WO2008151510A1 - Préparation de 4-(fluorophenyl)-6-isopropyl-2-(n-methyl-n-methylsulfonylamino)- 5-formyl-pyrimidine - Google Patents

Préparation de 4-(fluorophenyl)-6-isopropyl-2-(n-methyl-n-methylsulfonylamino)- 5-formyl-pyrimidine Download PDF

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WO2008151510A1
WO2008151510A1 PCT/CN2008/001083 CN2008001083W WO2008151510A1 WO 2008151510 A1 WO2008151510 A1 WO 2008151510A1 CN 2008001083 W CN2008001083 W CN 2008001083W WO 2008151510 A1 WO2008151510 A1 WO 2008151510A1
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chloride
compound
formula
acid
methyl
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PCT/CN2008/001083
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Chinese (zh)
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Qingyun Huang
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Anhui Qingyun Pharmaceutical And Chemical Co., Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur 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
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid

Definitions

  • the invention relates to a method for preparing a pharmaceutical compound, in particular to an intermediate of the hypolipidemic drug rosuvastatin calcium, 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonyl).
  • Rosuvastatin calcium is a clinically used hypolipidemic drug with the chemical name (+) - (3R, 5S) -7-[4-(4-fluorophenyl)-6-isopropyl-2 - (N-Methyl-N-methylsulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6(E)-heptenoic acid calcium (2:1), the chemical structural formula is as follows -
  • U.S. Patent No. 5,260,440 discloses rosuvastatin and methods for its synthesis.
  • the method comprises the following steps: (1), (3 R) -3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphine methylene hexanoate and 4 (4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde (referred to as substituted pyrimidine-5-formaldehyde) condensation; (2), off The protecting group on the 3-hydroxy group is a hydroxy keto ester; (3) reducing the 5-carbonyl group to give a chiral 3,5-dihydroxyheptenoate; (4) hydrolyzing 3, 5-dihydroxyglycidyl The acid ester is converted to a calcium salt.
  • the preparation is as follows:
  • reaction raw material DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • DDQ 4-methylmorphine-N-oxide
  • TPAP peric acid tetra Propyl ammonium
  • diisobutyl aluminum hydride are expensive;
  • the technical problem to be solved by the present invention is to overcome the above-mentioned deficiencies, and to provide a preparation of 4-(4-fluorophenyl)-6-isopropyl- 2_(N-A) which is low in cost, simple in reaction, and suitable for industrial production.
  • the present invention provides a method of rosuvastatin intermediate 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde.
  • the method of the present invention specifically includes the following steps:
  • Another object of the present invention is to provide a dihydropyrimidinone compound of the formula 2 having a melting point of from 174 ° C to 178 ° C.
  • This compound is obtained by reacting isobutyrylacetonitrile with 4-fluorobenzaldehyde and urea in the presence of a protic compound and a metal salt.
  • a further object of the present invention is to provide a hydroxypyrimidine compound of the formula 3 having a melting point of 199. rc (decomposed). This compound is obtained by oxidizing a dihydropyrimidinone compound of the formula 2.
  • Still another object of the present invention is to provide a 2-(N-methyl-N-methylsulfonylamino)pyrimidine compound of the formula 4 which has a melting point of from 208 °C to 212 °C.
  • This compound is obtained by reacting a hydroxypyrimidine compound of the formula 3 with an organic sulfonyl halide or an organic sulfonic acid anhydride, and reacting the resulting reaction product with N-methylmethanesulfonamide.
  • step 1 :
  • Isobutyrylacetonitrile is reacted with 4-fluorobenzaldehyde in the presence of a protic compound and a metal salt.
  • the protic compound may be an inorganic acid or a salt thereof, such as sulfuric acid, hydrochloric acid, boric acid, phosphoric acid, nitric acid or sodium hydrogen sulfate; an organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid or substituted benzenesulfonic acid; and the like; Acetic acid, propionic acid or benzoic acid; etc.; alcohol, such as methanol, ethanol or butanol.
  • protic acids such as sulfuric acid, hydrochloric acid, boric acid, methanesulfonic acid and acetic acid. More preferred is sulfuric acid.
  • Protic compounds can be used singly or in combination.
  • the proton compound is preferably used in an amount of from 0.01 to 1 mole, more preferably from 0.1 to 1 mole, per mole of the isobutyryl acetonitrile.
