WO1997021687A1 - Process for making dihydropyrimidinones - Google Patents
Process for making dihydropyrimidinones Download PDFInfo
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- WO1997021687A1 WO1997021687A1 PCT/US1996/019651 US9619651W WO9721687A1 WO 1997021687 A1 WO1997021687 A1 WO 1997021687A1 US 9619651 W US9619651 W US 9619651W WO 9721687 A1 WO9721687 A1 WO 9721687A1
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- alkyl
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- alkoxy
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- 0 CC([C@@](C(C(*)=O)=C(C*)N1*)NC1=O)=CC=CC=C Chemical compound CC([C@@](C(C(*)=O)=C(C*)N1*)NC1=O)=CC=CC=C 0.000 description 3
- ZZQDAVSMSTUQAQ-UHFFFAOYSA-N CC(NC(NC1c2ccccc2)=O)=C1C(OC)=O Chemical compound CC(NC(NC1c2ccccc2)=O)=C1C(OC)=O ZZQDAVSMSTUQAQ-UHFFFAOYSA-N 0.000 description 1
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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
- C07D239/20—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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Abstract
The present invention provides a process for forming 5-(alkyl or alkoxy)carbonyl-6-alkyl-4-(aryl or alkyl)-3,4-2(1H)-dihydropyrimidinones by combining a β-keto ester or diketone, an aldehyde and urea in the presence of a boron reagent, a metal salt (e.g., Cu2O) and a catalyst (e.g., acid). The reaction is typically run in one pot in a solvent to afford dihydropyrimidinones in higher yields and with easier work up than previously known methods.
Description
TITLE OF INVENTION
PROCESS FOR MAKING DIHYDROPYRIMIDINONES
FIELD OF THE INVENTION This application is related to U.S. Serial No. 60/008,641 , filed as a provisional application on December 14, 1995, the contents of which are hereby incorporated by reference.
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 β-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.
BACKGROUND OF THE INVENTION
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 hypeφlasia (BPH). [See PCT International Patent Application publication no. WO 96/14846, published 23 May 1996] The reaction of numerous aldehydes with urea and a β-keto ester to give a tetrahydropyrimidinone was discovered by [Biginelli, Gazz. Chim. Hal, 23, 360 (1893)]. The Biginelli reaction has been studied, improved upon and a mechanism of formation of tetrahydropyrimidinone proposed. [K. Folkers and T.B. Johnson, J. Am. Chem. Soc, 55, 3784 (1933); J.D. Fissekis, and F. Sweet, J. Am. Chem. Soc, 95, 8741 (1973)]. Thus in the past, the synthesis of dihydropyrimidinones was most often effected using β-keto ester, aryl aldehyde and urea following the principles of Folkers' method, i.e., catalytic amount of acid (e.g., HCl, H2SO4) in protic solvents (e.g.,
MeOH, EtOH, AcOH) and heating to reflux for a few hours. [K. Folkers and T.B. Johnson, supra]
There are, however, several disadvantages associated with using Folkers method. First, most of the yields were either around or below 50%. Second, HPLC assays often indicate that a substantial portion of the β-keto ester and aryl aldehyde starting materials are consumed to form alkylidene side product. Third, in cases where acetic acid is used as the solvent system, large amounts of aqueous bases are needed to work up the reaction and the use of sodium bicarbonate or sodium carbonate solutions result in violent bubbling.
More recently, alternative stepwise methods for making dihydropyrimidinones have been proposed (See e.g., K.S. Atwal and B.C. O'Reilly, Heterocycles , 26 (5), 1185 (1987); H. Cho et al., J. Org. Chem., 50, 4227 (1985)]. However, these methods required several steps and the yields from these methods was still often relatively low.
Thus, a need remains for an improved method for making dihydropyrimidinones having reduced formation of unwanted side products resulting in higher yields and easier work-up.
It is therefore an object of the invention to identify an improved method for making dihydropyrimidinone compounds of formula (I).
It is a further object of the invention to identify an improved method for making aryl-dihydropyrimidinone compounds of formula (III) which are useful 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 alkoxycarbonylated as described in Cho
et al., J. Med. Chem 32, 2399 (1989)) to afford calcium channel blocking agents.
