceutically acceptable salt thereof, wherein R is as defined above for a compound of formula

(V).

In one embodiment of the invention, the [R~(R*,R*)]-2-(4-fluorophenyl)- β, δ-dihydroxy-5-(1- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid (Va) is a pharmaceutically acceptable salt thereof, i.e., a compound of formula (Vl):

A compound of formula (Vl) is also known as atorvastatin calcium or [R-(R*,R*)]-2-(4-fluorophenyl)- β, δ- dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate.

The invention further provides a process as described above wherein R is tert-butyl; and R₁ and R₂ together with the atoms to which they are attached form a cyclopentylidene group.

The invention further provides a process as described above wherein R is isopropyl; and R₁ and R₂ together with the atoms to which they are attached form a cyclopentylidene group.

The invention further provides a process as described above wherein R is tert-butyl; and R₁ and R₂ together with the atoms to which they are attached form a cyclohexylidene group.

The invention further provides a process as described above wherein R is isopropyl; and R₁ and R₂ together with the atoms to which they are attached form a cyclohexylidene group.

The invention further provides a compound of formula (I)-(VI), and (Ia)-(Va), each as described herein.

The invention further provides a compound of formula (I):

prepared by a process of the invention, as described herein, wherein R, R₁ and R₂ are each as defined herein for a compound of formula (I).

The invention further provides a compound of the formula (II):

prepared by a process of the invention, as described herein, and wherein R, R-i and R₂ are each as defined herein for a compound of formula (II).

The invention further provides a compound of the formula (III):

or a pharmaceutically acceptable salt thereof, prepared by a process of the invention, as described herein, and wherein R, R₁ and R₂ are each as defined herein for a compound of formula (III). The invention further provides a compound of the formula (IV):

or a pharmaceutically acceptable salt thereof, prepared by a process of the invention, as described herein, and wherein R, R-, and R₂ are each as defined herein for a compound of formula (IV). The invention further provides a compound of the formula (V):

or a pharmaceutically acceptable salt thereof, prepared by a process of the invention, as described herein, and wherein R is as defined herein for a compound of formula (V). The invention further provides a compound of the formula (Vl):

prepared by a process of the invention, as described herein.

According to the invention, each of the chiral centers at the C-3 and C-5 position for compounds (I)-(VI) can have the same or different R or S configuration.

The invention further provides a compound of the formula (Ha):

prepared by a process of the invention, as described herein, and wherein R, R₁ and R₂ are each as defined herein for a compound of formula (II).

The invention further provides a compound of the formula (Ilia):

or a pharmaceutically acceptable salt thereof prepared by a process of the invention, as described herein, and wherein R, R₁ and R₂ are each as defined herein for a compound of formula (III). The invention further provides a compound of the formula (IVa):

or a pharmaceutically acceptable salt thereof prepared by a process of the invention, as described herein, and wherein R, R₁ and R₂ are each as defined herein for a compound of formula (IV). The invention further provides a compound of the formula (Va):

or a pharmaceutically acceptable salt thereof prepared by a process of the invention, as described herein, and wherein R, Ri and R₂ are each as defined herein for a compound of formula (V). The invention further provides a compound of the formula (Vl):

prepared by a process of the invention, as described herein. The invention further provides a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), (Vl), (Ia), (Ha), (Ilia), (IVa), or (Va) prepared by a process of the invention as described herein and a pharmaceutically acceptable diluent, carrier or excipient.

According to the invention, the term "suitable reaction conditions" as used herein refers to those reaction conditions known and understood by one of skill in the art needed to accomplish the recited reaction or transformation, including those described herein.

A compound of formula (II) or (Ha) may be prepared from, respectively, a compound of formula (I) or (Ia) using any suitable diol protecting reaction known in the art. The use of 1,1-dialkoxyalkanes or cycloalkanes to form cyclic acetals from 1 ,2 or 1,3 diols is well known (e.g., see Corey et al, J. Amer. Chem. Soc. 123, 1877 (2001)). Thus a compound of formula (II) or (ila) may be prepared by addition of the appropriate 1,1 -dimethoxycycloalkane in the presence of an acid catalyst.

