GB2388596A - Novel compounds - Google Patents

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GB2388596A
GB2388596A GB0221679A GB0221679A GB2388596A GB 2388596 A GB2388596 A GB 2388596A GB 0221679 A GB0221679 A GB 0221679A GB 0221679 A GB0221679 A GB 0221679A GB 2388596 A GB2388596 A GB 2388596A
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alkyl
preparation
hydrogen
aryl
haloalkyl
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Alan John Whittle
Joseph John Swanborough
David Rees Parry
Andrew Jonathan Knee
Raymond Leo Sunley
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Syngenta Ltd
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Syngenta Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
    • A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Rodenticidal compounds of formula (I) <EMI ID=1.1 HE=46 WI=103 LX=555 LY=494 TI=CF> <PC>or a stereoisomer or salt thereof, wherein: A is oxygen or sulphur; K is CH or N; X is a group of formula II to XV; Y is a group of formula XVI to XVIII; each Z is independently oxygen, sulphur, optionally substituted -(CH2)n-, alkenylene, alkynylene, -(CH2)n-O-(CH2)n-, -O(CH2)n-, -(CH2)nO-, -O(CH2)nO- -CO-, -CO2-, (CH2)nCO, -S(CH2)n-, -(CH2)nS-, -SO(CH2)n-, -(CH2)nSO-, -SO2(CH2)n-, -(CH2)nSO2-, -SO-, -SO2-, -NH- or -N(alkyl)-; R<1>, R<2>, R<3>, R<4>, R<5> and R<6> are each independently hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, haloalkyl, haloalkoxy, haloalkenyl, haloalkynyl, alkenyloxy, alkynyloxy, hydroxy, nitro, amino, alkylamino, dialkylamino, optionally substituted aryl, aryloxy, arylalkoxy, -S-alkyl, -SO-alkyl, -SO2-alkyl, -S-haloalkyl, -SO-haloalkyl, -SO2-haloalkyl, -S-alkenyl, -SO-alkenyl, -SO2-alkenyl, -S-alkynyl, -SO-alkynyl, -SO2-alkynyl, -CO-alkyl, -CO-haloalkyl, -CO2H, -CO2-alkyl, -CO2-haloalkyl, -CO-aryl, -S-aryl, -SO-aryl, -SO2-aryl, -SF5, -CO-amino, -CO-alkylamino, -CO-dialkylamino, -CO2-amino, -CO2-alkylamino, -CO2-dialkylamino, alkoxycarbonyl, alkenyloxycarbonyl or alkenyloxycarbonyl, or when R<1> and R<2> are attached to adjacent carbon atoms in the groups of formulae II, III and V to XV, they may join to form an optionally substituted fused benzene ring; n is 1 or 2; m is 0 or 1; and p is 0 or 1.

Description

GB 2388596 A continuation (72) Inventor(s): (58) Field of Search:
Alan John Whittle UK CL (Edition V) C2C CTU Joseph John Swanborough INT CL7 C07D 311/00 405/00 David Rees Parry Other: ON LIN E: CAS-ON LIN E, EPODOC, JAPIO & Andrew Jonathan Knee WPI Raymond Leo Sunley (74) Agent and/or Address for Service: Syngenta Limited PO Box 3538, Intellectual Property Department, Jealotts Hill Research Centre, BRACKNELL, Berks, R&42 6YA, United Kingdom f
- 1 NOVEL COMPOUNDS
This invention relates to novel compounds useful as rodenticides and as human and veterinary medicinal agents, to chemical processes useful for their preparation, to compositions comprising them and to a method of killing rodents or of reducing a population 5 of rodents using the compositions.
Derivatives of 4-hydroxycoumarin which exhibit anticoagulant activity and which are useful as rodenticides have been described. These compounds are characterized principally by various complex substituents at the 3position of the coumarin fused ring system.
3-(1-Phenyl)oxcalkyl derivatives are disclosed in US Patent No. 2427578 and UK Patent No. 0 701111. 3-(1,2,3,4-Tetrahydro- 1-naphthyl) derivatives are disclosed in US Patent Nos. 2952689 and 3957824 and in European Patent Application No. 0098629-A.
3-(3-Hydroxypropyl) and 3-(3-hydroxybutyl) derivatives are described in US Patent No. 3764693. 3-(1,1-Diphenylmethyl) derivatives are disclosed by Kralt et al in Rec. Trav.
Chirn. Pays-gas, 86(10), 961-970 (1967) and by Ziegler et al in Monatsh. Chem., 88(4), 5 587-596 (1957) and also in German Patent No. 1000395.
According to the present invention there is provided a compound of formula (I), and stereoisomers and salts thereof, wherein: A is oxygen or sulphur; KisCHorN; 20 X is a group of formula It to XV; Y is a group of formula XVI to XVIII; each Z is independently oxygen, sulphur, optionally substituted -(CH2)n-, alkenylene, alkynylene, -(CH2)n-O-(CH2)n-, -O(CH2)n- , -(CH2)nO-, -O(CH2)DO-, -CO-,-CO2-, (CH2)nCO, -S(CH2)n-, -(CH2)nS -, SO(CH2)n- (cH2)nso-, so2(cH2)n-, (cH2)nso2- -SO- -SO2-, 25 NH- or N(alkyl)-; R', R2, R3, R4, R5 and R6 are each independently hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, haloalkyl, haloalkoxy, haloalkenyl, haloalkynyl, alkenyloxy, alkynyloxy, hydroxy, nitro, amino, alkylamino, dialkylamino, optionally substituted aryl, aryloxy, arylalkoxy, -S-alkyl, -SO-alkyl, -SO2-alkyl, -S-haloalkyl, 30 -SO-haloalkyl, -SO2-haloalkyl, -S-alkenyl, -SO-alkenyl, -SO2-alkenyl, S-alkynyl, -SO-alkynyl, -SO2-alkynyl, -CO-alkyl, -CO-haloalkyl, -CO2H, CO2 Alkyd, -CO2-haloalkyl, -CO-aryl, -S-aryl, -SO-aryl, -SO2-aryl, -SFs, CO-amino, -CO-alkylamino, -CO-dialkylamno, -CO2-amino, -CO2-alkylamino, CO2-dialkylamino, alkoxycarbonyl,
- 2 alkenyloxycarbonyl or alkenyloxycarbonyl, or when R' and R2 are attached to adjacent carbon atoms in the groups of formulae II, m and V to XV, they may join to form an optionally substituted fused benzene ring; n is 1 or 2; 5 m isOor l; and pisOor 1.