(III)
It is a further object of the invention to identify an improved method for making dihydropyrimidinone compounds of formulas (I) and (III) resulting in higher yields and easier work up than the previously known methods described above.
SUMMARY OF THE INVENTION The present invention provides a method of forming a compound of formula I
in the presence of a boron reagent, a metal salt and a catalyst to form the compound (I)
(I) wherein
R 1 , R7 and R^ are each independently selected from hydrogen, halogen, halogenated Cl -lθ 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
each R4 is independently selected from hydrogen, halogen, cyano, Cl-6 alkoxy, halogenated Cl- alkoxy, nitro, Cl -10 alkyl or halogenated Cl -10 alkyl; each R5 is independently selected from hydrogen or Cl -10 alkyl; R is selected from unsubstituted or substituted Cl -10 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 Cl -6 alkoxy; or unsubstituted or substituted aryl; and n is an integer from one to five. Preferably, R9 is hydrogen; more preferably, R^, R^ and R9 are hydrogen and the compound I has the formula
In one embodiment of the present 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 or palladium (II) acetate;
the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr PPh3 or NH4θAc;
Rl is selected from hydrogen or Cl -8 alkyl;
R2 is Ci-8 alkyl or OR6;
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.
In a class of the invention is the method further comprising the step of isolating the compound I
In a subclass of the invention is the method comprising reacting
Illustrative of the invention is the method comprising reacting
(III)
wherein all variables are as defined above (i.e., each of the variables can be defined both as described in the broadest description of the general process and as described in the first embodiment of the present invention).
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. Preferably, the solvent is selected
fro tetrahydrofuran, methanol, methylene chloride or acetic acid. Most preferably, 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-Et2θ, BF3-Me2θ, BF3 t-BuOMe, BF3 CH3OH or
BF3 CH3CH2CH2OH. Preferably, 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.
Preferably, 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. Further illustrating the invention is the method wherein the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr PPh3, NH4OAC, triethylamine, pyridine, cinchonine, quinine or quinidine. Preferably, 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.
Further exemplifying the invention is the method wherein 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. Preferably, the metal salt is copper (I) oxide, the catalyst is acetic acid and the solvent is tetrahydrofuran. Most preferably, 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,
wherein 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
each R4 is independently selected from hydrogen, halogen, cyano, Cl -6 alkoxy, halogenated Cl -6 alkoxy, nitro, Cl - 10 alkyl or halogenated Cl _io alkyl; each R5 is independently selected from hydrogen or Ci .10 alkyl;
R6 is selected from unsubstituted or substituted Cl-io alkyl wherein the substituent on the alkyl is selected from Cl -6 alkoxy, halogenated Cl -6 alkoxy or aryl; unsubstituted C3-6 cycloalkyl or mono-, di- or tri- substituted C -6 cycloalkyl wherein the substitutents on the cycloalkyl are independently selected from hydroxy, Cl-6 alkyl, halogenated
Cl -6 alkyl, Cι _6 alkoxy or halogenated Cj-6 alkoxy; or unsubstituted or substituted aryl; and n is an integer from one to five.
In one particular embodiment of this aspect of the invention, R 1 is selected from hydrogen or Cl- alkyl;
R2 is selected from Cl-8 alkyl or OR6, where R6 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.
DETAILED DESCRIPTION OF THE INVENTION
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 Cι_6 alkoxy, halogenated Cl-6 alkoxy or aryl; R2 is Cl-10 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 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
each R4 is independently selected from hydrogen, halogen, cyano, C l -6 alkoxy, halogenated Cl-6 alkoxy, nitro, Cpio alkyl or halogenated C 1 - 10 alkyl; each R5 is independently selected from hydrogen or Cl -10 alkyl;
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. Preferably, R7, R8 and R are hydrogen and the compound I has the formula
In a preferred embodiment of the instant invention is the improved process for forming 4-aryl-pyrimidinones of the formula (II) as shown below.
