AU705409B2 - Process for making dihydropyrimidinones - Google Patents
Process for making dihydropyrimidinones Download PDFInfo
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- AU705409B2 AU705409B2 AU13316/97A AU1331697A AU705409B2 AU 705409 B2 AU705409 B2 AU 705409B2 AU 13316/97 A AU13316/97 A AU 13316/97A AU 1331697 A AU1331697 A AU 1331697A AU 705409 B2 AU705409 B2 AU 705409B2
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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
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Description
Process for Making Dihydropyrimidinones Field of the Invention The present invention provides a process for forming 5-(alkyl or alkoxy)carbonyl-6alkyl-4-(aryl or alkyl)-3, 4 -2(1H)-dihydropyrimidinones by combining a p-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 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 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 hyperplasia (BPH). [See PCT International 15 Patent Application publication no. W096/14846, published 23 May 1996] The reaction of numerous aldehydes with urea and a p-keto ester to give a tetrahydropyrimidinone was discovered by [Biginelli, Gazz. Chim. Ital., 23, 360 (1893)].
The Biginelli reaction has been studied, improved upon and a mechanism of formation of tetrahydropyrimidinone proposed. Folkers and T.B. Johnson, J. Am. Chem. Soc., 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 p-keto ester, aryl aldehyde and urea following the principles of Folkers' methods, catalytic amount of acid HC1, H2SO 4 in protic solvents [N:\LIBC03829:MEF WO 97/21687 PCT/US96/19651 -2- MeOH, EtOH, AcOH) and heating to reflux for a few hours. 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 P-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 K.S. Atwal and B.C.
O'Reilly, Heterocycles 26 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 0
R
3 R9 R2 N-R
R
8 R N l O R1
R
s
(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 acylated as described in U.S. Patent No. 4,675,321, or alkoxycarbonylated as described in Cho WO 97/21687 PCT/US96/19651 -3et al., J. Med. Chem 32, 2399 (1989)) to afford calcium channel blocking agents.
0 R 4 n i NH (IIl) It is a further object of the invention to identify an improved method for making dihydropyrimidinone compounds of formulas and (III) resulting in higher yields and easier work up than the previously known methods described above.
SUMMARY OF THE INVENTION 0 The present invention provides a method of forming a compound of formula I
R
(1) comprising reacting 0 0
R
7
R
8
R
7
R
8
O
3 R R 9 and R IHN
R
5 HN NHR in the presence of a boron reagent, a metal salt and a catalyst to form the compound (I) WO 97/21687 PCT/US96/19651 -4- 0 R3 R9 R2 N-R R1 R
(I)
wherein
R
1
R
7 and R 8 are each independently selected from hydrogen, halogen, halogenated Ci-10 alkyl, unsubsituted or substituted aryl, or unsubstituted or substituted C 1-10 alkyl wherein the substituent on the alkyl is selected from C1-6 alkoxy, halogenated C1-6 alkoxy or aryl;
R
2 is C1-10 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, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy or halogenated C1-6 alkoxy;
R
3 and R 9 are each independently selected from hydrogen, C1-10 alkyl or A-
(R
4 )n each R 4 is independently selected from hydrogen, halogen, cyano, C1-6 alkoxy, halogenated C1-6 alkoxy, nitro, CI-10 alkyl or halogenated C -10 alkyl; each R 5 is independently selected from hydrogen or CI-10 alkyl;
R
6 is selected from unsubstituted or substituted C -10 alkyl wherein the substituent on the alkyl is selected from C1-6 alkoxy, halogenated C1-6 alkoxy or aryl; unsubstituted C3-6 cycloalkyl or mono-, di- or trisubstituted C3-6 cycloalkyl wherein the substitutents on the cycloalkyl are independently selected from hydroxy, C1-6 alkyl, halogenated C 1-6 alkyl, C1-6 alkoxy or halogenated C1-6 alkoxy; or unsubstituted or substituted aryl; and n is an integer from one to five. Preferably, R 9 is hydrogen; more preferably, R 7
R
8 and R 9 are hydrogen and the compound I has the formula WO 97/21687 PCT/US96/19651 0 R 3 R2- N-R N 0
R
1
R