A compound of formula (III) or (Ilia) may be prepared from, respectively, a compound of formula (II) or (Ha) using any suitable reduction reaction known in the art that selectively reduces the cyano (CN) group to an aminomethyl group. The reduction of cyano to aminomethyl is well known and the best known catalyst is Raney or sponge nickel. See, for example, WO8907598A2.

A compound of formula (IV) or (IVa)may be prepared from, respectively, a compound of formula (III) or (Ilia) using any suitable Paal-Knorr reaction conditions known in the art (e.g., see WO89/07598A2 and WO2004/046105.

A compound of formula (V), (Va), and (Vl) may be prepared from, respectively, a compound of formula (IV) or (IVa) using methods known in the art including, for example, hydrolysis reaction conditions. A process of the invention offers significant advantages over the prior art processes. A process of the invention significantly reduces the number of synthetic steps required to convert a compound of formula (I), as described herein, to the final desired product. According to a process of the invention, such a conversion requires only four or five synthetic operations while previous methods consisted of as many as eight or nine synthetic steps for the same conversion. The reduction in the number of synthetic steps offers the advantage of not only a more cost effective method but also a more environmentally friendly method since less reagents and organic solvents are used. A process of the invention also provides a health benefit to operators since they are exposed to fewer organic solvents and reagents. A process of the invention is also amenable to large-scale synthesis. In addition to greater simplicity and efficiency, another advantage offered by a process of the invention is greater yields of a compound of formula (II) or (Ila), which can be obtained in yields of typically >90% in a one pot synthesis. According to a process of the invention, a compound of formula (II) or (Ha) has been found to be less soluble in the reaction mixture such that addition of the appropriate 1,1- dimethoxycycloalkane to the diol of formula (I) or (Ia) resulted in the immediate precipitation or falling out of the corresponding compound of formula (II) or (Ila). The diol of formula (I) or (Ia) can be also pre- reacted with trimethyl orthoformate and subsequently with cyclopentanone or cyclohexanone to yield the solid compound (II) or (Ila), each as described above. As a result, a compound of formula (II) or (Ila) offers the advantage of a simpler non-aqueous work-up in the diol protection step, i.e., the conversion of a compound of formula (I) or (Ia) to a compound of formula (II) or (Ila). The surprisingly lower solubility of the compounds of formula (II) or (Ila) also led to the advantage of higher yields or isolation efficiencies in the subsequent process steps. DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS

Unless indicated otherwise, the following terms are defined as follows: The article "a" or "an" as used herein refers to both the singular and plural form of the object to which it refers.

The term "comprising" as used herein has the meaning "including, but not limited to". The term "alkyl" as used herein refers to a linear or branched hydrocarbon of from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n propyl, isopropyl, n butyl, sec butyl, isobutyl, tert-butyl, pentyl, and hexyl. The alkyl group may be further substituted with any substituent that will not adversely effect the reaction chemistry such as, for example, halo, alkoxy, and alkyl substituents.

The term "stereoisomer" as used herein refers to both geometric (e.g., cis and trans isomers) and/or optical isomers (e.g., R and S enantiomers) of a compound of the invention. Racemic, enantiomeric, diastereomeric and epimeric mixtures of such isomers as well as the individual enantiomer, diastereomer, and epimer are contemplated by the present invention.

The term "a pharmaceutically acceptable salt" as used herein refers to those acid addition salts and/or base addition salts of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of. the compounds of the invention.

The term "a pharmaceutically acceptable salt" refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free form with a suitable organic or inorganic acid or base and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non toxic ammonium, quaternary ammonium, and amine cations including, but not limited to.ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, Berge S.M., et al., "Pharmaceutical Salts," J. Pharm. ScI., 1977;66:1 19, which is incorporated herein by reference.) The free base form may be regenerated by contacting the salt form with a base. While the free base may differ from the salt form in terms of physical properties, such as solubility, the salts are equivalent to their respective free bases for the purposes of the present invention. Certain compounds of the present invention can exist in unsolvated form as well as solvated form including hydrated form. In general, the solvated form including hydrated form is equivalent to the unsolvated form and is intended to be encompassed within the scope of the present invention.

Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration. For example, compounds of formulae (I)-(VI) and (Ia)-(Va) can have a (3R, 5S), (3S, 5S), (3S, 5R) or (3R, 5R) configuration. If a compound of the invention further contains another chiral center(s), then that center(s) could independently have either an R or S configuration. The present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Such stereoisomers may be obtained, if desired, by methods known in the art including, for example, the separation of stereoisomers by chiral chromatographic columns and by chiral synthesis.

The present invention contains compounds that can be synthesized in a number of ways familiar to one skilled in organic synthesis. The following non-limiting reaction schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, all variables in the reaction schemes and the discussion that follow are defined above. Also all solvents and reagents are commercially available unless indicated otherwise. As would be understood by one of skill in the art, individual compounds may require manipulation of the conditions in order to accommodate various functional groups. A variety of protecting groups known to one skilled in the art may be required. Purification, if necessary, may be accomplished on a silica gel column eluted with the appropriate organic solvent system. Also, reverse phase HPLC or recrystallization as well as other conventional methods known in the art may be employed. In following Schemes 1 and 2, "diketone" is:

Te/f-butyl 3,5-dihydroxy-6-cyanohexanoate may be prepared according to methods known in the art. See Brower, Philip L; Butler, Donald E.; Deering, Carl F.; Le, Tung V.; Millar, Alan; Nanninga, Thomas N.; Roth, Bruce D. Parke-Davis Pharm. Res. Div., Warner Lambert Co., Holland, Ml₁ USA, "The synthesis of (4R-cls)- 1, 1-dimethylethyl 6-cyanomethyl-2, 2-dimethyl- 1, 3-dioxane-4-acetate, a key intermediate for the preparation of CI-981, a high potent, tissue selective inhibitor of HMG-CoA reductase", Tetrahedron Letters (1992), 33(17), 2279-82.

Scheme 1

(1)

Ho/Ni "0 Diketone

HoN O' NEt₃ /pivalicacid

(2)

(4) Scheme 2

(S) cid

(4) EXAMPLES

Example 1. Synthesis of Tert-Butyl Cyclopentylidene Nitrite (1) Method 1

(1)

Te/f-butyl 3,5-dihydroxy-6-cyanohexanoate (5Og active; 0.218 mol), trimethyl orthoformate (92.55 g, 0.87 moles), methanesulfonic acid (MSA) (1.05g, 5 mol %), and n-hexane (500 mL) were charged to a 500 mL reaction flask (desired pH<2). The resulting reaction mixture was cooled to 0-10⁰C under nitrogen. Cyclopentanone (73.35.g, 0.87 mmol) was charged slowly to the flask over 15- 20 minutes. Upon addition of the cyclopentanone, the desired product tert-butyl cyclopentylidene nitrile (1) precipitated out of solution. The resulting reaction mixture was stirred for 1-2 hours at 20-25⁰C. Triethylamine (1.1Og, 5mol%) was charged to the reaction flask to neutralise the MSA and the reaction mixture was stirred at at 20-25⁰C for 30 minutes. The batch was heated to a head temperature of 38-42°C and ca. 10OmL of distillate was collected. The batch was held at 40-45⁰C for 1 hour and then cooled to 20-25⁰C over 1 hour. The batch was then cooled to 0-5°C and held at this temperature for 2 hours. The product (1 ) was recovered by filtration and washed with heptane (200 mL). The yield of dry product (1) was 57.1 g (89% from fe/f-butyl 3,5-dihydroxy-6-cyanohexanoate).

