WO2006128954A1 - Procede de preparation de n-[4-(4-fluorophenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-n-methylmethanesulfonamide - Google Patents

Procede de preparation de n-[4-(4-fluorophenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-n-methylmethanesulfonamide Download PDF

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Publication number
WO2006128954A1
WO2006128954A1 PCT/FI2006/000170 FI2006000170W WO2006128954A1 WO 2006128954 A1 WO2006128954 A1 WO 2006128954A1 FI 2006000170 W FI2006000170 W FI 2006000170W WO 2006128954 A1 WO2006128954 A1 WO 2006128954A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
halogen
protecting group
fluorophenyl
Prior art date
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PCT/FI2006/000170
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English (en)
Inventor
Arne Grumann
Pekka PIETIKÄINEN
Inese Reine
Original Assignee
Fermion Oy
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from FI20050586A external-priority patent/FI20050586A0/fi
Application filed by Fermion Oy filed Critical Fermion Oy
Priority to EP06755392A priority Critical patent/EP1893585A1/fr
Publication of WO2006128954A1 publication Critical patent/WO2006128954A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/30—Halogen atoms or nitro radicals

Definitions

  • the present invention is directed to a method for the preparation of N-[4-(4- fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide having a structure of formula I
  • Rosuvastatin is a HMG-CoA reductase inhibitor used as a calcium salt in the treatment of hypercholesterolemia, hyperlipodemia and atherosclerosis. Its chemical name is (+)-(3R,5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)-pyrimidin-5-yl]-3,5-dihydroxy-6(E)heptenoic acid.
  • Other statins used as lipid-lowering drugs are e.g. simvastatin, atorvastatin, lovastatin and pravastatin.
  • Rosuvastatin and a process for its preparation is disclosed in US patent no 5,260,440.
  • the preparation process described contains four steps: a) condensation of methyl (3R)-3-[tert-butylmethylsilyl)-oxy]-5-oxo-6-triphenylphosphoranylidene hexanoate with N-[4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl]-N- methylmethanesulfonamide, b) deprotection of the 3-hydroxyl group to give the keto alcohol, c) reduction of 5-oxo to obtain the chiral dihydroxy heptenate, and d) hydrolysis of the dihydroxy heptenate.
  • N-[4-(4-fluorophenyl)-5- formyl-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide (referred later as pyrimidine compound) is prepared from 4-fluorobenzaldehyde, 4-methyl-3-oxo- pentanoic acid ethyl ester and S-methylisothiourea.
  • the preparation of the pyrimidine compound requires eight synthetic steps and involves the use of expensive and hazardous reagents and solvents like 2,3-dichloro-5,6-dicyano-l,4-benzoquinone, m- chloroperoxybenzoic acid, tetrapropylammonium perruthenate, and hexamethylphosphoramide. Also, the pyrimidine compound is obtained only in moderate yield.
  • the starting material for rosuvastatin, N- [4-(4-fluorophenyl)-5 -formyl-6-isopropylpyrimidin-2-yl] -N-methylmethane- sulfonamide can be prepared economically starting from 2,4,6- trihalogenopyrimidme-5-carbaldehyde, which can be made from 2,4,6- trioxohexahydropyrimidine (barbituric acid) or from 2,4,6-trihalogenopyrirnidine.
  • One aspect of the present invention is the process for the preparation of a compound of formula I
  • Rl is OR5 or SR5 and R2 is OR5 or SR5 or NR5 and R5 is substituted or non substituted alkyl chain and they together form a linear or cyclic aldehyde protecting group and N-R4 is an aldehyde protecting group wherein R4 is e.g. NMe 2 , OMe or OBn.