The definition K is CH or N. means that the ring to which the substituents R4 and R5 are attached is either a benzene ring or a pyrirnidine ring. For the avoidance of doubt, R4 andlor R5, which are shown in formula (I) as "floating" substituents, may be attached to a K 0 carbon atom when K is CH. In this case one K may be CR4 and the other K may be CR5.
Usually, however, both K's are unsubstituted.
When any one or more of Z. R', R2, R3, R4, R5 and R6 is alkyl, or contains an alkyl moiety, it can be straight or branched chain and is preferably C-6 alkyl, for example, methyl, ethyl, n-propyl, so-propyl, n- butyl, sec-butyl, so-butyl, t-butyl, n-pentyl or n-hexyl.
5 When any one or more of R', R2, R3, R4, R5 and R6 is cycloalkyl or cycloalkenyl it is preferably a C3-6 cycloalkyl or a C5-6 cycloalkenyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl.
When any one or more of R', R2, R3, R4, R5 and R6 is alkoxy, or contains an alkoxy moiety, it can be straight or branched chain and is preferably C,-6 alkoxy, for example, 20 methoxy, ethoxy, propoxy or butoxy.
When any one or more of R', R2, R3, R4, Rs and R6 is haloalkyl, it is preferably C' 6 haloalkyl, for example, trifluoromethyl, trifluoroethyl or pentafJuoroethyl.
When any one or more of Z. R', R2, R3, R4, R5 and R6 is alkenyl, or contains an alkenyl moiety, it can be straight or branched chain and is preferably C2 6 alkenyl, for example, allyl, 2s methallyl, crotyl, butenyl, or pentenyl.
When any one or more of Z. R, R2, R3, R4, R5 and R6 is alkynyl, or contains an alkynyl moiety, it can be straight or branched chain and is preferably C2 6 alkenyl, for example, propargyl, propyn-l-yl or butynyl.
When any one or more of R', R2, R3, R4, Rs and R6 is haloalkoxy, it is preferably Cn6 30 haloalkoxy, for example, trifluoromethoxy, trifluoroethoxy or pentafluoroethoxy.
When-any one or more of R', R2, R3, R4, R5 and R6 is alkylamino or dialkylamino, it is preferably C-6 alkylarnno or di-C 6-alkylamino, for example methylamino, dimethylamino,
- 3 - ethylarnino or diethylarnino. It can also be a cyclic compound, preferably a 3-6 membered ring, for example, piperidine or pyrrolidine.
When any one or more of R', R2, R3, R4, Rs and Ret is halogen, it is preferably fluorine, chlorine or bromine.
5 When any one or more of R', R2, R3, R4, R5 and R6 is aryl, it is preferably C3-6 aryl, for example phenyl. It can also be a heteroaryl, preferably a 3-6 membered ring containing O. N or S as the heteroatom, for example, pyridine, pyrrole, furan or thiophene.
When any one or more of Ri, R2, R3, R4, R5 and R6 is substituted aryl or R' and R2 join to form a substituted fused benzene ring, preferred substituents are halogen, for example, lo fluorine, chlorine or bromine, C'-6 alkyl, nitro, cyano, S-alkyl containing up to 6 carbon atoms, SOalkyl containing up to 6 carbon atoms, SO2-alkyl containing up to 6 carbon atoms, C'.6 alkoxy, C-6 haloalkyl or C haloalkoxy. Examples of the alkyl and alkoxy containing substituents are as defined for R', R2, R3, R4 and R5.
In one aspect of the present invention there is provided a compound of formula (I) or 5 a stereoisomers or salt thereof, wherein: A is oxygen or sulphur; K is CH; X is a group of fomula n to XV; Y is a group of fomula XVI to XVU1; 20 each Z is independently oxygen, sulphur, -(CH2)n-, alkenylene, alkynylene, (CH2)n0(CH2), O(CH2)n, -(CH2)nO-, O(CH2)nO, (CH2) nCO, -S (CH2)n, -(CH2)nS-, -SO(CH2)n-, -(CH2)nSo-' so2(cH2)n-' -(CH2)nSO2. -SO-, or -SO2-; R', R2, R3, R4, R5 and R6 are each independertly hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, haloalkyl, haloalkoxy, haloalkenyl, haloalkynyl, 25 alkenyloxy, alkynyloxy, hydroxy, nitro, amino, allcylamino, dialkylarnino, optionally substituted aryl, aryloxy, arylalkoxy, -S-alkyl, -SO-alkyl, -SO2-alkyl, -S-haloalkyl, -SO-haloalkyl, -SO2-haloalkyl, -S- alkenyl, -SO-alkenyl, -SO2-alkenyl, -S -alkynyl, -SO-alkynyl, -SO2- alkynyl, -CO-alkyl, -CO2-alkyl, -CO-ary}, -S-aryl, -SO-aryl, -SO2-aryl, - SF5, -CO-amino, -CO-alkylamino, -CO-dalkylamino, alkoxycarbonyl, alkenyloxycarbonyl 30 or alkenyloxycarbonyl, or when R' and R2 are attached to adjacent carbon atoms in the groups of formulae lI, III and V to XV, they may join to form an optionally substituted fused benzene ring; n is I or 2;
4 - m is 0 or I; and p is 0 or 1.