NMR data for (1): 1H NMR: δ (ppm, CDCI3): 1.31-1.92 (17H, m), 2.36-2.55 (6H, m), 4.03-4.22 (2H, sym m)

13C NMR: δC (ppm): 22.42, 24.32, 24.78, 28.06, 31.20, 35.46, 40.05, 42.28, 66.52, 67.30, 80.79, 111.11, 116.83, 169.84

Method 2 Cyclopentanone (56.53g, 0.61 mmol) and methanesulfonic acid (1.05g, 8.6 mmol, 5 mol%) were charged to a 500 mL reaction flask. The resulting solution was cooled to 0⁰C and trimethyl orthoformate (71.38 g, 0.67 moles) was slowly added to the flask over 1 hour. A temperature increase of ca. 20⁰C was observed during this addition. The resulting reaction mixture was stirred for 1 hour. Tert-butyl 3,5-dihydroxy-6- cyanohexanoate (5Og; 0.168 mol) in heptane (150 mL) was added to the reaction mixture over 1 hour. The product precipitated out of solution towards the end of this addition. The resulting reaction mixture was stirred at ambient for 1hour, followed by the addition of triethylamine (0.85g, 8.4 mmol) to quench the reaction. Heptane (200 mL) was added to aid mobilization of the slurry and the reaction mixture was cooled slowly to -50C and held for 1 hour. The product fert-butyl cyclopentylidene nitrile (1) was recovered by filtration and washed with heptane (100 mL). The recovered fe/f-butyl cyclopentylidene nitrile (1) was then dried (41.2 g, 88% from diol). Spectral characteristics were consistent with those reported above for ferf-butyl cyclopentylidene nitrile (1) made by Method 1.

Example 2. Preparation of Fe/f-Butyl Cyclopentylidene Amine (2) from Tert-Butyl Cyclopentylidene Nitrile (1 )

(D (2)

Raney Nickel 12.5g (active), terf-butyl cyclopentylidene nitrile (1) (10Og, 0.34 moles; prepared according to Example 1 ), toluene (600 ml_), methanol (66 mL) and ammonia in methanol (7N, 81.2 mL) were charged to a hydrogenator. The resulting suspension was hydrogenated at about 3-4 bar at 350C for 5 hours or until hydrogen uptake was complete. The hydrogenator was then vented followed by purging of the hydrogenator with nitrogen. The Raney Nickel was then removed by filtration. The resulting filtrate was distilled under vacuum to approximately half the original volume and until the solution is clear. The toluene solution was cooled to 25°C. Pre-made brine solution (45g NaCI in 150 mL water) was added to the toluene solution followed by vigorous stirring for 10 mins. The aqueous and organic layers were allowed to separate. The organic toluene layer was then collected and distilled to give ferf-butyl cyclopentylidene amine (2) as an oil. The amine oil (2) containing residual toluene was charged directly to the next step as exemplified in Example 3.

NMR data for (2):

1H NMR: δ (ppm, CDCI3): 1.27-1.96 (25H, m), 2.32-2.41 (2H, m), 3.87 (1H, bs), 4.17 (1H, bs). 13C NMR: δ_c (ppm): 22.42, 24.33, 28.05, 31.19, 36.62, 40.28, 46.11, 67.62, 69.32, 66.71, 80.43, 110.56, 170.21

Example 3. Preparation of atorvastatin cyclopentylidene acetal t-butyl ester (3) from tert-butyl cyclopentylidene amine (2)

Terf-butyl cyclopentylidene amine (2) oil (50.Og, 0.17 moles; prepared according to Example 2), atorvastatin diketone (72.29g, 0.175 moles; prepared according to procedures known in the art including, for example, Baumann, Kelvin L, Tetrahedron Letters (1992), 33(17), 2283-4), methyl ferf-butyl ether (MTBE) (73g), THF (146g) and triethylamine (17.01g, 0.17 moles) was charged to a 1000 mL 2-neck round bottom flask, and contents were heated to 50⁰C. Pivalic acid (17.17g, 0.23 moles) was added and the reaction mixture was heated at reflux under Dean-Stark conditions and an inert atmosphere for 96 hours. The reaction solution was cooled to < 30°C under an Argon atmosphere. The reaction mixture was distilled down to a paste and the product was taken up in isopropyl alcohol (IPA) (200 mL) and the resulting slurry was heated to 60⁰C and held at this temperature for 0.5 h. The slurry was then cooled to -5⁰C and held for 1 hour. The desired product, atorvastatin cyclopentylidene acetal t-butyl ester (3), was obtained as an off white solid (71 g, 62%). NMR data for (3):

