WO2008075165A1 - Nouveau procédé pour la synthèse de l'acide [r-(r*, r*)]-2-(4-fluorophényl)-bêta, delta-dihydroxy-5-(1-méthyléthyl)-3-phényl-4-[(phénylamino)carbonyl]-1h-pyrrole-1-heptanoïque ou d'un sel pharmaceutiquement acceptable de celui-ci - Google Patents

Nouveau procédé pour la synthèse de l'acide [r-(r*, r*)]-2-(4-fluorophényl)-bêta, delta-dihydroxy-5-(1-méthyléthyl)-3-phényl-4-[(phénylamino)carbonyl]-1h-pyrrole-1-heptanoïque ou d'un sel pharmaceutiquement acceptable de celui-ci Download PDF

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Publication number
WO2008075165A1
WO2008075165A1 PCT/IB2007/003902 IB2007003902W WO2008075165A1 WO 2008075165 A1 WO2008075165 A1 WO 2008075165A1 IB 2007003902 W IB2007003902 W IB 2007003902W WO 2008075165 A1 WO2008075165 A1 WO 2008075165A1
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compound
formula
atoms
process according
pharmaceutically acceptable
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PCT/IB2007/003902
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English (en)
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Timothy Jay Chopra
Padraig Mary O'neill
Philippa Brenda Wilkes
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Pfizer Products Inc.
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Publication of WO2008075165A1 publication Critical patent/WO2008075165A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems

Definitions

  • HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A
  • 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)- ⁇ , ⁇ -dihydroxy-S ⁇ I-methylethyO-S-phenyM- ⁇ phenylaminoJcarbonyll-IH- pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate and the formula
  • 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.
  • the object of the present invention is to provide an improved process for the preparation of [R- (R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H- pyrrole-1-heptanoic acid or a pharmaceutically acceptable salt thereof.
  • the invention provides a process for making atorvastatin or a pharmaceutically acceptable salt thereof comprising the steps of:
  • R is an alkyl group; alternatively, R is a C 1 -C 4 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):
  • R is as defined above and R 1 and R 2 taken together with the atoms to which they are attached form a cyclopentylidene or cyclohexylidene group;
  • R 1 R 1 and R 2 are each as defined above;
  • R is H or as defined above, R-i and R 2 are each as defined above;
  • the invention provides a process for the preparation of [R-(R*, R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ - 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):
  • R is as defined above for a compound of formula (II) and R 1 and R 2 taken together with the atoms to which they are attached form a cyclopentylidene or cyclohexylidene group;
  • the [R ⁇ (R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -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)- ⁇ , ⁇ - 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 R 1 and R 2 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 R 1 and R 2 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 R 1 and R 2 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 R 1 and R 2 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):
  • the invention further provides a compound of the formula (II):
  • the invention further provides a compound of the formula (III):
  • 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):
  • the invention further provides a compound of the formula (Ilia):
  • 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.
  • suitable reaction conditions 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)).
  • 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.
  • 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.
  • 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.
  • 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.
  • alkyl 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.
  • stereoisomer 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.
  • a pharmaceutically acceptable salt 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.
  • 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.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
  • non toxic ammonium, quaternary ammonium, and amine cations including, but not limited to.ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • 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.
  • each center may exist in the R or S configuration.
  • 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.
  • 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 0-10 0 C under nitrogen. Cyclopentanone (73.35.g, 0.87 mmol) was charged slowly to the flask over 15- 20 minutes.
  • 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).
  • 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.
  • 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 50 0 C.
  • 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
  • MTBE methyl ferf-butyl ether
  • THF 146g
  • triethylamine 17.01g
  • 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 50 0 C. 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.
  • a 10% solution of sodium hydroxide in deionized water (DIW) (169 g) was added and the pH was checked to ensure that pH >13..
  • DIW deionized water
  • the contents of the flask were heated at 50 0 C 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).
  • 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
  • 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 t ⁇ rf-Butyl Cyclohexylidene Amine (6) as an oil. The fert-butyl cyclohexylidene amine (6) oil containing residual toluene was charged directly to the next step.
  • 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 6O 0 C 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%).
  • 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).
  • DIW deionized water
  • the reaction was conducted under an argon atmosphere in the dark.
  • the reaction solution was cooled to 25-35 0 C 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 25-35 0 C for about 1h.
  • 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.

