SK77398A3 - Process for making 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

Process for preparing dihydropyrimidinones

Technical field

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

BACKGROUND OF THE INVENTION

This application is related to U.S. Pat. 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 agents against elevated blood pressure [cf. 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. Pat. No. 4,675,321, issued June 23, 1987]. Recently, a variety of dihydropyrimidinones have been identified as alpha 1A receptor antagonist compounds useful for the treatment of benign prostatic hyperplasia (BPH) [see, e.g. PCT published international patent application no. WO 96/14846, published May 23, 1996].

The reaction of many aldehydes with urea and β-ketosteres to give tetrahydropyrimidinones has been discovered by Biginelli, Gazz. Chim. Ital., 23, 360 (1893). The Biginelli reaction has been studied, improved and a mechanism for the formation of tetrahydropyrimidinone has been 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)]. In the past, the synthesis of dihydropyrimidinones was most commonly performed using the β-ketoester, arylaldehyde and urea by the Folker method, i. catalyst

-2-amount of acid (e.g. HCl, H ₂ SO ₄ ) in protic solvents (e.g. MeOH, EtOH, AcOH) and refluxing for several hours [K. Folkers and TB Johnson, supra],

However, several disadvantages are associated with the use of the Folker 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 by-product. Third, in cases where a large amount of acetic acid is used as the solvent, a large amount of aqueous bases is required to carry out the reaction, and the use of sodium bicarbonate or sodium carbonate in the solutions results in a strong gas evolution.

Recently, alternative methods have been devised for the production of dihydropyrimidinones in several steps [cf. for example, K. S. Atwal and B. C. O'Reilly, Heterocycles, 26 (5), 1185 (1987); H. Oho et al., J. Org. Chem. 50, 4227 (1985)]. However, several steps are necessary for these methods and their yields are often still relatively low.

Accordingly, there is still a need for an improved process for the production of dihydropyrimidinones which results in less undesirable by-products, higher yields and easier processing.

SUMMARY OF THE INVENTION

It is therefore an object of the invention to identify an improved process for the production of dihydropyrimidinone compounds of formula I.

(I)

Another object of the invention is to identify an improved process for the preparation of aryldihydropyrimidinone compounds of formula III which are useful as calcium channel blockers or 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.

(III)

It is a further object of the invention to provide an improved process for the preparation of the dihydropyrimidinone compounds of formulas I and III, which would result in higher yields and easier processing than the previously known methods mentioned above.

The present invention provides a process for the preparation of a compound of formula I

(I) involving the reaction

in the presence of a boron compound, a metal salt and a catalyst to form compound I

wherein R ¹ , R ⁷ and R ⁸ are each independently selected from hydrogen, halogen, halogenated alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted C 1-6 alkyl, wherein the alkyl substituent is selected from alkoxy, halogenated alkoxy or aryl ;

R ² is C ^ Q alkyl, ^OR6, unsubstituted C _{3. 6} cycloalkyl or mono-, di- or tri-substituted C _{3. 6} cycloalkyl, wherein the substituents on the cycloalkyl are independently selected from hydroxy, _v6 alkyl, halogenated _Ο ν6 alkyl, halogenated alkoxy or _{v6 Ο} ν6 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, alkoxy _{V6, Ο} ν6 halogenated alkoxy, nitro, C ^ Q alkyl or halogenated Ο,., ο alkyl;

each R ⁵ is independently selected from hydrogen or Ο _1-10 alkyl;

R ⁶ is selected from unsubstituted or substituted Ο; ₁₀ alkyl, wherein the substituent on the alkyl is selected from C _v6 alkoxy, halogenated _Ο ν6 alkoxy or aryl; unsubstituted C ₃ . ₆ cycloalkyl or mono-, di- or tri-substituted C _{3. 6} cycloalkyl, wherein the substituents on the cycloalkyl are independently selected from hydroxy, alkyl, halogenated _Ο ν6 alkyl, alkoxy or halogenated _{V6 Ο} ν6 alkoxy; or unsubstituted or substituted aryl; and n is an integer from 1 to 5. Preferably, R ⁹ is hydrogen; 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 method wherein the metal salt is selected from copper (I) chloride, copper (I) oxide, copper (I) chloride, copper (II) sulfate, copper (II) acetate, nickel (II) or palladium (II) bromide; 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 1-6 alkyl;