1H NMR: δ (ppm, CDCI3): 1.43 (9H, s), 1.41-1.92 (18H, m), 2.26-2.39 (2H, m), 3.56-3.63 (2H, m), 3.79- 3.86 (1H, m), 4.03-4.11 (2H, m,), 6.87- 7.26 (14H, ArH)

13C NMR: δC (ppm): 21.58, 21.67, 22.42, 24.37, 26.06, 31.15, 36.02, 37.87, 40.18, 40.92, 42.3, 67.64, 67.99, 80.67, 98.72, 115.33 (d), 119.52, 121.73, 123.47, 126.54, 128.20, 128.23 (d), 128.77, 130.48, 133.11 (d), 133.09, 133.21, 162.32 (d), 164.77, 170.17

Example 4. Preparation of Atorvastatin Calcium (4) from atorvastatin cyclopentylidene acetal t- butyl ester (3)

(4)

Atorvastatin cyclopentylidene acetal t-butyl ester (3) (20.4g, 30.5 mmol; prepared according to Example 3) methanol (45 ml_) and MTBE (91ml) were added to a 500 mL 3-necked round bottomed flask fitted with a thermometer and a condenser. The contents of the flask were heated to 50⁰C. A solution of 37% aqueous hydrochloric acid (0.66g) in water (6 mL) was then charged and the contents of the flask were heated to reflux with agitation and held at this temperature for 5 hours. After 5 hours, a 10% solution of sodium hydroxide in deionized water (DIW) (169 g) was added and the pH was checked to ensure that pH >13.. The contents of the flask were heated at 50⁰C for 1 hour. The reaction solution was cooled to 25-35°C and the pH was checked to ensure that pH >10. The phases were separated and methyl terf-buty ether (MTBE) (68 mL) was charged to the bottom aqueous phase, the mixture was stirred at 25-350C for about 1 hour. The bottom aqueous phase was separated, this was followed by two further washes with MTBE (68 mL). In a separate flask a solution of calcium acetate hemihydrate (2.63g) in DIW (81 mL) was prepared. The calcium acetate solution was charged to the batch over 60 to 90 minutes at 47-57°C, after 5 mins the addition was stopped and the reaction was seeded with Atorvastatin Calcium (300mg). The reaction mixture was stirred at 47-57°C for 0.5h. and cooled to 15-25°C. The product (4) is isolated by filtration and washed with a mixture of 66 mL DIW/34 mL MeOH followed by DIW (100 mL). The product is dried at 60-700C until Karl Fischer titration (KF) < 4.8%. Atorvastatin Calcium (4) is obtained as a white solid (17.3g, 94%) based on atorvastatin cyclopentylidene acetal t-butyl ester (3).

HPLC analysis: The product (4) was shown to be 99%+ (by area) by HPLC. The retention time of the product (4) produced by the method of the invention is identical to that produced by prior art methods.

Atypical powder X-ray diffraction profile of (4) derived from atorvastatin cyclopentylidene acetal t-butyl ester (3) is outlined below. Pos. Height [cts] FWHM d-spacing ReI. Int. Tip width f°2Th.l [°2Th.l [Al [%l [°2Th.l