In one embodiment of the present invention is the method wherein the metal salt is selected from copper chloride, copper oxide, copper (II) chloride, copper (II) sulfate, copper (II) acetate, nickel (II) bromide or palladium acetate; the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr-PPh3 or R1 is selected from hydrogen or C1-8 alkyl;
R
2 is C1-8 alkyl or OR 6
R
3 is selected from Cl-8 alkyl or k (R4)n each R 4 is independently selected from hydrogen, halogen, C1-5 alkoxy, nitro, C1-8 alkyl or halogenated C1-8 alkyl; each R5 is independently selected from hydrogen or Cl-8 alkyl;
R
6 is C1-8 alkyl;
R
7
R
8 and R 9 are hydrogen; and WO 97/21687 PCT/US96/19651 -6n 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 O
R
3 R9 R 2 R' N N -R
R
8
R'
R
1
R
(I)
In a subclass of the invention is the method comprising reacting 0 0 (R 4 )n 0 2 ,C(0)Rand H2N in the presence of a boron reagent, a metal salt and a catalyst to form the compound (II) S(R 4)
O
R9 R2 NH R
I
R
1
R
(11) wherein all variables are as defined above 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). Preferably, R 9 is hydrogen; more preferably, R 7
R
8 and R 9 are hydrogen and the compound II has the formula WO 97/21687 PCT/US96/19651 -7- Illustrative of the invention is the method comprising reacting 0 0 (R4)n R lOR 6
CHO
0 and
H
2 N iNH 2 in the presence of a boron reagent, a metal salt and a catalyst to form the compound (III)
(III)
wherein all variables are as defined above 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 WO 97/21687 PCT/US96/19651 -8from 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-Et20, BF3-Me20, BF3-t-BuOMe, BF3-CH30H or BF3-CH3CH2CH20H. Preferably, the boron reagent is BF3*Et20.
An example of the invention is the method wherein the metal salt is selected from copper chloride, copper 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 chloride, copper (I) oxide, copper (II) chloride, copper (II) sulfate, copper acetate, nickel (II) bromide or palladium acetate. More preferably, the metal salt is selected from copper oxide, copper chloride, nickel (II) bromide or palladium (II) acetate. Most preferably, the metal salt is copper 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, 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 NH40Ac. 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 oxide, copper 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 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 pot.
WO 97/21687 PCT/US96/19651 -9- More particularly illustrating the invention is the method wherein the reaction is run at a temperature range of about 40 0 C to 100'C. Preferably, the reaction is run at a temperature of about 65 0
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 and salts thereof, 0 C1-8 alkyl 0 R 3
R
9 R N-R 5 C,-a alkyl N-R RR N O and R N O
R
1
R
5
R
1
R
(IV)
(V)
wherein R1, R 7 and R 8 are each independently selected hydrogen, halogen, halogenated C -10 alkyl, unsubsituted or substituted aryl, or unsubstituted or substituted C -10 alkyl wherein the substituent on the alkyl is selected from C1-6 alkoxy, halogenated C1-6 alkoxy or aryl;
R
2 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, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy or halogenated C1-6 alkoxy;
R
3 and R 9 are each independently selected from hydrogen, CI-10 alkyl or
(R
4 )n each R 4 is independently selected from hydrogen, halogen, cyano, C1-6 alkoxy, halogenated C1-6 alkoxy, nitro, C- 10 alkyl or halogenated CI-10 alkyl; each R 5 is independently selected from hydrogen or C1-10 alkyl; WO 97/21687 PCT/US96/19651
R
6 is selected from unsubstituted or substituted C -10 alkyl wherein the substituent on the alkyl is selected from C1-6 alkoxy, halogenated C1-6 alkoxy or aryl; unsubstituted C3-6 cycloalkyl or mono-, di- or trisubstituted C3-6 cycloalkyl wherein the substitutents on the cycloalkyl are independently selected from hydroxy, C1 -6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy or halogenated C1-6 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 C1-8 alkyl;
R
2 is selected from C1-8 alkyl or OR 6 where R 6 is C1-8 alkyl;
R
3 is selected from C1-8 alkyl or A C__I (R4 )n each R 4 is independently selected from hydrogen, halogen, cyano, C1-5 alkoxy, nitro, C1-8 alkyl or halogenated C1-8 alkyl; each R 5 is independently selected from hydrogen or C1-8 alkyl;