R ² is. Alkyl, β alkyl or OR ⁶ ;

R ³ is selected from 0 ,. ₈ alkyl, or

each R ⁴ is independently selected from hydrogen, halogen, C _1-5 alkoxy, nitro, C 1-6 alkyl or halogenated C 1-6 alkyl;

each R ⁵ is independently selected from hydrogen or C ₁₈ alkyl;

R ⁶ is C _V8 alkyl;

R ⁷ , R ⁸ and R ⁹ are hydrogen; and n is an integer from 1 to 3.

Also within the scope of the invention is a process further comprising the step of isolating the compound of formula I

-6 (I)

A subgroup of the invention is a process comprising the reaction

in the presence of a boron compound, a metal salt and a catalyst to form a compound of formula II

(H) wherein all variables are as defined above (ie all variables may be defined according to the broadest variant of the description of the general method as well as 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 the compound of formula II has the formula

An illustration of the invention is a process comprising a reaction

OR ⁶

in the presence of a boron reagent, a metal salt and a catalyst to form a compound of formula III

(III) wherein all variables are as defined above (i.e., all variables may be defined according to both the broadest variant of the general method description and the description in the first embodiment of the present invention).

An illustration of the invention is a process wherein the reaction is carried out in a single reactor.

Illustrative of the invention is a process wherein the reaction is carried out in a solvent selected from an ether, an alcohol, a halogenated hydrocarbon or an acid. Preferably, the solvent is selected from tetrahydrofuran, methanol, methylene chloride or acetic acid. The most preferred solvent is tetrahydrofuran.

An example of the invention is a method 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 -t-BuOMe

-8BF 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, cuprous oxide, cuprous chloride, cuprous sulfate, cuprous acetate, nickel bromide, acetate, palladium, cuprous bromide or. copper (II) or palladium (II) acetacetate. Preferably, the metal salt is selected from cuprous chloride, cuprous oxide, cuprous chloride, cuprous sulfate, cuprous acetate, nickel bromide or palladium acetate. Even more preferably, the metal salt is selected from cuprous oxide, cuprous chloride, nickel bromide or palladium acetate. Most preferably, the metal salt is copper (I) oxide.

Another embodiment of the invention is a process wherein the catalyst is selected from acetic, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr.PPh ₃ , NH ₄ OAc triethylamine, pyridine, cinchonine, quinine or quinidine. Preferably, the catalyst is selected from acetic, 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. The most preferred catalyst is acetic acid.

Another example of the invention is a method 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. Preferably, the metal salt is cuprous oxide, the catalyst is acetic acid, and the solvent is tetrahydrofuran. Most preferably, the metal salt is cuprous oxide, the catalyst is acetic acid, the solvent is tetrahydrofuran, and the reaction is carried out in a single reactor.

The invention better illustrates a process wherein the reaction is carried out at a temperature in the range of about 40 ° C to 100 ° C. Preferably, the reaction is carried out at a temperature of about 65 ° C.

An even more specific example of the invention is a process in which the reaction mixture is heated for from 1 to 20 hours, preferably from 6 to 20 hours, and most preferably about 18 hours.

