CZ184098A3 - Process for preparing dihydropyrimidinones - Google Patents

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 beta -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

The present invention provides a process for the production of 5-(alkyl or alkoxy)carbonyl-6-alkyl-4-(aryl or alkyl)-3,4-2(1H)5 dihydropyrimidinones by a combination of β-ketoester or diketone, aldehyde and urea. The reaction in particular takes place in one reactor in the presence of a reagent which is a compound of boron, a metal salt and a catalyst and provides much higher yields than are achieved by conventional methods.

Current state of the art

This application is related to US application no. 60/008,641, filed December 14, 1995, the contents of which are incorporated herein by reference.

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., US Patent No. 4,675,321, issued June 23, 1987]. Recently, a variety of dihydropyrimidinones have been identified as alpha 1a receptor antagonizing compounds useful for the treatment of benign prostatic hyperplasia (BPH) [see PCT Pub. International Patent Application No. WO 96/14846, published May 23, 1996].

The reaction of numerous aldehydes with urea and β-ketoesters to give tetrahydropyrimidinone was discovered by: Biginelli,

Gazz. Chem. Ital., 23, 360 (1893). The Biginelli reaction was studied, improved, and a mechanism for the formation of tetrahydropyrimidinone was proposed

-2 [K. Folkers and TB Johnson, J. Am. Chem. Soc., 55, 3784 (1933); JD Fissekis, and F. Sweet, J. Am. Chem. Soc., 95, 8741 (1973)]. In the past, the synthesis of dihydropyrimidinones was most often carried out using a β-ketoester, arylaldehyde and urea by the Folker method, i.e. a catalytic amount of acid (e.g. HCI, H ₂ SO ₄ ) in protic solvents (e.g. MeOH, EtOH, AcOH) and heating under reflux cooler for several hours [K. Folkers and TB Johnson, supra.1

However, there are several disadvantages associated with using Folker's method. First, most yields were around 50% or even lower. Second, HPLC analyzes often show that substantial amounts of the β-ketoester and arylaldehyde starting materials are consumed to form the alkylidene byproduct. Third, in cases where large amounts of acetic acid are used as solvents, large amounts of aqueous bases are needed to carry out the reaction, and the use of sodium bicarbonate or sodium carbonate in solutions leads to strong gas evolution.

Alternative methods for the multistep production of dihydropyrimidinones have recently 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 require several steps and their yields are often still relatively low.

Thus, there is still a need for an improved process for the production of dihydropyrimidinones that results in lower formation of undesired by-products, higher yields, and easier processing.

The essence of the invention

The object of the invention is therefore to identify an improved method for the production of dihydropyrimidinone compounds of formula (I).

(O

Another object of the invention is to identify an improved process for the production of aryldihydropyrimidinone compounds of formula (III) that are useful as calcium channel blockers or as intermediates that can be further derivatized at the N-3 position (e.g., acylated as described in US Patent No. 4,675,321, or alkoxycarbonylated as described in Cho et al., J. Med. Chem. 32, 2399 (1989)) to obtain calcium channel blocking agents.

Another object of the invention is to obtain an improved method for the production of dihydropyrimidinone compounds of formulas (I) and (III), which would lead to higher yields and easier processing than the previously known Z methods mentioned above.

The present invention provides a process for the production of a compound of formula (I)

(I) involving the reaction

O o

R ⁷ R ⁸

O

Ϊ r ⁵ hn nhr ⁵ in the presence of a reagent which is a compound of boron, a metal salt and a catalyst to form compound (I)

R ¹ , R ⁷ and R ⁸ are always independently selected from hydrogen, halogen, halogenated C 1-10 alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted

C 1-10 alkyl, wherein the alkyl substituent is selected from C _1-6 alkoxy, halogenated C _1-6 alkoxy or aryl;

