WO1996027598A1

WO1996027598A1 - A method of preparing a rodenticide/anticoagulant compound

Info

Publication number: WO1996027598A1
Application number: PCT/NL1995/000085
Authority: WO
Inventors: Barend Christiaan Buurman Bezuidenhoudt
Original assignee: Implico B.V.
Priority date: 1995-03-06
Filing date: 1995-03-06
Publication date: 1996-09-12
Also published as: AU1825295A

Abstract

A method of stereoselectively preparing a β-benzyl substituted carbonyl compound of general formula (3), in which R6 is selected from aryl and substituted aryl and R7 is a chiral auxiliary, includes reacting an α,β-unsaturated carbonyl compound of general formula (2), in which R6 and R7 are as defined above with an organocuprate reagent of the general formula (1): PhCH2CuX, in which X is TMEDA. The β-benzyl substituted carbonyl compound (3) is cyclised to give a tetralin of general formula (5), which is reduced and condensed with 4-hydroxycoumarin to produce a compound of general formula (4).

Description

A method of preparing a rodenticide/anticoagulant compound

THIS INVENTION relates to an organocuprate reagent, to a method of preparing an organocuprate reagent, to a method of preparing a β-benzyl-substituted carbonyl compound and to a method of preparing a rodenticide/anticoagulant compound. It relates, in particular, to an organocuprate reagent, to a method of stereoselectively preparing a β-benzyl-substituted carbonyl compound and to a method of stereoselectively preparing a rodenticide/anticoagulant compound.

According to a first aspect of the invention, there is provided an organocuprate reagent of the general formula ( 1)

PhCH₂Cu X ( 1 ) in which

X is R ₁ R₂NR₃NR₄R₅, and

R₁, R₂, R₄ and R ₅ are lower alkyl , lower alkylene or cycloalkyl; and

R₃ is lower alkylene.

The term lower alkyl is meant to include saturated and unsaturated C₁-C₅ aliphatic groups, such as methyl, ethyl and propyl groups. The term cycloalkyl is meant to include substituted or unsubstituteel C₃-C₆ rings. The term lower alkylene is meant to include (CH₂)n wherein O < n < 4. In particular, R₁ , R₂, R₄ and R₅ may be methyl and R₃ may be ethylene. X may thus be N, N, N ¹ , N'-tetramethylethylenediamine (TMEDA).

When R₁ , R₂, R₄ and R₅ are lower alkylene, R₁R₂N and/or R₄R₅N represent a substituted or unsubstituted C₂N-C₅N ring. According to a further aspect of the invention, there is provided a method of preparing an organocuprate reagent of the general formula (1)

PhCH₂Cu X ( 1 ) in which

X is R₁R₂NR₃NR₄R₅, and

R₁, R₂, R₄ and R₅ are lower alkyl. lower alkylene or cycloalkyl; and

R₃ is lower alkylene, the method including the step of reacting a Cu (I) salt with a benzylmagnesium halide and an amine of the formula R₁R₂NR₃NR₄R₅ in an inert solvent.

The groups R₁ , R₂, R₃, R₄ and R₅, may be as hereinbefore defined. The Cu (I) salt may be a Cu (1) halide. in particular Cu (I) iodide.

The benzylmagnesium halide may be benzylmagnesium chloride. The inert solvent may be an aprotic solvent such as an ether, for example, tetrahydrofuran (THF). The reaction may be conducted at a temperature of between about -100° and -20°C and is preferably conducted at a temperature of about -78°C. The reaction is preferably conducted under anhydrous conditions under an inert atmosphere eg. an atmosphere of argon or nitrogen. The reaction will typically be carried out by dissolving Oil in a solution of TMEDA and THF at a temperature of -78°C and adding a tetrahydrofuran solution of benzylmagnesium chloride to the resulting mixture.

The organocuprate reagent (1) is suitable for carrying out 1 ,4-addilion reactions of benzyl groups to α ,β-unsaturated carbonyl compounds. The invention extends to an organocuprate reagent whenever prepared by the method as hereinbefore described.

According to a further aspect of the invention, there is provided a method of preparing a β-benzyl-substituted carbonyl compound, the method including the step of reacting an α,β-unsaturated carbonyl compound with an organocuprate reagent as hereinbefore described.

The α,β-unsaturated carbonyl compound may have the general formula (2)

in which

R₆ is aryl or substituted aryl,

R₇ is selected from OR₈, 1 -imidazolidinyl , binaphthol , 4-substilnted-2-oxazolidinone,

10-dicyclohexylsulfamoyl isoborneol , 3-[ N-benzcnesulfonyl-N-(3,5-dimethylphenyl) amino] 2-bornanol, and

R₈ is lower alkyl and the β-benzyl substituted carbonyl compound may (hen have the general formula (3)

in which

Bz is benzyl.

In particular, R₆ may be phenyl, substituted phenyl , biphenyl or substituted biphenyl. The substituted biphenyl may be 4'-bromo-p-biphenyl.

The α,β- unsaturated carbonyl compound may, thus, be an α,β-unsaturated ester or a 5-(substituted-2-propenoyl) imidazolidinone. The method may involve the further step of trapping an enolate formed in the reaction as an enol ether intermediate and hydrolysing the intermediate to form the desired β-benzyl substituted carbonyl compound of general formula (3). The enolate may be trapped with a trialkylsilyl chloride. Thus, for example, the enolate may be trapped with a trialkylsilyl chloride, to produce an O-silylated enol ether intermediate which may be hydrolysed to form the desired β-benzyl substituted carbonyl compound of general formula (3). The silylating reagent may be trimethylsilyl chloride (TMS-chloride).

Instead, the β-benzyl substituted carbonyl compound may be prepared by reacting the α,β unsaturated carbonyl compound with the organocuprate reagent in the presence of di-n-butylboron triflate as a Lewis acid.

Thus, for example, the reaction may be carried out by dissolving Cul in a solution of TMEDA in dry THF, cooling the TMEDA solution to -78°C, and adding a solution of benzylmagnesium chloride to the TMEDA solution to produce the organocuprate reagent, adding a solution of an α,β-unsaturaled carbonyl compound and TMS-chloride to the organocuprate reagent, allowing the temperature to rise to -40°C. and hydrolysing the resulting benzyl-substituted trimethyl silyl enol ether to produce the desired β- benzyl-substituted carbonyl compound.