  • the metal salt used in the reaction may be cuprous chloride (I:), copper chloride (11), copper acetate (11), ferrous chloride ( ⁇ ), ferric chloride (m), aluminum chloride, Nickel bromide ( ⁇ ), tin chloride ( ⁇ ), titanium tetrachloride or magnesium bromide.
  • cuprous chloride (I) copper chloride (11), iron (III) chloride and nickel bromide (11).
  • cuprous chloride (I) and the metal salt may contain water of crystallization, which may be used singly or in combination.
  • the urea may be preferably used in an amount of from 0.5 to 10 moles, more preferably from 1.5 to 3 moles, per mole of the isobutyrylacetonitrile.
  • the reaction can be carried out in the presence or absence of a solvent, and solvents which can be used include alcohols such as methyl alcohol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol and tert-butanol; Ethers such as diethyl ether, isopropyl ether, tetrahydrofuran and dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane , chloroform and carbon tetrachloride; aromatics such as benzene, toluene and xylene; halogenated aromatic hydrocarbons such as chlorobenzene; and nitrated aromatic hydrocarbons such as nitrobenzene.
  • solvents which can be used include alcohol
  • methanol, ethanol or isopropanol is especially preferred.
  • the solvent can be used singly or in combination.
  • the amount of the solvent used may be preferably from 0.1 to 10 liters, more preferably from 0.3 to 2 liters per mole of the isobutyryl acetonitrile. The amount can vary depending on the uniformity and dispersibility of the reaction mixture.
  • the reaction can be carried out by reacting isobutyrylacetonitrile, 4-fluorobenzaldehyde and urea in a solvent in the presence of a protic compound and a metal salt in an inert gas atmosphere.
  • the reaction can be preferably carried out at a temperature of from -10 Torr to 200 ° C, more preferably from 30 ° C to 100 ° C. There are no specific restrictions on environmental stress.
  • the product formed by the reaction i.e., the dihydropyrimidinone compound of the formula 2, can be isolated and purified according to a conventional method such as distillation, crystallization, recrystallization, and column chromatography.
  • the dihydropyrimidinone compound of the formula 2 i.e., the reaction product of the step (1), is oxidized to give a hydroxypyrimidine compound of the formula 3.
  • the oxidation (or dehydrogenation) can be carried out by various conventional methods, and it is preferred to use an oxidation process of nitric acid because the oxidation process is easy to proceed and the post-treatment of the reaction product is easy.
  • the nitric acid may be preferably used in an amount of 1 to 20 moles, more preferably .3 to 15 moles per 1 mole of the dihydropyrimidinone compound of the formula 2.
  • a concentration of from 40 to 80%, more preferably from 50 to 70%, of nitric acid can be used.
  • the oxidation can be carried out in the presence or absence of a solvent, and there is no particular limitation with respect to the solvent to be used.
  • the solvent includes a carboxylic acid such as acetic acid, propionic acid and butyric acid.
  • the solvent can be used singly or in combination.
  • the amount of the solvent is preferably used in an amount of from 0.1 to 7 liters, more preferably from 0.5 to 3 liters per gram of the dihydrodipyridone compound.
  • the amount can vary depending on the uniformity and dispersibility of the reaction mixture.
  • Oxidation can be carried out by allowing the dihydropyrimidinone compound and nitric acid to be carried out in a solvent or not in an inert gas atmosphere.
  • the oxidation may preferably be carried out at a temperature of -10 ° C to 10 (TC, more preferably - 5 ° C - 5 (TC).
  • TC -10 ° C to 10
  • a reaction initiator such as sodium nitrite may be added to the reaction system. Accelerate the oxidation rate.
  • the product formed by the reaction i.e., the hydroxypyrimidine compound of the formula 3, can be isolated and purified according to a conventional method such as distillation, crystallization, recrystallization, and column chromatography.
  • the hydroxypyrimidine compound that is, the reaction product of the step (2) is reacted with an organic sulfonyl halide having the formula 5:
  • R' is a hydrocarbon group and X is a halogen atom
  • reaction product of the step (2) is reacted with an organic sulfonyl halide having the formula 5
  • the resulting product is further reacted with N-methyl-N-methanesulfonamide.
  • R' is a hydrocarbon group which may have one or more substituents.
  • the hydrocarbon group include an alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a decyl group, a heptyl group, an octyl group, a decyl group and a fluorenyl group, and more specifically a group having 1 to 6 carbon atoms.