R ² means Cvw alkyl, OR ⁶ , unsubstituted C ₃ -6 cycloalkyl or mono-, di- or trisubstituted C ₃ -e cycloalkyl, where the substituents on the cycloalkyl are independently selected from the group of hydroxy, Ci_s alkyl, halogenated Ci-e alkyl, C C 1-6 alkoxy or halogenated C _1-6 alkoxy;

R ³ and R ⁹ are always independently selected from hydrogen, C 1-6 alkyl or

>

-5 each R ⁴ is independently selected from the group hydrogen atom, halogen, cyano, Ci. ₆ -Alkoxy, halogenated CG-C 6-Alkoxy, nitro, C1-10 alkyl or halogenated C1-10 alkyl;

each R ^s is independently selected from hydrogen or C _1-10 alkyl;

R ⁶ is selected from unsubstituted or substituted C 1-10 alkyl, wherein the substituent on the alkyl is selected from the group Ci. _with alkoxy, halogenated Ci. ₆ alkoxy or aryl; unsubstituted C ₃ . ₆ cycloalkyl or mono-, di- or tri-substituted C ₃ . ₆ cycloalkyl where the substituents on the cycloalkyl are independently selected from the groups hydroxy, C1-8 alkyl, halogenated C1-8 alkyl, C-1. _s- Alkoxy or halogenated _C1-6- Alkoxy; or unsubstituted or substituted aryl; an is an integer from one to five. Preferably, R ⁹ is a hydrogen atom; more preferably R ⁷ , R ⁸ and R ⁹ are hydrogen atoms and compound (I) has the formula

One embodiment of the present invention is a process where the metal salt is selected from copper chloride, copper oxide, copper chloride, copper sulfate, copper acetate, nickel bromide, or palladium acetate;

the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr PPh ₃

2s or NH ₄ OAc;

R ¹ is selected from hydrogen or C _1-8 alkyl;

R ² is C 8 alkyl or OR ⁶ ;

R ³ is selected from C _1-8 alkyl or

each R ⁴ is independently selected from hydrogen, halogen, Ci. ₅ alkoxy, nitro, alkyl or halogenated C 1-6 alkyl;

each R ^s is independently selected from hydrogen or C 1-6 alkyl; R ⁶ is C 1-6 alkyl;

R ⁷ , R ⁸ and R ⁹ represent a hydrogen atom; an is an integer from one to three.

The scope of the invention also includes a method that further includes the step of isolating compound (I) n ³ _O 9

Ri R ⁵ (I)

A subgroup of the invention is a process involving a reaction

in the presence of a reagent which is a boron compound, a metal salt and a catalyst to form compound (II)

where all variables are as defined above (ie all variables can be defined both according to the broadest variant of the description of the general method and also according to the description in the first embodiment of the present invention). Preferably, R ⁹ is a hydrogen atom; more preferably, R ⁷ , R ⁸ and R ⁹ are hydrogen atoms and compound (II) has the formula

An illustration of the invention is a method comprising a reaction

About O

VA··, <^(R ⁴ )n and

CHO

NH ₂ in the presence of boron reagent, metal salt and catalyst to form compound (III)

(lol)

- 8 where all variables are as defined above (ie all variables can be defined both according to the broadest variant of the description of the general method and also according to the description in the first embodiment of the present invention).

An illustration of the invention is a method where the reaction is carried out in one reactor.

An illustration of the invention is a method where the reaction is carried out in a solvent selected from ether, alcohol, halogenated hydrocarbon or acid. The solvent is preferably selected from tetrahydrofuran, methanol, methylene chloride or acetic acid. Most preferably, the solvent is tetrahydrofuran.

An example of the invention is a method where the reagent, which is a boron compound, is selected from BF ₃ , BF ₃ -2H ₂ O, BF ₃ Me ₂ S, BF ₃ HOAc, BF ₃ Et ₂ O, BF ₃ Me ₂ O, BF ₃ t-BuOMe, BF ₃ CH ₃ OH or BF ₃ CH ₃ CH ₂ CH ₂ OH. Preferably, the boron compound is BF ₃ Et ₂ O. An example of the invention is a method in which the metal salt is selected from copper chloride, copper oxide, copper chloride, copper sulfate, copper acetate, nickel bromide, palladium acetate, copper or copper bromide, or of palladium acetoacetate. With benefit

2o is a metal salt selected from copper chloride, copper oxide, copper chloride, copper sulfate, copper acetate, nickel bromide or palladium acetate. Even more preferably, the metal salt is selected from copper oxide, copper chloride, nickel bromide or palladium acetate. Most preferably, the metal salt is copper oxide.