The β-benzyl substituted carbonyl compounds (3) posses at least one asymmetric carbon atom, or chiral centre, and may, therefore, exist in different stereoisomeric forms. The product (3) can thus be a mixture of isomers. These isomers could, in principle, be resolved. Alternatively, by incorporation of a suitable chiral auxiliary in the or β-unsaiuratetl carbonyl compound (2), a preferred stereoisomer (3) can be produced. This can be achieved, for example, by incorporating a chiral auxiliary in the α,β-unsaturated carbonyl compound (2). For example, where the R₇ substituent is selected from 1-imidazolidinyl , binaphthol , 4-substituted-2-oxazolidinone, 10-dicyclohexylsulfamoyl isoborneol . and 3-[N-benzenesulfonyl-N-(3,5-dimethylphenyl) amino]-2-bornanol, the said substituent may be chiral. Thus, where the a,β- unsaturated carbonyl compound (2) is substituted, for example, by an imidazolidinyl group, ie where R₇ of general structure (2) is imidazolidinyl, the imidazolidinyl group may be chiral. In particular, owing to the high induction ability and ready availabilityof (+)- and (-)-3,4-dimethyl-5-phenyl-2-imidazolidinone,the R₇ substitutent may be selected from (+) - and (-) - 1 - (3,4-dimethyl-5-phenyl-2-imidazolidinyl) substituents. The compounds (+) - and (-) 3,4-dimethyl-5-phenyl-2-imidazolidinone are readily prepared in one step from urea and ( + ) - or (-) - ephedrine hydrochloride accord ing to the method of Close (LJ Close, J Org Chem, 1950, 15, 1 131 ) as shown in Reaction Scheme 1 .

Thus for example, and with reference to Reaction Scheme 3, the α,β-unsaturated esters (8) may be hydrolysed and converted to the corresponding (-) - or ( + ) - imidazolidinones ( 13) in 70 -74 % yield by reaction of the corresponding acid chlorides with

( + ) - or (-) 3,4-dimethyl-5-phenyl-2-imidazolidinone ( 14). Reaction of the imidazolidinones

[ 13, ( + ) - or (-) - isomers respectively] with the organocuprate reagent of general formula

(1) gives the corresponding benzyl substituted imidazolidinones ( 15) in 86 - 88% yields with 93 - 99% diastereomeric excess (de).

The invention thus, further, provides a method for the stereoselective 1 ,4-addition of a benzyl group to an α,β-unsaturnted carbonyl compound.

The invention extends to a β-benzyl-subslituted carbonyl compound whenever prepared by a method as hereinbefore described.

According to a further aspcet of the invention, there is provided a method of preparing a compound of general formula (4) in which R₆ is as hereinbefore described,

the method including the steps of

cyclising a β-benzyl substituted carbonyl compound as hereinbefore described to produce a tetralin- 1 -one of general formula (5)

reducing the tetralin- 1 -one of general formula (5) to produce a benzyl alcohol of general formula (6);

and

condensing the benzyl alcohol of general formula (6) with 4-hydroxycoumarin to produce the compound of general formula (4).

R₆ may, in particular, be p-biphenyl or 4'-bromo-p-biphenyt. The compounds (4) may thus be diphenacoum or brodifacoum respectively. The invention thus provides a method for the, optionally stereoselective, synthesis of the rodenticide/anticoagulant compounds diphenacoum (4, R₆=p-biphenyl) and brodifacoum (4, R₆=4'-bromo-p -biphenyl).

The compounds of general formula (4) possess at least two chiral centres and, accordingly, can exist as one of, or as a racemic mixture of, at least four stereoisomers. When R₆ is p-biphenyl or 4'-bromo-p-biphenyl no selectivity was obtained in the condensation step in the case of the 3'R-isomers of compound (4) but a cis.trans of 3:2 for the 3'S-isomers was obtained. All of the diastereoiners of diphenacoum and brodifacoum were separable by chromatography leading to the steroisomers ( 17 - 24, Figure 1 ).

When R₇ is OR₈, ie when the β-benzyl substituted carbonyl compound (3) is an ester, the cyclisation step is preferably carried out in the presence of a Lewis acid . The cyclisation step may, for example, be carried out in toluene in the presence of aluminium chloride at a temperature of about 90°C. When R₇ is a 1 -imidazolidinyl substitutent the cycl isation may be carried out in the presence of trifluoromethane sulphonic acid. The imidazolidinones (3, R₇ = imidazolidinyl) were generally cyclised to the tetralin- 1-ones (5) in 79 - 85 % yields. The ( + ) -, or (-)- 3,4-dimethyl-5-phenyl-2-imidazolidinones liberated during the cyclisation may be recovered in 85 - 92 % yields for recycling. Direct cyclisation of the imidazolidinones (3, R₇= 1 -imidazolidinyl) has the advantage over the ester cyclisation in that reaction times are shorter, dry toluene is not required as a solvent and the product obtained is relatively easily isolated by chromatographic techniques.

The invention extends to a method of carrying out a Friedel-Crafts acylation of an aromatic substrate, the method including the step of reacting the aromatic substrate, in (he presence of an acid, with an acylating agent of general formula (25)

in which R is alkyl or aryl-substituted alkyl and Im is a 2-imidazolidinyl substituent.

The acid may be trifluoromethane sulphonic acid. The imidazolidinyl substituent may be a chiral substituent and may be as hereinbefore described.