  • An alkyl group especially a fluorenyl group having 1 to 4 carbon atoms; a fluoroalkyl group such as a trifluoromethyl group, a nonafluorobutyl group, a decafluorohexyl group, a heptadecafluorooctyl group, and a hexafluoroaryl group; a cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group; and an aryl group such as a benzyl group, a phenylethyl group and a phenylpropyl group; and an aryl group including an unsubstituted and substituted phenyl group Or naphthyl, such as phenyl, naphthyl, tolyl, dimethyl Phenyl, trimethylphenyl, triisopropy
  • a hydrocarbyl group may carry one or more substituents provided that the substituent does not interfere with the reaction involved, and the hydrocarbyl group may be in any isomeric configuration, such as n-, iso-, and t-.
  • substituents when R' is aryl include, for example, phenyl or naphthyl (especially phenyl) which is unsubstituted or carries 1, 2 or 3 substituents.
  • the substituents may be independently selected, for example, a fluorenyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen, and a nitro group.
  • X is a halogen atom such as fluorine, chlorine, bromine and iodine.
  • sulfonyl halide examples include methanesulfonyl chloride, ethanesulfonyl chloride, 1-propylsulfonyl chloride, 2-propanesulfonyl chloride, trifluoromethylsulfonyl fluoride, trifluoromethylsulfonyl chloride, nonafluorobutylsulfonyl fluoride, and ten.
  • sulfonic acid anhydride examples include methanesulfonic anhydride, trifluoromethanesulfonic anhydride, benzenesulfonic anhydride, and p-toluenesulfonic anhydride. Preferred are trifluoromethanesulfonic anhydride, benzenesulfonic anhydride and p-toluenesulfonic anhydride.
  • the sulfonyl halide or sulfonic acid anhydride may be preferably used in an amount of from 0.1 to 20 moles, more preferably from 0.5 to 5 moles, and most preferably from 1 to 2 moles per 1 mole of the hydroxy compound. .
  • N-methylmethanesulfonamide may be preferably used in an amount of from 0.1 to 30 mol, more preferably from 1 to 5 mol, per 1 mol of the hydroxypyrimidine compound.
  • the reaction of the step (3) is preferably carried out in the presence of a base.
  • the base examples include alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates such as sodium hydrogencarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alcohols Salts such as sodium methoxide, sodium t-butoxide, potassium t-butoxide and sodium t-pentoxide; and tertiary amines such as triethylamine, triisopropylamine, diisopropylethylamine and pyridine. Preference is given to sodium carbonate, potassium carbonate, potassium t-butoxide, potassium t-amylate, triethylamine and pyridine. Potassium carbonate, sodium t-butoxide and triethylamine are especially preferred. Most preferred are potassium carbonate and sodium t-butoxide.
  • the bases can be used singly or in combination.
  • the base may preferably be 0.1 to 30 moles, more preferably 1 to 5 moles per 1 mole of the hydroxypyrimidine compound. The amount is used. The entire amount of the base may be added to the reaction system before the start of the reaction or the base may be added to the reaction system in portions after the start of the reaction.
  • the reaction can be carried out in the presence or absence of a solvent, and there is no particular limitation with respect to the solvent to be used, as long as the solvent does not disturb the reaction.
  • the solvent include water; ketones such as acetone, methyl ethyl ketone and diethyl ketone; ethers such as diethyl ether and tetrahydrofuran; esters such as ethyl acetate, ethyl propionate, and butyl acetate; nitriles such as acetonitrile and propionitrile; For example, N, N-dimethylformamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; ureas such as N,N-dimethylimidazolidinone.
  • acetone tetrahydrofuran
  • ethyl acetate butyl acetate
  • acetonitrile N,N-dimethylformamide and dimethyl sulfoxide.
  • ethyl acetate butyl acetate and acetonitrile.
  • butyl acetate and acetonitrile are preferred.
  • the solvent can be used singly or in combination.
  • the solvent is preferably used in an amount of from 0.01 to 100 liters, more preferably from 0.5 to 5 liters per 1 mole of the hydroxypyrimidine compound.
  • the amount can vary depending on the uniformity and dispersibility of the reaction mixture.
  • the reaction can be carried out by reacting a hydroxypyrimidine compound and an organic sulfonyl halide or a sulfonic acid anhydride in a solvent in an inert gas atmosphere under stirring in the presence of a base.
  • the reaction can be preferably carried out at a temperature of from - 30 ° C to 250 ° C, more preferably from 0 ° C to 15 ° C.