A further object of the invention are compounds of formulas IV and V and salts thereof,

0 C _1-8 alkyl 0 R ³ R ⁹ VR ⁸ jp NR ⁵ _R0 alkyl C T | NR ⁵ R ⁸ , R ⁷ - ¥ R ¹ Ŕ ⁵ R ⁹ and R ¹ 'νΆ Ŕ ⁵ (IV) (IN)

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 substituent on the alkyl is selected from 0 1-6 alkoxy, halogenated alkoxy or aryl; R ² is a Ο, .10 alkyl, ^OR6, unsubstituted C _{3. 6} cycloalkyl or mono-, di- or tri-substituted C ₃ cycloalkyl, wherein the substituents on the cycloalkyl are independently selected from hydroxy, 0 ,. C _1-6 alkyl, halogenated with 0-6. C _1-6 alkyl, C _1-6 alkoxy or halogenated O 2; ₆ alkoxy;

R ³ and R ⁹ are independently selected from hydrogen, Ο,. ₁₀ alkyl or

each R ⁴ is independently selected from hydrogen, halogen, cyano, O,. ₆ alkoxy, halogenated C ₆ alkoxy, nitro, Ο ,. C ₁₀ alkyl or halogenated C 1-6 alkyl. ₁₀ alkyl;

each R ⁵ is independently selected from hydrogen or Ο. ₁₀ alkyl;

R ⁶ is selected from unsubstituted or substituted C 1-6 alkyl, wherein the substituent on the alkyl is selected from C 1-6 alkyl. ₆ alkoxy, halogenated 0 ,. ₆ alkoxy or aryl; unsubstituted C ₃ . ₆ cycloalkyl or mono-, di- or tri-substituted C _3. C 6-6 cycloalkyl wherein the substituents on the cycloalkyl are independently selected from hydroxy, C _1-6 cycloalkyl; ₆ alkyl,

-Halogenated C 1. C _1-6 alkyl. ₆ alkoxy or halogenated C _1-6 alkoxy; ₆ alkoxy; or unsubstituted or substituted aryl; and n is an integer from 1 to 5.

In a particular embodiment of the invention is

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

R ² is selected from C 18 alkyl or OR ⁶ wherein R ⁶ is C 18 alkyl;

R ³ is selected from C 1-6. ₈ alkyl, or

each R ⁴ is independently selected from hydrogen, halogen, cyano, 0, 5 alkoxy, nitro, Ο, β alkyl or halogenated C 1-6 alkyl; ₈ alkyl;

each R ⁵ is independently selected from hydrogen or C 1-6 alkyl. _C8 alkyl;

R ⁷ , R ⁸ and R ⁹ are hydrogen; and n is an integer from 1 to 3.

The invention provides a process for producing dihydropyrimidinones in high yields according to the following reaction scheme:

BF ₃ , metal salt, O catalyst ⁺ A, Δ

R ⁵ HN ^Z NHR ⁵ C

(D

R ^@ 11, R ^{@ 7} and R @ ⁸ are each independently selected from hydrogen, halogen, halogenated. ₁₀ alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted by alkyl ,. ™, wherein the susbtituent the alkyl is selected from the group Ο and _6, alkoxy, halogenated Ο ,. ₆ alkoxy or aryl;

R ^{2 e} j θι ιο-alkyl, ^OR6, unsubstituted C _{3. 6} cycloalkyl or mono-, di- or tri-substituted C _{3. 6} cycloalkyl, wherein the substituents on the cycloalkyl are independently selected from hydroxy, Ο ,. ₆ alkyl, halogenated; _C1-6 alkyl, 0-6 alkoxy or halogenated 0-6 alkyl; ₆ alkoxy;

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

each R ⁴ is independently selected from hydrogen, halogen, cyano, 0, _ ₆ alkoxy, halogenated 0 ,. ₆ alkoxy, nitro, Ο,. C ₁₀ alkyl or halogenated C 1-6 alkyl. ₁₀ alkyl;

each R ⁶ is independently selected from hydrogen or C ^1-6 alkyl; 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 of alkoxy, halogenated with 0, 1, 2, 3, 4, 10, or 10; ₆ alkoxy or aryl; unsubstituted C ₃ . ₆ cycloalkyl or mono-, di- or tri-substituted C _3. C 6-6 cycloalkyl wherein the substituents on the cycloalkyl are independently selected from hydroxy, C _1-6 cycloalkyl; C ₆ alkyl. C _1-6 alkyl, O,. ₆ alkoxy; or unsubstituted or substituted aryl; and n is an integer from 1 to 5. 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, the method of manufacture is improved

4-aryl-pyrimidinones of formula II as shown below.