Reduclion of the telralin- 1 -one (5) to produce the benzyl alcohol (6) may be carried out with any suitable reducing agent of the type known to a person skilled in the art. It may, for example, be carried out with NaBH₄ in a mixture of ethanol and THF. Condensation of the benzyl alcohol (6) with 4-hydroxycoumarin is preferably carried out in the present of an acid catalyst in the absence of a solvent. It may, for example, be carried out at a temperature of about 160°C under an atmosphere of HCI over a period of about 30 min. The α, β-unsaturated ester intermediates of general formula (2, R₇ = OR₈) may be prepared as the trans isomers by Wittig condensations between the corresponding aldehydes and (alkoxycarbonyl) methylene triphenyl phosphonium chloride according to standard procedures. For example, the α, β-unsaturated intermediates 8 (Reaction Scheme 2) were prepared as the irons isomers (8, R = H) in 92% and (8, R = Br) 87% yields respectively by Wittig condensations of the corresponding unsubstituted or substituted aldehydes (9) and ethoxycarbonylmethylene triphenylphosphonium chloride. Biphenylcarboxaldehyde (9, R = H) was obtained commercially. The p-bromo derivative (9, R = Br) was prepared in 95 % yield by monoformylation of p-dibromobiphenyl (7) with N, N-dimethylformamide according to a published procedure (S G Davies and M R Shipton, J. Chem. Soc. Perkin 1 , 1991. 501) (Reaction Scheme 2).

The tetralin- 1-ones ( 1 1 ; 16) (Reaction Schemes 2 and 3) which are key intermediates in the synthesis of racemic diphenacoum ( 12, R = l l) and brodifacoum (12. R = Br) and their diastereomers (17 - 24) may thus be prepared from biphenylcarboxaldehyde (9. R = H) and p -bromodiphenylcarboxaldehyde (9, R = Br) respectively, in three or four steps respectively.

The crucial step in the synthetic sequence for the production of racemic diphenacoum and brodifacoum involves the 1 ,4-addition of a benzyl group to the α, β-unsaturaied ester intermediates (2, R₇ = OR₈). The crucial step in the synthetic sequence for the production of the diastereomers of diphenacoum and brodifacoum involves the 1 ,4-addition of a benzyl group to the α,j3-unsaturated carbonyl compound ( 13) in which the imidazolidinyl substituent is selected from ( -f-)- and (-)- 1-(3,4-dimethyl-5-phenyl-2-imidazolidinyl)substituents. These reactions may be achieved with the organocuprate reagent ( 1) of the invention. The invention extends to racemic diphenacoum and brodifacoum and to the diastereomers of diphenacoum and brodifacoum whenever prepared by a method as hereinbefore described.

The invention extends to an anti-coagulant composition which comprises, as an active agent, an effective amount of at least one of compounds (17 - 24). It extends, further, to a compound, selected from compounds ( 17 - 24), for use as an anti-coagulant.

The invention extends, further, to a rodenticide composition which comprises, as an active agent, an effective amount of at least one of compounds ( 17 - 24). It extends, further, to a compound, selected from compounds (17 - 24), for use as a rodenticide. The invention extends, still further, to a method of destroying a rodent which method comprises administering to the rodent an effective amount of a rodenticide composition comprising, as an active agent, at least one of compounds ( 17 - 24).

The invention will now be described, by way of example, with reference to the accompanying single Figure, which shows, generically, the structures of the four diastereomers of diphanacoum and brodifacoum, the Examples which exemplify the syntheses of racemic diphenacoum and brodifacoum and their diastereomers, the reaction schemes and the single Table. Synthesis of Racemic Diphenacoum and Brodifacoum

(Reaction Scheme 1)

Example 1

p-Bromobiphenylcarboxaldehyde (9, R = Br): To a solution of 4,4¹-dibromobiphenyl (7) in dry tetrahydrofuran (THF) (2 g in 20 mf) under argon at -78°C, n-butyllithium (3,93 mf of a 1 ,63 M solution in hexanes) was added dropwise with constant stirring. After 15 minutes, dry N,N-dimethylformamide (DMF) (20 mf ) was added and the temperature was allowed to rise to room temperature over a period of 2 hours, while stirring was continued. Water (50 mf) was added and the product was extracted into ether (3 × 50 mf). The ether extract was dried (Na₂SO₄) and, after evaporation of the ether, flash chromatography (hexane : acetone

9: 1) gave the desired product (9, R = H) as a white powder ( 1 ,6 g; 95 %); ¹H NMR (CDCl₃) δ 7,50 (2H , d, J 8.5 Hz), 7,61 (2H, d, J 8.5 Hz), 7,72 (2H, d, J 8.5 Hz), 7,72 (2H, d, J 8.5 Hz), and 10,06 ( 1 H, s).

Example 2

Ethyl p-phenylcinnamate (8, R = H): A suspension of sodium methoxide in dry DMF, (1 ,3 g in 100 mf), was added to ethoxycarbonyimethylene triphenylphosphonium chloride (4,6 g) and the mixture was stirred at room temperature for 12 hours. A solution of the carboxaldehyde (9, R = H, 2,0 g in 50 mf of dry DMF) was added over a period of I hour and stirring was continued for 48 hours. Water ( 150 m f ) was added and the product was extracted into ether (3 × 150 mf). The ether extract was successively washed with water (50 mf ), 0, 1 N HCI solution (2 × 100 mf). and water (50 mf ). Drying over Na₂SO₄ and evaporation of the ether followed by flash chromotagraphy (hexanes : acetone 9: 1 ) gave the product (8,R = H as a white solid (2,6 g, 92 %); ¹H NMR (CDCI₃) δ 1 ,35 (3H, t, J 7.0 Hz), 4,28 (2H, q, J 7.0 Hz), 6,47 ( 1 H , d. J 16.0 Hz), 7,40 (3H , m), 7,60 (6H , m), and 7,72 ( 1 H, d, J 16.0 Hz).

Example 3

Ethyl 4-(4 '-bromophenyl)cinnamate (8, R = Br): This compound (5,5 g, 87 %) was prepared by reacting a suspension of sodium methoxide (3.2 g in 200 mf of DMF) and ethoxycarbonyimethylene triphenylphosphonium chloride (1 1 ,5 g) with the carboxaldehyde (9, R = Br, 5,0 g in 200 mf of DMF) as described in Example 2: ¹H NMR (CDCI₃) δ 1 ,35 (3H, t, J 7.0 Hz), 4,30 (2H, q, J 7.0 Hz), 6,50 (1H, d, J 16.0 Hz), 7,50 (2H, m), 7,60 (6H, m), and 7,70 (1H, d, J 16.0 Hz).