  • Another aspect of the present invention is the reaction of the the pyrimidine compound of formula I prepared according to the invention to produce rosuvastatin or a pharmaceutically acceptable salt thereof.
  • the first step is the addition of a suitable group to protect the aldehyde.
  • Suitable protective groups as well as processes for their addition are described in textbooks, e.g. in Greene and Wuts (T. W. Greene and P.G.M. Wuts, Protective groups in organic synthesis, John Wiley & Sons, Inc., 3 rd . ed, New York, 1999), which is incorporated here as a reference, hi the process of the invention the preferable groups used are e.g. acyclic or cyclic acetal, monothioacetal or dithioacetal. If e.g.
  • 1,3-dioxolane (cyclic acetal), is used as a protective group
  • the process maybe the following: 2,4,6-trihalogenopyrimidine-5-carbaldehyde is dissolved in a suitable organic solvent, which can be e.g. an aromatic hydrocarbon or ethylene glycol or a mixture thereof, or the reagent, like ethylene glycol, may be used as a solvent.
  • a suitable organic solvent which can be e.g. an aromatic hydrocarbon or ethylene glycol or a mixture thereof, or the reagent, like ethylene glycol, may be used as a solvent.
  • Acid catalyst e.g. Lewis acid or protic acid may be used in the reaction.
  • the mixture is typically reacted at ambient or reflux temperature for the process to complete, and thereafter the product is isolated and purified using the methods known in the art.
  • the product from the previous step is dissolved in a suitable organic solvent, e.g. ethers like tetrahydrofuran, aromatic hydrocarbons like toluene or xylene, aprotic polar solvents like N-methylpyrrolidinone or mixtures thereof may be used.
  • a suitable organic solvent e.g. ethers like tetrahydrofuran, aromatic hydrocarbons like toluene or xylene, aprotic polar solvents like N-methylpyrrolidinone or mixtures thereof may be used.
  • the isopropyl group can be added using an isopropyl metallic compound, such as an isopropyl magnesium halide, e.g. bromide or chloride using transition metal catalysis e.g. Fe, Ni or Cu compounds can be used, preferably Li 2 CuCl 4 is used as a catalyst.
  • An aqueous work up and purification as known in the art, such as column chromatography or crystallization may be used
  • the process may be continued in one pot to step c) without isolation of the intermediate from step b).
  • Compound of formula IV is reacted with a 4-fluorophenyl metallic compound (4-F-C 6 H 4 -M) in a suitable solvent, e.g. ethers like tetrahydrofuran, nonpolar hydrocarbons like toluene or xylene, polar double or triple bond containing solvents like acetonitrile, other polar aprotic solvents like N,N-dimethylformamide, and polar protic solvents like alcohols or water or mixtures thereof may be used.
  • Suitable metallic substituents (M) include e.g.
  • Non-metallic substituents (M) like Si can also be used in this reaction step.
  • the reaction maybe catalyzed by transition metal catalysts e.g. Fe, Ni, Cu or Pd compounds, preferably Pd(H) or Pd(O) compounds are used.
  • An aqueous work up and purification as known in the art such as column chromatography or crystallization may be used to provide the adduct in good purity.
  • a compound of formula V is reacted with N-methylmethanesulfonamide or its anion in a suitable solvent.
  • the anion can be formed with a suitable base, which can be e.g. carbonate, hydroxide, alkoxide, hydride, amidine, or alkylmetal compound.
  • Suitable solvent is dependent on the base used, e.g. ethers, aprotic polar solvents, aromatic or aliphatic hydrocarbons or mixtures thereof can be used.
  • Typical base-solvent combinations include e.g.