6.2445 263.29 0.1632 14.14268 25.31 0.1360

9.2695 735.64 0.2856 9.53305 70.72 0.2380

9.5763 469.08 0.2040 9.22829 45.09 0.1700

10.4284 572.86 0.1632 8.47608 55.07 0.1360

10.6944 223.09 0.1632 8.26579 21.45 0.1360

11.9663 498.72 0.3264 7.38995 47.94 0.2720

12.3098 278.89 0.2040 7.18448 26.81 0.1700

13.8916 26.90 0.4896 6.36979 2.59 0.4080

15.2976 98.33 0.2448 5.78735 9.45 0.2040

17.1719 423.60 0.4488 5.15966 40.72 0.3740

18.3650 140.36 0.3264 4.82705 13.49 0.2720

19.6179 439.51 0.1836 4.52151 42.25 0.1530

21.7339 1040.28 0.2856 4.08583 100.00 0.2380

22.7426 319.49 0.4080 3.90685 30.71 0.3400

23.3682 393.91 0.2448 3.80365 37.87 0.2040

23.8490 420.06 0.2448 3.72804 40.38 0.2040

24.4980 247.53 0.2856 3.63074 23.79 0.2380

26.3607 81.79 0.5712 3.37825 7.86 0.4760

27.5268 91.71 0.4896 3.23774 8.82 0.4080

28.9501 187.86 0.3264 3.08171 18.06 0.2720

30.2794 108.57 0.4896 2.94938 10.44 0.4080

31.9412 51.14 0.3264 2.79962 4.92 0.2720

33.1282 50.69 0.6528 2.70197 4.87 0.5440

37.1384 62.97 0.6528 2.41890 6.05 0.5440

39.3432 61.63 0.4080 2.28828 5.92 0.3400

43.0929 50.71 1.1424 2.09745 4.87 0.9520

Example 5. Synthesis of Fert-Butyl Cyclohexylidene Nitrile (5)

(5)

Cyclohexanone (59.98, 0.61 mmol) and methanesulfonic acid (7.65 mmol, 5 mol%) were charged to a 500 mL reaction flask. Trimethyl orthoformate (64.87 g, 0.61 moles) was slowly added to the flask over 1 hour. Atemperature increase of ca. 2O⁰C was observed during this addition. The resulting reaction mixture was stirred for 1 hour, ferf-butyl 3,5-dihydroxy-6-cyanohexanoate (50g; 0.153 mol) was added to the reaction mixture. The resulting reaction mixture was stirred at ambient temperature for 4h, followed by the addition of triethylamine (0.77g, 7.65 mmol) to quench the reaction. 1,1-Dimethoxycyclohexane (ca. 42 mL) and methyl formate were distilled off at 85-9O⁰C under vacuum. Heptane (100 mL) was added to the hot solution and the reaction mixture was cooled slowly to -50C and held for 1h. The product fert-Butyl

Cyclohexylidene Nitrile (5) was recovered by filtration and washed with heptane (100 mL). The yield of dry fert-Butyl Cyclohexylidene Nitrile (5) was 47.3 g (91% from Terf-butyl 3,5-dihydroxy-6- cyanohexanoate). NMR data for (5):

1H NMR: δ (ppm, CDC13): 1.25-1.80 (2OH, m), 1.99 (1H, dd), 2.30-2.47 (2H, sym m), 2.52 (2H, d), 4.16- 4.33 (2H, sym m) 13C NMR: δC (ppm) 22.25, 24.97, 25.15, 28.05, 28.43, 35.61, 38.44, 46.04, 64.21, 64.88, 80.77, 99.52, 116.93, 170.02

Example 6: Preparation of Tert-Butyl Cyclohexylidene Amine (6) from Terf-Butyl Cyclohexylidene IMitrile (5)

(5) (⁶)

Raney Nickel 19g (active), fe/t-Butyl Cyclohexylidene Nitrite (5) (148.2g, 0.48 moles; prepared according to Example 5), toluene (900 ml_), methanol (100 mL) and ammonia in methanol (7N, 121.8 mL) were charged to a hydrogenator. The resulting suspension was hydrogenated at 50-600C for 23h or until hydrogen uptake was complete. The hydrogenator was then vented followed by purging of the hydrogenator with nitrogen. The Raney Nickel was removed by filtration. The resulting filtrate was distilled under vacuum to approximately half the original volume and until the solution was clear. The toluene solution was cooled to 25°C. Pre made brine solution (45g NaCI in 150 mL water) was added to the toluene solution followed by vigorously stirring for 10 mins. The aqueous and organic layers were allowed to separate. The organic toluene layer was distilled to give tørf-Butyl Cyclohexylidene Amine (6) as an oil. The fert-butyl cyclohexylidene amine (6) oil containing residual toluene was charged directly to the next step.

NMR data for (6):

1H NMR: δH (ppm, CDCI3) 1.15-1.90 (25H, m), 2.24-2.43 (2H₁ m), 2.82 (1H, bs), 3.90-4.02(1H₁ m), 4.25- 4.32 (1 H, m).