(II) wherein R l , R2, R4, R5; R6, R7, R8? R9 an n are as defined above. Preferably, R^, R^ and R9 are hydrogen and the compound II has the formula
In the most preferred embodiment of the instant invention is the improved process for forming 4-aryl-pyrimidinones of the formula (III) as shown below. und,
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. Preferably, the solvent is selected from tetrahydrofuran, methanol, methylene chloride or acetic acid. Most preferably, the solvent is tetrahydrofuran.
A wide array of β-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^. Moreover, in addition to aryl aldehydes, it is also possible to utilize alkyl aldehydes in the instant invention to afford alkyl - pyrimidinones of the formula (IV)
(iv)
Additionally, N-substituted ureas and O-substituted ureas (e.g., O- methylisourea) 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 reaction of β-keto ester or diketone (A), aldehyde or ketone (B) and urea (C) in one pot with an unprecedented combination of a boron reagent, a metal salt and a catalyst affords 5-(alkyl or alkoxy)carbonyl-6-alkyl-4-(aryl or alkyl)-3, 4-2(1 H)- dihydropyrimidinone (I) in higher yields than obtained by known methods. 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. More specifically, the boron reagent is selected from BF3, BF3 2H2O, BF3-Me2S, BF3 HOAC, BF3 R2O (e.g., BF3-Et2θ, BF3-Me2θ, BF3 tert-butyl methyl etherate), BF3 ROH (e.g., BF3 CH3OH, BF3 CH3CH2CH2OH). Preferably, the boron reagent is BF3-Et2θ.
A variety of metal salts can be utilized in the novel reaction of the present invention. For example, 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. Preferably, 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. More preferably, the metal salt is copper (I) oxide, copper (I) chloride, nickel (II) bromide or palladium (II) acetate. Most preferably, 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. For example, 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. Preferably, 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.
In a particularly preferred embodiment of the instant invention, 1 eq. of β-keto ester (A), 1 eq. of arylaldehyde (B), 1.5 eq.
urea (C) are reacted in the presence of 1.3 eq. BF3-Et2θ, 10 mol% Cu2θ, and 10 mol % AcOH in THF at 65 °C for 18 h to afford the dihydropyrimidinone (I) in high yield.
Abbreviations used in the instant specification are as follows:
AcOH or HO Ac = acetic acid
DMSO = dimethyl sulfoxide
Et = ethyl
EtOAc = ethyl acetate
EtOH = ethanol eq. = equivalent
Me = methyl
MeOH = methanol
MsOH = methanesulfonic acid
NH40Ac = ammonium acetate
Ph = phenyl
THF = tetrahydrofuran
The term "alkyl," as used herein, 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.).
The term "halogenated alkyl," as used herein, 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).
The term "alkoxy," as used herein, 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.).
The term "halogenated alkoxy," as used herein, 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).
The term "aryl," as used herein, refers to unsubstituted, mono-, di-, tri- or tetra- or penta-substituted aromatic groups such as phenyl or naphthyl. Preferably, me aryl group is unsubstituted, mono-, di- or tri-substituted. Examples of 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.
As used herein, the term "halogen" shall include, iodine, bromine, chlorine and fluorine.
The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples.
EXAMPLE 1
5-Methoxycarbonyl-6-methyl-4-phenyl-3. 4-dihydropyrimidin-2(l H)-one
To a dry round bottom flask containing methyl acetoacetate (0.2322 g, 2.0 mmol), benzaldehyde ( 0.2122 g, 2.0 mmol) and urea (0.18 g, 3.0 mmol) in 3.6 ml of dry THF (0.5M) was added AcOH (10mol%), CuCl (10mol%) and 1.3 equivalent of BF3-Et2θ (2.6 mmol). The reaction was heated at 65°C for 18 h. The reaction was quenched with one volume equivalent of 10% Na2C03 solution and diluted with EtOAc (one volume equivalent). The organic layer containing the product was
rurned over to toluene and the title compound was crystallized in 88% yield; mp 204-208°C.
I H NMR (250 MHz, CDC13) δ 8.08 (s, IH), 7.30 (M, 5H), 5.70 (s, IH), 5.39 (d, IH), 3.62 (s, 3H), 2.34 (s, 3H).