In this particular aspect one preference is that rn+n - 0 or 2. Another preference is that X is a group of formula (m), (V), (X) or (XI); Ri, R2, R3, R5 and R6 are hydrogen; R4, which 5 is preferably in the 4-position, is -SCH3, -SOCH3, -SO2CH3, Br, Cl, F. CN or hydrogen; m=0, p=0; Y is a group of formula (XVI), and A is oxygen.
In another aspect of the present invention there is provided a compound of formula (I) or a stereoisomer or salt thereof, wherein K is CH; X is the group (II), Y is the group (XVI); m is 0; p is 0 or 1 and Z. R', R2, R3, R4, Rs and R6 and R6 are as hereinbefore defined.
0 Preferably R3 and R6 are both hydrogen and R', R2, R4 and R5 are in the 3 and/or 4 positions of the phenyl rings to which they are attached. More preferably R2, R3, R5 and R6 are all hydrogen are R' and R4 are in the 4positions of their respective phenyl rings. Particularly preferred in this aspect of the invention are the compounds of formula (I) wherein R' is hydrogen, cyano or halogen; R2 is hydrogen; R4 is hydrogen, halogen, C'-6 haloalkoxy, nitro 5 or cyano; Rs is hydrogen; R3 and R6 are hydrogen; p is 0 or 1; and Z is oxygen, -OCH2, -CH 2- or -(CH2)2 when p is 1. The most preferred compounds according to this aspect if the invention are those of formula (I) and stereoisomers and/or salts thereof, wherein R' is hydrogen, 4-cyano, 4-chloro, 4-bromo or 4-fluoro; RZ ts hydrogen; R4 is hydrogen, 4-chloro, 4-bromo, 4-fluoro, 4-C' 6haloalkoxy, 4-nitro or 4cyano; R5 is hydrogen; and R3 and R6 are 20 also hydrogen.
In yet another aspect of the present invention there is provided a compound of formula (I) or a stereoisomer or a salt thereof, wherein K is N; X is the group (II); Y is the group (XVI); m is 0; p is 1; R. R. R. R and R are each independently hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, haloalkyl, haloalkoxy, 2s halosubstituted alkenyl, halo-substituted alkynyl, alkenyloxy, alkynyloxy, hydroxyl, ntro, amino, alkylamino, dialkylamino, optionally substituted aryl, aryloxy, arylalkoxy, -S-alkyl, -SO-alkyl, -SO2-alkyl, -S-haloakyl, SO-haloalkyl, -SO2-haloalkyl, -S-alkenyl, -SO-alkenyl, -SO2-alkenyl, -Salkynyl, -SO-alkynyl, -SO2-alkynyl, -CO-alkyl, -CO2-alkyl, -CO-aryl, -Saryl, -SO-aryl, -SO2-aryl, -SF5, -CO2-amino, -CO2-alkylamino, -CO2dialkylamino, 30 alkoxycarbonyl, alkenyloxycarbonyl and alkenyloxycarbonyl; R6 is hydrogen, halogen, alkyl, or CF3; Z is oxygen, sulphur, -SO-, -SO2-, -CH2O-, -CH2S-. -NH- or -N(alkyl)-; and
- 5 A is oxygen or sulphur. Preferred compounds of this aspect of the invention are those of formula (I) where R' and R4 are as previously defined and R. R3 and R5 are hydrogen. The R and R substituents are preferably respectively in the 4-position on the phenyl ring and the 5position on the pyrimidine ring. Particularly preferred are the compounds of formula (I) 5 wherein R is hydrogen, cyano, carboxy, NH2CO-, or monoor discs 6 alkylCO- or halogen; R is hydrogen, C' 6 alkyl, halogen, Cal 6 haloalkoxy, nitro, cyano, carboxy, NH2CO or mono- or di- C' 6 alkylNCO-; R2, R3, R5 and R are all hydrogen; A is oxygen and Z is oxygen. The most preferred compounds according to this aspect of the invention are those of formula (I) and stereoisomers and/or salts thereof, wherein Ret is hydrogen, 4-cyano, 4 o chloro, 4-bromo or 4-fluoro; R4 is hydrogen, 5chloro, 5-bromo, 5-fluoro, 5-C-6 haloalkoxy, for example 5trifluoromethoxy, 5-nitro, 5-cyano, 5-carboxy, 5-C'-6 alkyl for example 5 methyl, R2, R3, Rs and R6 are hydrogen; A is oxygen and Z is oxygen.
The compounds of formula (I) exist as RIS enantiomers around the occarbon atom.
When X is -SO(CH2)n-, -(CH2)nSO-, or -S(O)-, or any of R', R2, R3, R4 or Rs is -SO-alkyl, 5 the compounds of formula (I) exist as enantiomers and diastereoisomers. Furthermore, when X is alkenyl, the compounds of formula (I) may also exist in the cis or bans forms. The scope of the present invention is to be understood to embrace all single isomenc forms of the compounds of formula (I) and all mixtures thereof, including raceme mixtures.
The compounds of formula (1) may also be prepared as salts, for example, sodium or 20 potassium salts.
Examples of compounds according to the invention are those presented in Table l to m and stereoisomers and salts thereof.
TABLE I
The compounds in Table I are of general formula (I) wherein A is oxygen, K is CH 25 (i.e. both Ks are CH such that the ring to which R4 and R5 are attached is a benzene ring), R3, R5 and R6 are all hydrogen and X, Y. Z. m, p, Ret, R2 and R4 have the values given.