Another illustration of the invention is a method in which the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr PPh ₃ , NH ₄ OAc, triethylamine, pyridine, cinchonine, quinine or quinidine. Advantageously, the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid,

MsOH, dichloroacetic acid, HBrPPh ₃ or NH ₄ OAc. Still

- 9 ···· · ·· ·· ·· ·« • ·· · ·· · · ·« · • · ··»· · · · · • * »· ·· · · ···· · · ·· ···· ··» more preferably, the catalyst is selected from acetic acid, trifluoroacetic acid or methanol. Most preferably, the catalyst is acetic acid.

Another example of the invention is a method where the metal salt is selected from copper oxide, copper chloride, nickel bromide or palladium 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 oxide, the catalyst is acetic acid and the solvent is tetrahydrofuran. Most preferably, the metal salt is copper oxide, the catalyst is acetic acid, the solvent is tetrahydrofuran, and the reaction is carried out in one reactor.

The invention is better illustrated by the method where the reaction takes place at a temperature in the range of about 40°C to 100°C. Preferably, the reaction is carried out at a temperature of approximately 65°C.

An even more specific example of the invention is a method in which the reaction mixture is heated for a period of from 1 to 20 hours, preferably from 6 to 20 hours, and most preferably for approximately 18 hours. Another aspect of the invention is the compounds of formulas (IV) and (V), and their salts,

where R ¹ , R ⁷ and R ⁸ are always independently selected from the group consisting of hydrogen atom, halogen, halogenated C 1-10 alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted C 1-W alkyl where the substituent on the alkyl is selected from C 1-6 alkoxy, halogenated C 1-6 alkoxy or aryl; R ² is C 1-10 alkyl, OR ⁶ , unsubstituted C 3-s cycloalkyl or mono-, di- or trisubstituted ♦ 4

-10C ₃ -6 cycloalkyl where the substituents on the cycloalkyl are independently selected from the group of hydroxy, C _1-6 alkyl, halogenated C 1-6 alkyl, C 6 alkoxy or halogenated C 1-6 . _6- Alkoxy;

R ³ and R ⁹ are independently selected from hydrogen, C1-10 alkyl, or each R ⁴ is independently selected from hydrogen, or halogen, cyano, alkoxy, halogenated C1. ₆ alkoxy, nitro, C 1-6 alkyl or halogenated C 1-6 alkyl;

each R ⁵ is independently selected from hydrogen or C 1-6 alkyl;

R ⁶ is selected from unsubstituted or substituted C 1-10 alkyl where the substituent on the alkyl is selected from the group Ci. _6- Alkoxy, halogenated C-C 5-Alkoxy or aryl; unsubstituted C ₃ . ₆ cycloalkyl or mono-, di- or trisubstituted C _3-6 cycloalkyl, _where the substituents on the cycloalkyl are independently selected from hydroxy, C _1-6 alkyl, halogenated alkyl, C _1-6 alkoxy or halogenated C _1-6 alkoxy; or unsubstituted or substituted aryl; and

2o n is an integer from one to five.

In a specific embodiment of this aspect of the invention, R ¹ is selected from hydrogen or C _1-8 alkyl;

R ² is selected from C 6 alkyl or OR ⁶ , where R ⁶ is C _1-8 alkyl;

R ³ is selected from C _V 3 alkyl or ri

each R ⁴ is independently selected from the group hydrogen atom, halogen, cyano, C-| _5- Alkoxy, nitro, Ci. ₈ alkyl or halogenated C 1-6 alkyl;

each R ⁵ is independently selected from hydrogen or Ci. ₈ alkyl; R ⁷ , R ⁸ and R ⁹ are hydrogen; an is an integer from one to three.