EXAMPLE 2
4-(3,4-Difluorophenyl)-6-ethyl-5-methoxycarbonyl-3,4-dihydro- pyrimidin-2( 1 HVone
To a dry round bottom flask containing methyl propionylacetate (2.0g, 15.4mmol), 3,4-difluorobenzaldehyde (2.1885g, 15.4mmol), and urea (1.39g, 23.1 mmol) in 28 ml of dry THF (0.5M) was added AcOH (10mol%), Cu2θ (10mol%) and 1.3 equivalent of BF3«OEt2 (20.0mmol). The reaction was heated at 65°C for 18h. Then, the reaction mixture was quenched with one volume equivalent of 10% Na2Cθ3 and diluted with one volume equivalent of EtOAc. The organic layer containing the product was turned over to toluene and the title compound was crystallized in 90% yield; mp 180-184°C.
NMR iH (250 MHz, DMSO-d6) δ 9.31 (s, IH), 7.80 (s, IH), 7.40 (m, IH), 7.20 (m, IH), 7.06 (m, I H), 5.14 (d, I H), 3.54 (s, 3H), 2.65 (m, 2H), 1.1 1 (t, 3H).
EXAMPLE 3
5-Methoxycarbonyl-6-methoxymethyl-4-(3.4-difluorophenyl -3.4- dihydropyrimidin-2( 1 H)-one
To a dry round bottom flask containing methoxy acetoacetate (2.0 g, 13.7 mmol), 3,4-difluorobenzaldehyde ( 1.95g, 13.7 mmol) and urea ( 1.23 g, 20.6 mmol) in 28 ml of dry THF (0.5M) was added AcOH (10mol%), CuCl ( 10mol%) or Cu(OAc)2 and 1.3 e.g. of BF3-Et2θ (2.6 mmol). The reaction was heated at 65°C for up to 18 h. The reaction was quenched with one volume equivalent of 10% Na2Cθ3 solution and diluted with EtOAc (one volume equivalent). The organic layer containing the product was turned over to toluene and the title compound was crystallized in 90% yield; mp: 116-120 °C.
iH NMR (250 MHz, CDCI3) δ 7.70 (br s, IH), 7.06 (m, 3H),
6.91 (br s, IH), 5.32 (s, IH), 4.62 (s, 2H), 3.63 (s, 3H), 3.44 (s, 3H).
The compounds shown below in Table 1 can be readily prepared by one of ordinary skill in the art according to the methods described in the above Examples by using readily available starting materials.
TABLE I
Chemical Name Structure
6-ethyl-5-methoxycarbonyl-
4-phenyl-3, 4-2(1 H)-dihydropyrimidinone
6-ethyl-5-methoxycarbonyl-4-(4-methoxy- phenyl)-3, 4-2(1 H)-dihydropyrimidinone
TABLE I (cont.)
Chemical Name
4-(4-chlorophenyl)-6-ethyl-5-methoxy- carbonyl-3, 4-2(1 H)-dihydropyrimidinone
6-ethyl -5 -methoxycarbonyl -4-(4-nitro- phenyl)-3, 4-2 ( lH)-dihydropyrimidinone
While the foregoing specification teaches the principles of the present invention, with examples for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.
Claims
WHAT IS CLAIMED IS:
A method of forming a compound of formula I
in the presence of a boron reagent, a metal salt and a catalyst to form the compound (I)
(I) wherein
Rl , R7 and R^ are each independently selected from hydrogen, halogen, halogenated C i _ιo 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- 10 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, C ι_ alkyl, halogenated Ci -6 alkyl, C l -6 alkoxy or halogenated Cl -6 alkoxy; R and R9 are each independently selected from hydrogen, Cpio alkyl or
each R4 is independently selected from hydrogen, halogen, cyano, Ci-6 alkoxy, halogenated Cp6 alkoxy, nitro, Cpio alkyl or halogenated Cp io alkyl; each R5 is independently selected from hydrogen or Cpio alkyl; R6 is selected from unsubstituted or substituted CpiO alkyl wherein the substituent on the alkyl is selected from Cj-6 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 Cl-6 alkoxy; or unsubstituted or substituted aryl; and n is an integer from one to five.
