Classifications

• • 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
  • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms

Definitions

• the present invention provides a process for forming 5- (alkyl or alkoxy )carbonyl-6-alkyl-4-(aryl or alkyl)-3, 4-2(1 H)- dihydropyrimidinones by combining a ⁇ -keto ester or diketone, an aldehyde and urea. More particularly, the reaction is run in one pot in the presence of a boron reagent, a metal salt and a catalyst to afford yields much higher than from currently accepted methods.
• Dihydropyrimidinone compounds have been extensively studied as calcium channel blockers useful as antihypertensive agents. [See e.g., K.S. Atwal et al., J. Med. Chem 34, 806 (1991); K.S. Atwal et al., J. Med. Chem 33, 2629 (1990); H. Cho et al., J. Med. Chem 32, 2399 ( 1989); Baldwin et al., U.S. Patent No. 4,675,321 , issued June 23, 1987]. More recently, a number of dihydropyrimidinones have been identified as alpha la antagonists useful for the treatment of benign prostatic hype ⁇ lasia (BPH). [See PCT International Patent Application publication no.
• acylated as described in U.S. Patent No. 4,675,321 or alkoxycarbonylated as described in Cho et al., J. Med. Chem 32, 2399 (1989)
• R 1 , R7 and R ⁇ are each independently selected from hydrogen, halogen, halogenated Cl -l ⁇ alkyl, unsubsituted or substituted aryl, or unsubstituted or substituted C l .10 alkyl wherein the substituent on the alkyl is selected from Cl -6 alkoxy, halogenated Cl -6 alkoxy or aryl;
• R2 is Cl -io alkyl, OR° ⁇ unsubstituted C3-6 cycloalkyl or mono-, di- or tri-substituted C3-6 cycloalkyl wherein the substitutents on the cycloalkyl are independently selected from hydroxy, Cl -6 alkyl, halogenated Cl -6 alkyl, Cl -6 alkoxy or halogenated Cl -6 alkoxy;
• R3 and R ⁇ are each independently selected from hydrogen, Cl -10 alkyl or
• R9 is hydrogen; more preferably, R ⁇ , R
• the metal salt is selected from copper (I) chloride, copper (I) oxide, copper (II) chloride, copper (II) sulfate, copper (II) acetate, nickel (II) bromide or palladium (II) acetate;
• the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr PPh3 or NH4 ⁇ Ac;
• Rl is selected from hydrogen or Cl -8 alkyl
• R2 is Ci-8 alkyl or OR 6 ;
• R3 is selected from Cl -8 alkyl or
• each R4 is independently selected from hydrogen, halogen, Cl -5 alkoxy, nitro, Cl -8 alkyl or halogenated Cl-8 alkyl;
• each R5 is independently selected from hydrogen or C l -8 alkyl
• R6 is Cl-8 alkyl
• R7, R8 and R9 are hydrogen; and n is an integer from one to three.
• R9 is hydrogen; more preferably, R7, R& and R ⁇ are hydrogen and the compound II has the formula
• Illustrative of the invention is the method comprising reacting
• Illustrating the invention is the method wherein the reaction is carried out in one pot.
• An illustration of the invention is the method wherein the reaction is run in a solvent selected from an ether, an alcohol, a halogenated hydrocarbon or an acid.
• the solvent is selected fro tetrahydrofuran, methanol, methylene chloride or acetic acid.
• the solvent is tetrahydrofuran.
• Exemplifying the invention is the method wherein the boron reagent is selected from BF3, BF3-2H20, BF3-Me2S, BF3 HOAC, BF3-Et2 ⁇ , BF3-Me2 ⁇ , BF3 t-BuOMe, BF3 CH3OH or
• the boron reagent is BF3 EGO.
• An example of the invention is the method wherein the metal salt is selected from copper (I) chloride, copper (I) oxide, copper (II) chloride, copper (II) sulfate, copper (II) acetate, nickel (II) bromide, palladium (II) acetate, copper bromide or palladium acetoacetate.
• the metal salt is selected from copper (I) chloride, copper (I) oxide, copper (II) chloride, copper (II) sulfate, copper (II) acetate, nickel (II) bromide or palladium (II) acetate. More preferably, the metal salt is selected from copper (I) oxide, copper (I) chloride, nickel (II) bromide or palladium (II) acetate. Most preferably, the metal salt is copper (I) oxide.
• the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr PPh3, NH4OAC, triethylamine, pyridine, cinchonine, quinine or quinidine.
• the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr PPh3 or NH4OAC More preferably, the catalyst is selected from acetic acid, trifluoroacetic acid or methanol. Most preferably, the catalyst is acetic acid.
• the metal salt is selected from copper (I) oxide, copper (I) chloride, nickel (II) bromide or palladium (II) acetate; the catalyst is selected from acetic acid, trifluoroacetic acid or methanol; and the solvent is selected from tetrahydrofuran, methanol or methylene chloride.
• the metal salt is copper (I) oxide, the catalyst is acetic acid and the solvent is tetrahydrofuran.
• the metal salt is copper (I) oxide, the catalyst is acetic acid, the solvent is tetrahydrofuran and the reaction is carried out in one pot. More particularly illustrating the invention is the method wherein the reaction is run at a temperature range of about 40°C to 100°C. Preferably, the reaction is run at a temperature of about 65°C.