  • Aldehyde protection made in step a) is removed by a suitable method known in the art to obtain a compound of formula I.
  • the starting compound of formula II can be made starting from barbituric acid or from 2,4,6-trihalogeno pyrimidine, which are commercially available compounds.
  • 2,4,6-trichloropyrimidine-5-carbaldehyde can be made from barbituric acid in one pot reaction e.g. in the following way.
  • Barbituric acid is reacted with suitable chlorinating and formylating agents in a suitable solvent to obtain 2,4,6-trichloropyrimidine-5-carbaldehyde.
  • suitable solvents may be e.g. polar aprotic or aromatic hydrocarbons like toluene or xylene, chlorinated hydrocarbons like 1,2-dichloroethane or chlorobenzene.
  • Possible chlorinating agents include but are not limited to POCl 3 , SOCl 2 , PCl 3 , PCl 5 , COCl 2 , or (COCl) 2 and as formylating agent e.g.
  • formamides like ⁇ iV-dimethylformamide, iV-methylformanilide, iV-formylpiperidine, N-formylmo ⁇ holine or other amides like A ⁇ JV-dimethylacetamide, N-methylpyrrolidone, N,N, dimethylbenzamide may be used.
  • Reaction temperature and time depend on the solvent used, e.g. reflux temperature may be used. Remaining halogenating agent is removed and the resulting 2,4,6-trichloropyrimidine-5-carbaldehyde may be isolated and purified by methods known in the art.
  • Compound of formula II may also be made in two steps comprising chlorination using the chlorinating agents as mentioned above and formylation separately by some method known in the art, or it may be obtained by formylation of commercially available halogenated compound of formula II by some methods known in the art, e.g. using n-butyllithium/ N,iV-dmiethylformamide, lithium diisopropylamide/ethylformate, and hexamethylenetetramine.
  • Chlorinated compound of formula II is the preferred compound used, but also other halogens can be used. e.g. bromo-compound may be made using e.g. PBr 3 as a halogenating agent.
  • 2,4,6-Trichloro-5 -[1,3] dioxolane-2-ylpyrimidine To the solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (10.0 g) in dry benzene (200 ml) were added ethylene glycol (8.0 ml) andp-toluenesulfonic acid (0.15 g). The mixture was refluxed for 20 h, the warm benzene layer was decanted and the residue was washed with warm benzene (2x50 ml). Combined benzene solution was evaporated, water (30 ml) was added and the suspension formed was neutralized with 9% NaHCO 3 . The precipitate was filtered to afford 10.3 g (85%) of 2,4,6-trichloro-5- [l,3]dioxolane-2-ylpyrimidine, m.p. 161-162 0 C.
  • This organozinc solution was added to a mixture of 2,4-dichloro-5- [l,3]dioxolane-2-yl-6-isopropylpyrimidine (0.5 g) and Pd(PPh 3 ) 4 (1 mol-%, 13 mg) in THF (15 ml).
  • the reaction mixture was heated at 55-60 0 C for 4.5 h. After cooling it was poured in 10% NH 4 Cl — ice mixture.
  • the organic layer was separated and aqueous phase was extracted with ethyl acetate (2x20 ml).
  • the combined organic extract was washed with 10% aq EDTA (15 ml) and saturated NaCl solution, and evaporated.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne une méthode pour préparer du N-[4-(4-fluorophényl)-5-formyl-6-isopropylpyrimidin-2-yl]-N-méthylméthanesulfonamide et l'utilisation de celui-ci pour préparer de la rosuvastatine ou un sel pharmaceutiquement acceptable de celle-ci.
PCT/FI2006/000170 2005-06-01 2006-05-31 Procede de preparation de n-[4-(4-fluorophenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-n-methylmethanesulfonamide WO2006128954A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06755392A EP1893585A1 (fr) 2005-06-01 2006-05-31 Procede de preparation de n-[4-(4-fluorophenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-n-methylmethanesulfonamide