Example 4

Ethyl 3-(p-biplιenyl)-4-phenylbutanoate (10, R = H): Cul (8,4 g) was dissolved in a mixture of dry THF (160 mf) and dry N.N.N'.N'-tetramethylethylenediamine (TMEDA) (8 mf), and the solution was cooled to -78°C before a solution of benzylmagnesium chloride (38 mf of a 1,17 M solution in THF) was added. After 15 minutes stirring, a solution of ethyl p-phenylcinnamate (8, R = H) and trimethylsilyl chloride (TMSCI) (14,2 mf) in THF (110 mf) was added under Ar and the temperature allowed to rise to -40°C. NH₄CI - NII₄OH (400 mf of a 9: 1 mixture of saturated NH₄CI and 15 M NH₄OH solution) was introduced after

48 hours and the mixture was extracted with ether (3 × 150 mf). The ether extract was washed with water (100 mf), dried (Na₂SO₄), and evaporated to dryness. Flash chromatography (hexanes: acetone 9: 1) gave (10, R = H) as a white solid (6,3 g, 84 %); ¹H NMR (CDCl₃) δ 1,11 (3H, t, J 7.0 Hz), 2,63 (1H, dd, J 15.5 and 8.0 Hz), 2,70 (1H, dd, J 15.5 and 6.5 Hz), 2,91 (1h, dd, J 14.0 and 8.0 Hz), 2,97 (1H, dd, J 14.0 and 7.0 Hz),

3,47 (1H, m), 3,99 (2H, q, J 7.0 Hz), and 7,04 - 7,59 (14H, m).

Example 5

Ethyl 3-[4-(4¹-bromophenyl)phenyl]-4-plιenylbiitanoate (10, R = Br): By the method of

Example 4, reaction of the PhCH₂Cu-TMEDA complex Iprepared by dissolving Cul (4,2 g) in a mixture of THF (80 mf) and TMEDA (4 mf) followed by addition of benzylmagnesium chloride (19 mf)| with ethyl 4-(4¹-bromophenyl)cinnamate (8, R = Br, 3,6 g in 55 mf of THF) in the presence of TMSCI (7,1 mf) led to the butanoate (10, R = Br) as a white solid (3.7 g.81 %); ¹H NMR (CDCI₃) δ 1,12 (311, t. J 7.0 Hz), 2,62 (1H, dd, J 16.0 and 8.5 Hz), 2,69 (1H, dd, J 16.0 and 7.0 Hz), 2,91 (1H, dd. J 14.0 and 8.0 Hz), 2,96 (1H, dd, J 14.0 and 7.5 Hz), 3,47 (1H, m), 3,99 (2H, q, J 7.0 Hz), and 7,05 - 7,55 (13H, m).

Example 6

3-(p-biphenyl)tetralin-1-one (11, R = H): Anhydrous AICI₃ (0,24 g) was added to a solution of the butanoate (10, R = H) in dry toluene (0,2 g in 40 mf) and the mixture was kept at 90°C for 16 hours. Following addition of 3 M HCI solution (30 mf), the organic solvent was removed at reduced pressure and the tetralin-1-one extracted into ethyl acetate (2 × 50 mf). The EtOAc phase was washed with water (50 mf), dried (Na₂SO₄) and evaporated to dryness to produce the desired product (11, R = H) as a white solid (0, 152 g, 88 %) following preparative tic (hexanes : acetone 9: 1); ¹H NMR (CDCI₃) δ 2,86 (1H, dd, J 17.0 and 13.0 Hz), 3,01 (1H, ddd, J 17.0, 4.0 and 2.0 Hz), 3,22 (2H. m), 3,50 (1H, M), 7,45 (12H, m), and 8,1 (1H, in).

Example 7

3-[4-(4'-bromophenyl)phenyl]tetralin-]-one (11, R = Br): Treatment of the butanoate (10, R = Br, 0.2 g) with AICl₃ (0,10 g) in toluene (40 mf), as described for Example 6, gave the tetralin-1-one (11, R = Br, 0,153 g, 86 %); ¹H NMR (CDCl₃) 52,89 (1H, ddd, J 17.0, 13.0, and 6.5 Hz), 3,03 (1H, m), 3,27 (2H, m), 3,53 (1H, in), 7,45 (11H, m), and 8,10 (1H, m).

Example 8

Diphenacoum (12, R = H): Sodium borohydride (0,08 g) was added to a solution of the tetralin-1-one (11, R = H, 0, 1 g) in EtOH-THF (5 mf of a 1:1 mixture) and the mixture was stirred for 4 hours. Excess borohydride was destroyed by the addition of acetone prior to removal of the solvents in vacuo and the addition of water (5 mf). The resulting benzyl alcohol was extracted into ether (3 × 10 mf), dried (Na₂SO₄), and isolated by evaporation of the ether.

Addition of 4-hydroxycoumarin (0,052 g) to the benzyl alcohol followed by heating of the mixture to 160°C under a HCI atmosphere for 30 minutes led to the formation of diphenacoum (12, R = H) which was isolated as a white powder (0,115 g, 78 %) by recrystallization from hexanes; ¹H NMR (CDCI₃) δ 2,50 (2H, m), 3,15 (211, m), 3,80 (1 H, m), 4,85 (1H, m), and 7,40 (16H, m).

Example 9

Brodifacoum (12, R = Br): Following the method of Example 8, the bromotetralin-1-one derivate (11, R = Br, 0,1 g) was reduced with sodium borohydride (0,08 g) and condsnsed with 4-hydroxycoumarin (0,052 g) to produce brodifacoum (12, R = Br, 0,103g, 74 %); ¹H NMR (CDCl₃)δ 2,49 (2H, m), 3,17 (2H, m), 3.80 (1H, m),4,86(1H, m), and 7.42 (17H, in).