• More specifically exemplifying the invention is the method wherein the reaction is heated for a period of from 1 to 20 hours, preferably, from 6 to 20 hours, most preferably, for about 18 hours.
• Another aspect of the invention are the compounds of the formulas (IV) and (V), and salts thereof,
• R 1 , R7 and R ⁇ are each independently selected hydrogen, halogen, halogenated Cl -10 alkyl, unsubsituted or substituted aryl, or unsubstituted or substituted Cl-10 alkyl wherein the substituent on the alkyl is selected from Cl-6 alkoxy, halogenated Cl-6 alkoxy or aryl;
• R2 is Ci-io alkyl, OR6, unsubstituted C3-6 cycloalkyl or mono-, di- or tri-substituted C3-6 cycloalkyl wherein the substitutents on the cycloalkyl are independently selected from hydroxy, C l -6 alkyl, halogenated Cl-6 alkyl, C l-6 alkoxy or halogenated Cl-6 alkoxy;
• R3 and R9 are each independently selected from hydrogen, Cl-10 alkyl or
• n is an integer from one to five.
• R 1 is selected from hydrogen or Cl- alkyl
• R 2 is selected from Cl-8 alkyl or OR 6 , where R 6 is C l -8 alkyl; R3 is selected from .g alkyl or
• each R4 is independently selected from hydrogen, halogen, cyano, Cl-5 alkoxy, nitro, Cl -8 alkyl or halogenated C l-8 alkyl; each R5 is independently selected from hydrogen or Cl -8 alkyl; R7, R ⁇ and R9 are hydrogen; and n is an integer of from one to three.
• the instant invention provides a process for preparing dihydropyrimidinones in high yields according to the following reaction scheme (I)
• R 1 , R7 and R& are each independently selected from hydrogen, halogen, halogenated Cl-i alkyl, unsubsituted or substituted aryl, or unsubstituted or substituted Cpio alkyl wherein the substituent on the alkyl is selected from C ⁇ _6 alkoxy, halogenated Cl-6 alkoxy or aryl;
• R2 is Cl-10 alkyl, OR 6 , unsubstituted C3-6 cycloalkyl or mono-, di- or tri-substituted C3-6 cycloalkyl wherein the substitutents on the cycloalkyl are independently selected from hydroxy, C l -6 alkyl, halogenated C l -6 alkyl, C 1 -6 alkoxy or halogenated C 1 _6 alkoxy;
• R3 and R9 are each independently selected from hydrogen, Cpio alkyl or
• R6 is selected from unsubstituted or substituted Cpio alkyl wherein the substituent on the alkyl is selected from Cl- alkoxy, halogenated Cl-6 alkoxy or aryl; unsubstituted C3-6 cycloalkyl or mono-, di- or tri- substituted C3-6 cycloalkyl wherein the substitutents on the cycloalkyl are independently selected from hydroxy, Cl -6 alkyl, halogenated Cl -6 alkyl, Cl-6 alkoxy or halogenated C ) -6 alkoxy; or unsubstituted or substituted aryl; and n is an integer from one to five.
• R7, R8 and R are hydrogen and the compound I has the formula
• R l , R2, R4, R5 ; R6, R7, R8 ? R9 an n are as defined above.
• R ⁇ , R ⁇ and R9 are hydrogen and the compound II has the formula
• R l , R4, R6 and n are as defined above.
• Compounds of formulas (I), (II) and (III) are useful as calcium channel blockers and as alpha la antagonists. More specifically, compounds of formula (III) are particularly preferred as calcium channel blockers, or as intermediates which can be further derivatized at the N-3 position (e.g., acylated as described in U.S. Patent No. 4,675,321 , or alkoxy carbony lated as described in Cho et al., J. Med. Chem 32, 2399 ( 1989)) to afford calcium channel blocking agents. Similarly, compounds of formula (III) are particularly preferred as alpha 1 a antagonists, or as intermediates which can be further derivatized at the N- 3 position as described in WO 96/14846, published 23 May 1996.
• the reaction is run in one pot in a solvent selected from an oxygenated organic solvent (e.g., alcohol, ether), a halogenated hydrocarbon or an acid.
• a solvent selected from an oxygenated organic solvent (e.g., alcohol, ether), a halogenated hydrocarbon or an acid.
• the solvent is selected from tetrahydrofuran, methanol, methylene chloride or acetic acid. Most preferably, the solvent is tetrahydrofuran.
• a wide array of ⁇ -keto esters or diketones (A) and substituted-benzaldehydes (B') are commercially available allowing one to make aryl -dihydropyrimidinones having a large variety of substituents for R l , R2 and R ⁇ .
• aryl aldehydes it is also possible to utilize alkyl aldehydes in the instant invention to afford alkyl - pyrimidinones of the formula (IV)
• N-substituted ureas and O-substituted ureas can be utilized in place of urea (C") to afford the corresponding N-substituted dihydropyrimidinones.
• a number of N- substituted ureas are commercially available and/or could be easily prepared by one of ordinary skill in the art.
• the ratio of starting materials is preferably 1 : 1 : 1.5 of A:B:C; however, varying the ratio (e.g., 2: 1 :3, 1 :1 :3 or 2:1 : 1.5 of A:B:C) also gave higher yields than the prior art methods (e.g., Folkers method).