2. The method of Claim 1 , 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 or palladium (II) acetate;
the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr PPh3 or NH4OAC;
Rl is selected from hydrogen or Cl - alkyl;
R2 is Ci- alkyl or OR6;
R3 is selected from Cl- alkyl or 
each R4 is independently selected from hydrogen, halogen, Cl -5 alkoxy, nitro, Cl -8 alkyl or halogenated Cl - alkyl;
each R^ is independently selected from hydrogen or C 1 -8 alkyl;
R6 is Cl - alkyl;
R7, R8 and R9 are hydrogen; and
n is an integer from one to three.
3. The method of Claim 1 , further comprising the step of isolating the compound I
4. The method of Claim 3, comprising reacting
in the presence of a boron reagent, a metal salt and a catalyst to form the compound (II) 
5. The method of Claim 4, comprising reacting
(III)
6. The method of Claim 1 , wherein the reaction is carried out in one pot.
7. The method of Claim 1 , wherein the reaction is run in a solvent selected from an ether, an alcohol, a halogenated hydrocarbon or an acid.
8. The method of Claim 7, wherein the solvent is selected from tetrahydrofuran, methanol, methylene chloride or acetic acid.
9. The method of Claim 8, wherein the solvent is tetrahydrofuran.
10. The method of Claim 7, wherein the boron reagent is selected from BF3, BF3 2H2O, BF3-Me2S, BF3 HOAC, BF3-Et2θ, BF3-Me2θ, BF3 t-BuOMe, BF3 CH3OH or BF3 CH3CH2CH2OH.
1 1. The method of Claim 10, wherein the boron reagent is BF3-Et2θ.
12. The method of Claim 10, 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.
13. The method of Claim 12, wherein the metal salt is selected from copper (I) oxide, copper (I) chloride, nickel (II) bromide or palladium (II) acetate.
14. The method of Claim 13, wherein the metal salt is copper (I) oxide.
15. The method of Claim 12, wherein the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr PPh3, NH4OAC, triethylamine, pyridine, cinchonine, quinine or quinidine.
16. The method of Claim 15, wherein the catalyst is selected from acetic acid, trifluoroacetic acid or methanol.
17. The method of Claim 16, wherein the catalyst is acetic acid.
18. The method of Claim 1 1 , wherein 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.
19. The method of Claim 18, wherein the metal salt is copper (I) oxide, the catalyst is acetic acid and the solvent is tetrahydrofuran.
20. The method of Claim 19, wherein the reaction is carried out in one pot.
21. The method of Claim 20, wherein the reaction is run at a temperature range of about 40°C to 100°C.
22. The method of Claim 21 , wherein the reaction is run at a temperature of about 65°C.
23. The method of Claim 21 , wherein the reaction is heated for a period of from 1 to 20 hours.
24. The method of Claim 23, wherein the reaction is heated for about 18 hours.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NZ326039A NZ326039A (en) | 1995-12-14 | 1996-12-12 | Process for making 3,4-dihydro-pyrimidin-2(1h)-one derivatives |
| KR1019980704443A KR19990072125A (en) | 1995-12-14 | 1996-12-12 | Method for preparing dihydropyrimidinone |
| EA199800562A EA199800562A1 (en) | 1995-12-14 | 1996-12-12 | METHOD OF OBTAINING DIHYDROPYRIMIDINONS |
| SK773-98A SK77398A3 (en) | 1995-12-14 | 1996-12-12 | Process for making dihydropyrimidinones |
| AU13316/97A AU705409B2 (en) | 1995-12-14 | 1996-12-12 | Process for making dihydropyrimidinones |
| BR9611933A BR9611933A (en) | 1995-12-14 | 1996-12-12 | Process to form a compound |