The invention provides a method for the production of dihydropyrimidinones in high yields according to the following reaction scheme.

R ²

O + ³ R^R (B)

BF ₃ , metal salt O catalyst .Λ

^R8 (A)

R ⁵ HN ^Z nhr ⁵ (C)

O)

R ¹ , R ⁷ and R ⁸ are always independently selected from the group of hydrogen atom, 2o halogen, halogenated C1-10 alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted C1- _W alkyl where the substituent on the alkyl is selected from the group of alkoxy, halogenated alkoxy or aryl;

R ² is C 1 -w alkyl, OR ⁶ , unsubstituted C ₃ , ₆ cycloalkyl or 25 mono-, di- or trisubstituted C ₃ . ₆ cycloalkyl where the substituents on the cycloalkyl are independently selected from the group of hydroxy, Ci- ₆ alkyl, halogenated Ci. ₆ alkyl, alkoxy or halogenated Ci. _6- Alkoxy;

R ³ and R ⁹ are independently selected from hydrogen, C _1-10 alkyl or ·

each R ⁴ is independently selected from the group hydrogen atom, halogen, cyano, C _1-6 alkoxy, halogenated C 1-6 alkoxy, nitro, Ci. ₁₀ alkyl or halogenated C 1-10 alkyl;

each R ⁶ is independently selected from hydrogen or C 1-10 alkyl;

R ⁶ is selected from unsubstituted or substituted C 1-6 alkyl, wherein the substituent on the alkyl is selected from C 6 -alkyl, halogenated alkoxy or aryl; unsubstituted C ₃ ^ cycloalkyl or mono-, di- or trisubstituted C ₃ - ₆ cycloalkyl, wherein the substituents on the cycloalkyl are independently selected from hydroxy, C 1 - 6 alkyl, halogenated C 1 -C ₆ alkyl, C 6 -6 alkyl, or halogenated C 6 -6 alkoxy; or unsubstituted or substituted aryl; an is an integer from one to five. Preferably, R ⁷ , R ⁸ and R ⁹ are hydrogen atoms and compound (I) has the formula

In a preferred embodiment of the present invention, an improved process for the production of 4-aryl-pyrimidinones of formula (II) is as shown below.

where R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and are as defined above. Preferably, the groups R ⁷ , R ⁸ and R ⁹ are hydrogen atoms and compound (II) has

In the most preferred embodiment of the present invention, there is an improved process for the production of 4-aryl-pyrimidinones of formula (III) as shown below.

• · · · oo ^R kAA (A)

STEED'

(lil) where R ¹ , R ⁴ , R ^{s and} n are as defined above.

The compounds of formula (I), (II) and (III) are useful as calcium channel blockers and as alpha 1a antagonists. More specifically, compounds of formula (III) are particularly preferred as calcium channel blockers or as intermediates that can be further derivatized at the N-3 position (e.g., acylated as described in US Patent No. 4,675,321, or alkoxycarbonylated as described in Cho et al., J. Med. Chem. 32, 2399 (1989)) for obtaining blocking agents

2o calcium channel. Compounds of formula (III) are particularly preferred as alpha 1a antagonists, or as intermediates which can be further derivatized at the N-3 position as described in WO 96/14846, published May 23, 1996.

The reaction is carried out in one reactor in a solvent selected from an oxygenated organic solvent (eg alcohol, ether), and a halogenated hydrocarbon or acid. The solvent is preferably selected from tetrahydrofuran, methanol, methylene chloride or acetic acid. The most preferred solvent is tetrahydrofuran.