R
7
R
8 and R 9 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 WO 97/21687 PCT/US96/19651 -11 O BF 3 metal salt, O O 3 R O KR9+catalyst 7 2
R
5 HN NHR
R
8
(C)
0 R 3 R9 R2 I 7 N O
R
1
R
(I)
R1, R 7 and R 8 are each independently selected from hydrogen, halogen, halogenated C -10 alkyl, unsubsituted or substituted aryl, or unsubstituted or substituted C1-10 alkyl wherein the substituent on the alkyl is selected from C1-6 alkoxy, halogenated C1-6 alkoxy or aryl;
R
2 is C-10o 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, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy or halogenated C1-6 alkoxy;
R
3 and R 9 are each independently selected from hydrogen, C -10 alkyl or 'N (R)n each R 4 is independently selected from hydrogen, halogen, cyano, C1-6 alkoxy, halogenated C1-6 alkoxy, nitro, C -10 alkyl or halogenated C -10 alkyl; each R 5 is independently selected from hydrogen or C1-10 alkyl;
R
6 is selected from unsubstituted or substituted CI-10 alkyl wherein the substituent on the alkyl is selected from C1-6 alkoxy, halogenated WO 97/21687 PCT/US96/19651 -12- C1-6 alkoxy or aryl; unsubstituted C3-6 cycloalkyl or mono-, di- or trisubstituted C3-6 cycloalkyl wherein the substitutents on the cycloalkyl are independently selected from hydroxy, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy or halogenated C1-6 alkoxy; or unsubstituted or substituted aryl; and n is an integer from one to five. Preferably, R 7
R
8 and R 9 are hydrogen and the compound I has the formula 0 R 3 RX N-R N0
R
1
R
In a preferred embodiment of the instant invention is the improved process for forming 4-aryl-pyrimidinones of the formula (II) as shown below.
O O 0(R4)n O BF 3 metal salt, RI 1 A AcOH R' R C(O)R 9
H
2 N NHR A
R
7
R
8 R 9
R
2 N H R1i
R
(II)
wherein R 1
R
2
R
4
R
5
R
6
R
7
R
8
R
9 and n are as defined above.
Preferably, R 7
R
8 and R 9 are hydrogen and the compound II has the formula WO 97/21687 PCT/US96/19651 13- 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.
O 0 R
ORA
6
(A)
4 R n
CHO
O BFa, Cu compound,
H
2
N
2 AcOH H2v NH 2 A6 1
NH
R1
H
(IlI) wherein R1, R 4
R
6 and n are as defined above.
Compounds of formulas (II) and (III) are useful as calcium channel blockers and as alpha la antagonists. More specifically, compounds of formula (Il) are particularly preferred as calcium channel blockers, or as intermediates which can be further derivatized at the N-3 position 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. Similarly, compounds of formula (III) are particularly preferred as alpha la WO 97/21687 PCT/US96/19651 -14antagonists, 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 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 P-keto esters or diketones and substituted-benzaldehydes are commercially available allowing one to make aryl-dihydropyrimidinones having a large variety of substituents for R 1
R
2 and R 3 Moreover, in addition to aryl aldehydes, it is also possible to utilize alkyl aldehydes in the instant invention to afford alkylpyrimidinones of the formula (IV) O C1-8 alkyl R2-' N-R N 0
R
1
R
(IV)
Additionally, N-substituted ureas and O-substituted ureas
O-
methylisourea) can be utilized in place of urea to afford the corresponding N-substituted dihydropyrimidinones. A number of Nsubstituted 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 2:1:3, 1:1:3 or 2:1:1.5 of A:B:C) also gave higher yields than the prior art methods Folkers method).
The reaction of p-keto ester or diketone aldehyde or ketone and urea 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(1H)dihydropyrimidinone in higher yields than obtained by known methods. The boron reagent used in the instant invention is BF3 which is WO 97/21687 PCT/US96/19651 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, BF3.2H20, BF3-Me2S, BF3-HOAc, BF3-R20 BF3-Et20, BF3-Me20, BF3-tert-butyl methyl etherate), BF3-ROH BF3-CH30H, BF3-CH3CH2CH20H). Preferably, the boron reagent is BF3-Et20.
A variety of metal salts can be utilized in the novel reaction of the present invention. For example, copper 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 chloride, copper oxide, copper (II) chloride, copper (II) sulfate, copper (II) acetate, nickel (II) bromide or palladium (II) acetate.
