WO2011083495A2 - Process for the preparation of dihydroxy protected derivatives and novel intermediate compounds - Google Patents

Process for the preparation of dihydroxy protected derivatives and novel intermediate compounds Download PDF

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WO2011083495A2
WO2011083495A2 PCT/IN2011/000011 IN2011000011W WO2011083495A2 WO 2011083495 A2 WO2011083495 A2 WO 2011083495A2 IN 2011000011 W IN2011000011 W IN 2011000011W WO 2011083495 A2 WO2011083495 A2 WO 2011083495A2
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formula
compound
methyl
pyrimidin
fluorophenyl
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PCT/IN2011/000011
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WO2011083495A8 (en
WO2011083495A3 (en
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Manne Satyanarayana Reddy
Srinivasan Thirumalai Rajan
Maramreddy Sahadeva Reddy
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Msn Laboratories Limited
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Publication of WO2011083495A3 publication Critical patent/WO2011083495A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D239/34—One oxygen 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to an improved process for the preparation of dihydroxy protected derivatives represented by structural formula- 1.
  • Dihydroxy protected compounds of general formula- 1 are important intermediates in the preparation of HMG-CoA reductase inhibitors, used to treat high cholesterol and related conditions, and to prevent cardiovascular disease.
  • the present invention relates to novel pyrimidine derivatives, its preparation and their use in the preparation of HMG-CoA reductase inhibitors.
  • the disclosed process involves the condensation of diphenyl [4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methyl sulfonyl) amino]pyrimidin-5-ylmethyl]phosphine with tert-butyl 2-[(4R,6S)-6- formyl-2,2-dimethyl-l,3-dioxan-4-yl]acetate in presence of sodiumbis(trimethylsilyl)amide to provide tert-butyl (E)-(6- ⁇ 2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl) amino]pyrimidin-5-yl ⁇ (4R,6S)-2,2-dimethyl[l,3]dioxan-4-yl)acetate.
  • the condensed protected compound is deprotected with acid and hydrolyzed with base followed by treatment with calcium ion source to provide the bis[(E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5-dihydroxyhept-6-enoic acid] calcium salt.
  • Pyrimidine derivatives are important intermediates in the preparation of HMG-CoA reductase inhibitors like bis[(E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5-dihydroxyhept-6-enoic acid] calcium salt.
  • EP 521471 disclosed the usage of pyrimidine derivative such as N-(4-(4-fluorophenyl)-5-(substituted)-6- isopropyl pyrimidin-2-yl)-N-methyl methane sulfonamide (where in substituents is either an acid, ester group, hydroxy methyl or aldehyde group) as an intermediate in the preparation of bis[(E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5- yl](3R,5S)3,5- dihydroxyhept-6-enoic acid] calcium salt.
  • pyrimidine derivative such as N-(4-(4-fluorophenyl)-5-(substituted)-6- isopropyl pyrimidin-2-yl)-N-methyl methane sulfonamide (where in substituents is either an acid, ester group,
  • the bis[(E)-7-[4( 4-fluorophenyl)-6- isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5- dihydroxyhept-6- enoic acid] calcium salt is one of the important drugs available in the market used to treat high cholesterol and related conditions, and to prevent cardiovascular disease.
  • the main objective of the present invention is to provide an improved process for the preparation of compound of formula- 1 which restricts the formation of unwanted isomer which is obtained in the prior art.
  • the present invention also provides pyrimidine derivative compounds, process for their preparation with high yields and purity and their use in the preparation of HMG-CoA reductase inhibitors such as bis[(E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5- dihydroxyhept-6-enoic acid] calcium salt.
  • HMG-CoA reductase inhibitors such as bis[(E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5- dihydroxyhept-6-enoic acid] calcium salt.
  • the first aspect of the present invention is to provide an improved process for the preparation of dihydroxy protected derivative compounds of general formula- 1 with low levels of unwanted Z-isomer, which comprises of reacting the N-(4-(4-fluorophenyl)-6-isopropyl- 5((1 -methyl- 1 H-benzo[d]imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methyl methane sulfonamide compound of formula-2 with aldehyde compound of formula-3 in presence of suitable alkali metal alkoxide base in a suitable solvent to provide the compounds of general formula- 1.
  • the second aspect of the present invention is to provide one-pot process for the preparation of N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-lH-benzo[d]imidazol-2-yl sulfonyl)methyl)pyrimidin-2-yl)-N-methyl methane sulfonamide compound of formula-2, which comprises of oxidizing the sulfide compound of fomula-6 with a suitable oxidizing agent in presence of a catalyst in a suitable solvent to provide the sulfone compound of formula-7, which on in-situ reaction with a suitable methylating agent provides the compound of formula-2.
  • the third aspect of the present invention is to provide one-pot process for the preparation of compound of formula-6, which comprises of reacting N-(4-(4-fluorophenyl)-5- (hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-4 with suitable brominating agent in a suitable solvent to provide the N-(5- (bromomethyl)-4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropyl pyrimidin-2-yl)-N- methylmethane sulfonamide compound of formula-5a, which on in-situ reaction with 1H- benzo[dJimidazole-2-thiol in presence of a base and a solvent to provide the compound of formula-6.
  • the fourth aspect of the present invention provides a process for the preparation of N- (5-(halo methyl)-4-(4-fluorophneyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compounds of general formula-5, comprises of reacting N-(4-(4-flurophenyl)-5- (hydroxymethyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-4 with a suitable halogenating agent in a suitable solvent to provide the N-(5-(halo methyl)-4-(4-fluorophneyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compounds of general formula-5.
  • the fifth aspect of the present invention is to provide novel pyrimidin-5-carboxamide compounds of general formula-8 represented by the following structure
  • Rj and R 2 independently selected from hydrogen, straight or branched chain alkyl group, cycloalkyl or cycloalkyl with one heteroatom; aralkyl group, aryl group and also includes the above groups with one or more substituents selected from halogen, nitro and alkyl group having 1 to 4 carbon atoms.
  • novel compounds of general formula-8 of the present invention are useful intermediates in the preparation of compound of formula-4 as well as HMG-CoA reductase inhibitors such as [(E)-7-[4(4-fluorophenyl)-6-isopropyl-2[methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5- dihydroxyhept-6-enoic acid] and its pharmaceutically acceptable salts.
  • HMG-CoA reductase inhibitors such as [(E)-7-[4(4-fluorophenyl)-6-isopropyl-2[methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5- dihydroxyhept-6-enoic acid] and its pharmaceutically acceptable salts.
  • the sixth aspect of the present invention is to provide 2-oxo-pyrimidin-5-carboxamide compounds of general formula- 10 represented by the following structure
  • the present invention further relates to a process for the preparation of 2-oxo- pyrimidin-5-carboxamide compounds of general formula- 10, comprises of reacting isobutyryl acetamide derivative compounds of general formula-9
  • the seventh aspect of the present invention is to provide the 2-hydroxy-pyrimidin-5- carboxamide compounds of general formula-11 represented by the following structure
  • the invention further relates to a process for the preparation of 2-hydroxy pyrimidin-5- carboxamide compounds of general formula-11, comprises of oxidizing the 2-oxo-pyrimidin-5- carboxamide compounds of general formula- 10 with a suitable oxidizing agent in presence or absence of a solvent.
  • the eighth aspect of the present invention is to provide the 2-sulfonyl pyrimidin-5- carboxamide compounds of general formula- 12 represented by the following structure
  • R & R 2 are as defined above; and R is selected from straight or branched chain alkyl group, cycloalkyl or cycloalkyl with one heteroatom; aralkyl group, aryl group and also includes the above groups with one or more substituents selected from halogen, nitro and alkyl group having 1 to 4 carbon atoms.
  • the invention further relates to the preparation of 2-sulfonyl pyrimidin-5 -carboxamide compounds of general formula- 12, which comprise of reacting the 2-hydroxy pyrimidin-5- carboxamide compounds of general formula- 11 with an organic sulfonyl halide having the followin formula
  • R is defined as above;
  • the ninth aspect of the present invention is to provide a process for the preparation of pyrimidin-5 -carboxamide compounds of general formula-8, which comprise of reacting the 2- sulfonyl pyrimidin-5-carboxamide compounds of general formula- 12 with N-methyl methane sulfonamide in presence of a suitable base and a solvent.
  • the tenth aspect of the present invention is to provide a process for the preparation of isobutyryl acetamide compounds of general formula-9, comprise of reacting the alkyl-4- methyl-3-oxopentanoate compounds of general formula- 13 with amide compounds of general formula- 14 (NRiR 2 ) in a suitable solvent and with out usage of a base.
  • R ⁇ and R 2 refers to independently hydrogen, straight or branched chain alkyl group, cycloalkyl or cycloalkyl with one heteroatom; aralkyl group, aryl group and also includes the above groups with one or more substituents selected from halogen, nitro and alkyl group having 1 to 4 carbon atoms.
  • R refers to straight or branched chain alkyl group, cycloalkyl or cycloalkyl with one heteroatom; aralkyl group, aryl group and also includes the above groups with one or more substituents selected from halogen, nitro and alkyl group having 1 to 4 carbon atoms.
  • R' refers to Ci -10 straight or branched chain alkyl groups.
  • organic acid refers to hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid or mixtures thereof.
  • organic acid refers to methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, p-bromobenzene sulfonic acid, acetic acid, propionic acid, butyric acid, benzoic acid or mixtures thereof.
  • metal salt refers to copper(I)chloride, copper (Il)chloride, copper(II)acetate, iron(II)chloride, aluminium chloride, nickel (Il)bromide, tin(IV)chloride, magnesium bromide or combination thereof.
  • organic base refers to alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal oxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof.
  • suitable solvent refers to the solvents selected from “polar solvents” such as water; "polar aprotic solvents” such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; nitrile solvents such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile and the like; “alcohol solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like; “hydrocarbon solvents” such as benzene, toluene, xylene, heptane, hexane, cyclohexane and the like; “chloro solvents” such as methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene and the like; “ketone solvents” such as acetone,
  • R is selected from alkyl or aryl
  • R is selected from alkyl or aryl
  • suitable alkali metal alkoxide base selected from sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide, or mixtures thereof in a suitable solvent selected from polar aprotic solvents, alcohols, hydrocarbons, polar solvent or mixtures thereof to provide the compound of formula- 1 with low level of Z isomer.