BF ₃ , metal salt, AcOH

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

In a most preferred embodiment of the present invention, the process for producing 4-arylpyrimdinones of formula III is improved as shown below.

-13 (Α)

(C)

BF ₃ , Cu compound, AcOH_____

Δ

(H1) wherein R ¹ , R ⁴ , R ⁶ and n are as defined above.

The compounds of formula I, II and III are useful as calcium channel blockers and as α 1a antagonists. More particularly, the compounds of formula III are particularly useful as calcium channel blockers or as intermediates which 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. Compounds of formula III are particularly preferred as α 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 a single reactor in a solvent selected from an oxygenated organic solvent (e.g., alcohol, ether) and a halogenated hydrocarbon or acid. Preferably, the solvent is selected from tetrahydrofuran, methanol, methylene chloride or acetic acid. The most preferred solvent is tetrahydrofuran.

A variety of β-ketoesters or diketones (A) and substituted bezaldehydes (B ') are commercially available, making it possible to produce aryldihydropyrimidinones with a wide range of substituents from 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 the alkylpyrimidinones of formula IV

(IV)

In addition, N-substituted ureas and O-substituted ureas (e.g., O-methylisourea) can be used instead of urea (C ') to yield the corresponding N-substituted dihydropyrimidinones. A variety of N-substituted ureas are commercially available; these compounds can also be obtained by methods known in the art.

The ratio of the starting materials is preferably 1: 1: 1.5 A: B: C; but changing the ratio (e.g., 2: 1: 3, 1: 1: 3 or 2: 1: 1.5 A: B: C) also yielded higher yields than prior art methods (e.g., the Folker method).

Reaction of β-ketoester or diketone (A), aldehyde or ketone (B) and urea (C) in a single reactor in a first-used combination of a boron compound, a metal salt and a catalyst provides 5- (alkyl or alkoxy) -carbonyl6- alkyl-4- (aryl or alkyl) -3,4-2 (1H) -dihydropyrimidinone of formula I in higher yields than can be obtained by known methods. The boron compound agent used in the present invention is BF ₃ , which is commercially available in a variety of forms that can be used in the method of the present invention. More particularly, the boron compound is selected from F _3, BF ₃ .2H ₂ O, BF ₃ * HOAc, BF _3, R ₂ O (e.g., BF ₃ · Et ₂ O, BF ₃ .Me ₂ O, BF ₃ .terc.butylmetyleterát) .

-15BF 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. As the metal salts, for example, copper (I) chloride, copper (I) oxide, copper (I) chloride, copper (II) sulfate, copper (II) acetate, nickel (II) bromide, palladium (II) acetate, copper or copper (II) bromide or palladium (II) acetate. Preferably, the metal salt is copper (I) chloride, copper (I) oxide, copper (I) chloride, copper (II) sulfate, copper (II) acetate, nickel (II) bromide or palladium (II) cotane. More preferably, the metal salt is copper (I) oxide, copper (I) chloride, nickel (II) bromide or palladium (II) acetate. The most preferred metal salt used is cuprous oxide. In the present reaction, catalytic amounts of the metal salt are preferably up to one whole equivalent.

The catalyst used in the present reaction may be a variety of Bronsted acids or bases or an alcohol. Preferred catalysts include, but are not limited to, acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr.PPh ₃ , NH ₄ OAc, triethylamine, pyridine, cinchonine, quinine, or quinidine. Preferably, the catalyst is selected from acetic, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr.PPh ₃ or NH ₄ OAc. Even more preferred is a catalyst selected from acetic acid, trifluoroacetic acid or methanol. The most preferred catalyst used is acetic acid.