More preferably, the metal salt is copper oxide, copper chloride, nickel bromide or palladium (II) acetate. Most preferably, the metal salt used in the reaction is copper 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, 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 NH40Ac. 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 to about 100 0 C. Preferably, the temperature is about 65 0 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 13-keto ester 1 eq. of arylaldehyde 1.5 eq.
WO 97/21687 PCT/US96/19651 -16urea are reacted in the presence of 1.3 eq. BF3-Et20, 10 mol% and 10 mol AcOH in THF at 65 0 C for 18 h to afford the dihydropyrimidinone in high yield.
Abbreviations used in the instant specification are as follows: AcOH or HOAc acetic acid DMSO dimethyl sulfoxide Et ethyl EtOAc ethyl acetate EtOH ethanol eq. equivalent Me methyl MeOH methanol MsOH methanesulfonic acid 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 alkyl), or any number within this range methyl, ethyl, 1propyl, 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 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 CF3).
The term "alkoxy," as used herein, refers to straight or branched chain alkoxides of the number of carbon atoms specified C1-6 alkoxy), or any number within this range methoxy, ethoxy, etc.).
The term "halogenated alkoxy," as used herein, includes both straight and branched chain alkoxides of the number of carbon WO 97/21687 PCT/US96/19651 -17atoms specified halogenated C1-6 alkoxy), or any number within this range, wherein one or more of the hydrogen atoms is replaced with a halogen atom 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, the 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, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl or halogenated C1-6 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-Methoxycarbonvl-6-methyl-4-phenyl-3. 4-dihvdropyrimidin-2(IH)-one
O
CH
3 0 NH CH N 0
H
3
H
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 CuCI (10mol%) and 1.3 equivalent of BF3-Et20 (2.6 mmol). The reaction was heated at 65 0 C for 18 h. The reaction was quenched with one volume equivalent of 10% Na2CO3 solution and diluted with EtOAc (one volume equivalent). The organic layer containing the product was WO 97/21687 PCT/US96/19651 -18turned over to toluene and the title compound was crystallized in 88% yield; mp 204-208 0
C.
1H NMR (250 MHz, CDC13) 6 8.08 1H), 7.30 5H), 5.70 1H), 5.39 1H), 3.62 3H), 2.34 3H).
EXAMPLE 2 4-(3, 4 -Difluorophenyl)-6-ethyl-5-methoxycarbonyl-3,4-dihydropyrimidin-2(1H)-one
F
F
CH
3 O NH
N^O
H
To a dry round bottom flask containing methyl propionylacetate (2.0g, 15.4mmol), 3,4-difluorobenzaldehyde (2.1885g, 15.4mmol), and urea (1.39g, 23.1mmol) in 28 ml of dry THF (0.5M) was added AcOH (10mol%), Cu20 (10mol%) and 1.3 equivalent of BF3*OEt2 (20.0mmol). The reaction was heated at 65 0 C for 18h. Then, the reaction mixture was quenched with one volume equivalent of Na2CO3 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 1H (250 MHz, DMSO-d6) 6 9.31 1H), 7.80 1H), 7.40 (m, 1H), 7.20 1H), 7.06 1H), 5.14 1H), 3.54 3H), 2.65 2H), 1.11 3H).
WO 97/21687 PCT/US96/19651 -19- EXAMPLE 3 5-Methoxvcarbonvl-6-methoxvmethyl-4-(3,4-difluorophenl)-3,4dihvdropyrimidin-2(1 H)-one
NH
NO
H
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-Et20 (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% Na2CO3 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.