  • the compounds of general formula- 1 prepared as per the present invention having the E/Z isomer content in the ratio of 97:3, preferably 99:1; more preferably 99.9:0.1.
  • the present invention provides a process for the preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethane sulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l ,3-dioxan-4-yl)acetate compound of formula- la,
  • the present invention provides the use of alkali metal alkoxide bases to improve the E isomer content in the condensation reaction between the N-(4-(4-fluorophenyl)-6- isopropyl-5((l-methyl-lH-benzo[d]imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-met ⁇ methane sulfonamide compound of formula-2 and aldehyde compounds of general formula-3.
  • the second aspect of the present invention provides a one pot process for the preparation of N-(4-(4-fluorophenyl)-6-isopropyl-5((l -methyl- lH-benzo[d]imidazol-2-yl sulfonyl)methyl)pyrimidin-2-yl)-N-methyl methane sulfonamide compound of formula-2,
  • a suitable oxidizing agent like meta chloro perbenzoicacid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydro peroxide, in the presence of an appropriate catalyst like ammonium hepta molybdate tetra hydrate in a suitable solvent selected from alcoholic solvents, chloro solvents or mixture thereof, to provide the sulfone compound of formula-7,
  • the third aspect of the present invention provides a one-pot process for the preparation of N-(5-((lH-benzo[d]imidazol-2-ylthio)methyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2- yl)-N-methylmethanesulfonamide compound of formula-6,
  • one pot process for the preparation of compound of formula-6 which comprises of reacting N-(4-(4-flurophenyl)-5-(hydroxymethyl)-6- isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-4 with phosphorus tribromide in methylene chloride to provide the N-(5-(bromomethyl)-4-(4- fluorophneyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-5, which on in-situ reaction with lH-benzo[d]imidazole-2-thiol in presence of sodium hydroxide in acetone to provide the compound of formula-6.
  • the fourth aspect of the present invention provides a process for the preparation of N- (5-(halo methyl)-4-(4-fluorophneyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compounds of general formula-5, comprises of reacting N-(4-(4-flurophenyl)-5- (hydroxymethyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-4
  • the suitable halogenating agent is selected from aqueous hydro bromic acid, thionyl chloride and aqueous hydro chloric acid;
  • the suitable solvent is selected from hydrocarbon solvents, alcohol solvents, ester solvents, ketone solvents.
  • the fifth aspect of the present invention provides novel pyrimidin-5-carboxamide compounds of general formula-8 represented by the following structure,
  • R ⁇ and R 2 are independently selected from hydrogen, straight or branched chain alkyl group, cycloalkyl or cycloalkyl with one heteroatom; aralkyl group, aryl group and also includes the above groups with one or more substituents selected from halogen, nitro and alkyl group having 1 to 4 carbon atoms.
  • novel pyrimidin-5 -carboxamide compounds of general formula-8 of the present invention were useful as intermediate in the preparation of HMG-CoA reductase inhibitors such as (E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5- yl](3R,5S)3,5-dihydroxyhept-6-enoic acid and its pharmaceutically acceptable salts, or in the preparation of pyrimidine intermediates like N-(4-(4-fluorophenyl)-5-(substituted)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide intermediate used in the preparation of (E)-7- [4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5- dihydroxyhept-6-en
  • the sixth aspect of the present invention provides the 2-oxo-pyrimidin-5-carboxamide compounds of general formula- 10 represented by the following structure
  • the invention further provides a process for the preparation of 2-oxo-pyrimidin-5- carboxamide compounds of general formula- 10, which comprise of reacting an isobutyryl acetamide derivative compounds of general formula-9
  • the acid used is either organic or inorganic acid and the reaction can be performed in the presence or absence of a solvent.
  • the solvents which can be used is selected from alcohols, nitriles, chloro solvents, hydrocarbon and ethers or mixtures thereof, preferably the reaction is carried out in presence alcohol solvent.
  • the reaction can be carried out at a suitable temperature ranges from -5 to 200°C, preferably 25 to 120°C.
  • the 2-oxo-pyrimidin-5- carboxamide compounds of general formula- 10 obtained can be isolated and can be purified by the conventional procedures such as distillation, crystallization and recrystallization.
  • the seventh aspect of the present invention provides the 2-hydroxy-pyrimidin-5- carboxamide compounds of general formula- 11 represented by the following structure
  • the invention further provides a process for the preparation of 2-hydroxy-pyrimidin-5 carboxamide compounds of general formula-11, which comprise of oxidizing the 2-oxo pyrimidin-5-carboxamide compounds of general formula- 10
  • Formula- 10 in presence of a suitable oxidizing agent like nitric acid in presence or absence of a solvent at suitable temperature ranges from 0 to 80°C.
  • the nitric acid can be employed in an amount of 1 to 25 moles, preferably 2 to 15 moles per one mole of compounds of general formula- 10; preferably the reaction is carried out in absence of solvent.
  • the reaction initiator such as sodium nitrite may also be utilized to accelerate the oxidation rate.
  • the resulting product can be isolated and purified by the conventional methods known in the art.
  • the eighth aspect of the present invention provides the 2-sulfonyl pyrimidin-5- carboxamide compounds of general formula- 12 represented by the following structure
  • R ⁇ & R 2 are as defined above; and R' is selected from straight or branched chain alkyl group, cycloalkyl or cycloalkyl with one heteroatom; aralkyl group, aryl group and also includes the above groups with one or more substituents selected from halogen, nitro and alkyl group having 1 to 4 carbon atoms.
  • the present invention further provides a preparation of 2-sulfonyl pyrimidin-5- carboxamide compounds of general formula- 12, which comprise of reacting the compounds of general formula- 11
  • R' is defined above;
  • reaction mixture in presence of a suitable base selected from inorganic or organic base, preferably inorganic base and a suitable solvent selected esters, alcohols, nitriles, chloro solvents ⁇ hydrocarbon and ethers or mixtures thereof, preferably ester solvent provides the compounds of general formula- 12.
  • a suitable base selected from inorganic or organic base, preferably inorganic base and a suitable solvent selected esters, alcohols, nitriles, chloro solvents ⁇ hydrocarbon and ethers or mixtures thereof, preferably ester solvent provides the compounds of general formula- 12.
  • a suitable base selected from inorganic or organic base, preferably inorganic base and a suitable solvent selected esters, alcohols, nitriles, chloro solvents ⁇ hydrocarbon and ethers or mixtures thereof, preferably ester solvent provides the compounds of general formula- 12.
  • the reaction mixture was carried out at a temperature in the range of -25 to 200°C.
  • the 2-sulfonyl pyrimidin-5-carboxamide compounds of general formula- 12 can be isolated as solid and purified using conventional methods known in the art.
  • the 2-hydroxy- pyrimidin-5-carboxamide compounds of general formula- 11 may also convert directly into to pyrimidin-5-carboxamide compounds of general formula-8 with out isolation or purification of 2-sulfonyl pyrimidin-5-carboxamide compounds of general formula- 12.
  • the organic sulfonyl halides used in the present invention may be selected from methanesulfonyl fluoride, methanesulfonyl chloride, ethanesulfonyl chloride, 1- propanesulfonyl chloride, 2-propanesulfonyl chloride, trifluoro methanesulfonyl fluoride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, 1 -naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, p-toluenesulfonyl fluoride, p-toluenesulfonyl chloride, 2,4, 6- trimethylbenzenesulfonyl chloride, 2,4, 6-triisopropylbenzenesulfonyl chloride, p- methoxybenzenesulfonyl chloride, p- me
  • the organic sulfonyl anhydrides used in the present invention may be selected from methanesulfonic anhydride, trifluoromethanesulfonic anhydride, benzenesulfonic anhydride, and p-toluenesulfonic anhydride.
  • the ninth aspect of the present invention provides a process for the preparation of pyrimidin-5-carboxamide compounds of general formula-8,
  • N-methyl methane sulfonamide in presence of a suitable base selected from organic or inorganic base; preferably inorganic base and in a suitable solvent selected from ester solvents, alcohol solvents, nitrile solvents, chloro solvents, hydrocarbon solvents and ether solvents or mixtures thereof, preferably hydrocarbon solvent, to provide the pyrimidin-5-carboxamide compounds of general formula-8.
  • a suitable base selected from organic or inorganic base; preferably inorganic base and in a suitable solvent selected from ester solvents, alcohol solvents, nitrile solvents, chloro solvents, hydrocarbon solvents and ether solvents or mixtures thereof, preferably hydrocarbon solvent, to provide the pyrimidin-5-carboxamide compounds of general formula-8.
  • the tenth aspect of the present invention provides a process for the preparation of isobutyryl acetamide derivative compounds of general formula-9,
  • & R 2 are as defined above which comprise of reacting the alkyl-4-methyl-3-oxopentanoate compounds of general formula- 13
  • R" is selected from alkyl group defined above,
  • R ⁇ & R 2 are as defined above;
  • the present invention avoids the usage of chromatographic techniques, and also conducts the reaction in absence of solvent and DMAR
  • HMG-CoA reductase inhibitors such as (E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S) 3,5-dihydroxyhept-6-enoic acid and its pharmaceutically acceptable salts or in the preparation of other pyrimidine derivatives such as N-(4-(4-fluorophenyl)-5-(substituted)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide used in the preparation of bis[(E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl
  • novel pyrimidine derivative compounds such as pyrimidin-5-carboxamide compounds of general formula-8, 2-oxo-pyrimidin-5-carboxamide compounds of general W formula- 10, 2-hydroxy-pyrimidin-5-carboxamide compounds of general formula- 11 and 2- sulfonyl pyrimidin-5-carboxamide compounds of general formula- 12 used as an important intermediates in the preparation of other pyrimidine derivatives and the same also be converted into (E)-7-[4(4-fluorophenyl)-6-isopropyl-2[methyl (methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)3,5-dihydroxyhept-6-enoic acid or its pharmaceutically acceptable salt.