| EP96944785A EP0882026A4 (en) | 1995-12-14 | 1996-12-12 | Process for making dihydropyrimidinones |
| PL96327147A PL327147A1 (en) | 1995-12-14 | 1996-12-12 | Method of obtaining dihydropyrimidinones |
| JP9522161A JP2000501734A (en) | 1995-12-14 | 1996-12-12 | Method for producing dihydropyrimidinone |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US864195P | 1995-12-14 | 1995-12-14 | |
| US60/008,641 | 1995-12-14 | ||
| GB9617968.4 | 1996-08-28 | ||
| GBGB9617968.4A GB9617968D0 (en) | 1996-08-28 | 1996-08-28 | Process for making dihydropyrimidinones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997021687A1 true WO1997021687A1 (en) | 1997-06-19 |
Family
ID=26309937
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1996/019651 WO1997021687A1 (en) | 1995-12-14 | 1996-12-12 | Process for making dihydropyrimidinones |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0882026A4 (en) |
| JP (1) | JP2000501734A (en) |
| KR (1) | KR19990072125A (en) |
| AU (1) | AU705409B2 (en) |
| BR (1) | BR9611933A (en) |
| CA (1) | CA2238924A1 (en) |
| CZ (1) | CZ184098A3 (en) |
| NZ (1) | NZ326039A (en) |
| PL (1) | PL327147A1 (en) |
| SK (1) | SK77398A3 (en) |
| WO (1) | WO1997021687A1 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999007695A2 (en) * | 1997-08-05 | 1999-02-18 | Merck & Co., Inc. | ALPHA 1a ADRENERGIC RECEPTOR ANTAGONIST |
| US6207444B1 (en) | 1997-08-05 | 2001-03-27 | Merck & Co., Inc. | Enzymatic process of making alpha 1a adrenergic receptor antagonists using protease |
| WO2003105854A3 (en) * | 2002-06-17 | 2004-04-08 | Vittal Mallya Scient Res Found | Substituted dihydropyrimidines and dihydropyrimidinethiones as calcium channel blockers |
| US7304156B2 (en) | 2001-07-13 | 2007-12-04 | Astrazeneca Uk Limited | Preparation of aminopyrimidine compounds |
| US7524955B2 (en) | 2002-12-16 | 2009-04-28 | Astrazeneca Uk Limited | Process for the preparation of pyrimidine compounds |
| US8034932B2 (en) | 2004-12-24 | 2011-10-11 | Astrazeneca Uk Limited | Chemical process |
| US8106062B1 (en) | 2002-09-12 | 2012-01-31 | Diakron Pharmaceuticals, Inc. | Calcium channel blockers |
| CN105037277A (en) * | 2015-07-09 | 2015-11-11 | 华南理工大学 | Synthesis method of 3,4-dihydropyrimidin/thinatoheterocyclic compound |
| CN105233870A (en) * | 2015-09-24 | 2016-01-13 | 齐鲁工业大学 | Pyridine ethylene coordination polymers capable of catalyzing dihydropyrimidinones synthesis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5459145A (en) * | 1988-01-19 | 1995-10-17 | Pfizer Inc. | Calcium independent camp phosphodiesterase inhibitor antidepressant |
| US5591853A (en) * | 1992-01-24 | 1997-01-07 | Lonza Ltd. | Products of a microbiological process for the production of 2-halo-pyrimidine-4-carboxylic acids |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60214778A (en) * | 1984-03-08 | 1985-10-28 | Suntory Ltd | N-substituted 3,4-dihydropyrimidine derivative, its preparation and use |
| US4675321A (en) * | 1986-02-07 | 1987-06-23 | Merck & Co., Inc. | Substituted pyrimidines useful as calcium channel blockers |
-
1996
- 1996-12-12 NZ NZ326039A patent/NZ326039A/en unknown
- 1996-12-12 KR KR1019980704443A patent/KR19990072125A/en not_active Application Discontinuation
- 1996-12-12 WO PCT/US1996/019651 patent/WO1997021687A1/en not_active Application Discontinuation
- 1996-12-12 BR BR9611933A patent/BR9611933A/en not_active Application Discontinuation
- 1996-12-12 PL PL96327147A patent/PL327147A1/en unknown
- 1996-12-12 CZ CZ981840A patent/CZ184098A3/en unknown