  • the product formed by the reaction i.e., the 2-(N-methyl-N-methylsulfonylamino)pyrimidine compound of the formula (4), can be isolated and purified according to a conventional method such as distillation, crystallization, recrystallization, and column chromatography.
  • step (3) the hydroxypyrimidine compound of the formula 3 and a halogenating agent such as a chlorinating agent, an organic sulfonyl halide of the formula 5:
  • R' is the same as defined above, X is a halogen atom, or a compound of formula (3) is reacted with an organic sulfonic anhydride of formula 5a:
  • R' has the same definition as above.
  • halogenating agent examples include phosphorus oxychloride and sulfuryl chloride.
  • the halogenating agents can be used singly or in combination.
  • the halogenating agent may preferably be used in an amount of from 0.1 to 50 moles, more preferably from 1 to 20 moles, and most preferably from 1. 5 to 10 moles per 1 mole of the hydroxypyrimidine compound.
  • organic sulfonyl halide and the sulfonic acid anhydride examples are those described above.
  • the organosulfonyl halide and the sulfonic acid anhydride are preferably used in an amount of from 0.1 to 20 moles, more preferably from 0.5 to 5 moles, and most preferably from 1 to 2 moles per 1 mole of the hydroxypyrimidine compound.
  • the reaction can be carried out in the presence or absence of a solvent
  • the solvent to be used is not particularly limited, and examples of the solvent include aromatic hydrocarbons such as toluene; halogenated aromatic hydrocarbons such as chlorobenzene; nitrated hydrocarbons such as nitrobenzene; Aliphatic hydrocarbons such as dichloromethane and 1,2-dichloroacetamidine; amides such as N,N-dimethylformamide; water (not suitable for chlorinating agents); nitriles such as acetonitrile and propionitrile; Carboxylic esters such as ethyl acetate, ethyl propionate and butyl acetate; ketones such as acetone, methyl ethyl ketone and diethyl ketone; and ethers such as diethyl ether and tetrahydrofuran.
  • aromatic hydrocarbons such as toluene
  • halogenated aromatic hydrocarbons such as chloro
  • the solvent may be preferably used in an amount of from 0.01 to 10 liters per 1 mole of the hydroxypyrimidine compound, more preferably in an amount of from 0.1 to 1 liter, for the reaction using a halogenating agent.
  • the amount can vary depending on the homogeneity and dispersibility of the reaction mixture.
  • the solvent may be preferably used in an amount of from 0.1 to 50 liters, more preferably from 0.5 to 2 liters per mole of the hydroxypyrimidine compound, using a sulfonyl chloride or a sulfonic acid anhydride.
  • the amount may vary depending on the uniformity of the reaction mixture.
  • the reaction can be carried out by reacting a hydroxypyrimidine compound and a halogenating agent in a solvent with or without stirring in an inert gas atmosphere.
  • the reaction can be preferably carried out at a temperature of from 0 ° C to 200 ° C, more preferably from 50 ° C to 150 ° C. There are no specific restrictions on environmental stress.
  • the reaction can be carried out by reacting a hydroxypyrimidine compound and a sulfonyl halide or a sulfonic acid anhydride in a solvent with or without stirring in an inert gas atmosphere.
  • the reaction can be preferably carried out at a temperature of from - 30 ° C to 20 (TC, more preferably from 0 to 80 Torr.
  • TC - 30 ° C to 20
  • the product formed by the reaction i.e., a 2-substituted pyrimidine compound such as a chloropyrimidine compound or a sulfonyloxypyrimidine compound
  • a 2-substituted pyrimidine compound such as a chloropyrimidine compound or a sulfonyloxypyrimidine compound
  • a conventional method such as distillation, crystallization, recrystallization, and column chromatography.
  • the 2-substituted pyrimidine compound prepared in the step (3) such as a chloropyrimidine compound or a sulfonyloxypyrimidine compound, is reacted with an amine compound having the formula 6:
  • ⁇ and ⁇ have the same definitions as above.
  • Examples of ⁇ and R 2 include a hydrogen atom, a fluorenyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, and a pentyl group. And a fluorenyl group; a mercaptosulfonyl group such as a methylsulfonyl group; and an arylsulfonyl group such as a benzenesulfonyl group and a p-toluenesulfonyl group.
  • the amine compound may preferably be used in an amount of from 0.1 to 30 moles, more preferably from 1 to 5 moles per 1 mole of the 2-substituted pyrimidine compound.