13C NMR: δC (ppm) 22.44, 22.58, 28.06, 28.53, 36.85, 38.75, 42.85, 65.30, 66.11, 66.71, 80.40, 98.61, 170.23

Example 7: Preparation of atorvastatin cyclohexylidene acetal t-butyl ester (7) from fert-Butyl Cyclohexylidene Amine (6)

atowastafin diketone

The fe/f-butyl cyclohexylidene nitrile (6) oil (72.Og, 0.23moles; prepared according to Example 6), atorvastatin diketone (98.9g, 0.24 moles), methyl fert-butyl ether (MTBE; 98.Og), tetrahydrofuran (THF; 63.Og) and triethylamine (23.3g, 0.23 moles) were charged to a 1000 ml_ 2-neck round bottom flask, and contents were heated to 50⁰C. Pivalic acid (23.3g, 0.23 moles) was added and the reaction mixture was heated at reflux under Dean-Stark conditions and an inert atmosphere for 96 hours. The reaction solution was cooled to < 30°C under an Argon atmosphere. The reaction mixture was distilled down to a paste and the product was taken up in IPA (144 ml_) and the resulting slurry was heated to 6O⁰C and held at this temperature for 0.5 h. The slurry was then cooled to -50C and held for 1 hour. The atorvastatin cyclohexylidene acetal t-butyl ester (7) product was obtained as an off white solid (116g, 73%).

NMR data for (7):

¹H NMR: δ_H(ppm, CDCI3) 1.44 (9H₁ s), 1.53 (8H, dd), 1.64-1.49 (4H, m) 2.16-2.41 (2H₁ m), 3.59-3.89 (3H, m), 4.17-4.29 (2H, m), 6.85- 7.26 (14H, ArH).

¹³C NMR: δC (ppm) 21.55, 21.66, 22.42, 25.64, 26.03, 28.06, 28.41, 36.24, 38.19, 38.67, 40.99, 42.62, 65.09, 65.50, 80.65, 98.72, 115.33 (d), 119.52, 121.71, 123.46, 126.54, 128.21, 128.23 (d), 133.1 (d), 128.81, 130.49, 133.09, 133.20, 162.25 (d), 164.77, 170.32.

Example 8: Preparation of Atorvastatin Calcium (4) from atorvastatin cyclohexylidene acetal t- butyl ester (7)

(4)

The atorvastatin cyclohexylidene acetal t-butyl ester (7) (5g, 7.2 mmol; prepared according to Example 7) and methanol (50 ml_) were added to a 500 mL 3-necked round bottomed flask fitted with a thermometer and a condenser. A solution of 37% aqueous hydrochloric acid (0.5 mL) in water (5 mL) was then charged and the contents of the flask were heated to reflux with agitation and held at this temperature for 18h. The reaction solution was cooled to ambient temperature followed by the addition of a solution of sodium hydroxide (0.24 g) in DlW (0.48 mL). The reaction solution was distilled down to a paste and methyl tert- butyl ether (MTBE) (23 mL) and Methanol (10.5 mL) were added followed by a solution of sodium hydroxide (0.29g ) in deionized water (DIW) (48 mL).The contents of the flask were heated to 47-52⁰C and held at this temperature for at least 1 h. The reaction was conducted under an argon atmosphere in the dark. The reaction solution was cooled to 25-35⁰C and the pH was checked. (pH, must be >10).The phases were separated and MTBE (20 mL) is charged to the bottom aqueous phase, the mixture is stirred at 25-35⁰C for about 1h. The bottom aqueous phase was separated, this was followed by two further MTBE (20 mL) washes. In a separate flask a solution of calcium acetate hemihydrate (0.91g) in DIW (28 mL) was prepared. The calcium acetate solution was charged to the batch over 60 to 90 minutes at 47- 57⁰C, after 5 mins the addition was stopped and the reaction was seeded with Atorvastatin Calcium. The reaction mixture was stirred at 47-57°C for 0.5h. and cooled to15-25°C. The product was isolated by filtration and washed with a mixture of 12 mL DIW/9 mL MeOH followed by DIW (25 mL). The product was dried at 60-70⁰C until Karl Fischer titration (KF) < 4.8%. Atorvastatin Calcium (4) was obtained as a white solid (3.9Og, 90%).