The reaction may be carried out in a temperature range of about 40 ° C to about 100 ° C. Preferably, the temperature is about 65 ° C. The reaction mixture is heated for 1 to 20 hours, depending on the starting materials used. Preferably, the reaction mixture is heated for 6 to 20 hours, most preferably about 18 hours.

In a particularly preferred embodiment of the present invention, one equivalent of β-ketoester (A), one equivalent of arylaldehyde (B), 1.5 equivalents of urea (C) 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 hours to give the dihydropyrimidinone of formula I in high yield.

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

DMSO = dimethyl sulfoxide

DMSO

et

EtOAc

EtOH = ethyl = ethyl acetate = ethanol

Me

MeOH = methyl = methanol

MsOH

NH ₄ OAc

ph

THF = methanesulfonic acid = ammonium acetate = phenyl = tetrahydrofuran

The term "alkyl" as used herein includes both straight and branched chain alkanes with a specific number of carbon atoms (e.g., Ο,., Alkyl) or any number of carbon atoms in that range (ie, 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 a given number of carbon atoms (e.g., halogenated Ο, ₁₀ alkyl), or with any number of carbon atoms within this range, wherein one or more hydrogen atoms of the alkyl chain is replaced 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., napríklad, θ alkoxy) or any number of carbon atoms in that range (i.e., methoxy, ethoxy, and the like).

The term "halogenated alkoxy" as used herein includes straight and branched chain alkoxides of the specified number of carbon atoms (e.g., halogenated C _1-6 alkoxy) or any number of carbon atoms within this range wherein one or more hydrogen atoms are replaced with a halogen atom ( for example OCF ₃ ).

The term "aryl" as used herein refers to unsubstituted mono-, di-, tri- or tetra- or pentasubstituted aromatic groups such as phenyl or naphthyl. Preferably, the aryl group is unsubstituted, mono-, di- or trisubstituted.

-17Príklady substituents which may be present on the phenyl or naphthyl group include, without limitation, halo, alkyl _Ο ν6, _Ο ν6 alkoxy, halogenated alkyl, C _V6 C _V6 or a halogenated alkoxy.

The term "halogen" as used herein includes iodine, bromine, chlorine or fluorine.

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

DETAILED DESCRIPTION OF THE INVENTION

Example 1

5-methoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidine-2 (1H) -one

CH ₃ O

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

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

-18Example 2

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

To a dry round 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 dry THF (0.5 M) were added AcOH (10 mol%), Cu ₂ O (10 mol%) and 1.3 equivalents of BF ₃ OEt ₂ (20.0 mmol). The reaction mixture was heated at 65 ° C for 18 hours. Then the reaction was 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 the title compound crystallized in 90% yield; mp 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, 2H), 1.11 (t, 3H).

Example 3

5-methoxycarbonyl-6-methoxymethyl-4- (3,4-difluorophenyl) -3,4-dihydropyrimidine-2 (1H) -one

MeO

-19 To a round 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 dry 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 at 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 crystallized in 90% yield; mp 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).

The compounds listed in Table 1 below can be prepared by one of ordinary skill in the art using readily available starting materials as described above.

Table 1

Chemical name

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

6-ethyl-5-methoxycarbonyl-4- (4-methoxyphenyl) -

3,4-2 (1H) -dihydropyrimidinone structure

CH ₃ O

OCH ₃

CH ₃ O

-204- (4-chloro-phenyl) -6-ethyl-5-methoxycarbonyl-

3,4-2 (1H) -dihydropyrimidinone

6-ethyl-5-methoxycarbonyl-4- (4-nitrophenyl) -

3,4-2 (1H) -dihydropyrimidinone

While the foregoing specifications illustrate the principle of the present invention, along with examples to illustrate, it is understood that embodiments of the invention include all conventional variations, adaptations and / or modifications as may occur within the following claims and their equivalents.