  • the reaction is preferably carried out in the presence of a base, and examples of the base are those described above.
  • the base may be preferably used in an amount of from 0.1 to 30 moles, more preferably from 1 to 5 moles per 1 mole of the 2-substituted hydroxypyrimidine compound.
  • the reaction can be carried out in the presence or absence of a solvent
  • the solvent to be used is not particularly limited, and examples of the solvent include water; ketones such as acetone, methyl ethyl ketone and diethyl ketone; ethers such as diethyl ether and tetrahydrofuran; Ethyl acetate, ethyl propionate and butyl acetate; nitriles such as acetonitrile and propionitrile; amides such as N, N-dimethylformamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide Sulfone; urea, such as N, N'-dimethylimidazolidinone.
  • acetone Preference is given to acetone, tetrahydrofuran, ethyl acetate, butyl acetate, acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide. Particularly preferred are ethyl acetate, butyl acetate and acetonitrile. Most preferred are butyl acetate and acetonitrile.
  • the solvent can be used singly or in combination.
  • the solvent is preferably used in an amount of from 0.01 to 100 liters, more preferably from 0.5 to 5 liters per mole of the 2-substituted pyrimidine compound.
  • the amount can vary depending on the uniformity and dispersibility of the reaction mixture.
  • the reaction can be carried out by allowing the 2-substituted pyrimidine compound and the amine compound to be carried out in a solvent in the presence of a base with or without stirring in an inert gas atmosphere.
  • the reaction can be preferably carried out at a temperature of from -20 ° C to 25 (TC, more preferably from 25 ° C to 150 ° C.
  • TC -20 ° C to 25
  • step (3) the reaction is carried out in the presence or absence of a phase transfer catalyst, and the reaction in the presence of a phase transfer catalyst can be carried out in two branched liquid phases.
  • the phase transfer catalyst include tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium fluoride, tetraethylammonium chloride, tetraethylammonium bromide, tetrapropylammonium bromide, tetrapropylamine.
  • tetrabutylammonium chloride Preferred are tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltriethylammonium chloride, and hexadecanyltriethylphosphonium hinge. Most preferred are tetrabutylammonium bromide, benzyltriethylammonium chloride, and hexadecanyltrimethylammonium chloride.
  • Each mole of 2-substituted pyrimidine compound, phase transfer catalyst may be 0. 01- 0. 5 moles, preferably 0. 05-0. The amount of 2 moles used.
  • the product formed by the reaction that is, 4-(4-fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino)pyrimidine of the formula 4 can be obtained according to a conventional method, for example Separation and purification are carried out by distillation, crystallization, recrystallization and column chromatography.
  • step (4) 4-(4-fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino)pyrimidine of the formula 4, ie, the step The reaction product of (3) is reacted with a reducing agent to obtain 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5-formaldehyde having the formula 1. .
  • the reducing agent may be diisobutylaluminum hydride, red aluminum, lithium tetrahydrogenate or the like. If diisobutylaluminum hydride is used, 4-(4-fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino)pyrimidine (Formula 4) The 5% ⁇ 65% diisobutylaluminum hydride toluene solution was added dropwise in an organic solvent under an inert gas atmosphere, and the reaction was continued for several hours after the completion of the dropwise addition. After the completion of the reaction, the substituted pyrimidine-5-formaldehyde was obtained by separation and purification. The reaction temperature is - 20 ° C to 150 ° C, preferably - 10 ° C to 50 ° C.
  • the organic solvent may be benzene, toluene, xylene, dichloromethane, chloroform, tetrahydrofuran, dioxane or other solvent which does not react with a reducing agent and a reaction raw material.
  • the molar ratio of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-2-(N-methyl-N-methylsulfonylamino)pyrimidine to diisobutylaluminum hydride is 1.0 0: 0-10. 0, Preferably 1. 0: 0. 8-4. 0.
  • the method of the invention does not need to use highly toxic, expensive raw materials, has low process cost, simple reaction, high product yield, and is suitable for industrial production.
  • Example 2 In the same manner as in Example 1, except that the amount of methanol was changed from 600 ml to 200 ml to obtain 103.5 g of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-3, 4-2 (1H)-
  • the dihydropyrimidinone has the solid product of the characteristics of Example 1. The yield was 85% (based on the amount of isobutyrylacetonitrile).