1 H NMR (250 MHz, CDC13) 5 7.70 (br s, 1H), 7.06 3H), 6.91 (br s, 1H), 5.32 1H), 4.62 2H), 3.63 3H), 3.44 3H).
WO 97/21687 WO 9721687PCTIUS96/19651 20 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)-dihydropyrirnidinone 6 -ethyl-5-methoxycarbonyl4(4-methoxyphenyl)-3, 4-2(1 H)-dihydropyrimidinone
NH
H
CH
3 0- NH
NO
H
WO 97/21687 PCT/US96/19651 -21 TABLE I (cont.) Chemical Name 4 -(4-chlorophenyl)-6-ethyl-5-methoxycarbonyl-3, 4 2 (1H)-dihydropyrimidinone Structure
CH
3
O'
6-ethyl-5-methoxycarbonyl-4-(4-nitrophenyl)-3, 4-2 (1H)-dihydropyrimidinone
"NH
NO
H
NO
2
NH
NO
H
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 (22)
1. A method of forming a compound of formula I -N -R A 0 comprising reacting 0 0 R 7 R 8 O 3 R R9 and HN NH R 5 HN NHR in the presence of a boron reagent, a metal salt and a catalyst to form the compound (I) 0 R 3 R9 R2 N-R R8 R 1 R (I) wherein R 1 R 7 and R 8 are each independently selected from hydrogen, halogen, halogenated CI-10 alkyl, unsubsituted or substituted aryl, or unsubstituted or substituted C -10 alkyl wherein the substituent on the alkyl is selected from C1-6 alkoxy, halogenated C -6 alkoxy or aryl; R 2 is CI-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, C1-6 alkyl, halogenated Cl-6 alkyl, C1-6 alkoxy or halogenated C1-6 alkoxy; WO 97/21687 PCT/US96/19651 -23- R 3 and R 9 are each independently selected from hydrogen, C1-10 alkyl or A\ '(R 4 )n each R 4 is independently selected from hydrogen, halogen, cyano, C1-6 alkoxy, halogenated C1-6 alkoxy, nitro, CI-10 alkyl or halogenated C1-10 alkyl; each R 5 is independently selected from hydrogen or C -10 alkyl; R 6 is selected from unsubstituted or substituted CI-10 alkyl wherein the substituent on the alkyl is selected from C1-6 alkoxy, halogenated C1-6 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, C1-6 alkyl, halogenated Cl-6 alkyl, C1-6 alkoxy or halogenated C1-6 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 chloride, copper oxide, copper (II) chloride, copper (II) sulfate, copper 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 R1 is selected from hydrogen or C1-8 alkyl; R 2 is C1-8 alkyl or OR 6 R 3 is selected from C1-8 alkyl or WO 97/21687 PCT/US96/19651 -24- (R 4 )n each R 4 is independently selected from hydrogen, halogen, C1-5 alkoxy, nitro, C1-8 alkyl or halogenated C1-8 alkyl; each R 5 is independently selected from hydrogen or C -8 alkyl; R 6 is C1-8 alkyl; R 7 R 8 and R 9 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 O R3 R9 R 8 R N-R R1 R (1)
4. The method of Claim 3, comprising reacting 0 o f (R 4 0 R 7 R C(O)Rand HN NHR in the presence of a boron reagent, a metal salt and a catalyst to form the compound (II) WO 97/21687 PCT/US96/19651 NH R' R The method of Claim 4, comprising reacting The method of Claim 4, comprising reacting 0 0 R1e S(R4)n CHO 0 and H 2 N NH 2 in the presence of a boron reagent, a metal salt and compound (III) a catalyst to form the R 6 0" N H N R 1 H (Ill)
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. WO 97/21687 PCT/US96/19651 -26-
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, BF3.2H20, BF3-Me2S, BF3-HOAc, BF3-Et20, BF3-Me20, BF3-t-BuOMe, BF3-CH30H or BF3-CH3CH2CH20H.
11. The method of Claim 10, wherein the boron reagent is BF3-Et20.
12. The method of Claim 10, wherein the metal salt is selected from copper chloride, copper oxide, copper 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 oxide, copper chloride, nickel (II) bromide or palladium (II) acetate.
14. The method of Claim 13, wherein the metal salt is copper oxide. The method of Claim 12, wherein the catalyst is selected from acetic acid, trifluoroacetic acid, methanol, sulfuric acid, MsOH, dichloroacetic acid, HBr-PPh3, NH40Ac, 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. F 27
18. The method of claim 11, wherein the metal salt is selected from copper (I) oxide, copper 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 oxide, the catalyst is acetic acid and the solvent is tetrahydrofuran. 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 0 C to 100 0 C.
22. The method of claim 21, wherein the reaction is run at a temperature of about 0 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. 15 25. A method for forming a 5-(alkyl or alkoxy)carbonyl-6-alkyl-4-(alkyl'or aryl)- 3,4-2(1H)-dihydropyrimidinone derivative, substantially as hereinbefore described with reference to any one of the Examples.