A wide range of β-ketoesters or diketones (A) and substituted benzaldehydes (B') are commercially available, which allows the production of aryldihydropyrimidinones with a wide range of substituents on the groups R ¹ , R ² and R ³ . In addition to the use of arylaldehydes, it is also possible in the present invention to use alkylaldehydes to obtain alkylpyrimidinones of the formula (IV)

In addition, N-substituted ureas and O-substituted ureas (eg, O-methylisourea) can be used in place of urea (C”) to obtain the corresponding N-substituted dihydropyrimidinones. A large number of N-substituted ureas are commercially available; these compounds can also be obtained by methods known in the art.

The ratio of starting materials is preferably 1:1:1.5 A:B:C; but changing the ratio (eg 2:1:3.1:1:3 or 2:1:1.5 A:B:C) also gave higher yields than prior art methods (eg Folker's method).

Reaction of β-ketoester or diketone (A), aldehyde or ketone (B) and urea (C) in one reactor in the first used combination Reagents which are a compound of boron, metal salt and catalyst provide

5-(alkyl or alkoxy)carbonyl-6-alkyl-4-(aryl or alkyl)-3,4-2(1H)dihydropyrimidinone (I) in higher yields than could be obtained by previously known methods. The boron compound reagent used in the present invention is BF ₃ , which is commercially available in a number of forms, all of which can be used in the process

- 16 according to the present invention. More specifically, the boron compound is selected from BF ₃ , BF ₃ -2H ₂ O, BF ₃ -.Me ₂ S, BF ₃ HOAc, BF ₃ R ₂ O (e.g. BF ₃ Et ₂ O, BF ₃ Me ₂ O, BF ₃ tert-butyl methyl etherate), BF ₃ ROH (e.g. BF ₃ CH ₃ OH, BF ₃ CH ₃ CH ₂ CH ₂ OH). Preferably, the boron compound is BF ₃ -Et ₂ O.

A variety of metal salts can be used in the novel reaction of the present invention. For example, copper chloride, copper oxide, copper chloride, copper sulfate, copper acetate, nickel bromide, palladium acetate, copper or copper bromide or palladium acetate can be used as metal salts. Preferably, the metal salt is copper chloride, copper oxide, copper chloride, copper sulfate, copper acetate, nickel bromide or palladium acetate. More preferably, the metal salt is copper oxide, copper chloride, nickel bromide or palladium acetate. Most preferably, the metal salt used is copper oxide. In the present reaction, the catalytic amounts of the metal salt are preferably up to one whole equivalent.

The catalyst used in the present reaction can be a variety of Bronsted acids or bases or an alcohol. Suitable catalysts include, but are not limited to, acetic acid,

2o trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBrPPh ₃ , NH ₄ OAc, triethylamine, pyridine, cinchonine, quinine or quinidine. Advantageously, the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr PPh ₃ or NH ₄ OAc. Even more preferably, the catalyst is selected from acetic acid, trifluoroacetic acid or methanol. Most preferably, the catalyst used is acetic acid.

The reaction can be carried out in a temperature range of approximately 40°C to approximately 100°C. Preferably, the temperature is approximately 65°C. The reaction mixture is heated for 1 to 20 hours depending on the starting materials used

3 about materials. Preferably, the reaction mixture is heated for 6 to 20 hours; preferably approximately 18 hours.

- 17 In a particularly advantageous embodiment of the present invention, one equivalent of β-ketoester (A), one equivalent of arylaldehyde (B), 1.5 equivalents of urea (C) reacts in the presence of 1.3 equivalents of BF ₃ Et ₂ O, 10 mol % Cu ₂ O, and 10 mol% AcOH in THF at 65 °C for 18 h to give the dihydropyrimidinone (I) in high yield.

The following abbreviations are used in the present invention: AcOH or HOAc = acetic acid

DMSO

Et

EtOAc

EtOH

Me

MeOH

MSOH

NH ₄ OAc

Ph.D

THF = dimethyl sulfoxide = ethyl = ethyl acetate = ethanol = methyl = methanol = methanesulfonic acid = ammonium acetate = phenyl = tetrahydrofuran

The term "alkyl" as used herein includes both straight and branched chain alkanes of a specified number of carbon atoms (e.g., C1.10 alkyl), or any number of carbon atoms in 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 straight and branched chain alkanes of a given number of carbon atoms (e.g., halogenated C1.10 alkyl), or any number of carbon atoms in that range where one or more hydrogen atoms of the alkyl chain are replaced by by a halogen atom (CF ₃ ).