Claims (24)

PATENT CLAIMS A process for the preparation of a compound of formula I / 7 # 43 (D) comprising the reaction NHR ⁵ in the presence of a boron compound, a metal salt and a catalyst to form a compound 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 _Ο νι0 or substituted alkyl wherein the substituent on the alkyl is selected from 0, .6 alkoxy, halogenated C _V6 alkoxy or aryl; R ² represents C 1-4 alkyl, OR ⁶ , unsubstituted C 3. ₆ cycloalkyl or mono-, di- or tri-substituted C _{3. 6} cycloalkyl, wherein the substituents on the cycloalkyl are independently selected -22zo hydroxy, _Ο ν6 alkyl, halogenated C _v6 alkyl, alkoxy or halogenated alkoxy _Ο ν6; 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} alkoxy, halogenated alkoxy, nitro, C 1-6 alkyl or halogenated 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, wherein the substituent on the alkyl is selected from alkoxy, halogenated C _1-6 alkoxy or aryl; unsubstituted C ₃ . ₆ cycloalkyl or mono-, di- or tri-substituted C _{3. 6} cycloalkyl, wherein the substituents on the cycloalkyl are independently selected from hydroxy, alkyl, halogenated _Ο ν6 alkyl, alkoxy or halogenated _V6 C _V6; alkoxy; or unsubstituted or substituted aryl; and n is an integer from 1 to 5. The method of claim 1, wherein the metal salt is selected from copper (I) chloride, copper (I) oxide, copper (I) chloride, copper (II) sulfate, copper (II) acetate, nickel (II) or palladium (II) bromide; the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr-PPh ₃ or NH ₄ OAc; R ¹ is selected from hydrogen or Ο; _C8 alkyl; R ² is C ₁₈ alkyl or OR ⁶ ; R ³ is selected from C _1-8 alkyl; Each R ⁴ is independently selected from hydrogen, halogen, alkoxy, nitro, _{ν 18} alkyl or halogenated _{ν 18} alkyl; each R ⁵ is independently selected from hydrogen or Ο _1-8 alkyl; R ⁶ is 0, 8 alkyl; R ⁷ , R ⁸ and R ⁹ are hydrogen; and n is an integer from 1 to 3. The method of claim 1, further comprising the step of isolating the compound of Formula I (I) A process according to claim 3, comprising reacting in the presence of a boron compound, a metal salt and a catalyst to form a compound of formula II (n). 5. The process of claim 4, comprising reacting in the presence of a boron reagent, a metal salt, and a catalyst to form a compound of formula III. Process according to claim 1, characterized in that the reaction is carried out in a single reactor. The process of claim 1, wherein the reaction is carried out in a solvent selected from an ether, an alcohol, a halogenated hydrocarbon, or an acid. The process of claim 7, wherein the solvent is selected from tetrahydrofuran, methanol, methylene chloride or acetic acid. 9. The process of claim 8 wherein the solvent is tetrahydrofuran. The method of claim 7, wherein the 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. The method of claim 10, wherein the boron compound agent is BF ₃ .Et ₂ O. The method of claim 10, wherein the metal salt is selected from copper (I) chloride, copper (I) oxide, copper (I) chloride, copper (II) sulfate, copper (II) acetate, nickel (II) bromide, palladium (II) acetate, copper (I) bromide or acetacetate. palladium. The method of claim 12, wherein the metal salt is selected from cuprous oxide, cuprous chloride, nickel bromide or palladium acetate. 14. The method of claim 13, wherein the metal salt is cuprous oxide. The process according to claim 12, wherein 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. 16. The process of claim 16, wherein the catalyst is selected from acetic acid, trifluoroacetic acid or methanol. 17. The process of claim 16, 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 copper oxide, the catalyst is acetic acid, and the solvent is tetrahydrofuran. The process according to claim 19, wherein the reaction is carried out in a single reactor. The process 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. 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.