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Abstract

L'invention concerne une synthèse perfectionnée pour la préparation de l'acide [R-(R*, R*)]-2-(4-fluorophényl)- β, δ-dihydroxy-5-(1-méthyléthyl)-3-phényl-4-[(phénylamino)carbonyl]-1 H-pyrrole-1-heptanoïque ou d'un sel pharmaceutiquement acceptable de celui-ci, ainsi que d'autres intermédiaires de valeur utilisés dans le procédé. Les composés préparés par un procédé de l'invention sont utiles dans le traitement de l'hyperlipidémie, de l'hypercholestérolémie, de l'ostéoporose, de l'hyperplasie prostatique bénigne ou de la maladie d'Alzheimer.
PCT/IB2007/003902 2006-12-19 2007-12-03 Nouveau procédé pour la synthèse de l'acide [r-(r*, r*)]-2-(4-fluorophényl)-bêta, delta-dihydroxy-5-(1-méthyléthyl)-3-phényl-4-[(phénylamino)carbonyl]-1h-pyrrole-1-heptanoïque ou d'un sel pharmaceutiquement acceptable de celui-ci WO2008075165A1 (fr)

Applications Claiming Priority (2)

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US87072806P 2006-12-19 2006-12-19
US60/870,728 2006-12-19

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WO2008075165A1 true WO2008075165A1 (fr) 2008-06-26

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JP (1) JP2008150376A (fr)
AR (1) AR064421A1 (fr)
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011131605A1 (fr) * 2010-04-19 2011-10-27 Dsm Ip Assets B.V. Production d'atorvastatine à faible teneur en impuretés éthers
WO2012034958A1 (fr) * 2010-09-16 2012-03-22 Dsm Sinochem Pharmaceuticals Netherlands B.V. Esters d'acides hexanoïques comme intermédiaires pour la préparation d'atorvastatine
WO2012093227A1 (fr) 2011-01-07 2012-07-12 Jacquot Epouse Guilmin Liliane Promédicaments pour une délivrance au niveau du foie d'une statine
US20140187794A1 (en) * 2007-08-03 2014-07-03 Pfizer Inc. Process for Preparing Chiral Compounds
US8816082B2 (en) 2010-05-28 2014-08-26 The Royal Institution For The Advancement Of Learning/Mcgill University Heterocyclyl-pyridinyl-based biphosphonic acid, pharmaceutically acceptable salt thereof, composition thereof and method of use thereof
US9290526B2 (en) 2010-05-28 2016-03-22 The Royal Institution For The Advancement Of Learning/Mcgill University Heterocyclyl-pyridinyl-based biphosphonic acid, pharmaceutically acceptable salt thereof, composition thereof and method of use thereof

Citations (1)

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WO2011131605A1 (fr) * 2010-04-19 2011-10-27 Dsm Ip Assets B.V. Production d'atorvastatine à faible teneur en impuretés éthers
US8816082B2 (en) 2010-05-28 2014-08-26 The Royal Institution For The Advancement Of Learning/Mcgill University Heterocyclyl-pyridinyl-based biphosphonic acid, pharmaceutically acceptable salt thereof, composition thereof and method of use thereof
US9290526B2 (en) 2010-05-28 2016-03-22 The Royal Institution For The Advancement Of Learning/Mcgill University Heterocyclyl-pyridinyl-based biphosphonic acid, pharmaceutically acceptable salt thereof, composition thereof and method of use thereof
WO2012034958A1 (fr) * 2010-09-16 2012-03-22 Dsm Sinochem Pharmaceuticals Netherlands B.V. Esters d'acides hexanoïques comme intermédiaires pour la préparation d'atorvastatine
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