  • novel pyrimidine derivative compounds of formula-8, 10, 11 & 12 of the present invention shown by the following schematic representation
  • R ⁇ & R 2 is ethyl group
  • R" is methyl group
  • R is p-toluene
  • the present invention provides the following compound of formula-8a
  • the present invention provides a process for the preparation of N,N-diethyl-4- (4-fluorophenyl)-6-isopropyl-2-(N-methyl methane sulfonamido) pyrimidine-5-carboxamide compound of formula-8a, which comprises of the following steps;
  • alkali metal alkoxide base refers to the bases selected from sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide and the like or mixtures thereof.
  • the present invention is schematically represented by the following scheme.
  • R is selected from alkyl or aryl Related substances and E and Z isomer content of compound of formula- 1 and la was analyzed by High Performance Liquid Chromatography using the following conditions:
  • a liquid chromatography is equipped with variable wavelength integrator and detector; Column: Lichrosphere; 250X4.0mm, 5 ⁇ or equivalent; Flow rate: 1.0 ml/min; Wavelength: 242 nm; Temperature: ambient; Load: 20 ⁇ and using mixture of acetonitrile and water in ratio of 80:20 as a diluent. Mixture of aqueous dihydrogen ortho phosphate buffer and acetonitrile as a mobile phase.
  • Example-1 Preparation of tert-butyl-2-(4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl- 2-(N-methylmethane sulfonamide)pyrimidin-5-yI)vinyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetate compound of formula-la:
  • Aqueous hydro bromic acid (170 ml) was added to a mixture of N-(4-(4-fluorophenyl)-5- (hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide (200 grams) in toluene (1000 ml) and tertiary butyl ammonium bromide (16 grams). Heated the reaction mixture to 90-95 °C and stirred for 90 minutes at same temperature. Cooled the reaction mixture to 40-45°C and separated the both aqueous and organic layers. Washed the organic layer with 10% aqueous sodium bicarbonate solution.
  • Phosphorous tribromide 14 ml was added to a solution of N-(4-(4-fluorophenyl)-5- (hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide (100 grams) in methylene chloride (500 ml) and stirred at 25-30°C. After completion of the reaction, quenched it with sodium bicarbonate solution at 10-15°C and the organic and aqueous layers were separated. The organic layer was washed with sodium thiosulphate solution followed by water. The solvent from the organic layer was distilled off completely under reduced pressure at below 40°C.
  • Aqueous hydro chloric acid 110 ml was added to a mixture of N-(4-(4-fluorophenyl)-5- (hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide (200 grams) in toluene (1000 ml) and tertiary butyl ammonium bromide (16 grams). Heated the reaction mixture to 90-95°C and stirred for 90 minutes at same temperature. Cooled the reaction mixture to 40-45 °C and separated the both aqueous and organic layers. Washed the organic layer with 10% aqueous sodium bicarbonate solution.
  • Example-6 Preparation of N-(5-(bromomethyl)-4-(4-fluorophneyl)-6-isopropyl pyrimidin -2-yl) -N-m ethyl methane sulfonamide compound of formula-5a:
  • Aqueous hydro bromic acid 85 ml was added to a mixture of N-(4-(4-fluorophenyl)-5- (hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide (100 grams) in toluene (500 ml) and tertiary butyl ammonium bromide (8 grams). Heated the reaction mixture to 90-95°C and stirred for 90 minutes at same temperature. Cooled the reaction mixture to 40- 45°C and separated the both aqueous and organic layers. Washed the organic layer with 10% aqueous sodium bicarbonate. The obtained organic layer was further utilized in the next stage with out isolated as a solid.
  • N,N-diethyl-4-(4-fluorophenyl)-6-isopropyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxamide (40 grams) was added to a pre cooled mixture of nitric acid (80 grams) and sodium nitrite (0.33 grams) at 5 to 10°C. The reaction temperature was raised to 25-35°C and stirred up to the completion of the reaction. The reaction mixture was cooled to 10°C and water(266 ml), followed by acetic acid (20 ml) was added to it. The reaction mixture was basified with aqueous sodium hydroxide and stirred for 3 hours. The solid formed was filtered, washed with water and dried to get the title compound.
  • Paratoluene sulfonyl chloride (58.5 grams) was added to a mixture of N,N-diethyl-4-(4- fluorophenyl)-2-hydroxy-6-isopropyl pyrimidine-5-carboxamide (85 grams), potassium carbonate (53.4 grams) in ethyl acetate (425 ml) at 25-35°C, heated to reflux and stirred up to completion of the reaction.
  • the reaction mixture cooled and quenched with water. Aqueous and organic layers were separated and aqueous layer extracted with ethyl acetate. The total organic layer was dried with sodium sulphate and distilled off the solvent completely under reduced pressure. The obtained residue was crystallized using petroleum ether.

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Abstract

The present invention relates to an improved process for the preparation of dihydroxy protected derivatives, which are important intermediates in the preparation of HMG-CoA reductase inhibitors.

Description

Process for the preparation of dihydroxy protected derivatives and novel intermediate compounds
Related Application:
This application claims the benefit of priority of our Indian patent application No:
41/CHE/2010 filed on 07/01/2010 and 471/CHE/2010 filed on 24/02/2010 which are incorporated herein by reference.
Field of the Invention:
The present invention relates to an improved process for the preparation of dihydroxy protected derivatives represented by structural formula- 1.
Dihydroxy protected compounds of general formula- 1 are important intermediates in the preparation of HMG-CoA reductase inhibitors, used to treat high cholesterol and related conditions, and to prevent cardiovascular disease.
The present invention relates to novel pyrimidine derivatives, its preparation and their use in the preparation of HMG-CoA reductase inhibitors.
Background of the Invention:
The compound of formula- 1 (wherein R is (CH3)3) and its use in the preparation of Bis[
(E)-7-[4(4-fluorophenyl)-6-isopropyl-2[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) 3,5 -dihydroxyhept-6-enoic acid]calcium salt was first disclosed in US 6784171. The disclosed process involves the condensation of diphenyl [4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methyl sulfonyl) amino]pyrimidin-5-ylmethyl]phosphine with tert-butyl 2-[(4R,6S)-6- formyl-2,2-dimethyl-l,3-dioxan-4-yl]acetate in presence of sodiumbis(trimethylsilyl)amide to provide tert-butyl (E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl) amino]pyrimidin-5-yl}(4R,6S)-2,2-dimethyl[l,3]dioxan-4-yl)acetate. The condensed protected compound is deprotected with acid and hydrolyzed with base followed by treatment with calcium ion source to provide the bis[(E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5-dihydroxyhept-6-enoic acid] calcium salt.
l International publication WO 2005/054207 disclosed a process for the preparation of compound of formula- 1 (wherein R is (CH3)3)> which involves the condensation of triphenyl[4- (4-flurophenyl)-6-isopropyl-2- [methyl(methylsulfony 1) amino] pyrimidin- 5 -ylmethyl] phosphonium bromide with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dixan-4- yl}acetate in presence of potassium carbonate in dimethyl sulfoxide to give tert-butyl(E)-(6-{2- [4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methyl sulfonyl)amino] pyrimidin-5-yl}(4R,6S)- 2,2-dimethyl[l,3]dioxin-4-yl) acetate which is further converted into free acid then to calcium salt by contacting with calcium source. In general, the disclosed process for the preparation of (E)-7-[4( 4-fluorophenyl)-6- isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5-dihydroxyhept-6- enoic acid and its pharmaceutically acceptable salts proceeds through the compound of formula- 1 and involves the usage of different bases like alkali metal hydroxide, alkali metal carbonates and amides. The above process suffers with the disadvantage of formation of high level unwanted Z isomer along with required E isomer. Hence there is a need in the art for an improved process which controls the formation of unwanted Z isomer.
When the present inventors were working on to solve this problem by varying the process parameters and regents it was surprisingly found that the usage of alkali metal alkoxide for the preparation of condensed compound of formula- 1 provided the product with less amount of unwanted Z isomer. Hence when the same has been used to produce the (E)-7-[4( 4- fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5- dihydroxyhept-6-enoic acid it led to formation of highly pure (E)-7-[4( 4-fluorophenyl)-6- isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5-dihydroxyhept-6- enoic acid and its pharmaceutically acceptable salts.
Pyrimidine derivatives are important intermediates in the preparation of HMG-CoA reductase inhibitors like bis[(E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5-dihydroxyhept-6-enoic acid] calcium salt. EP 521471 disclosed the usage of pyrimidine derivative such as N-(4-(4-fluorophenyl)-5-(substituted)-6- isopropyl pyrimidin-2-yl)-N-methyl methane sulfonamide (where in substituents is either an acid, ester group, hydroxy methyl or aldehyde group) as an intermediate in the preparation of bis[(E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5- yl](3R,5S)3,5- dihydroxyhept-6-enoic acid] calcium salt. The bis[(E)-7-[4( 4-fluorophenyl)-6- isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5- dihydroxyhept-6- enoic acid] calcium salt is one of the important drugs available in the market used to treat high cholesterol and related conditions, and to prevent cardiovascular disease.
The process for the preparation of ethyl 4-(4-fluorophenyl)-6-isopropyl-2- methylsulfonyl pyrimidine-5-carboxylate is also disclosed in patents like EP 521471 and US 6579984. It seems to be that the process disclosed for the said intermediate is not suitable for the commercial scale up since over all yields are very low and it involves the usage of toxic raw material such as cyanogen chloride.
As bis[(E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5-dihydroxyhept-6-enoic acid] calcium salt is one of the HMG-CoA reductase inhibitors which are available in the market for cholesterol reduction. It is advantageous to have alternate novel pyrimidine derivative compounds which can be utilized in the preparation of N-(4-(4-fluorophenyl)-5-(substituted)-6-isopropyl pyrimidin-2-yl)-N- methylmethanesulfonamide and bis[(E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5- dihydroxyhept-6-enoic acid] calcium salt. Hence the present invention provides novel pyrimidine derivative compounds as well as process for their preparation with high yields and purity which are useful in the preparation of HMG-CoA reductase inhibitors.