- 6 TABLE I
Compd X Y Z m P R' R2 R4 No I n XVII - 0 0 H H H 2 II xvn - 0 0 4-CI H 4CI 3 II xvn 0 0 1 4-CI H H 4 xvm - 0 0 4-CI H 4-CI s m XVI - 0 0 5-CI H 4Br 6 m XVI - O O H H H 7 IV XVI - 0 0 2-SCH3 H H
8 VI XVI - O O H H 4-Br 9 vn XVI - O O H H H 10 VII XVI - O O H H 4-Br 11 I:X XVI - O O H H H
12 Xl XVI - O O H H H 13 X XVI - 0 0 4-CH3 5-CH3 H
14 X XVI - O O H H 4-Br 15 V XVI - O O H H 4-Br 16 XVI -CH2CH2- 1 0 4- CI H H
17 Xll XVI - O O H H 4-Br 18 XII XVI - O O S-Br H 4-Br 19 XIII XVI - O 0 5-CI H 4-Br 20 xm XVI - 0 0 5-CI H H 21 III XVI - O O H H 4-Br 22 n xvm 0 0 H H 4-CI 23 II XVII O O 1 H H H
24 IV XVI - 0 0 2-SCH3 H 4-Br 25 X XVI - 0 0 4,5-C4H4* H
26 X XVI - O O H H H
27 VIII XVT - O O H H H
28 xm XVI - O O H H 4-Br
TABLE I (continued) Compound X Y Z m P R R2 R4 No 29 VI XVI - O O H H H
30 XI XVI - 0 0 H H H
31 VI XVI - 0 0 1-CH3 H 4-Br 32 V XVI - 0 0 H H H
33 XV XVI - 0 0 H H H
34 XV XVI - 0 0 H H 4-Br 35 xrv XVI - O O H S-CH3 H 36 XIV XVI - O O H SCH3 4-Br 37 II XVI -CH2CH2- 1 0 4-C6H5 H H
38 II XVI -CH2CO- 1 0 H H 4-Br * In compound No. 25, R' and R2 join to fonn a fused benzene ring, ie X is 2-benzothiazolyl s TABLE II
The compounds of Table II are of the general formula (I) where n A is oxygen, K is I CH (both Ks), m is 0, X is the group n, Y is the group XVI, R and R6 are both hydrgen and R', R2, R4, R5 and Z have the values given. Where Z is "-", p is 0. Otherwise p is 1.
- 8 - TABLE II
Compound No Rl R2 R4 R5 Z I H H 4-Br H 2 H H 4-C1 H
3 4-CI H 4-CI H -
4 4-CI H 4-Br H S H H 4-CF3 H
6 H H 4-NO2 H -
7 H H 4-SO2CH3 H -
8 H H 4-OCF3 H
9 H H 4-CH3 H
10 H H 4-F H -
11 H H 4-CN H
12 H H 4-C(0)CH3 H
13 4-F H 4-CN H -
14 4-F H 4-F H
15 H H 4-CI H OCH2 1
16 H H 4-CI H CH2 1
17 H H 4-CI H O I
18 H H 4-CI H S I
19 H H 4-CI H SO 1
20 H H 4-CI H SO2 1
21 H H 4-Br H SO2 1 22 H H 4-Br H CH2 1 23 H H 4-Br H O I 24 H H 4-Br H S 25 H H 4-Br H SO2 26 H H 4-Br H -CH=CH (cis) 27 H H 4-Br H -CH=CH (trans) 28 H H H H O
- 9 - TABLE II (continued) Compound No Ri R2 R4 R5 Z 29 H H 4-CF H CH2
30 H H 4-NO2 H CH2
31 H H 4-NO2 H O
32 H H 4-SOCH3 H O
33 H H SCH3 H CH2
34 H H 4-COzCH3 H O 35 H H 4-CO2CH3 H S
36 H H 4-OCF3 H O
37 H H 4-OCF3 H S
38 H H 4-OCF3 H OCH2
39 H H 4-OCF3 H CH20
40 H H 4-OCF3 H SO2
41 H H 4-CH3 H CH2
42 H H 4-CH3 H O
43 H H 4-F H O I
44 H H 4-F H CH2 I
45 H H 4-CN H CH2 I
46 H H 4-CN H OCH2 I
47 H H 4-CN H S
48 H H 4-OCH3 H CHzO 49 H H 4-OCH3 H S I
50 H H H H O I
51 H H H H S I
52 H H H H CH2
53 H H H H SO2
54 H H H H -CH2=CH
(cis) 55 H H H H -CH=CH
(trans) 56 4-F H 4-CE3 H O
- 10 TABLE n (continued) Compound No R' R2 R4 85 Z 57 4-F H 4-OCF3 H S
58 4-F H 4-CI H OCH2
59 4-F H 4-Br H OCH2 60 4-F H 4-CF3 H OCH2
61 4-F H 4-SOCH3 H CH:
62 4-F H 4-NO2 H CH2O
63 H H 4-Cl 2-CI 64 H 3-CI 4-Br H 65 4-CI H 4-CI H -
66 4-C1 3-CI 4-CI H -
67 H H 4-CI H
68 H 3-F 4-Br H 69 H H H 3-CI
70 H 3-CI H H
7 l 4-CI H H H 72 4-CI H 4-NO2 H 1
73 4-CI H 4-NO2 H OCH2 1
74 4-CI H 4-NO2 H CH2 1
75 4-CI H 4-NO2 H O 1
76 4-Cl H H H OCH2 1 77 4-CI H H H CH2 I
78 4-CI H H H O
79 4-CI H 4-Br H OCH2 80 4-CI H 4-Br H CH2 81 4-CI H 4-Br H O 82 4- C6Hs H H H 83 H H H H -
84 4-CI H 4-OCH3 H -
- 11 TABLE II (continued) Compound No Ri R2 R4 Rs Z 85 4-CN H H H
86 H H 4COOH H -
87 H H 4-CH3 H
88 H H 4-CN H -
89 H H 4-COOC(CH3)3 H
90 H H 4-CooCH(CH3)3 H 91 H H 4-SCH3 H -
92 H H 4-OSiCH3[C(CH3)3]2 H 93 H H 4-SCF3 H -
94 H H 4-OH H -
95 H H 4-OCH(CH3)3 H
96 4-F H H H -
97 H H 4-F 3-CI -
98 H H 4-N(CH3)2 H
99 H H 4-C(0)CF3 H
100 H H 4-CF3 4-CF3
101 H H 4-CH2F H
102 H H 4-CH=CH2 H -
103 H H 4-CHF2 H -
104 H H 4-OCH2CH3 H
105 H H 4-CH2CH3 H
106 H H 4-SOCH3 H
107 H H 4-OCH2CF3 H
108 H H 4-C(CH33 H
109 H H 4-CH(CH3)2 H
110 H H 4-CON(CH3)2 H
111 H H 3-F 5-F
112 H H 4-CF3 H OCH2
1 13 H H H H OCH2
114 H H H H OC(O)
TABLE m
r - 12 The compounds of Table m are of the general formula (I) wherein A is oxygen, K is N (i.e. both Ks are N such that the ring to which R4 and Rs are attached is a pyrimidine ring), m is 0, X is the group II, Y is the group XVI, p is l, R2, R3, Rs and R6 are all hydrogen and Rt, R4 and Z have the values given.