  • Example 2 In the same manner as in Example 1, except that the amount of urea was changed from 49.4 g (0.82 raol) to 56.63 g (0.94 mol) to obtain 106.3 g of 4-(4-fluorophenyl)-6-isopropyl-5-cyano group. - 3, 4-2 (1H)-Dihydropyrimidinone has the solid product of the characteristics of Example 1. The yield was 87.2% (based on the amount of isobutyrylacetonitrile).
  • the reaction mixture was poured into 162 ml of water, and the aqueous mixture was neutralized by adding 78. lg of an aqueous sodium hydroxide solution (45 wt%), and the aqueous mixture was crystallized by precipitation.
  • the crystalline product was collected by filtration and dried to give 28.3 g of 4-(4- fluorophenyl) - 2 - s yl -6 - isopropyl - 5-cyanopyrimidine as white crystals.
  • the yield was 93% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-3,4-2(1H)-dihydropyrimidinone).
  • the mixture was reacted at a temperature of from 10 ° C to 15 ° C for 2 hours. After the completion of the reaction, 500 ml of water was poured into the reaction mixture, and the aqueous mixture was precipitated by adding 137 g of an aqueous aqueous sodium hydroxide solution (45 wt%) to precipitate crystals. The crystalline product was collected by filtration and dried to give 40. 6 g of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-cyanopyrimidine as a colorless crystal. The yield was 92% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-cyano-3,4-2(1H)-dihydropyrimidinone).

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Abstract

Cette invention concerne la préparation de 4-(fluorophenyl)-6-isopropyl-2-(n-methyl-n-methylsulfonylamino)- 5-formyl-pyrimidine, un produit intermédiaire de la rosuvastatine, laquelle préparation consiste à faire réagir un acétonitrile isobutyryl représenté par la formule (CH3)2CH-C(=O)-CH2-CN avec 4-fluorobenzaldehyde et de l'urée, puis à procéder à une oxydation, à une substitution et à une réduction et enfin de synthétiser le produit intermédiaire pyrimidine aldéhyde de la rosuvastatine.
PCT/CN2008/001083 2007-06-11 2008-06-02 Préparation de 4-(fluorophenyl)-6-isopropyl-2-(n-methyl-n-methylsulfonylamino)- 5-formyl-pyrimidine WO2008151510A1 (fr)

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CN200710041850A CN101323597B (zh) 2007-06-11 2007-06-11 4-(4-氟苯基)-6-异丙基-2-(n-甲基-n-甲磺酰氨基)嘧啶-5-甲醛的制备方法
CN200710041850.6 2007-06-11

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CN115677598A (zh) * 2022-11-11 2023-02-03 南通常佑药业科技有限公司 一种合成嘧啶二酮类化合物的制备方法

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WO2012013325A1 (fr) 2010-07-26 2012-02-02 Lek Pharmaceuticals D.D. Procédé de préparation d'intermédiaires clés pour la synthèse de statines ou sels pharmaceutiquement acceptables de ceux-ci
EP2423195A1 (fr) 2010-07-26 2012-02-29 LEK Pharmaceuticals d.d. Procédé pour la préparation d'intermédiaires clé pour la synthèse de statines ou de ses sels pharmaceutiquement acceptables
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WO2012172564A1 (fr) * 2011-05-25 2012-12-20 Dr. Reddy's Laboratories Limited Procédé de préparation de calcium de rosuvastatine
WO2016116589A1 (fr) * 2015-01-23 2016-07-28 Dsm Sinochem Pharmaceuticals Netherlands B.V. Procédé amélioré de préparation de précurseur de statine
CN107428703A (zh) * 2015-01-23 2017-12-01 中化帝斯曼制药有限公司荷兰公司 用于制备他汀前体的改进的方法
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CN107428703B (zh) * 2015-01-23 2021-01-12 灿盛制药有限公司荷兰公司 用于制备他汀前体的改进的方法
WO2016151104A1 (fr) * 2015-03-26 2016-09-29 Dsm Sinochem Pharmaceuticals Netherlands B.V. Procédé amélioré pour la préparation d'un précurseur de statine
CN107428702A (zh) * 2015-03-26 2017-12-01 中化帝斯曼制药有限公司荷兰公司 经改进的制备他汀前体的方法
CN115677598A (zh) * 2022-11-11 2023-02-03 南通常佑药业科技有限公司 一种合成嘧啶二酮类化合物的制备方法

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