The main objective of the present invention is to provide an improved process for the preparation of compound of formula- 1 which restricts the formation of unwanted isomer which is obtained in the prior art.
The present invention also provides pyrimidine derivative compounds, process for their preparation with high yields and purity and their use in the preparation of HMG-CoA reductase inhibitors such as bis[(E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5- dihydroxyhept-6-enoic acid] calcium salt. Brief description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of dihydroxy protected derivative compounds of general formula- 1 with low levels of unwanted Z-isomer, which comprises of reacting the N-(4-(4-fluorophenyl)-6-isopropyl- 5((1 -methyl- 1 H-benzo[d]imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methyl methane sulfonamide compound of formula-2 with aldehyde compound of formula-3 in presence of suitable alkali metal alkoxide base in a suitable solvent to provide the compounds of general formula- 1. The second aspect of the present invention is to provide one-pot process for the preparation of N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-lH-benzo[d]imidazol-2-yl sulfonyl)methyl)pyrimidin-2-yl)-N-methyl methane sulfonamide compound of formula-2, which comprises of oxidizing the sulfide compound of fomula-6 with a suitable oxidizing agent in presence of a catalyst in a suitable solvent to provide the sulfone compound of formula-7, which on in-situ reaction with a suitable methylating agent provides the compound of formula-2.
The third aspect of the present invention is to provide one-pot process for the preparation of compound of formula-6, which comprises of reacting N-(4-(4-fluorophenyl)-5- (hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-4 with suitable brominating agent in a suitable solvent to provide the N-(5- (bromomethyl)-4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropyl pyrimidin-2-yl)-N- methylmethane sulfonamide compound of formula-5a, which on in-situ reaction with 1H- benzo[dJimidazole-2-thiol in presence of a base and a solvent to provide the compound of formula-6.
The fourth aspect of the present invention provides a process for the preparation of N- (5-(halo methyl)-4-(4-fluorophneyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compounds of general formula-5, comprises of reacting N-(4-(4-flurophenyl)-5- (hydroxymethyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-4 with a suitable halogenating agent in a suitable solvent to provide the N-(5-(halo methyl)-4-(4-fluorophneyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compounds of general formula-5.
The fifth aspect of the present invention is to provide novel pyrimidin-5-carboxamide compounds of general formula-8 represented by the following structure
Figure imgf000006_0001
Formula-8
where in Rj and R2 independently selected from hydrogen, straight or branched chain alkyl group, cycloalkyl or cycloalkyl with one heteroatom; aralkyl group, aryl group and also includes the above groups with one or more substituents selected from halogen, nitro and alkyl group having 1 to 4 carbon atoms.
The novel compounds of general formula-8 of the present invention are useful intermediates in the preparation of compound of formula-4 as well as HMG-CoA reductase inhibitors such as [(E)-7-[4(4-fluorophenyl)-6-isopropyl-2[methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5- dihydroxyhept-6-enoic acid] and its pharmaceutically acceptable salts.
The sixth aspect of the present invention is to provide 2-oxo-pyrimidin-5-carboxamide compounds of general formula- 10 represented by the following structure
Figure imgf000006_0002
Formula- 10
where in R\ and R2 are as defined above. The present invention further relates to a process for the preparation of 2-oxo- pyrimidin-5-carboxamide compounds of general formula- 10, comprises of reacting isobutyryl acetamide derivative compounds of general formula-9
Figure imgf000007_0001
Formula-9
where in Rj and R2 are as defined above,
with 4-fluorobenzaldehyde and urea in the presence of a suitable acid and metal salt in presence or absence of a solvent.
The seventh aspect of the present invention is to provide the 2-hydroxy-pyrimidin-5- carboxamide compounds of general formula-11 represented by the following structure
Figure imgf000007_0002
Formula- 1
where in Ri and R2 are as defined above.
The invention further relates to a process for the preparation of 2-hydroxy pyrimidin-5- carboxamide compounds of general formula-11, comprises of oxidizing the 2-oxo-pyrimidin-5- carboxamide compounds of general formula- 10 with a suitable oxidizing agent in presence or absence of a solvent.
The eighth aspect of the present invention is to provide the 2-sulfonyl pyrimidin-5- carboxamide compounds of general formula- 12 represented by the following structure
Figure imgf000008_0001
Formula- 12
wherein R & R2 are as defined above; and R is selected from straight or branched chain alkyl group, cycloalkyl or cycloalkyl with one heteroatom; aralkyl group, aryl group and also includes the above groups with one or more substituents selected from halogen, nitro and alkyl group having 1 to 4 carbon atoms.
The invention further relates to the preparation of 2-sulfonyl pyrimidin-5 -carboxamide compounds of general formula- 12, which comprise of reacting the 2-hydroxy pyrimidin-5- carboxamide compounds of general formula- 11 with an organic sulfonyl halide having the followin formula
Figure imgf000008_0002
(RS02)20
wherein R is defined as above;
in presence of a suitable base and a solvent.
The ninth aspect of the present invention is to provide a process for the preparation of pyrimidin-5 -carboxamide compounds of general formula-8, which comprise of reacting the 2- sulfonyl pyrimidin-5-carboxamide compounds of general formula- 12 with N-methyl methane sulfonamide in presence of a suitable base and a solvent.
The tenth aspect of the present invention is to provide a process for the preparation of isobutyryl acetamide compounds of general formula-9, comprise of reacting the alkyl-4- methyl-3-oxopentanoate compounds of general formula- 13 with amide compounds of general formula- 14 (NRiR2) in a suitable solvent and with out usage of a base. Detailed description of the Invention:
As used herein the term R\ and R2 refers to independently hydrogen, straight or branched chain alkyl group, cycloalkyl or cycloalkyl with one heteroatom; aralkyl group, aryl group and also includes the above groups with one or more substituents selected from halogen, nitro and alkyl group having 1 to 4 carbon atoms.
As used herein the term R refers to straight or branched chain alkyl group, cycloalkyl or cycloalkyl with one heteroatom; aralkyl group, aryl group and also includes the above groups with one or more substituents selected from halogen, nitro and alkyl group having 1 to 4 carbon atoms.
As used herein the term R' refers to Ci-10 straight or branched chain alkyl groups.
As used herein the term "inorganic acid" refers to hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid or mixtures thereof.
As used herein the term "organic acid" refers to methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, p-bromobenzene sulfonic acid, acetic acid, propionic acid, butyric acid, benzoic acid or mixtures thereof.
As used herein the term "metal salt" refers to copper(I)chloride, copper (Il)chloride, copper(II)acetate, iron(II)chloride, aluminium chloride, nickel (Il)bromide, tin(IV)chloride, magnesium bromide or combination thereof. As used herein the term "inorganic base" refers to alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal oxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof.
As used herein the presented invention, the term "suitable solvent" refers to the solvents selected from "polar solvents" such as water; "polar aprotic solvents" such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; nitrile solvents such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like; "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane, cyclohexane and the like; "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene and the like; "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like; "ethers solvents" such as diethyl ether, diisopropylether, tetrahydrofuran and dimethoxyethane; "esters solvents" such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; and their mixtures thereof. Accordingly the first aspect of the invention provides a process for the preparation of dihydroxy protected derivative compounds of general formula- 1
Figure imgf000010_0001
Formula- 1
wherein R is selected from alkyl or aryl;
with low level of unwanted Z-isomer, which comprises of reacting the N-(4-(4-fluorophenyl)-
6-isopropyl-5((l-methyl-lH-benzo[d]imidazol-2-ylsulfonyl)i pyrimidin-2-yl)-N- methylmethane sulfonamide compound of formula-2
Figure imgf000010_0002
Formula-2
with aldehyde compounds of general formula-3
Figure imgf000011_0001
Formula-3
wherein R is selected from alkyl or aryl;
in presence of suitable alkali metal alkoxide base selected from sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide, or mixtures thereof in a suitable solvent selected from polar aprotic solvents, alcohols, hydrocarbons, polar solvent or mixtures thereof to provide the compound of formula- 1 with low level of Z isomer.
According to the present invention the alkoxide base used in the ratio of 0.8 to 2.3 moles with respect to N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-lH-benzo[d]imidazol-2- ylsulfonyl)methyl) pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-2 and the condensation reaction is carried out at -30°C to 70°C, preferably at -20 to 5°C.
Even though number of processes reported for the preparation of compounds of general formula- 1, the E/Z isomers ratio is not satisfactory. In general, the compounds of general formula- 1 prepared as per the prior art have the E and Z isomers ratio of 70:30. For example when compounds of general formula- 1 (wherein R is alkyl) prepared as per the process disclosed in WO 2005/054207 is having E/Z isomers in the ratio of 75:25. The compounds of general formula- 1 prepared as per the process disclosed in WO
2007/125547 via Julia olefination provides the formula- 1 with E/Z isomer content in the ratio of 95:5. Even though the process reduces the Z isomer content still the Z isomer content is high and more over the condensation reaction take place in presence of potassium carbonate at 70- 75 °C, led to the degradation of starting material and decrease the yields and purity. The same has been avoided by the present inventors in the preparation of compounds of general formula- 1, by replacing the potassium carbonate with alkali metal alkoxide and carrying out the reaction at low temperature, which avoids the degradation of starting material and provides the final compound with high purity and low Z isomer content. Hence the process provides the product with high purity in good yields. It was possible to bring down the Z isomer content to less than 0.1% by using alkali metal alkoxide bases in the reaction itself. The compounds of general formula- 1 prepared as per the present invention having the E/Z isomer content in the ratio of 97:3, preferably 99:1; more preferably 99.9:0.1. When the same compounds of general formula-1 used in the preparation of (E)-7-[4( 4-fluorophenyl)-6- isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5-dihydroxyhept-6- enoic acid or its pharmaceutically acceptable salts will leads to the (E)-7-[4(4-fluorophenyl)-6- isopropyl-2[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) 3,5 -dihydroxyhept-6-enoic acid or its salt with low levels of unwanted isomer i.e., E/Z isomer in the ratio of 99:1 and preferably 99.9:0.1. In a preferred embodiment, the present invention provides a process for the preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethane sulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l ,3-dioxan-4-yl)acetate compound of formula- la,
Figure imgf000012_0001
Formula- la
which comprise of reacting the compound of formula-2 with tert-butyl 2-[(4R,6S)-6-formyl- 2,2-dimethyl-l,3-dioxan-4-yl]ac
Figure imgf000012_0002
Formula-3a
in presence of sodium or potassium tertiary butoxide, more preferably sodium tertiary butoxide in a suitable polar aprotic solvent, more preferably tetrahydrofuran to provide the compound of formula- la.