Synthesis of the diastereomers of Diphenacoum and Brodifacoum

Reaction Scheme 3

Example 10

(E)-4'-Phenylcinnamoyl chloride:

Ethyl-p-phenylcinnamate (8, R = H, 1,0 g; 3,90 mmol) was dissolved in a mixture of aqueous KOH-solution (1,0 g in 5mf) and ethanol (15 mf) and the reaction mixture was heated at 60°C until completion of the hydrolysis (tic). The mixture was acidified to pH 2 [HCI(c)], the ethanol removed under vacuum, and the acid extracted into ethyl acetate (3 × 50 mf). The ethyl acetate extract was dried (Na₂SO₄) and the free acid obtained as an amorphous solid (0,87 g; 98%) by evaporation of the solvent.

A solution of the acid (500 mg; 2.23 mmol) in thionyl chloride (0,33 mf; 4,46 mmol, 2 eq) was stirred at room temperature under anhydrous conditions for 12 hours, and the excess of thionyl chloride was removed by evaporation under reduced pressure at room temperature. The product was taken up in dry hexane (3 × 2 mf) and the hexane removed by evaporation under reduced pressure giving the solid chloride as a white amorphous solid (536 mg; 99%).

Example 11 (4S,5R)-(+)-1-[3'-(p-Biphenyl)-2'(E)-propenoyl]-3,4-dimethyl-5-phenyl-2-imidazolidinone [13, R=H,(-) imidazolidinone]:

To a solution of (4S,5R)-(-)-3,4-dimethyI-5-phenyl-2-imidazolidinone|(14) (-)-isomer, 470 mg: 2,45 mmol)] and Ph₃CH (10mg) in dry THF (8 mf) under argon at 0°C was added "BuLi (1,85 mf of a 1,35 M solution in hexanes) until a colour change to pink was observed. A solution of the acid chloride (541 mg; 2.23 mmol, 0.9 eq), prepared as described in

Example 10, in dry THF (3 mf) was added at 0°C and the mixture was stirredJor 1 hour. Saturated aqueous NaHCO₃ solution (30 mf) was added and the product extracted into ethyl acetate (3 × 50 mf). The ethyl acetate extract was washed with saturated aqueous NaCl solution (30 mf) and water (20 mf ), dried (Na₂SO₄) and the solvent removed by evaporation under reduced pressure. The imidazolidinone [13, R = H,(-)imidazolidinone, R_f 0.2] was obtained by preparative tic (hexane-benzene-acetone, 6:3: 1) as a white amorphous solid (663 mg, 75%); mp 170°C (Found: M ⁺; 396.1819. C₂₆,H₂₄O₂N₂ requires M⁺; 396,1837); m/z 396 (M ⁺ ; 8%), 307 (10), 207(18), 189(14), 178 (16), 149 (29), 131 (100), 117(13), 103 (26), and 91 (14); ¹H nmr (CDCI₃) 58,24 (1H, d, J 15.5 Hz, H-β), 7,75 (1H, d, J 15.5 Hz, H-α).7,66 (2H, d, J 8.5 Hz,Ph), 7,62 - 7,17 (12H, m, Ph), 5,43 (1H, d, J 8.5 Hz, H-5), 3,93 (1H, dq J 8.5 and 6.5 Hz, H-4), 2,86 (3H, s, NMe), 0,82 (3H, d, J 6.5 Hz, 4-Me); cd (c 0.010 in MeOH) [θ]₂₂₈ - 1,8 × 10⁴, [θ]₂₄₀ - 1,3 × 10⁴, [θ]₂₅₇ - 2,4 × 10⁴, [θ]₃₀₀ - 0,28 × 10⁴ [θ]₃₁₅0, [θ]₃₃₃0,38 × 10⁴, [θ]₃₇₂0; [α]_D 31,6° (c 1,00 in CHCI₃).

Example 12

(3'R,4S,5R)-(-)-1-[3'-(p-Biphenyl)-4'-phenylbutanoyl]-3,4-dimethyl-5-phenyl-2-imidazolidinone [15, R = H,(-) imidazolidinone]:

Cul (192 mg; 10,01 mmol; 2 eq) was added to a mixture of dry THF (5,4 mf) and dry TMEDA (0.15 mf; 1.21 mmol; 2,2eq) and the mixture was stirred at room temperature under argon for 10 min. The temperature was lowered to -78°C and the benzyl Grignard reagent (0,78 mf of a 1.3 M solution in THF; 1,01 mmol; 2 eq) was added. After complete formation of the alkylcopper reagent (negative Gillman test, ca 15 min) a mixture of the unsaturated imidazolidinone (13) (200 mg, 0,50 mmol) (Example 11) and "Bu₂BOTI (0,61 mf; 0,61 mmol; 1,2 eq) in dry THF (3,3 mf) was added and the mixture was stirred at -30°C (12 hours). A mixture of saturated ammonium chloride-ammonium hydroxide (3:2, 20 mf) was added and the product was extracted into ether (3 × 50 mf). The ether extract was washed with water (50 mf), dried (Na₂SO₄), and the product [15, R = H,

(-)imidazolidinone, R_f0.3] obtained by evaporation of the ether and tic purification (hexane-benzene-acetone, 6:3:1) as a white amorphous solid (217 mg, 88%); mp 135°C; m/z 488 (M ⁺ , 0%), 397 (76), 335 (10), 256 (22), 232 (50), 207 (100), 191 (27), 178 (24).165 (21), 113 (14), and 91 (15); ¹H nmr (CDCI₃) δ 7,55 (2H, m, Ph), 7,47 - 7,02 (17H, m, Ph), 5,09 (1H, d, J 8.5 Hz, H-5).3,74 (1H, dd, .1 16.0 and 9.5 Hz, 2'-CH), 3,66 (1H. dq, J 8.5 and 6.5 Hz, H-4), 3,60-3,50 (1H, m, H-3'), 3,16 (1H, dd, J 16.0 and 5.4 Hz, 2'-CH), 2,95 (1H, dd, J 14.0 and 8.0 Hz) and 2,90 (1H, dd, 14.0 and 7.5 Hz, 4'-CH₂), 2,76 (3H, s, NMe), 0,71 (3H, d, J 6.5 Hz, 4-Me); cd (c 0.054 in MeOH) [θ]₂₂₀-2,4 × 10⁴, [θ]₂₃₇ O,[θ]₂₄₅ 0,50 × 10⁴, [θ]₂₈₂0; [α]_D -21,1° (c 1,00 in CHCI₃). Example 13