The term "Alkoxy" as used herein refers to straight or branched chain alkoxides of a given number of carbon atoms (e.g. Ci. _with • · · · • · · · · · · · • · · · · · · 0 · · · • · «··· ♦ » · · • · · · »· · * «··· * ··· · · · · · · » • · ··· ·· ·· ·· ··

-18 alkoxy), or any number of carbon atoms in this range (ie, methoxy, ethoxy, etc.).

The term "halogenated alkoxy" as used herein includes both straight and branched chain alkoxides of the indicated number of carbon atoms (eg, halogenated C _1-6 alkoxy), or any number of carbon atoms in this range where one or more hydrogen atoms are replaced by halogen (e.g. OCF ₃ ).

The term "aryl" as used herein refers to unsubstituted, mono-, di-, tri- or tetra- or pentasubstituted aromatic io groups such as phenyl or naphthyl. Preferably, the aryl group is unsubstituted, mono-, di- or tri-substituted. Examples of substituents that may be present on a phenyl or naphthyl group include, but are not limited to, halogen, alkyl, Ci. ₆ alkoxy, halogenated C _1-6 alkyl or halogenated alkoxy.

As used herein, the term halogen is intended to include iodine, bromine, chlorine and fluorine.

The following examples are provided to further illustrate the present invention without, however, limiting the scope of the invention to the particular examples given.

Examples of embodiments of the invention

Example 1

5-Methoxyvcarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one

2S

AND

- 19 To a 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 (0.5 M) was added AcOH (10 mol %), CuCl (10 mol %) and 1.3 equiv of BF ₃ -Et ₂ O (2.6 mmol). The reaction mixture was heated at 65 °C for 18 h. The reaction was quenched with one volume equivalent of 10% Na ₂ CO ₃ and diluted with EtOAc (1 volume equivalent). The organic layer containing the product was taken up in toluene and the title compound was crystallized in 88% yield; melting point 204 - 208 °C.

io ¹ H NMR (250 MHz, CDCl ₃ ) δ 8.08 (s,1H), 7.30 (Μ, 5H), 5.70 (s,1H), 5.39 (d,1H), 3, 62 (s, 3H), 2.34 (s, 3H).

Example 2

4-(3,4-Difluorophenyl-6-ethyl-5-methoxycarbonyl-3,4-dihydropyrimidine-15-2(1H)-one F

To a dry round bottom flask containing methyl propionyl acetate (2.0 g, 15.4 mmol), 3,4-difluorobenzaldehyde (2.1885 g, 15.4 mmol), and urea (1.39 g, 23.1 mmol) in 28 mL of dry THF (0.5 M) was added AcOH (10 mol %), Cu ₂ O (10 mol %) and 1.3 equivalents of BF ₃ OEt ₂ (20.0

2s mmol). The reaction mixture was heated to 65 °C for 18 hours. The reaction was then quenched with one volume equivalent of 10% Na ₂ CO ₃ and diluted with one volume equivalent of EtOAc. The organic layer containing the product was taken up in toluene and titled

the compound was crystallized in 90% yield; melting point 180 184 °C.

¹ H NMR (250 MHz, DMSO-d ₆ ) δ 9.31 (s,1H), 7.80 (s,1H), 7.40 (m,1H), 7.20 (m,1H), 7 .06 (m, 1H), 5.14 (d, 1H), 3.54 (s, 3H), 2.65 (m, s 2H), 1.11 (t, 3H).