Further the present invention provides the use of alkali metal alkoxide bases to improve the E isomer content in the condensation reaction between the N-(4-(4-fluorophenyl)-6- isopropyl-5((l-methyl-lH-benzo[d]imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-met^ methane sulfonamide compound of formula-2 and aldehyde compounds of general formula-3.
The second aspect of the present invention provides a one pot process for the preparation of N-(4-(4-fluorophenyl)-6-isopropyl-5((l -methyl- lH-benzo[d]imidazol-2-yl sulfonyl)methyl)pyrimidin-2-yl)-N-methyl methane sulfonamide compound of formula-2,
Figure imgf000013_0001
Formula-6
with a suitable oxidizing agent like meta chloro perbenzoicacid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydro peroxide, in the presence of an appropriate catalyst like ammonium hepta molybdate tetra hydrate in a suitable solvent selected from alcoholic solvents, chloro solvents or mixture thereof, to provide the sulfone compound of formula-7,
Figure imgf000013_0002
Formula-7 which on in-situ reaction with a suitable methylating agent like dimethyl sulfate in presence of a suitable base selected from alkali metal hydroxides in a suitable solvent selected from chloro solvents to provide the compound of formula-2. In a preferred embodiment, one pot process for the preparation of N-(4-(4- fluorophenyl)-6-isopropyl-5((l -methyl- 1 H-benzo[d]imidazol-2-ylsulfonyl)methyl) pyrimidin- 2-yl)-N-methyl methane sulfonamide compound of formula-2, which comprises of oxidizing the sulfide compound of fomula-6 with hydrogen peroxide in presence of ammonium hepta molybdate tetra hydrate in methylene chloride to provide the sulfone compound of formula-7, which on in-situ reaction with a dimethyl sulfate in presence of aqueous sodium hydroxide in methylene chloride to provide the compound of formula-2.
The third aspect of the present invention provides a one-pot process for the preparation of N-(5-((lH-benzo[d]imidazol-2-ylthio)methyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2- yl)-N-methylmethanesulfonamide compound of formula-6,
Figure imgf000014_0001
Formula-6
which comprises of reacting N-(4-(4-flurophenyl)-5-(hydroxymethyl)-6-isopropyl pyrimidin-2- yl)-N-methylmethane sulfonamide compound of formula-4
Figure imgf000014_0002
Formula-4 with suitable brominating agent selected from phosphorus tribromide in a suitable solvent selected from chloro solvent to provide the N-(5-(bromomethyl)-4-(4-fluorophneyl)-6- isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-5a,
Figure imgf000015_0001
Forrmila-5a
which on in-situ reaction with lH-benzo[d]imidazole-2-thiol in presence of a suitable base selected from alkali metal hydroxide like sodium hydroxide and a solvent selected from ketone, chloro solvent, polar aprotic solvent preferably keto solvent to provide the compound of formula-6.
In a preferred embodiment, one pot process for the preparation of compound of formula-6, which comprises of reacting N-(4-(4-flurophenyl)-5-(hydroxymethyl)-6- isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-4 with phosphorus tribromide in methylene chloride to provide the N-(5-(bromomethyl)-4-(4- fluorophneyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-5, which on in-situ reaction with lH-benzo[d]imidazole-2-thiol in presence of sodium hydroxide in acetone to provide the compound of formula-6.
The fourth aspect of the present invention provides a process for the preparation of N- (5-(halo methyl)-4-(4-fluorophneyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compounds of general formula-5, comprises of reacting N-(4-(4-flurophenyl)-5- (hydroxymethyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-4
Figure imgf000016_0001
Formula-4
with suitable halogenating agent in a suitable solvent to provide the N-(5-(halo methyl)-4-(4- fluorophneyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compounds of general formula-5,
Figure imgf000016_0002
Formula-5
wherein X is halogen; 5 a) X = Br and 5b) X = CI
The suitable halogenating agent is selected from aqueous hydro bromic acid, thionyl chloride and aqueous hydro chloric acid; the suitable solvent is selected from hydrocarbon solvents, alcohol solvents, ester solvents, ketone solvents.
The fifth aspect of the present invention provides novel pyrimidin-5-carboxamide compounds of general formula-8 represented by the following structure,
Figure imgf000016_0003
Formula-8 where in R\ and R2 are independently selected from hydrogen, straight or branched chain alkyl group, cycloalkyl or cycloalkyl with one heteroatom; aralkyl group, aryl group and also includes the above groups with one or more substituents selected from halogen, nitro and alkyl group having 1 to 4 carbon atoms.
The novel pyrimidin-5 -carboxamide compounds of general formula-8 of the present invention were useful as intermediate in the preparation of HMG-CoA reductase inhibitors such as (E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5- yl](3R,5S)3,5-dihydroxyhept-6-enoic acid and its pharmaceutically acceptable salts, or in the preparation of pyrimidine intermediates like N-(4-(4-fluorophenyl)-5-(substituted)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide intermediate used in the preparation of (E)-7- [4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5- dihydroxyhept-6-enoic acid (where in substituents is either an acid, ester group, hydroxy methyl or aldehyde group).
The sixth aspect of the present invention provides the 2-oxo-pyrimidin-5-carboxamide compounds of general formula- 10 represented by the following structure
Figure imgf000017_0001
Formula- 10
wherein R\ & R2 are as defined above,
The invention further provides a process for the preparation of 2-oxo-pyrimidin-5- carboxamide compounds of general formula- 10, which comprise of reacting an isobutyryl acetamide derivative compounds of general formula-9
Figure imgf000017_0002
Formula-9 wherein Rj & R2 are as defined above,
with 4-flurobenzaldehyde and urea in the presence of an acid and metal salt.
The acid used is either organic or inorganic acid and the reaction can be performed in the presence or absence of a solvent. The solvents which can be used is selected from alcohols, nitriles, chloro solvents, hydrocarbon and ethers or mixtures thereof, preferably the reaction is carried out in presence alcohol solvent. The reaction can be carried out at a suitable temperature ranges from -5 to 200°C, preferably 25 to 120°C. The 2-oxo-pyrimidin-5- carboxamide compounds of general formula- 10 obtained can be isolated and can be purified by the conventional procedures such as distillation, crystallization and recrystallization.
The seventh aspect of the present invention provides the 2-hydroxy-pyrimidin-5- carboxamide compounds of general formula- 11 represented by the following structure
Figure imgf000018_0001
Formula-11
wherein R\ & R2 are as defined above,
The invention further provides a process for the preparation of 2-hydroxy-pyrimidin-5 carboxamide compounds of general formula-11, which comprise of oxidizing the 2-oxo pyrimidin-5-carboxamide compounds of general formula- 10
Figure imgf000018_0002
Formula- 10 in presence of a suitable oxidizing agent like nitric acid in presence or absence of a solvent at suitable temperature ranges from 0 to 80°C. The nitric acid can be employed in an amount of 1 to 25 moles, preferably 2 to 15 moles per one mole of compounds of general formula- 10; preferably the reaction is carried out in absence of solvent. The reaction initiator such as sodium nitrite may also be utilized to accelerate the oxidation rate. The resulting product can be isolated and purified by the conventional methods known in the art.
The eighth aspect of the present invention provides the 2-sulfonyl pyrimidin-5- carboxamide compounds of general formula- 12 represented by the following structure
Figure imgf000019_0001
Formula- 12
wherein R\ & R2 are as defined above; and R' is selected from straight or branched chain alkyl group, cycloalkyl or cycloalkyl with one heteroatom; aralkyl group, aryl group and also includes the above groups with one or more substituents selected from halogen, nitro and alkyl group having 1 to 4 carbon atoms.
The present invention further provides a preparation of 2-sulfonyl pyrimidin-5- carboxamide compounds of general formula- 12, which comprise of reacting the compounds of general formula- 11
Figure imgf000019_0002
Formula- 11
with an organic sulfonyl halide having the following formula R'S02X
where in R' is defined as above and X is halogen
or organic sulfonic anhydride having the following formula
(R'S02)20
wherein R' is defined above;
in presence of a suitable base selected from inorganic or organic base, preferably inorganic base and a suitable solvent selected esters, alcohols, nitriles, chloro solvents^ hydrocarbon and ethers or mixtures thereof, preferably ester solvent provides the compounds of general formula- 12. The reaction mixture was carried out at a temperature in the range of -25 to 200°C.
The 2-sulfonyl pyrimidin-5-carboxamide compounds of general formula- 12 can be isolated as solid and purified using conventional methods known in the art. The 2-hydroxy- pyrimidin-5-carboxamide compounds of general formula- 11 may also convert directly into to pyrimidin-5-carboxamide compounds of general formula-8 with out isolation or purification of 2-sulfonyl pyrimidin-5-carboxamide compounds of general formula- 12.
For example, the organic sulfonyl halides used in the present invention may be selected from methanesulfonyl fluoride, methanesulfonyl chloride, ethanesulfonyl chloride, 1- propanesulfonyl chloride, 2-propanesulfonyl chloride, trifluoro methanesulfonyl fluoride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, 1 -naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, p-toluenesulfonyl fluoride, p-toluenesulfonyl chloride, 2,4, 6- trimethylbenzenesulfonyl chloride, 2,4, 6-triisopropylbenzenesulfonyl chloride, p- methoxybenzenesulfonyl chloride, p-chloro benzenesulfonyl chloride and 2- nitrobenzenesulfonyl chloride.
For example, the organic sulfonyl anhydrides used in the present invention may be selected from methanesulfonic anhydride, trifluoromethanesulfonic anhydride, benzenesulfonic anhydride, and p-toluenesulfonic anhydride.