(3R)-(+)-3-(p-Biphenyl)-1-tetralone[16, R=H, (R)-(+)-isomer]:

Trifluoromethanesulfonic acid (1 mf) was added to a solution of saturated imidazolidinone [15, R = H,(-)Isomer] in benzene (264 mg, 0.54 mmol, in 1 mf) and the mixture was refluxed (3 hours). Ice was added and the pH raised to 13 by addition of 4M NaOH solution. The aqueous phase was extracted with dichloromethane (3 × 10 mf), the dichloromethane extract dried (Na₂SO₄), and the solvent evaporated. Preparative tic (hexane- acetone, 9: 1) afforded the tetralone (16, R_f 0.3) as a white amorphous solid (134 mg, 84%); mp 95°C (lit 92 - 94°C); ¹H nmr (CDCI₃) δ 8,09 (1H, dd, J 8.0 and 1.5 Hz, H-8), 7,62 -7,28 (12H, m, Ph), 3,57 -3,46 (1H, m, H-3), 3,31 - 3,18 (2H, n, 4-CH₂), 3,05 -2,99 (1H, m)and 2,87 (1H, dd, J 16.5 and 12.5 Hz, 2-CH₂); cd (c 0.035 in MeOH) [θ] ₂₁₅1,3 × 10⁴,

[θ]₂₃₅0- [θ]₂₄₃ -0,12 × 10⁴, [θ]₂₅₀0, [θ]₂₅₇0,23× 10⁴, [θ]₂₆₆0, [θ]₂₇₂-0.09 × 10⁴, [θ]₂₈₁0. [θ]₂₉₇0,23 × 10⁴, [θ]₃₁₄0; [α]_D +26,9° (c 0,95 CHCI₃).

Example 14

Coupling of (3R)-3-(p-Biphenyl)-1-tetratol and 4-Hydwxycoumarin

Powdered NaBH₄ (67 mg; 1,77 mmol; 4 eq) was added to a solution of tetralone

|16, R = H,(R)-( + )- isomer; 132 mg, 0,44 mmol] in THF-EtOH (1:1,6 mf) at room temperature and the mixture was stirred for 6 hours. Acetone was added and the solvents removed by evaporation at reduced pressure. Water (20 mf) was added and the mixture extracted with ethyl acetate (3 × 10 mf), the EtOAc extract was washed with water (30 mf) and dried (Na₂SO₄) to give the crude tetralol (R_f 0.4, hexane-benzene-acetone, 6:3:1) after evaporation of the solvent.

A mixture of 4-hydroxycoumarin (136 mg; 0,84 mmol; 2eq) and the tetralol (126 mg; 0,42 mmol) was heated at 160°C for 30 min, while HCI was bubbled through the mixture. The reaction mixture was allowed to cool down, before flash column chromatography (hexane, benzene-acetone, 6:3:1) yielded two fractions (R_f 0,1 and R_f 0,3 in the same solvent). Example 15

(1'S,3'S)-3-[3'-(p-Biphenyl)-1',2',3',4'-tetrahydro-1'-naphtyl]-4-hydroxycoumarin (21): The R_f 0,3 fraction, which was identified as the trans product (21), was obtained as a brownish amorphous solid (46 mg, 26%); mp 213°C (lit 215 -217°C for the mixture of isomers); H nmr (CDCI₃) δ 7,63 (1H, dd, J 8.0 and 1.5 Hz,Ph), 7,52 - 7,48 (2H, m, Ph), 7,40 (2H,d, J 8.0 Hz, Ph).7,26 - 6,72 (12H, m, Ph), 6,17 (br s, OH), 4,84 (1H, dd, J 6.0 and 2.5 Hz, H-1'), 3,10 - 2,99 (1H, m, H-3'), 2,88 - 2,79 (1H, m) and 2,68 - 2,58 (1H, m 4'-CH₂), 2,53 - 2,45 (1H, m) and 2,18 - 2,06 (1H,m, 2'-CH₂); cd (c0.040 in MeOH) [θ]²²³ -3,1 × 10⁴, [θ]₂₃₄ -0,85 × 10⁴, [θ]₂₃₈ -0,98 × 10⁴, [θ]₂₅₀ - 0,11 × 10⁴, [θ]₂₇₃ -1,09 × 10⁴, [θ]₂₈₄ -1,8 × 10⁴, [θ]₃₀₆ -1,8 × 10⁴ [θ]₃₄₈; [α]_D-154° (c 1,03 in CHCI₃). Example 16

(1 'R, 3 'S)-3-[ 3 '-(p-Biphenyl)- 1 ',2',3',4'-tetrahydro-1'-naphthyl]-4-hydroxycoumarin (23): The second fraction (R_f 0,1), which was identified as the as product (23) . was obtained as a brownish amorphous solid (79 mg, 43%); mp 216°C; ¹H nmr (CDCI₃) δ 7,72 -7,62 (br. s, OH), 7,54 (2H,dd, J 8.0 and 1.5 Hz, Ph), 7,47 (2H,d, J 8.0 Hz, Ph), 7,29- 6,77 (1311, m, Ph), 5,02 - 4,92 (1H, br s, H-1'), 2,85 - 2,65 (4H, br s) and 2,40- 2.30 (111, br s, 2'-

CH₂, H-3', and 4'-CH₂); cd (c 0,060 in MeOH) [θ]₂₁₉2,0 x 10⁴, [θ]₂₃₅0,24 × 10⁴, [θ]₂₅₆ 1,2 × 10⁴, [θ]₂₇₂0, [θ]₂₈₃-0,68 × 10⁴. [θ]₃₂₈0; [α]_D + 73° (c 1,02 in CHCI₃).

The other diastereomers of diphenacoum and brodifacoum were prepared in the same way and their yields are given in Figure 1. The yields of the other diastereomers of compounds (15) and (16) and the diastereomeric enrichments of compounds (15) are given in Reaction Scheme 3. The anti-coagulant 3-[4-(p-substituted phenyl)-1 ,2,3,4-tetrahydro- 1-naphthyl]-4- hydroxy coumarin compounds of formula (12), namely diphenacoum and brodifacoum are rodenticides which are active against both Warfarin-sensitive and Warfarin-resistant rats. The anti-coagulant properties of the these compounds also allow them to be used at extremely low concentrations in humans suffering from circulatory diseases.