Example 3

5-Methoxycarbonyl-6-methoxymethyl-4-(3,4-difluorophenyl)-3,410

To a round bottom flask containing methoxyacetoacetate (2.0 g, 13.7 mmol), 3,4-difluorobenzaldehyde (1.95 g, 13.7 mmol) and urea (1.23 g, 20.6 mmol) in 28 mL of dry To THF (0.5 M) was added AcOH (10 mol %), CuCl (10 mol %) or Cu(OAc) ₂ and 1.3 equivalents of BF ₃ -Et ₂ O (2.6 mmol). The reaction mixture was heated to 65 °C for 18 hours. The reaction was quenched by the addition of one volume equivalent of 10% Na ₂ CO ₃ and diluted with EtOAc (one volume equivalent). The organic layer containing the product was taken up in toluene and the title compound was crystallized in 90% yield; melting point: 116 - 120 °C.

¹ H NMR (250 MHz, CDCl ₃ ) δ 7.70 (br s,1H), 7.06 (m, 3H), 6.91 (br s,1H), 5.32 (s,1H), 4 .62 (s, 2H), 3.63 (s, 3H), 3.44 (s, 3H).

• · · 4 and * 4 · · · 4 · 4 · · ·· 4 · ♦ * 44·· ·

4··· · · · ·· ·4· ·· *· ·♦ ··

-21 The compounds listed below in Table 1 can be easily prepared by a person skilled in the art by the methods described above using readily available starting materials.

⁵ Table I

Chemical name

Structure

6-ethyl-5-methoxycarbonyl-4-phenyl-3,42(1H)-dihydropyrimidinone

6-ethyl-5-methoxycarbonyl-4-(4-methoxyphenyl)-3,4-2(1H)dihydropyrimidinone

i • 4

4 > « 44

-224-(4-Chlorophenyl)-6-ethyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone

6-Ethyl-5-methoxycarbonyl-4-(4-nitrophenyl)-3,4-2(1H)-dihydropyrimidinone

Although the foregoing specification shows the principles of the present invention together with examples for the purpose of illustration, it is understood that the embodiments of the invention include all customary variations, adaptations and/or modifications as may be within the scope of the following claims and their equivalents

2o occur.

Claims (22)