The product was shown to be 98%+ (by area) by HPLC. The retention time of the product produced by the method of the invention is identical to that produced by prior art methods.

All publications, including but not limited to, issued patents, patent applications, and journal articles, cited in this application are each herein incorporated by reference in their entirety. Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. Accordingly, the invention is limited only by the following claims.

Claims

CLAIMSWhat is claimed is: _

1. A process comprising the steps of: (i) reacting a compound of formula (I):

wherein R is an alkyl group, under suitable reaction conditions to form a compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein R, R₁ and R₂ are each as defined above;

(iii) reacting a compound of formula (III) under suitable reaction conditions to form a compound of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein R is H or as defined above, and R-i and R₂ are each as defined above; and

(iv) reacting a compound of formula (IV) under suitable reaction conditions to form 2-(4-._. fluorophenyl)- β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrroIe-1- heptanoic acid (V):

or a pharmaceutically acceptable salt thereof, wherein R is H or as defined above.

2. A process according to claim 1, wherein R is a CrC₄ alkyl group.

3. A process according to claim 2, wherein R is isopropyl or tert-butyl.

4. A process according to claim 3, wherein R is fert-butyl.

5. A process according to claim 4, wherein R-i and R₂ together with the atoms to which they are attached form a cyclopentylidene group.

6. A process according to claim 4, wherein R-i and R₂ together with the atoms to which they are attached form a cyclohexylidene group.

7. A process according to claim 3, wherein R is isopropyl.

8. A process according to claim 7, wherein R-i and R₂ together with the atoms to which they are attached form a cyclopentylidene group.

9. A process according to claim 7, wherein R₁ and R₂ together with the atoms to which they are attached form a cyclopentylidene group.

10. A process comprising the steps of:

(i) reacting a compound of formula (Ia):

wherein R is an alkyl group, under suitable reaction conditions to form a compound of formula (Ha):

(iii) reacting a compound of formula (Ilia) under suitable reaction conditions to form a compound of formula (IVa):

or a pharmaceutically acceptable salt thereof, wherein R is H or as defined above, and R₁ and R₂ are each as defined above; and

(iv) reacting a compound of formula (IVa) under suitable reaction conditions to form [R-(R*,R*)]-2- (4-fluorophenyl)- β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1- heptanoic acid (Va):

11. A process according to claim 10, wherein R is a C₁-C₄ alkyl group.

12. A process according to claim 11, wherein R is isopropyl or fert-butyl.

13. A process according to claim 12, wherein R is terf-butyl.

14. A process according to claim 13, wherein R-i and R₂ together with the atoms to which they are attached form a cyclopentylidene group.

15. A process according to claim 13, wherein R-i and R₂ together with the atoms to which they are attached form a cyclohexylidene group.

16. A process according to claim 12, wherein R is isopropyl.

17. A process according to claim 16, wherein R₁ and R₂ together with the atoms to which they are attached form a cyclopentylidene group.

18. A process according to claim 16, wherein Ri and R₂ together with the atoms to which they are attached form a cyclopentylidene group.

19. A process according to claim 10, wherein the compound of formula (Va) is a compound of formula (Vl):

[R-(R*,R*)]-2-(4-fluorophenyi)-β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H- pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate.

20. A compound of the formula (II):

wherein R is an alkyl group and R-i and R₂ together with the atoms to which they are attached form a cyclopentylidene or a cyclohexyliden group.

21. A compound according to claim 20, wherein R is a C₁-C₄ alkyl group.

22. A compound according to claim 21, wherein R is isopropyl or te/f-butyl.

23. A compound according to claim 22, wherein R is tert-butyl.

24. A compound according to claim 23, wherein R₁ and R₂ together with the atoms to which they are attached form a cyclopentyiidene group.

25. A compound according to claim 23, wherein R₁ and R₂ together with the atoms to which they are attached form a cyclohexylidene group.

26. A compound according to claim 22, wherein R is isopropyl.

27. A compound according to claim 26, wherein R₁ and R₂ together with the atoms to which they are attached form a cyclopentylidene group.

28. A compound according to claim 26, wherein Ri and R₂ together with the atoms to which they are attached form a cyclopentylidene group.