5 TABLE m
Compound No R' R4 Z l H 5-Br O 2 H 5-Br S 3 H 5-Cl O 4 H 5-Cl S 5 H 5- CH3 O
6 H 5-CH3 S
7 H H O
8 H H S
9 H 5-CN O
lO H 5-CN S 11 H 5-NO2 O
12 H 5-NO2 S
l 3 5-CN 5-Br O 14 H 5-CO2H O
15 H 5-CONH2 O
16 5-CN 5-Br S 17 H 5-CONH2 S
18 5-Cl 5-Br S 19 5-Cl 5-Br O 20 5-CONH2 5-CI S
21 5-CONH2 5-Br O 22 H 5-SCH3 O
23 H 5-SCH3 O
- 13 -
TABLE m (continued) Compound No R' R4 Z 24 H 5-SCH3 O
25 5-SCH3 5-SCH3 S
26 H 5-Br SO 27 H 5-Br SO2 Examples of compounds wherein A is sulphur are exactly the same as those listed in Tables I, II and m except that sulphur replaces oxygen as the value of A. s TABLE IV
Table IV shows melting points where measurable, selected proton NMR data obtained at 270MHz or mass spectrographic data for certain compounds described in Tables I to m.
Chemical shifts are measured at 20 C in ppm from tetramethylsilane and deuterochloroform was used as solvent. The following abbreviations are used: lo s = singlet ppm = parts per million M+ - molecular ion as determined by mass spectrometery
( - 14
Compound No Melting Point Proton NMR Data (is) Mass Spec.
(Table No.) C ppm M+ _ I.1 145
I.2 215-216
_ I.3 457
I.4 474/476
I.5 518/520
_ I.6 407
1.7 2.55(3H,s); 5.90 (lH,s) 453 _ I.8 484/486
_ 1.9 406
_. 1.10 6.2(1H,s) 1.11 275
_. 1.12 474/476
1.13 439
__ 1.14 489/491
1.15 6.3(1H,s) ._ 1.16 90.6-92.6
_._ 1.17 193-196
_._ 1.18 207
_ 1.19 212-214
II.1 139-141
II.2 184-186
_. _ __
n.4 202-204 n.s 97-99 11.8 153-154
_ II.10 190-191
II.12 99.5-100.5
II.63 194- 196
- 15 Compound No Melting Point Proton rnvDR Data (is) Mass Spec.
(Table No.) C ppm M+ II.71 199-203
H.72 265-267
B.78 80-83
B.81 229-231
II.82 104-108
II.83 128-231
II.84 186-189
_ H.85 200-202
n.86 255-257 B.87 221-223
B.88 233-235
H.89 107-108
B.90 115-116
ll.9l 173-176 H.92 109-111
B.93 129-130
B.94 123-127
B.95 93^95
n.96 182-184 B.97 98-100
H.98 126-126.5
B.99 97.5-98.5
B.100 541
_.. II.102 436
B.103 454
B.104 195.5-196.5
- 16 Compound No Melting Point Proton Now Data (a) Mass Spec.
(Table No.) C _ M+ U.105 433
II.106 149-153
Il.107 502 II.108 460
II.109 446
. II.110 134-136
. _ II.111 192-193
. II.112 113-116
II.113 -- 434
II.114 194-196.
m.3 72-76 m.5 81-85 _. m.7 90-92 Compounds of formula (I) may generally be prepared by the means indicated in Scheme I, in which the moiety -Z-YZ-(optionally substituted) phenyl is represented, unless indicated otherwise, by the biphenyl-4-yl system.
5 Thus compounds of formula (I) may be prepared by reaction of an appropriately substituted 4-hydroxycoumarin or thiacoumarin with a compound of formula (XIX) wherein K, X, Y. Z. m, p, R4 and R5 have the meanings given hereinbefore, preferably under acidic conditions, with elimation of one molecule of water. Suitable conditions include heating the reactants together, optionally in an inert solvent in the presence of an acid catalyst such as p 10 toluenesulphonic acid, with removal of water (e.g. by distillation) from the reaction mixture.
The compounds of formula (XIX) may be prepared by a number of procedures, the optimum procedure being selected on the basis of normal skill in the art according to the particular values of K, X, Y. Z. m, p, R4 and R5. A preferred and generally applicable method of preparation of a compound of formula (XIX) is by reduction of the corresponding compound 5 of formula (XX) using a suitable reducing agent such as sodium borohydride, or alternatively using alurninium tri-tsopropoxide and acetone under the conditions of the Meerwen Ponodorf-Verley reaction.