- 1996-12-12 SK SK773-98A patent/SK77398A3/en unknown
- 1996-12-12 JP JP9522161A patent/JP2000501734A/en active Pending
- 1996-12-12 AU AU13316/97A patent/AU705409B2/en not_active Ceased
- 1996-12-12 EP EP96944785A patent/EP0882026A4/en not_active Withdrawn
- 1996-12-12 CA CA002238924A patent/CA2238924A1/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5459145A (en) * | 1988-01-19 | 1995-10-17 | Pfizer Inc. | Calcium independent camp phosphodiesterase inhibitor antidepressant |
| US5591853A (en) * | 1992-01-24 | 1997-01-07 | Lonza Ltd. | Products of a microbiological process for the production of 2-halo-pyrimidine-4-carboxylic acids |
Non-Patent Citations (1)
| Title |
|---|
| See also references of EP0882026A4 * |
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999007695A3 (en) * | 1997-08-05 | 1999-06-17 | Merck & Co Inc | ALPHA 1a ADRENERGIC RECEPTOR ANTAGONIST |
| US6207444B1 (en) | 1997-08-05 | 2001-03-27 | Merck & Co., Inc. | Enzymatic process of making alpha 1a adrenergic receptor antagonists using protease |
| US6320049B1 (en) | 1997-08-05 | 2001-11-20 | Merck & Co., Inc. | Alpha 1a adrenergic receptor antagonists |
| WO1999007695A2 (en) * | 1997-08-05 | 1999-02-18 | Merck & Co., Inc. | ALPHA 1a ADRENERGIC RECEPTOR ANTAGONIST |
| US7816528B2 (en) | 2001-07-13 | 2010-10-19 | Astrazeneca Uk Limited | Preparation of aminopyrimidine compounds |
| US7304156B2 (en) | 2001-07-13 | 2007-12-04 | Astrazeneca Uk Limited | Preparation of aminopyrimidine compounds |
| US8614320B2 (en) | 2001-07-13 | 2013-12-24 | Astrazeneca Uk Limited | Preparation of aminopyrimidine compounds |
| US8222412B2 (en) | 2001-07-13 | 2012-07-17 | Astrazeneca Uk Limited | Preparation of aminopyrimidine compounds |
| WO2003105854A3 (en) * | 2002-06-17 | 2004-04-08 | Vittal Mallya Scient Res Found | Substituted dihydropyrimidines and dihydropyrimidinethiones as calcium channel blockers |
| US7687511B2 (en) | 2002-06-17 | 2010-03-30 | Phani Kumar Pullela | Substituted dihydropyrimidines, dihydropyrimidones and dihydropyrimidinethiones as calcium channel blockers |
| US8106062B1 (en) | 2002-09-12 | 2012-01-31 | Diakron Pharmaceuticals, Inc. | Calcium channel blockers |
| US8273878B2 (en) | 2002-12-16 | 2012-09-25 | Astrazeneca Uk Limited | Process for the preparation of pyrimidine compounds |
| US7524955B2 (en) | 2002-12-16 | 2009-04-28 | Astrazeneca Uk Limited | Process for the preparation of pyrimidine compounds |
| US8034932B2 (en) | 2004-12-24 | 2011-10-11 | Astrazeneca Uk Limited | Chemical process |
| CN105037277A (en) * | 2015-07-09 | 2015-11-11 | 华南理工大学 | Synthesis method of 3,4-dihydropyrimidin/thinatoheterocyclic compound |
| CN105037277B (en) * | 2015-07-09 | 2017-12-01 | 华南理工大学 | One kind 3, the synthetic method of 4 dihydropyrimidinonesands/thioketones heterocyclic compounds |
| CN105233870A (en) * | 2015-09-24 | 2016-01-13 | 齐鲁工业大学 | Pyridine ethylene coordination polymers capable of catalyzing dihydropyrimidinones synthesis |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0882026A4 (en) | 1999-04-07 |
| MX9804766A (en) | 1998-10-31 |
| NZ326039A (en) | 1999-08-30 |
| AU1331697A (en) | 1997-07-03 |
| CZ184098A3 (en) | 1998-11-11 |
| SK77398A3 (en) | 1999-02-11 |
| CA2238924A1 (en) | 1997-06-19 |
| KR19990072125A (en) | 1999-09-27 |
| JP2000501734A (en) | 2000-02-15 |
| AU705409B2 (en) | 1999-05-20 |
| EP0882026A1 (en) | 1998-12-09 |
| PL327147A1 (en) | 1998-11-23 |
| BR9611933A (en) | 1999-03-02 |
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