• the boron reagent used in the instant invention is BF3 which is commercially available in a variety of forms, all of which can be used in the method of the instant invention.
• the boron reagent is selected from BF3, BF3 2H2O, BF3-Me2S, BF3 HOAC, BF3 R2O (e.g., BF3-Et2 ⁇ , BF3-Me2 ⁇ , BF3 tert-butyl methyl etherate), BF3 ROH (e.g., BF3 CH3OH, BF3 CH3CH2CH2OH).
• the boron reagent is BF3-Et2 ⁇ .
• metal salts can be utilized in the novel reaction of the present invention.
• copper (I) chloride, copper (I) oxide, copper (II) chloride, copper (II) sulfate, copper (II) acetate, nickel (II) bromide, palladium (II) acetate, copper bromide or palladium acetoacetate can all be used as the metal salt.
• the metal salt is copper (I) chloride, copper (I) oxide, copper (II) chloride, copper (II) sulfate, copper (II) acetate, nickel (II) bromide or palladium (II) acetate.
• the metal salt is copper (I) oxide, copper (I) chloride, nickel (II) bromide or palladium (II) acetate.
• the metal salt used in the reaction is copper (I) oxide. Catalytic amounts of the metal salt are preferable to one full equivalent in the instant reaction.
• the catalyst used in the instant reaction can be a number of different Bronsted acids or bases or an alcohol.
• suitable catalysts include, but are not limited to, acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr PPh3, NH4OAC, triethylamine, pyridine, cinchonine, quinine or quinidine.
• the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr PPh3 or NH4OAC. More preferably, the catalyst is selected from acetic acid, trifluoroacetic acid or methanol. Most preferably, acetic acid is used as the catalyst.
• the reaction can be run at a temperature range of about 40°C to about 100°C. Preferably, the temperature is about 65°C.
• the reaction mixture is heated for a period of 1 to 20 hours depending on the starting materials used. Preferably, the reaction mixture is heated for a period of 6 to 20 hours; most preferably, for about 18 hours.
• ⁇ -keto ester (A) 1 eq. of ⁇ -keto ester (A), 1 eq. of arylaldehyde (B), 1.5 eq. urea (C) are reacted in the presence of 1.3 eq. BF3-Et2 ⁇ , 10 mol% Cu2 ⁇ , and 10 mol % AcOH in THF at 65 °C for 18 h to afford the dihydropyrimidinone (I) in high yield.
• Ph phenyl
• alkyl includes both straight and branched chain alkanes of the number of carbon atoms specified (e.g., Cl -10 alkyl), or any number within this range (i.e., methyl, ethyl, 1 - propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).
• halogenated alkyl includes both straight and branched chain alkanes of the number of carbon atoms specified (e.g., halogenated Cl -10 alkyl), or any number within this range, wherein one or more of the hydrogen atoms on the alkyl chain is replaced with a halogen atom (e.g., CF3).
• alkoxy refers to straight or branched chain alkoxides of the number of carbon atoms specified (e.g., Cl-6 alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc.).
• halogenated alkoxy includes both straight and branched chain alkoxides of the number of carbon atoms specified (e.g., halogenated Cl-6 alkoxy), or any number within this range, wherein one or more of the hydrogen atoms is replaced with a halogen atom (e.g., OCF3).
• aryl refers to unsubstituted, mono-, di-, tri- or tetra- or penta-substituted aromatic groups such as phenyl or naphthyl.
• me aryl group is unsubstituted, mono-, di- or tri-substituted.
• substituents which can be present on the phenyl or naphthyl group include, but are not limited to, halogen, Ci-6 alkyl, Cl -6 alkoxy, halogenated C l-6 alkyl or halogenated C 1 -6 alkoxy.
• halogen shall include, iodine, bromine, chlorine and fluorine.

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• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
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• Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)

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• 1996
  • 1996-12-12 CZ CZ981840A patent/CZ184098A3/cs unknown
  • 1996-12-12 WO PCT/US1996/019651 patent/WO1997021687A1/en not_active Application Discontinuation
  • 1996-12-12 BR BR9611933A patent/BR9611933A/pt not_active Application Discontinuation
  • 1996-12-12 EP EP96944785A patent/EP0882026A4/en not_active Withdrawn
  • 1996-12-12 PL PL96327147A patent/PL327147A1/xx unknown
  • 1996-12-12 JP JP9522161A patent/JP2000501734A/ja active Pending
  • 1996-12-12 NZ NZ326039A patent/NZ326039A/xx unknown
  • 1996-12-12 KR KR1019980704443A patent/KR19990072125A/ko not_active Application Discontinuation
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  • 1996-12-12 CA CA002238924A patent/CA2238924A1/en not_active Abandoned
  • 1996-12-12 AU AU13316/97A patent/AU705409B2/en not_active Ceased

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