The ninth aspect of the present invention provides a process for the preparation of pyrimidin-5-carboxamide compounds of general formula-8,
Figure imgf000021_0001
Formula-8
which comprise of reacting the 2-sulfonyl pyrimidin-5-carboxamide compounds of general formula- 12
Figure imgf000021_0002
Formula- 12
wherein Ris R2 & R are as defined above
with N-methyl methane sulfonamide in presence of a suitable base selected from organic or inorganic base; preferably inorganic base and in a suitable solvent selected from ester solvents, alcohol solvents, nitrile solvents, chloro solvents, hydrocarbon solvents and ether solvents or mixtures thereof, preferably hydrocarbon solvent, to provide the pyrimidin-5-carboxamide compounds of general formula-8.
The obtained compounds of general formula-8 can be isolated and purified as per the process known in the art.
The tenth aspect of the present invention provides a process for the preparation of isobutyryl acetamide derivative compounds of general formula-9,
Figure imgf000021_0003
Formula-9
wherein & R2 are as defined above which comprise of reacting the alkyl-4-methyl-3-oxopentanoate compounds of general formula- 13
Figure imgf000022_0001
Formula- 13
wherein R" is selected from alkyl group defined above,
with an amide compounds of general formula- 14
Figure imgf000022_0002
Formula- 14
wherein R\& R2 are as defined above;
in presence of a suitable polar aprotic solvent and without usage of a base at suitable temperature ranges from 30 to 100°C, preferably 70-80°C to provide the isobutyryl acetamide derivative compounds of general formula-9.
As per the prior art, the isobutyryl acetamide derivative compounds of general formula- 9 (wherein Rj&R2 are ethyl) prepared in presence of DMAP and in solvent and obtained as a oily compound after purified by radial chromatography. The present invention avoids the usage of chromatographic techniques, and also conducts the reaction in absence of solvent and DMAR Further the pyrimidine derivatives compounds of formula-8, 10, 11 and 12 of present invention were novel compounds, which were useful as intermediates in the preparation of HMG-CoA reductase inhibitors such as (E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S) 3,5-dihydroxyhept-6-enoic acid and its pharmaceutically acceptable salts or in the preparation of other pyrimidine derivatives such as N-(4-(4-fluorophenyl)-5-(substituted)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide used in the preparation of bis[(E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5- dihydroxyhept-6-enoic acid] calcium salt.
The novel pyrimidine derivative compounds such as pyrimidin-5-carboxamide compounds of general formula-8, 2-oxo-pyrimidin-5-carboxamide compounds of general W formula- 10, 2-hydroxy-pyrimidin-5-carboxamide compounds of general formula- 11 and 2- sulfonyl pyrimidin-5-carboxamide compounds of general formula- 12 used as an important intermediates in the preparation of other pyrimidine derivatives and the same also be converted into (E)-7-[4(4-fluorophenyl)-6-isopropyl-2[methyl (methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)3,5-dihydroxyhept-6-enoic acid or its pharmaceutically acceptable salt. The use of novel pyrimidine derivative compounds of formula-8, 10, 11 & 12 of the present invention shown by the following schematic representation
Figure imgf000023_0001
Figure imgf000023_0002
a preferred embodiment of the present invention, R\ & R2 is ethyl group, R" is methyl group and R is p-toluene.
In a preferred embodiment, the present invention provides the following compound of formula-8a
Figure imgf000024_0001
Formula-8a
Further the present invention provides a process for the preparation of N,N-diethyl-4- (4-fluorophenyl)-6-isopropyl-2-(N-methyl methane sulfonamido) pyrimidine-5-carboxamide compound of formula-8a, which comprises of the following steps;
a) Reacting the methyl-4-methyl-3 -oxopentanoate compound of formula- 13a
Figure imgf000024_0002
Formula- 13a
with diethylamine compound of formula- 14a
C2H5
HN
Formula- 14a
provides the N,N-diethyl-4-methyl-3-oxopentanamide compound of formula-9a,
Figure imgf000024_0003
Formula-9a
b) reacting the N,N-diethyl-4-methyl-3-oxopentanamide compound of formula-9a with 4- flurobenzaldehyde and urea in the presence of an organic or inorganic acid and metal salt in presence of a suitable solvent selected from alcohols, nitriles, chloro solvents, hydrocarbon and ethers or mixtures thereof, to provide the N,N-diethyl-4-(4-fluorophenyl)- 6-isopropyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxamide compound of formula-lOa,
Figure imgf000025_0001
Formula- 10a
c) oxidizing the compound of formuala-lOa with nitric acid provides the N,N-diethyl-4-(4 fluorophenyl)-2-hydroxy-6-isopropylpyrimidine-5-carboxamide compound of formula-lla
Figure imgf000025_0002
Formula-l la
d) reacting the compound of formula-4a with an para toluene sulfonyl chloride in presence of a suitable inorganic or organic base in a suitable solvent selected esters, alcohols, nitriles, chloro solvents or mixtures thereof provides the 5-(diethyl carbamoyl)-4-(4-fiuorophenyl)- 6-isopropylpyrimidin-2-y -4-methyl benzene sulfonate compound of formula- 12a,
Figure imgf000025_0003
Formula- 12a
e) reacting the compound of formula- 12a with N-methyl methane sulfonamide in presence of a suitable organic or inorganic base in a suitable solvent selected from esters, alcohols, nitriles, chloro solvents, hydrocarbon and ethers or mixtures thereof, provides the compound of formula-8a.
As used herein the present invention "alkali metal alkoxide base" refers to the bases selected from sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide and the like or mixtures thereof.
The present invention is schematically represented by the following scheme.
Figure imgf000026_0001
Formula-1 Rosuvastatin calcium
Wherein R is selected from alkyl or aryl Related substances and E and Z isomer content of compound of formula- 1 and la was analyzed by High Performance Liquid Chromatography using the following conditions:
Apparatus: A liquid chromatography is equipped with variable wavelength integrator and detector; Column: Lichrosphere; 250X4.0mm, 5μιη or equivalent; Flow rate: 1.0 ml/min; Wavelength: 242 nm; Temperature: ambient; Load: 20 μΐ and using mixture of acetonitrile and water in ratio of 80:20 as a diluent. Mixture of aqueous dihydrogen ortho phosphate buffer and acetonitrile as a mobile phase.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:
Example-1: Preparation of tert-butyl-2-(4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl- 2-(N-methylmethane sulfonamide)pyrimidin-5-yI)vinyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetate compound of formula-la:
Sodium tertiary butoxide (36.8 grams) was added to a mixture of N-(4-(4-fluorophenyl)-6- isopropyl-5-( 1 -methyl- 1 H-benzo[i/]imidazol-2-ylsulfonyl)pyrimidin-2-yl)-N-methylmethane sulfonamide (185 grams) in tetrahydrofuran (400 ml) and this mixture was added to tert-butyl 2-((4R,6R)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate (100 grams) in tetrahydrofuran (200 ml) at -20 to -15°C and stirred. After the completion of reaction, quenched it with sodium bicarbonate solution. The reaction mixture was stirred for 4 hours at 25-30°C. The solid was filtered and washed with water. The wet solid was recrystallized from methanol to get the title compound.
Yield: 165 grams
Purity by HPLC: 99.62%; 0.03% (Z isomer) Example-2: Preparation of N-(4-(4-fluorophenyI)-6-isopropyl-5-((l-methyl-lH- benzo[d]imidazol-2-ylsulfonyl)methyI)pyrimidin-2-yl)-N-methylmethane sulfonamide of formula-2:
A solution of hydrogen peroxide (70 ml) with ammonium heptamolybdate tetra hydrate (2 grams) was added to a mixture of N-(5-((lH-benzo[d]imidazol-2-ylthio)methyl)-4-(4- fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide (100 grams), tertiary butyl ammonium bromide (2 grams) and methylene chloride (200 ml) at 10-20°C and stirred. After completion of the reaction, quenched it with sodium sulphite solution and stirred. Sodium bicarbonate solution followed by aqueous sodium hydroxide was added and stirred for 30 minutes at RT. Dimethyl sulfate (23.5 grams) was added to the reaction mixture and stirred for 2 hours at RT. The organic and aqueous layers were separated and organic layer washed with water. The solvent from the organic layer was distilled off completely under reduced pressure at below 40°C. Methanol was added to the obtained residue and heated to reflux temperature then stirred for 30 minutes. The reaction mixture was cooled to -5 to 0°C and stirred for an hour. The solid obtained was filtered and washed with methanol. The wet solid was dissolved in methylene chloride and the solvent was distilled off under reduced pressure at below 40°C. Water was added to the obtained residue and stirred for 60 minutes. The solid obtained was filtered, washed with water and dried to get the title compound.
Yield: 92 grams
Purity by HPLC: 98.12% ExampIe-3: Preparation of N-(5-(lH-benzo[d]imidazol-2-yIthio)methyl)-4-(4- fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methyImethanesulfonamide compound of formula-6:
Aqueous hydro bromic acid (170 ml) was added to a mixture of N-(4-(4-fluorophenyl)-5- (hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide (200 grams) in toluene (1000 ml) and tertiary butyl ammonium bromide (16 grams). Heated the reaction mixture to 90-95 °C and stirred for 90 minutes at same temperature. Cooled the reaction mixture to 40-45°C and separated the both aqueous and organic layers. Washed the organic layer with 10% aqueous sodium bicarbonate solution. This organic layer was added slowly to the mixture of aqueous sodium hydroxide (22.6 grams in 60 ml of water), 1H- benzo[d]imidazole-2-thiol (85 grams) and acetone (500 ml) at 25-30°C and stirred for 90 minutes. The solvent was distilled off completely under reduced pressure, water was added to the obtained residue and stirred for 30 minutes at 60-65°C. The solid formed was filtered, washed with water and dried to get the title compound.