- 17 Suitable procedures for the preparation of compounds of formula (XX) will depend upon the nature of the substituents R4 and R5 and the variables K, X, Y. Z. m and p. The choice of such procedures will be readily apparent to those skilled in the art. Examples of procedures, which may be more generally applicable, in the particular case of compounds of s formula (XX) wherein X is the group (If), Y is the group (XVI), R3 in (XVI) is hydrogen, K is CH and m and p are both 0, are shown in Scheme II. Examples of procedures suitable for the preparation of intermediates of formula (XIX) wherein X is the group (II), Y is the group (X\lI), K is CH, p is 0, m is 1 and Z is O or OCH2 are shown in Schemes m and IV.
Reduction of the keto group to a secondary alcohol group may be achieved using, for lo example, sodium borohydride.
Compounds of formula (XX) wherein X is the group (II), Y is the group (XVI), m is 0, p is l and Z has the meaning given hereinbefore may be prepared by condensation of the corresponding compounds of formula (XXI) and (XXII) where Hal is a displaceable halogen such as chlorine or bromine, in the presence of a base, for example an alkali metal carbonate 5 such as potassium carbonate. Compounds of formula (XXII) may be prepared by standard synthetic procedures appropriate to the substitution pattern and nature of R4 and Rs. An example of a procedure suitable for the preparation of compounds of formula (XXII) in which Rs is hydrogen and R4 is a 5-substituent such as 5-alkyl is shown in Scheme V. Further details of procedures suitable for the preparation of compounds according to 20 the invention may be found in the Examples.
Compounds of formula (I) exert powerful anticoagulant activity. They may therefore be suitable for use in appropriate doses as therapeutic anticoagulants for medicinal and veterinary use. Administration of the compounds for such usage is normally in the form of a therapeutic composition comprising a compound of formula (I) as hereinbefore defined, or a 2s therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier or diluent.
The compounds of formula (I) are particularly useful as rodenticides and for the control of rodent populations. In such use, the compounds of formula (1) are normally formulated into compositions comprising a rodenticidally effective amount of a compound of 30 formula (l) as hereinbefore described and an inert carrier or diluent.
The compositions of the present invention may be used against a wide range of rodent pests, including the following comrnensal species: Rattus species, particularly Rattus norve:aicus (Brown or Norway rat), Rattus rattus (Black rat), Rattus argentiventer (Cotton or
- 18 -
Ricefield rat); Mus species, particularly Mus musculus (House mouse); as well as
non-commensal species which occur particularly as pests of agricultural crops or stored produce in various parts of the world, such as for example voles of the family Cricetidae including Microtus spp. such as M. arestis, and Arivicola spp. such as A. terrestrs, rats and s mice of the family Muridae, including Apodemus spp. such as A. svlvaticus, Acomys caharinus, Akodon spp., Arvicanthis nilotica, Holochilus braziliensis, Mastomvs natalensis, Mus booduga, Mus platvthrix, Neotoma spp., Peromyscus spp., Rattus exulans, Rattus meltada, Rattus tiomanicus, Siamodon hispidus and other rodents such as Nesokia indica, Tatera indica, Sperrnophilus spp., Meriones spp., Eutamias spp., Citellus spp, Bandicota 0 spp., Cricetus cricetus, Ondatra zibetheca, and Myocastor cous, although this is not intended to be an exhaustive list.
The rate of active ingredient in the rodenticidal composition of the present invention which is effective is dependent on the inherent activity of the selected compound, the size of the rodent and on susceptibility of the rodent. Thus, the rodenticidally effective rate of active 5 ingredient can vary greatly but generally will be from 0.01 mg/kg to 200 mglkg and preferably from 0.05 mglkg to 100 mg/kg for conunensal rodents. The rodenticidal composition of the present invention generally contains from 0.5 to 2000 parts per million of the compound of formula (I), preferably from 0.5 to 500 parts per million.
Rodenticidal compositions according to the invention are preferably in the form of bait 20 compositions. The rodenticidal bait composition of the present invention may be formulated in accordance with procedures well known in the art and using any suitable bait base which constitutes an edible canter, for example, meat by-products, fats, bone meal or ground, whole or cut cereal grains such as wheat and wheat by-products, oatmeal, ground or cracked corn, soybean products or rice. Any grain can be the base of such a composition. The bait s composition may be formulated as for example, a drinking composition, a tracking powder, pellets, wax blocks or wax pellets, micro-encapsulated granules, wick devices or may simply be added to the food base eg, whole or cracked wheat grains. The wax blocks or wax pellets use a cereal base such as wheat combined with wax to produce a more weather resistant bait.
* Oats and maize are also often used, and it is sensible to produce baits that are similar in 30 content to the natural food of the target rodent. Liquid baits are used in dry environments such as seed stores, where there is abundant alternative food but little free water. Fatty rodentcidal bait compositions are regularly made with inert ingredients such as peanut butter, other nut butters, milk solids, animal fats and vegetable oils.
( - 19
Tracking powders are composed of rodenticidal compounds dispersed in powdered solids.
Virtually any powder can be used, including talc, chalk, ground clays, flour, nut shell flour, and powdered stone.
Toxic materials mixed with an inert base material such as a dust or gel are termed 5 contact preparations. These are placed in the harbourages or runways so that the rodent's pelage becomes covered in the composition. The toxicant is then ingested during the grooming process.