Preliminary evaluation of the toxicity of the different stereoisomers of brodifacoum showed little variation. However, the isomers (21 , 23) of diphenacoum, obtained by the use of the less expensive (-)-imidazolidinone (14) displayed LD₅₀ values comparable to that of brodificoum.

As can be seen from the Table the diastereomers 23 of diphenacoum (LD₅₀ 0,3 - 0,9 mg/kg) has a toxicity comparable to that of the brodifacoum isomers (LD₅₀ 0,4 - 0,5 mg/kg) whilst the diastereomers 17 and 19 were considerably less toxic (LD₅₀ 2.5 - 5.0 mg/kg). It is noteworthy that the more active diastereomers of diphenacoum, namely compound 23, is obtainable through the use of a chiral auxiliary which is available in one step from a readily available inexpensive starting material.

Brodifacoum and diphenacoum, which differ in structure only with respect to a bromine atom, are substantially more poisonous than related compounds such as coumatetralil and warfarin. Brodifacoum and diphenacoum are also biodegradable and, as it does not contain any halogen substituents, diphenacoum biodegrades in an environmentally friendly fashion.

It is an advantage that the method of the invention gives higher yields and produces the anti-coagulant compounds ( I ) in fewer steps than prior art procedures known to the Applicant. The Applicant has found that the overall yield of diphenacoum and brodifacoum is approximately twice that reported for said prior art procedures and the number of steps in the synthesis is reduced from 8 or 9 to 5 and 6 respectively in the case of the racemic compounds. It is also an advantage of the invention that the starting materials are commercially available at relatively low cost and exotic reagents are not required. The chiral process, although of necessity involving more steps than the process leading to the racemic compounds, has the advantage that good diastereomeric enrichment is obtained and the chiral auxiliaries, ie the chiral imidazolidinones. are recoverable.

Claims

CLAIMS:

1. An organocuprate reagent of the general formula (1)

PhCH₂Cu X (1) in which:

X is R₁R₂NR₃NR₄R₅, and

R₁, R₂, R₄and R₅ are each lower alkyl, lower alkylene or cycloalkyl; and

R₃ is lower alkylene.

2. An organocuprate reagent as claimed in Claim 1, in which R₁, R₂, R₄ and R₅ are methyl.

3. An organocuprate reagent as claimed in Claim 1 or Claim 2 in which, R₃ is ethylene.

4. A method of preparing an organocuprate reagent of the general formula (1)

PhCH₂Cu X (I) in which:

X is R₁R₂NR₃NR₄R₅, and

R₃ is iower alkylene,

the method including the step of reacting a Cu (I) salt with a benzylmagnesium halide and an amine of formula R₁R₂NR₃NR₄R₅ in an inert solvent.

5. A method as claimed in Claim 4, in which R₁, R₂, R₄ and R₅ are methyl.

6. A method as claimed in Claim 4 or Claim 5, in which R₃ is ethylene.

7. A method as claimed in any one of Claims 4 to 6 inclusive, in which the Cu (I) salt is a Cu (I) halide.

8. A method as claimed in Claim 7, in which the Cu (I) halide is Cu (I) iodide.

9. A method as claimed in any one of Claims 4 to 8 inclusive, in which the benzylmagnesium halide is benzylmagnesium chloride.

10. A method as claimed in any one of Claims 4 to 9 inclusive, which is conducted at a temperature of between - 100° and -20°C.

1 1 . A method of preparing a β-benzyl substituted carbonyl compound, the method including the step of reacting an α,β- unsaturated carbonyl compound with an organocuprate reagent as claimed in any one of Claims 1 to 3 inclusive.

12. A method as claimed in Claim 1 1 , in which the α,β-unsaturated carbonyl compound has the general formula (2)

in which

R₆ is aryl,

R₇ is selected from the group consisting of OR₈, binaphlhol, 4- subslituted-2-oxazolidinone, 10-dicyclohexylsulfamoyl isoborneol , 3-[ N- benzenesulfonyl-N-(3,5-dimethylphenyl)amino]-2-bornanol, 1 -imidazolidinyl; and

R₈ is lower alkyl

and the β-benzyl-substiluted carbonyl compound has the general formula (3)

in which Bz is benzyl.

13. A method as claimed in Claim 12, in which R₆ is selected from the group consisting of phenyl, substituted phenyl, biphenyl and substituted biphenyl.

14. A method as claimed in Claim 12 or Claim 13, which includes the step of trapping an enolate formed in the reaction as an enol ether intermediate and hydrolysing the intermediate to form the desired β-benzyl substituted carbonyl compound of general formula (3).

15. A method as claimed in Claim 14 in which the enolate is trapped with a trialkylsilyl chloride.

16. A method as claimed in Claim 12 or Claim 13, which is carried out in the presence of di-n-butyl boron triflate.

17. A method as claimed in any one of Claims 12 to 16 inclusive, in which the R₇ substitutent is a chiral 1 -imidazolidinyl substituent.

18. A method as claimed in Claim 17, in which the R₇ substituent is selected from ( -1- )- and (-)- 1 -(3,4-dimethyl-5-phenyl-2-imidazolidinyl) substituents.

19. A β-benzyl-substituted carbonyl compound, whenever prepared according to a method as claimed in any one of Claims 12 to 1 8 inclusive.

20. A method of preparing a compound selected from the group consisting of the diastereomers and a racemic mixture of the diastereomers of general formula (4)

the method including the steps of cyclising a ß-benzyl substituted carbonyl compound of general formula (3)

in which R₆ is aryl

R₇ is selected from the group consisting of OR₈, binaphthol, 4- substituled-2-oxazolidinonc, 10-dicyclohexylsulfamoyl isoborneol, 3- [ N-benzenesul fonyl-N-(3,5-dimethylphenyl)amino)2-bornanol , 1 - imidazolidinyl ;

and

R₈ is lower alkyl to produce a telralin- 1 -one of general formula (5),

reducing the tetralin- 1-one of general formula (5) to produce a benzyl alcohol of general formula (6) general formula (6)

and condensing the benzyl alcohol of general formula (6) with 4-hydroxycoumarin to produce the said compound.