26. A 5-(alkyl or alkoxy)carbonyl-6-alkyl-4-(alkyl or aryl)-3,4-2(1H)- dihydropyrimidinone derivative produced by the method of any one of claims 1 to 20 Dated 13 July, 1998 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON a [n:\libc]03829:MEF
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US864195P | 1995-12-14 | 1995-12-14 | |
| US60/008641 | 1995-12-14 | ||
| GB9617968 | 1996-08-28 | ||
| GBGB9617968.4A GB9617968D0 (en) | 1996-08-28 | 1996-08-28 | Process for making dihydropyrimidinones |
| PCT/US1996/019651 WO1997021687A1 (en) | 1995-12-14 | 1996-12-12 | Process for making dihydropyrimidinones |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU1331697A AU1331697A (en) | 1997-07-03 |
| AU705409B2 true AU705409B2 (en) | 1999-05-20 |
Family
ID=26309937
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU13316/97A Ceased AU705409B2 (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) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2297889A1 (en) * | 1997-08-05 | 1999-02-18 | Norihiro Ikemoto | 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 |
| WO2003006439A1 (en) | 2001-07-13 | 2003-01-23 | Astrazeneca Uk Limited | Preparation of aminopyrimidine compounds |
| AU2003237544A1 (en) | 2002-06-17 | 2003-12-31 | Vittal Mallya Scientific Research Foundation | Substituted dihydropyrimidines and dihydropyrimidinethiones as calcium channel blockers |
| AU2003270562B2 (en) | 2002-09-12 | 2010-09-16 | Diakron Pharmaceuticals, Inc. | Calcium channel blockers |
| DK1578731T3 (en) | 2002-12-16 | 2010-02-15 | Astrazeneca Uk Ltd | Process for Preparation of Pyrimidine Compounds |
| GB0428328D0 (en) | 2004-12-24 | 2005-02-02 | Astrazeneca Uk Ltd | Chemical process |
| 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 |
Family Cites Families (4)
| 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 |
| US5459145A (en) * | 1988-01-19 | 1995-10-17 | Pfizer Inc. | Calcium independent camp phosphodiesterase inhibitor antidepressant |
| CZ279305B6 (en) * | 1992-01-24 | 1995-04-12 | Lonza A.G. | 2-halogenpyrimidine-4-carboxylic acids, process of their preparation and their use for the preparation of derivatives of 2-substituted pyrimidine-4-carboxylic acids and derivatives of substituted pyrimidine--carboxylic acids |
-
1996
- 1996-12-12 AU AU13316/97A patent/AU705409B2/en not_active Ceased
- 1996-12-12 BR BR9611933A patent/BR9611933A/en not_active Application Discontinuation
- 1996-12-12 SK SK773-98A patent/SK77398A3/en unknown
- 1996-12-12 KR KR1019980704443A patent/KR19990072125A/en not_active Application Discontinuation
- 1996-12-12 EP EP96944785A patent/EP0882026A4/en not_active Withdrawn
- 1996-12-12 JP JP9522161A patent/JP2000501734A/en active Pending
- 1996-12-12 CZ CZ981840A patent/CZ184098A3/en unknown
- 1996-12-12 CA CA002238924A patent/CA2238924A1/en not_active Abandoned
- 1996-12-12 PL PL96327147A patent/PL327147A1/en unknown
- 1996-12-12 NZ NZ326039A patent/NZ326039A/en unknown
- 1996-12-12 WO PCT/US1996/019651 patent/WO1997021687A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| BR9611933A (en) | 1999-03-02 |
| NZ326039A (en) | 1999-08-30 |
| AU1331697A (en) | 1997-07-03 |
| PL327147A1 (en) | 1998-11-23 |
| CA2238924A1 (en) | 1997-06-19 |
| KR19990072125A (en) | 1999-09-27 |
| JP2000501734A (en) | 2000-02-15 |
| WO1997021687A1 (en) | 1997-06-19 |
| SK77398A3 (en) | 1999-02-11 |
| EP0882026A1 (en) | 1998-12-09 |
| MX9804766A (en) | 1998-10-31 |
| EP0882026A4 (en) | 1999-04-07 |
| CZ184098A3 (en) | 1998-11-11 |
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