A process for the preparation of a compound of formula (I) (O) comprising reacting O ³ fAr ^9a SAA R ⁷ R ^a O I HN R ⁵ NHR ⁵ in the presence of an agent which is a boron compound, a metal salt and a catalyst to form the compound (I) (I) wherein R ¹ , R ⁷ and R ⁸ are each independently selected from hydrogen, halogen, halogenated C 1-10 alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted C 1-10 alkyl, wherein the alkyl substituent is selected from C _1-6 alkoxy, halogenated C 1-4 alkoxy or aryl; ···················· <9 • 4 · 99 R ² is CVIOs alkyl, ^OR6, unsubstituted C ₃ -e cycloalkyl or mono-, di- or tri-substituted C ₃ -e cycloalkyl wherein the substitutents on the cycloalkyl are independently selected from hydroxy, Ci-e alkyl, halogenated C ₆ alkyl, C _1-6 alkoxy or halogenated C 1-6 alkoxy; R ³ and R ⁹ are each independently selected from hydrogen, C 1-10 alkyl or each R ⁴ is independently selected from hydrogen, halogen, cyano, C 1-6 alkyl; ₆ alkoxy, halogenated C 1-6; ₆ alkoxy, nitro, Ci-io alkyl, or halogenated C ₁₀ alkyl; each ^R is independently selected from hydrogen or C-io alkyl; R ⁶ is selected from unsubstituted or substituted Ci.w alkyl wherein the substituent on the alkyl is selected from the group C _vs. alkoxy, halogenated Ci-e alkoxy, or aryl; unsubstituted C ₃ . _C 6-6 cycloalkyl or mono-, di- or trisubstituted C ₃ . ₆ cycloalkyl wherein the substitutents on the cycloalkyl are independently selected from hydroxy, alkyl, halogenated alkyl, alkoxy or halogenated C alkoxy; or unsubstituted or substituted aryl; and n is an integer from one to five. The method of claim 1 wherein the metal salt is selected from cuprous chloride, cuprous oxide, cuprous chloride, cuprous sulfate, cuprous acetate, nickel bromide, or palladium acetate; 2. the catalyst is selected from acetic, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr PPh ₃ or NH ₄ OAc; R ¹ is selected from hydrogen or C _1-8 alkyl; R ² is C 1-6 alkyl or OR ⁶ ; R ³ is selected from C _1-3 alkyl or each R ⁴ is independently selected from hydrogen, halogen, C 1-5 alkoxy, nitro, C 1-6 alkyl; C ₈ alkyl or halogenated C _1-8 alkyl; each R ⁵ is independently selected from hydrogen or C _1-8 alkyl; R ⁶ to Ci. ₈ alkyl; R ⁷ , R ⁶ and R ⁹ are hydrogen atoms; and n is an integer from one to three. The method of claim 1, further comprising the step of isolating compound (I) (I). -26 10 • · · · 9 99 9 9 9 9 9 9 9 99 99 99 9 9 9 9 9 9 9 99 99 99 9999 8 9 9 9 9 9 The method of claim 3, wherein and O Λ ₅ H, N ^from NHR ⁵ in the presence of a boron compound, a metal salt and a catalyst to form compound (II) The method of claim 4, comprising the reaction - (R ⁴ ) n ^{R 1, R 1,} and _D 6 and STEED CHO O Λ h ₂ n ^/ nh ₂ in the presence of a reagent that is a boron compound, a metal salt and a catalyst to form compound (III) (III) · * * * • • • • • • • • • • • • • • • • • • • • • • The process of claim 1, wherein the reaction is carried out in a single reactor. A method according to claim 1, characterized in that Wherein the reaction is carried out in a solvent selected from the group of ether, alcohol, halogenated hydrocarbon or acid. 8. The process of claim 7 wherein the solvent is selected from tetrahydrofuran, methanol, 10 methylene chloride or acetic acid. 9. The process of claim 8 wherein the solvent is tetrahydrofuran. 15 Dec The method of claim 7, wherein the boron compound agent is selected from BF ₃ , BF ₃ -2H ₂ O, BF ₃ Me ₂ S, BF ₃ HOAc, BF ₃ -Et ₂ O, BF ₃ Me ₂ O, BF ₃ tBuOMe, BF ₃ -CH ₃ OH or BF ₃ CH ₃ CH ₂ CH ₂ OH. 20 May The method of claim 10, wherein the boron compound is BF ₃ Et ₂ O. The method of claim 10, wherein the metal salt is selected from cuprous chloride, an oxide Copper (II), copper (I) chloride, copper (II) sulfate, copper (II) acetate, nickel (II) bromide, palladium (II) acetate, copper or copper (II) bromide or palladium (II) acetate. The method of claim 12, wherein the metal salt is selected from cuprous oxide, cuprous chloride, nickel bromide, or palladium acetate. 14. The process of claim 13 wherein the metal salt is cuprous oxide. 15. The method of claim 12, wherein also the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr _PPh3 NH ₄ 0Ac, triethylamine, pyridine, cinchonine, quinine or quinidine . 15 Dec 16. The process of claim 15 wherein the catalyst is selected from acetic acid, trifluoroacetic acid or methanol. A method according to claim 16, characterized in that 20 wherein the catalyst is acetic acid. The method of claim 11, wherein the metal salt is selected from cuprous oxide, cuprous chloride, nickel bromide, or palladium 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 process of claim 18 wherein the metal salt is selected from cuprous oxide, the catalyst is acetic acid, and the solvent is tetrahydrofuran. 5 20. The process of claim 19 wherein the reaction is carried out in a single reactor. The method of claim 20, wherein the reaction is carried out at a temperature in the range of about 40 ° C to 100 ° C. The method of claim 21, wherein the reaction is carried out at a temperature of about 65 ° C. 15 Dec The process of claim 21, wherein the reaction mixture is heated for from 1 to 20 hours. 24. The process of claim 23, wherein the reaction mixture is heated for about 18 hours.