2 1. A method as claimed in Claim 20 in which R₆ is selected from the group consisting of p-biphenyl and 4'-bromo-p-biphenyl.

22. A method as claimed in Claim 20 or Claim 2 1 , in which R₇ is OR₈, and the cyclisation step is carried out in the presence of a Lewis acid.

23. A method as claimed in Claim 20 or Claim 2 1 , in which R₇ is a 1 -imidazolidinyl substituent and the cycl isation is carried out in the presence of trifluoromethane suphonic acid.

24. A method of acylating an aromatic substrate, the method including the steps of reacting the aromatic substrate, in the presence of an acid, with an acylating agent of general formula (25)

in which R is selected from the group consisting of alkyl and aryl-substituled alkyl and Im is a 2-imidozolidinyl substituent.

25. A method as claimed in Claim 24, in which the acid is trifluoromethanc sulphonic acid.

26. A method as claimed in Claim 25, in which the imidazolidinyl substituent is chiral.

27. A method as claimed in Claim 26, in which the chiral imidazolidinyl substituent is selected from (+)- and (-)-1(3,4-dimethyl-5-phenyI-2-imidazolidinyl)substituents.

28. The compound (1'R,3'S)-3-[3'-(p-Biphenyl)-1',2',3",4'-letrahydro-1'-naphthyl]-4- hydroxycoumarin.

29. The compound (1'R,3'R)-3-[3'-(p-Biphenyl)-1',2',3',4^,-tetrahydro-1'-naphthyl]-4- hydroxycoumarin.

30. The compound (1'S,3'R)-3-[3'-(p-Biphenyl)-1',2',3',4^,-tetrahydro-1'-naphthyl]-4- hydroxycoumarin.

31. The compound (1'S,3'S)-3-[3'-(p-Biphenyl)-1',2',3',4'-tetrahydro-1'-naphthyl]-4- hydroxycoumarin.

32. The compound (1'R,3'S)-3-[3'-(4"-bromo-p-Biphenyl)-1',2',3',4'-tetrahydro-1'- naphthyl]-4-hydroxycoumarin.

33. The compound (1'R,3'S)-3-[3'-(4"-bromo-p-Biphenyl)-1',2',3',4'-tetrahydro-1'- naphthyl]-4-hydroxycoumarin.

34. The compound (1'R,3'S)-3-[3^,-(4"-bromo-p-Biphenyl)-1',2^,,3',4'-tetrahydro-1'- naphthyl]-4-hydroxycoumarin.

35. The compound (1'R,3'S)-3-[3'-(4"-bromo-p-Biphenyl)-1',2',3',4'-tetrahydro-1'- naphlhyl]-4-hydroxycoumarin.

36. The compound (4S,5R)-(+)-1-[3'-(p-Biphenyl)-2'(E)-propenoyl]-3,4-dimethyl-5- phenyl-2-imidazolidinone.

37. The compound (4R,5S)-(-)-1-[3'-(p-Biphenyl)-2'(E)-propenoyl]-3,4-dimethyl-5-phenyl- 2-imidazolidinone.

38. The compound (4S,5R)-(+)-1-[3'-(4"-Bromo-p-Biphenyl)-2'(E)-propcnoyl]-3,4- dimethyl-5-phenyl-2-imidazoIidinone.

39. The compound (4R,5S)-(-)-1-[3'-(4"-Bromo-p-Biphenyl)-2'(E)-propenoyl]-3,4- dimethyI-5-phenyI-2-imidazolidinone.

40. The compound (3'R, 4S,5R)-(-)-1-[3'-(p-Biphenyl)-4'-phenylbutanoyl]-3,4- dimethyl-5-phenyl-2-imidazolidinone.

41. The compound (3'S, 4R,5S)-(+)-1-[3'-(p-Biphenyl)-4'-phenylbutanoyl]-3,4- dimethyl-5-phenyl-2-imidazolidinone.

42. The compound (3'R,4S,5R)-(-)-1-[3'-(4"-Bromo-p-Biphenyl)-4^,-phenylbutanoyl]- 3,4-dimethyl-5-phenyl-2-imidazolidinone.

43. The compound (3'S,4R,5S)-(+)-1-[3'-(4"-Bromo-p-Biphenyl)-4^,-phenylbutanoyl]- 3,4-dimethyl-5-phenyl-2-imidazolidinone.

44. The compound (3R)-(+)-3-(p-Biphenyl)-1-tetralone.

45. The compound (3S)-(-)-3-(p-Biphenyl)-1-tetralone.

46. The compound (3R)-(+)-3-(4"-Bromo-p-biphenyl)-1-tetralone.

47. The compound (3S)-(-)-3-(4"-Bromo-p-biphenyl)-1-tetralone.

48. An anti-coagulant composition which comprises, as an active agent, an effective amount of at least one compound as claimed in any one of Claims 28 to 35 inclusive.

49. A rodenticide composition which comprises, as an active agent, an effective amount of at least one compound as claimed in any one of Claims 28 to 35 inclusive.

50. A method of destroying a rodent which method comprises administering to the rodent, an effective amount of a rodenticide compositon comprising, as an active agent, at least one compound as claimed in any one of Claims 28 to 35 inclusive.

51. A compound as claimed in any one of Claims 28 to 35 inclusive for use as an ant i- coagulant.

52. A compound as claimed in any one of Claims 28 to 35 inclusive for use as a rodenticide.

53. A new method of preparing an organocuprate reagent, substantially as herein described.

54. A new method of preparing a ß-benzyl substituted carbonyl compound, substantially as herein described.

55. A new method of preparing a compound of general formula (4). substantially as herein described.

56. A new method of acylating an aromatic substrate, substantially as herein described.

57. A new anti-coagulant composition substantially as herein described.

58. A new rodenticide composition substantially as herein described.