Yield: 270 grams
Purity by HPLC: 97.81 %
Example-4: Preparation of N-(5-(lH-benzo[d]imidazol-2-ylthio)methyl)-4-(4- fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide compound of formula-6:
Phosphorous tribromide (14 ml) was added to a solution of N-(4-(4-fluorophenyl)-5- (hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide (100 grams) in methylene chloride (500 ml) and stirred at 25-30°C. After completion of the reaction, quenched it with sodium bicarbonate solution at 10-15°C and the organic and aqueous layers were separated. The organic layer was washed with sodium thiosulphate solution followed by water. The solvent from the organic layer was distilled off completely under reduced pressure at below 40°C. The obtained residue was dissolved in methanol (400 ml) and this solution was added to mixture of aqueous sodium hydroxide (11.3 grams in 30 ml of water) and 1H- benzo[d]imidazole-2-thiol (42.5 grams) at 25-30°C and stirred for 90 minutes. The solvent was distilled off completely under reduced pressure, water was added to the obtained residue and stirred for 30 minutes at 25-30°C. The solid formed was filtered, washed with water and dried to get the title compound.
Yield: 132 grams
Example-5: Preparation of N-(5-(lH-benzo[d]imidazol-2-yIthio)methy.)-4-(4- fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide compound of formula-6:
Aqueous hydro chloric acid (110 ml) was added to a mixture of N-(4-(4-fluorophenyl)-5- (hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide (200 grams) in toluene (1000 ml) and tertiary butyl ammonium bromide (16 grams). Heated the reaction mixture to 90-95°C and stirred for 90 minutes at same temperature. Cooled the reaction mixture to 40-45 °C and separated the both aqueous and organic layers. Washed the organic layer with 10% aqueous sodium bicarbonate solution. This organic layer was added slowly to the mixture of aqueous sodium hydroxide (22.6 grams in 60 ml of water), 1H- benzo[d]imidazole-2-thiol (85 grams) and acetone (500 ml) at 25-30°C and stirred for 90 minutes. The solvent was distilled off completely under reduced pressure, water was added to the obtained residue and stirred for 30 minutes at 60-65°C. The solid formed was filtered, washed with water and dried to get the title compound.
Yield: 260 grams
Example-6: Preparation of N-(5-(bromomethyl)-4-(4-fluorophneyl)-6-isopropyl pyrimidin -2-yl) -N-m ethyl methane sulfonamide compound of formula-5a:
Aqueous hydro bromic acid (85 ml) was added to a mixture of N-(4-(4-fluorophenyl)-5- (hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide (100 grams) in toluene (500 ml) and tertiary butyl ammonium bromide (8 grams). Heated the reaction mixture to 90-95°C and stirred for 90 minutes at same temperature. Cooled the reaction mixture to 40- 45°C and separated the both aqueous and organic layers. Washed the organic layer with 10% aqueous sodium bicarbonate. The obtained organic layer was further utilized in the next stage with out isolated as a solid.
ExampIe-7: Preparation of N,N-diethyl-4-methyl-3-oxopentanamide of formuIa-9a:
Mixture of methyl -4-methyl-3-oxopentanoate (100 grams) and diethyl amine (100 grams) in dimethyl sulfoxide (100 ml) was heated to reflux temperature and stirred, till the completion of the reaction. Diethylamine was distilled off completely under reduced pressure at below 80°C and then cooled to RT. The reaction mixture was quenched with water and then extracted into ethyl acetate. Ethyl acetate layer was dried over sodium sulfate and distilled off ethyl acetate completely under reduced pressure to get the title compound.
Yield: 120 grams Example-8: Preparation of N,N-diethyl-4-(4-fluorophenyl)-6-isopropyI-2-oxo-l,2,3,4- tetrahydropyrimidine-5-carboxamide of formula-lOa:
A mixture of N,N-diethyl-4-methyl-3-oxopentanamide (110 grams),4-fluoro benzaldehyde (81.1 ml), urea (68.8 grams), copper(I)chloride (0.88 ml), sulfuric acid (8.8 ml) and methanol (550 ml) was heated to reflux temperature and stirred upto the completion of the reaction. The solvent from the reaction mixture was completely distilled off under reduced pressure and water (1100 ml) was added to it. The reaction mixture was stirred for 90 minutes at 25-30°C, filtered the obtained solid, washed with water followed by cyclohexane and then dried to get the title compound.
Yield: 175 grams
Melting Range: 157-168°C
Example-9: Preparation of N,N-diethyI-4-(4-fluorophenyl)-2-hydroxy-6-isopropyl pyrimidine-5-carboxamide of formula-lla:
N,N-diethyl-4-(4-fluorophenyl)-6-isopropyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxamide (40 grams) was added to a pre cooled mixture of nitric acid (80 grams) and sodium nitrite (0.33 grams) at 5 to 10°C. The reaction temperature was raised to 25-35°C and stirred up to the completion of the reaction. The reaction mixture was cooled to 10°C and water(266 ml), followed by acetic acid (20 ml) was added to it. The reaction mixture was basified with aqueous sodium hydroxide and stirred for 3 hours. The solid formed was filtered, washed with water and dried to get the title compound.
Yield: 36.2 grams
Melting Range: 198-208°C
Example-10: Preparation of 5-(diethylcarbamoyl)-4-(4-fIuorophenyl)-6-isopropyI pyrimidin-2-yl-4-methyl benzene sulfonate of formula-12a:
Paratoluene sulfonyl chloride (58.5 grams) was added to a mixture of N,N-diethyl-4-(4- fluorophenyl)-2-hydroxy-6-isopropyl pyrimidine-5-carboxamide (85 grams), potassium carbonate (53.4 grams) in ethyl acetate (425 ml) at 25-35°C, heated to reflux and stirred up to completion of the reaction. The reaction mixture cooled and quenched with water. Aqueous and organic layers were separated and aqueous layer extracted with ethyl acetate. The total organic layer was dried with sodium sulphate and distilled off the solvent completely under reduced pressure. The obtained residue was crystallized using petroleum ether.
Yield: 108 grams
Melting Range: 113 18°C Example-ll: Preparation of N,N-diethyl-4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl methane sulfonamido) pyrimidine-5-carboxamide of formula-8a:
A mixture of 5-(diethylcarbamoyl)-4-(4-fluorophenyl)-6-isopropyl pyrimidin-2-yl-4-methyl benzene sulfonate (23 grams), potassium carbonate (16.7 grams), N-methyl methane sulfonamide (12.6 grams) in toluene (115ml) was heated to reflux and stirred at reflux under azeotropic mode upto the completion of the reaction. The reaction mixture was cooled to RT and quenched it with water. The organic and aqueous layers were separated and aqueous layer was extracted with toluene. Total organic layer was dried and distilled off under reduced pressure. The obtained residue was crystallized from methanol.
Yield: 8 grams; M.R: 138-143°C

Claims

We claim:
1) A process for the preparation of dihydroxy protected derivative compounds of general formula- 1,
Figure imgf000033_0001
Formula- 1
wherein R is selected from alkyl or aryl,
with low levels of unwanted Z-isomer, which comprises of reacting the N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-lH-benzo[d]imidazol-2-ylsulfonyl)methyl) pyrimidin-2-yl)-N-methyl methane sulfonamide compound of formula-2
Figure imgf000033_0002
Formula-2
with aldehyde compounds of general formula-3
Figure imgf000033_0003
Formula-3
wherein R is selected from alkyl or aryl,
in presence of suitable alkali metal alkoxide base in a suitable solvent to provide the compound of formula- 1.
2) The process according to claim 1, the suitable alkali metal alkoxide is selected from sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide, or mixtures thereof.
3) The process according to claim 1, the suitable alkali metal alkoxide is sodium tertiary butoxide.
4) The process according to claim 1, the suitable solvent is selected from polar aprotic solvents, alcohol solvents, ether solvents, hydrocarbon solvents and polar solvents or mixtures thereof.
5) The process according to claim 1 , the suitable solvent is tetrahydrofuran.
6) A process for the preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6- isopropyl-2-(N-methylmethanesulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3- dioxan-4-yl)acetate compound of formula- la with low levels of unwanted Z-isomer,
Figure imgf000034_0001
Formula- la
which comprises of reacting the N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-lH- benzo[d]imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-2 with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4- yljacetate compound of formula-3a
Figure imgf000034_0002
Formula-3a
in presence of sodium or potassium tertiary butoxide in tetrahydrofuran to provide the compound of formula- la.
1 7) The process according to any of the preceding claims wherein the alkoxide base is used in the ratio of 0.8 to 2.3 moles with respect to N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl- lH-benzo[d]imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methyl methane sulfonamide compound of formula-2 and the reaction is carried out at a temperature ranges from -20°C to 40°C.
8) The process according to any of the preceding claims, wherein the compound of formula- 1 or la having E/Z content in the ratio of 98:2, preferably 99:1 and more preferably 99.9:0.1. 9) A process for the preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6- isopropyl-2-(TSi-methylmethanesulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3- dioxan-4-yl)acetate compound of formula- la having Z isomer content less than 1%, which comprises of reacting the N-(4-(4-fluorophenyl)-6-isopropyl-5((l -methyl- lH-benzo[d] imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methyl methane sulfonamide compound of formula-2 with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl]acetate compound of formula-3a in presence of sodium tertiary butoxide in tetrahydrofuran to provide the compound of formula- la, characterized in that the sodium tertiarybutoxide used in the mole ratio of 0.8 to 2.5 mole with respect to the compound of formula-2 at a temperature ranges from -20 to 50°C.
10) Usage of alkali metal alkoxide bases to improve the E isomer content in the condensation reaction between the N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-lH- benzo [d] imidazol-2-ylsulfonyl) methyl)pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-2
Figure imgf000035_0001
Formula-2
and aldehyde compounds of general formula-3
Figure imgf000036_0001
Formula-3
wherein R is selected from alkyl or aryl. 11) One pot process for the preparation of N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-lH- benzo[d]imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methyl methane sulfonamide compound of formula-2,
Figure imgf000036_0002
Formula-2
which comprises of oxidizing the sulfide compound of fomula-6
Figure imgf000036_0003
Formula-6
with a suitable oxidizing agent like metachloroperbenzoic acid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydro peroxide, in the presence of an appropriate catalyst like ammonium hepta molybdate tetra hydrate in a suitable solvent selected from alcoholic solvents like chloro solvents or mixture thereof, to provide the sulfone compound of formula-7,
Figure imgf000037_0001
Formula-7
which on in-situ reaction with a suitable methylating agent like dimethyl sulfate in presence of a suitable base selected from alkali metal hydroxides in a suitable solvent selected from chloro solvents to provide the compound of formula-2.