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US68589005P 2005-06-01 2005-06-01
US60/685,890 2005-06-01
FI20050586 2005-06-01
FI20050586A FI20050586A0 (fi) 2005-06-01 2005-06-01 Menetelmä N-[4-(4-fluorofenyyli)-5-formyyli-6-isopropyylipyrimidiini-2-yyli]-N-metyylimetaanisulfonamidin valmistamiseksi

Publications (1)

Publication Number Publication Date
WO2006128954A1 true WO2006128954A1 (fr) 2006-12-07

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EP (1) EP1893585A1 (fr)
WO (1) WO2006128954A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009024323A2 (fr) * 2007-08-20 2009-02-26 Ratiopharm Gmbh Procédé de préparation de dérivés de pyrimidine
WO2010081861A1 (fr) 2009-01-14 2010-07-22 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de rosuvastatine
US8212034B2 (en) 2006-12-13 2012-07-03 Aurobindo Pharma Ltd. Process for preparing rosuvastatin calcium
CN105622521A (zh) * 2014-12-01 2016-06-01 重庆安格龙翔医药科技有限公司 一种瑞舒伐他汀钙关键中间体的制备方法
CN105622522A (zh) * 2014-12-01 2016-06-01 重庆安格龙翔医药科技有限公司 一种瑞舒伐他汀钙关键中间体的合成方法
CN105712939A (zh) * 2014-12-01 2016-06-29 重庆安格龙翔医药科技有限公司 一种合成瑞舒伐他汀钙关键中间体的方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2310334A1 (de) * 1972-03-03 1973-09-13 Gerot Pharmazeutika Verfahren zur herstellung von teilweise neuen 4,6-dichlorpyrazolo-(3,4-d)-pyrimidinderivaten
US5260440A (en) * 1991-07-01 1993-11-09 Shionogi Seiyaku Kabushiki Kaisha Pyrimidine derivatives
WO2003097614A2 (fr) * 2002-05-21 2003-11-27 Ranbaxy Laboratories Limited Procede de preparation de rosuvastatine
WO2004052867A1 (fr) * 2002-12-10 2004-06-24 Ranbaxy Laboratories Limited Procede de preparation de rosuvastatine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2310334A1 (de) * 1972-03-03 1973-09-13 Gerot Pharmazeutika Verfahren zur herstellung von teilweise neuen 4,6-dichlorpyrazolo-(3,4-d)-pyrimidinderivaten
US5260440A (en) * 1991-07-01 1993-11-09 Shionogi Seiyaku Kabushiki Kaisha Pyrimidine derivatives
WO2003097614A2 (fr) * 2002-05-21 2003-11-27 Ranbaxy Laboratories Limited Procede de preparation de rosuvastatine
WO2004052867A1 (fr) * 2002-12-10 2004-06-24 Ranbaxy Laboratories Limited Procede de preparation de rosuvastatine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WATANABE M ET AL: "SYNTHESIS AND BIOLOGICAL ACTIVITY OF METHANESULFONAMIDE PYRIMIDINE-AND N-METHANESULFONYL PYRROLE-SUBSTITUTED 3,5-DIHYDROXY-6-HEPTENOATES, A NOVEL SERIES OF HMG-COA REDUCTASE INHIBITORS", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 5, no. 2, 1997, pages 437 - 444, XP000882043, ISSN: 0968-0896 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8212034B2 (en) 2006-12-13 2012-07-03 Aurobindo Pharma Ltd. Process for preparing rosuvastatin calcium
WO2009024323A2 (fr) * 2007-08-20 2009-02-26 Ratiopharm Gmbh Procédé de préparation de dérivés de pyrimidine
WO2009024323A3 (fr) * 2007-08-20 2009-08-06 Ratiopharm Gmbh Procédé de préparation de dérivés de pyrimidine
WO2010081861A1 (fr) 2009-01-14 2010-07-22 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de rosuvastatine
EP2752407A1 (fr) 2009-01-14 2014-07-09 Krka Tovarna Zdravil, D.D., Novo Mesto Sel de calcium trihydrate de rosuvastatine cristallisé
CN105622521A (zh) * 2014-12-01 2016-06-01 重庆安格龙翔医药科技有限公司 一种瑞舒伐他汀钙关键中间体的制备方法
CN105622522A (zh) * 2014-12-01 2016-06-01 重庆安格龙翔医药科技有限公司 一种瑞舒伐他汀钙关键中间体的合成方法
CN105712939A (zh) * 2014-12-01 2016-06-29 重庆安格龙翔医药科技有限公司 一种合成瑞舒伐他汀钙关键中间体的方法
CN105622522B (zh) * 2014-12-01 2018-01-16 重庆安格龙翔医药科技有限公司 一种瑞舒伐他汀钙关键中间体的合成方法
CN105622521B (zh) * 2014-12-01 2018-01-16 重庆安格龙翔医药科技有限公司 一种瑞舒伐他汀钙关键中间体的制备方法
CN105712939B (zh) * 2014-12-01 2018-01-23 重庆安格龙翔医药科技有限公司 一种合成瑞舒伐他汀钙关键中间体的方法

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