Rodenticidal compositions in drinking water comprise suspensions or dispersions of the compounds. 10 Micro-encapsulation of the toxic material has the beneficial effect of further delaying the onset of toxic symptoms so that the animal does not associate the effect with the treatment and therefore the animal will feed on the bait again. Micro- encapsulation also serves to increase the palatability of the composition. The active ingredient may be micro-encapsulated by known techniques, for example co-acervation of gelatin and/or gum 5 arabic or interracial condensation polymerization using various polymers such as polyurea or polyamides. The bait ingredients generally include but are not limited to a base, hardening agents and optionally, a palatability agent/attractant and a colouring agent. The base can be any cereal flour or meal such as for example, wheat flour, oat flour, maize flour or rice flour, and 20 the hardening agents include, for example, kaolin, talc, diatomaceous earth and mineral fillers, for example, porcelain (pharmaceutical grade). When the base is a cereal flour or a bait it should be of a quality acceptable for food. A palatability agent/attractant may be added to the bait composition to increase the attraction of the bait. The particular agent depends on the target species, for example, protein hydrolysate, powdered milk, monosodium 25 glutamate, sugar or sucrose may be used for attracting field rodents. Similarly, other agents
can be included such as, an aversive agent, for example, graphite as abird aversive agent, preserving agents, for example, chlorinated phenols, a moisture retaining agent, for example, polyethylene glycol. Colouring agents may be included to indicate the nature of the active ingredient, for example, Prussian Blue, Rubine toner or Acid Red 9.
30 The invention further provides a method of killing or reducing a population of rodents which comprises supplying to a locus frequented by the rodents a rodenticidally effective amount of a rodenticdal composition comprising an inert carrier and as active ingredient a
-- 2 0 -
rodenticdally effective concentration of a compound of formula (I) wherein the meanings of X, Y. W and Z are as defined above. G The rodenticidal composition may also take the form of a powder or liquid concentrate of the active ingredient for local formulation in the form of a bait.
5 Various further preferred features and embodiments of the present invention will now be described in futher detail with reference to the following illustrative examples in which the following abbreviations are used: mp = melting point; bp = boiling point; g = grammes; GC or gc - gas chromatography; Now = nuclear magnetic resonance; s = singlet; d = doublet; dd = double doublet; t = triplet; q = quartet; m = multiples; br = broad; M=mole; lo rnM=millimoles; CDC13 = deuteriochloroform, d6-DMSO = deuterated dimethyl sulphoxide.
Chemical shifts (a) are measured in parts per million from tetramethylsilane. CDCI3 was used as solvent for Now spectra unless otherwise stated. MS = Mass spectrometry, M+ = molecular ion as determined by mass spectrometry; FAB = fast atom bombardment; TLC or tic = thin layer chromatography.
5 The synthesis of a number of intermediate compounds of use in the preparation of compounds according to the invention is given below. Some of these compounds are known in the art.
PREPARATION I
This Preparation illustrates the of 5-bromo-furan-2-carbonyl chloride.
20 Thionyl chloride (9Ocm3) was added to 5-bromo-2-furoic acid (11.46g) and the solution was heated to the ref}ux temperature for a period of 4 hours. After cooling to the ambient temperature, the excess thionyl chloride was removed by evaporation under reduced pressure.
Toluene was added and again removed by evaporation under reduced pressure (to azeotropically remove any traces of thionyl chloride) to give 5-bromofuran-2-carbonyl 25 chloride as a white solid, which was used in Preparation 2 without further purification. IR (cm-1) 1764cm'.
PREPARATION 2
This Preparation illustrates the preparation of (4'-bromo-biphenvl4vl)-(5bromo-furan 2-vl)-methanone. 30 Aluminium chloride (9.61g) was added to 5bromo-furan-2-carbonyl chloride (11.31g, Preparation 1) in dry dichloromethane (60cm3) over 15 minutes. After stirring for one hour at the ambient temperature, a solution of 4-bromobiphenyl ( 1 1.1 fig) in dichloromethane (60cm3) was added dropwise over a period of 30 minutes. The mixture was stirred for a
- 21 -
period of three hours, after which time a thick precipitate had formed. The reaction mixture was then allowed to stand overnight before it was poured into ice/water, and the buff coloured solid so formed collected at the pump. Recrystallisation from ethanol gave (4' bromo-biphenyl4-yl)furan-2-yl-methanone (15.9g) as an off-white solid. OH 1<MR: s 8.06(d.2H); 7.68(d,2H); 7.62(d,2H); 7.50(d,2H); 7.22(d,}H); 6.56(d,1H).
PREPARATION 3
This Preparation illustrates the preparation of (4'-bromo-biphenyl4-yl)(5-bromo furan-2-vl)-methanol. Aluminium isopropoxide (3.67g) was added to a stirred suspension of (4'-bromo-biphenyl 0 4yl)-(5-bromo-furan-2-yl)methanone (2.44g, Preparation 2) in dry isopropanol (60cm3). The reaction mixture was heated at the reflex temperature for a period of three hours, by which time the suspension had become a cloudy solution. After cooling to the ambient temperature, the solvent was removed by evaporation under reduced pressure to give a pale yellow gum, which was treated with a mixture of ice and aqueous ammonium chloride solution. The 5 aqueous mixture was then extracted into ethyl acetate (twice) and the combined organic layers water washed, dried (MESON), filtered and the solvent removed by evaporation under reduced pressure to give 4'-bromo-biphenyl-4yl)-(5-bromo-furan-2-yl)-methanol as a yellow oil (2.2g). lH NMR: 7.6-7. 4(m,8H); 6.23(d,1H); 6.10(d,1H); 5.80(s,1H); 2.64(s,1H).
PREPARATION 4
20 This Preparation illustrates the preparation of (4'-bromo-biphenyl-4yl) -furan-2-yl-methanone.
2-Furyl chloride (3.13g) was reacted with 4-bromo-biphenyl (4.66) in a similar manner to that illustrated in Preparation 2, to give (4'-bromobiphenyl4yl)-furan-2-yl-methanone as an off-white solid (5.21g) with mp 104-6OC. OH NMR (CDCI3): 8.07(d,2H); 7.72(d,1H); 7.68(d,2H); 7.62(d,2H); 7.52(d,2H); 7.28(d,1H); 6.62(dd,1H).