12) One pot process for the preparation of N-(4-(4-fluorophenyl)-6-isopropyl-5((l-methyl-lH- benzo [d] imidazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methyl methane sulfonamide compound of formula-2, which comprises of oxidizing the sulfide compound of fomula-6 with hydrogen peroxide in the presence of ammonium hepta molybdate tetra hydrate in methylene chloride to provide the sulfone compound of formula-7, which on in-situ reaction with dimethyl sulfate in presence of a suitable base selected from alkali metal hydroxides in a suitable solvent selected from chloro solvents to provide the compound of formula-2.
13) A process for the preparation of N-(5-(halomethyl)-4-(4-fluorophenyl)-5-(hydroxymethyl)- 6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compounds of general formula-
Figure imgf000037_0002
Formula-5
wherein X = halogen .
comprises of reacting N-(4-(4-flurophenyl)-5-(hydroxymethyl)-6-isopropyl pyrimidin yl)-N-methylmethane sulfonamide compound of formula-4
Figure imgf000038_0001
Formula-4
with a suitable halogenating agent in a suitable solvent.
14) The process according to claim 13, the suitable halogenating agent is selected from aqueous hydro bromic acid, aqueous hydro chloric acid, thionyl chloride.
15) The process according to claim 13, the suitable halogenating agent is aqueous hydrobromic acid
16) The process according to claim 13, the suitable halogenating agent is aqueous hydrochloric acid
17) The process according to claim 13, the suitable solvent is selected from hydrocarbon solvents.
18) The process according to claim 13, the suitable solvent is toluene.
19) One pot process for the preparation of compound of formula-6,
Figure imgf000038_0002
Formula-6 which comprises of reacting N-(4-(4-flurophenyl)-5-(hydroxymethyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-4
Figure imgf000039_0001
Formula-4
with suitable brominating agent selected from phosphorus tribromide in a suitable solvent selected from chloro solvent to provide the N-(5-(bromomethyl)-4-(4-fluorophenyl)-5- (hydroxymethyl)-6-isopropyl pyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-5a,
Figure imgf000039_0002
Formula-5a
which on in-situ reaction with lH-benzo[d]imidazole-2-thiol in presence of a suitable base selected from alkali metal hydroxide like sodium hydroxide and a solvent selected from ketone, chloro solvent, polar aprotic solvent or mixtures thereof to provide the compound of formula-6.
20) One pot process for the preparation of N-(5-((lH-benzo[d]imidazol-2-ylthio)methyl)-4-(4- fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide compound of formula-6, which comprises of reacting N-(4-(4-flurophenyl)-5-(hydroxymethyl)-6- isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide compound of formula-4 with phosphorus tribromide in methylene chloride to provide the N-(5-(bromomethyl)-4-(4- fluorophneyl)-5-6-isopropylpyrimidin-2-yl)-N-methylmethane sulfonamide compound of formula-5a, which on in-situ reaction with lH-benzo[d]imidazole-2-thiol in presence of sodium hydroxide in acetone to provide the compound of formula-6.
21) Compounds having the following structural formulae
Figure imgf000040_0001
Formula-8 Formula-10
Figure imgf000040_0002
Formula-11 Formula-12
Wherein R , Rj and R2 independently selected from hydrogen, straight or branched chain alkyl group, cycloalkyl or cycloalkyl with one heteroatom; aralkyl group, aryl group and also includes the above groups with one or more substituents selected from halogen, nitro and alkyl group having 1 to 4 carbon atoms, provided R is not a hydrogen. 22) Compounds having the following structural formulae
Figure imgf000040_0003
Formula-8a Formula-lOa
Figure imgf000041_0001
Formula-lla FormuIa-12a
23) Use of pyrimidine derivatives compounds as claimed in claim 21 & 22 as an intermediate or processing aid in the preparation of HMG-CoA reductase inhibitors such as (E)-7-[4( 4- fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5- dihydroxyhept-6-enoic acid and its pharmaceutically acceptable salts or in the preparation of pyrimidine derivatives like N-(4-(4-fluorophenyl)-5-(substituted)-6-isopropylpyrimidin- 2-yl) -N-methylmethane sulfonamide intermediates which were used in the preparation of (E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[methyl (methylsulfonyl) amino] pyrimidin-5- yl](3R,5S)3,5- dihydroxyhept-6-enoic acid.
24) Process for the preparation of 2-oxo-pyrimidin-5-carboxamide compounds of general formula- 10,
Figure imgf000041_0002
Formula- 10
which comprise of reacting an isobutyryl acetamide derivative compounds of general formula-9
Figure imgf000041_0003
Formula-9
with 4-flurobenzaldehyde and urea in the presence of an acid selected from inorganic or organic acid and a metal salt in presence or absence of a solvent, if solvent used which may be selected from alcohols, nitriles, chloro solvents, hydrocarbon and ethers or mixtures thereof, provides the 2-oxo-pyrimidin-5-carboxamide compounds of general formula- 10. 25) Process for the preparation of 2-hydroxy-pyrimidin-5-carboxamide compounds of general formula-11,
Figure imgf000042_0001
Formula-11
which comprise of oxidizing the 2-oxo-pyrimidin-5-carboxamide compounds of general formula- 10
Figure imgf000042_0002
Formula- 10
in presence of a suitable oxidizing agent like nitric acid in presence or absence of a solvent.
26) Process for the preparation of 2-sulfonyl pyrimidin-5-carboxamide compounds of general formula- 12,
Figure imgf000042_0003
Formula- 12 which comprise of reacting the 2-hydroxy-pyrimidin-5-carboxamide compounds of general formula- 11
Figure imgf000043_0001
Formula- 11
with an organic sulfonyl halide having the following formula
R'S02X
wherein R is defined as above and X is halogen
or organic sulfonic anhydride having the following formula
(R'S02)20
wherein R is defined as above;
in presence of a suitable base selected from inorganic or organic base in presence of a suitable solvent selected esters, alcohols, nitriles, chloro solvents, hydrocarbon and ethers or mixtures thereof, to provide the 2-sulfonyl pyrimidin-5-carboxamide compounds of general formula- 12.
27) Process for the preparation of pyrimidin-5-carboxamide compounds of general formula-8,
Figure imgf000043_0002
which comprise of reacting the 2-sulfonyl pyrimidin-5-carboxamide compounds of general formula- 12
Figure imgf000044_0001
Formula- 12
with N-methyl methane sulfonamide in presence of a suitable base selected from organic or inorganic base, in a suitable solvent selected from esters, alcohols, nitriles, chloro solvents, hydrocarbon and ethers or mixtures thereof, to provide the pyrimidin-5-carboxamide compounds of general formula-8.
28) A process for the preparation of isobutyryl acetamide derivative compounds of general formula-9,
Figure imgf000044_0002
which comprise of reacting the alkyl-4-methyl-3-oxopentanoate compounds of general formula- 13
Figure imgf000044_0003
Formula- 13
wherein R" is selected from alkyl group,
with an amide compounds of general formula- 14
NRjR2
Formula- 14
where in Rj& R2 are as defined above;
in presence of a suitable polar aprotic solvent and without use of a base at a suitable temperature ranges from 30 to 100°C to provide the compounds of general formula-9.
29) A process for the preparation of N,N-diethyl-4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl methane sulfonamido) pyrimidine-5-carboxamide compound of formula-8a, which comprises of the following steps;
a) Reacting the methyl-4-methyl-3 -oxopentanoate compound of formula- 13a
Figure imgf000045_0001
Formula- 13a
with diethylamine compound of formula- 14a
/ 2 h>
HN
\
C2H5
Formula- 14a
provides the N,N-diethyl-4-methyl-3-oxopentanamide compound of formula- 9a,
Figure imgf000045_0002
Formula-9a
b) reacting the N,N-diethyl-4-methyl-3-oxopentanamide compound of formula- 9a with 4- flurobenzaldehyde and urea in the presence of organic or inorganic acid and metal salt in presence of a suitable solvent selected from alcohol solvents, nitrile solvents, chloro solvents, hydrocarbon solvents and ether solvents or mixtures thereof, to provide the N,N-diethyl-4-(4-fluorophenyl)-6-isopropyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5- carboxamide compound of formula- 10a,
Figure imgf000045_0003
Formula- 10a
c) oxidizing the compound of formuala-lOa with nitric acid provides the N,N-diethyl-4- (4-fluorophenyl)-2-hydroxy-6-isopropylpyrimidine-5-carboxamide compound of formula- 11 a,
Figure imgf000046_0001
Formula-lla
d) reacting the compound of formula-lla with para toluene sulfonyl chloride in presence of a suitable inorganic or organic base in a suitable solvent selected from ester solvents, alcohol solvents, nitrile solvents, chloro solvents or mixtures thereof to provide the 5- (diethylcarbamoyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl-4-methyl benzene sulfonate compound of formula-l 2a,
Figure imgf000046_0002
Formula- 12a
e) reacting the compound of formula- 12a with N-methyl methane sulfonamide in presence of a suitable organic or inorganic base in a suitable solvent selected from esters, alcohols, nitriles, chloro solvents, hydrocarbon and ethers or mixtures thereof, to provide the N,N-diethyl-4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl methane sulfonamido) pyrimidine-5-carboxamide compound of formula-8a.
30) A process for the preparation of (E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[ methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5- dihydroxyhept-6-enoic acid or its pharmaceutically acceptable salts thereof, which comprise of preparing the N,N- diethyl-4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethanesulfonamido) pyrimidine-5- carboxamide compound of formula-8a as per the process claimed in claim 29 and converting into (E)-7-[4( 4-fluorophenyl)-6-isopropyl-2[methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R,5S)3,5-dihydroxyhept-6-enoic acid or its pharmaceutically acceptable salts thereof.
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