2s PREPARATION 5 This Preparation illustrates the preparation of (4'bromo-biphenyl4-Yl)-furan-2-Yl-methanol.
(4'-Bromo-biphenyl-4yl)-furan-2-yl-methanone (0.665g, Preparation 4) was suspended in ethanol (lOcm3). Sodium borohydride (0.115g) was added and the reaction mixture stirred for a period of two hours at the ambient temperature. The reaction mixture was then poured 30 into ice/water and the white solid so formed collected at the pump, water washed and air dried to give (4'-bromo-biphenyl-4-yl)-furan-2-yl-methanol as a white solid. 'H NMR: 7.6 7.4(m,9H); 6.35(m,1H); 6.18(D,1H); 5.87(D,1H); 2.43(D, 1H) PREPARATION 6
- 22 -
This Preparation illustrates the preparation of (4'-bromo-biphenyl4-vl)(5-chloro-thiophen-2 vl)-methanone. 5-Chloro-thiophene-2-carbonyl chloride (6.52g) was reacted with 4-bromo-biphenyl (4.66g) in a similar manner to that illustrated in Preparation 2, to give (4'-bromo-biphenyl-4- yl)-(5 s chloro-thiophen-2-yl)-methanone as an off-white solid (7.02g). 'H NMR: 7.90(d,2H); 7.70 7.55(m, 4H); 7.55-7.45(m, 3H); 7.02 (d,lH).
PREPARATION 7
This Preparation illustrates the of (4'-bromo-biphenyl-4-vl)-(5-chlorothiophen-2-vl) methanol. 0 (4'-Bromo-biphenyl4yl)-(5-chloro-thiophen-2-yl) -methanone (6.04g, Preparation 6) was reacted with sodium borohydride (1. 22g) according to the method illustrated in Preparation 5 to give (4'bromo-biphenyl-4-yl)-(5-chloro-thiophen-2-yl)-methanol (5.16g) as an offwhite solid with mp 104-6OC. 'H NMR: 7.60-7.40(m, 8H); 6.77(d,1H); 6.68(d, 1H); 5.98(d,1H); 2.55(d,1H). 5 PREPARATION 8
This Preparation illustrates the preparation of (4.6-dimethvl-2-ohenYlpvrirndin-5-vl) phenyl-methanone. 3-Benzylidene-acetylacetone (18cm3) was dissolved in glacial acetic acid (120cm3) at 20 C, and benzaldehyde (20cm3) added in one portion. The mixture was warmed to 50 C with 20 stirring, and ammonium acetate (90g) added at this temperature. Heatng was continued at 60-70 C for 20 minutes, the solution becoming increasingly cloudy. The reaction was then allowed to stand at 20 C for 24 hours to complete precipitation of product. The product was collected at the pump, washed with a small volume of 50% aqueous methanol, then copiously wth water, and air dried, yielding 11.2g (41%) of (4,6-dimethyl- 2-phenyl
r - 23 -
pyrimidin-5-yl)-phenyl-methanone. 1H NMR: S 8.65(dd,2H); 7.6(m,3H); 7. 45(m,3H); 7.2(d,2H); 4.25(s,2H); 2.75(s,6H).
PREPARATION 9
This Preparation illustrates the of 5-benzoyl-2-phenyl-pyrirnidine.6dicarboxylic acid.
5 (4,6-Dimethyl-2-phenyl-pyrimidin-5-yl)-phenyl-methanone (2.25g, Preparation 8) was added to a solution of potassium permanganate (5.25g) in deionised water (525cm3), and the mixture heated and stirred at the reflux temperature for 24 hours. Sodium metabisulphite solution was added to the cooled reaction mixture to decompose excess permanganate, and the product filtered to remove magnese dioxide. After washing the precipitate with further 0 water, the combined aqueous phases were evaporated to roughly one third volume under reduced pressure. A small amount of white insoluble material was filtered off and discarded, and the aqueous filtrate acidified with dilute hydrochloric acid to give, after filtration and drying at the pump, 5-benzoyl-2-pheny]-pyrirnidine4,6- dicarboxylic acid as a white solid (1.035g, 36o). IH NMR: 8.6(dd,2H); 7. 85-7.4(m,8H).
15 PREPARATION 10
This Preparation illustrates the preparation of (2-phenvl-pvrimidin-5-yl)phenYI-methanone.
5-Benzoyl-2-phenyl-pyrimidine-4,6-dicarboxylic acid (l.lg, Preparation 9) was dissolved in a mixture of acetic acid (8cm3) and acetic anhydride ( I. 4cm3), and heated under gentle reflux in a nitrogen atmosphere for five hours. After cooling to the ambient temperature, the 20 solvent was removed by evaporation under reduced pressure to give an oil, which crystallised on trituration with hexane to give (2-phenyl-pyrimidin-5-yl)phenyl-methanone as a buff solid (0.67g, 82%). OH NMR: 9.2(s,2H); 8.55(dd, 2H); 7.85(dd,2H); 7.7-7.5(m,6H).
PREPARATION I 1
This Preparation illustrates the preparation of (2-phenyl-pyrimidin-5-yl)phenyl-methanol.
25 (2-Phenyl-pyrimidin-5-yl)-phenyl-methanone (1.5g, Preparation 10) was ground to a fine powder, and added to sopropanol (30cm3). Sodium borohydnde (0.22g) was slowly added, with waterbath cooling keeping the reaction temperature below 26 C. After 30 minutes the reaction solvent was removed by evaporation under reduced pressure, the crude product partitioned between ethyl acetate and brine, the organic phase dried (MgSO4) and the solvent 30 removed by evaporation under reduced pressure. Purification of the required alcohol was effected by column chromatography (slica, using a 1:2 by volume mixture of ethyl acetate and hexane as eluent) to yield (2-phenyl-pyrimidin-5-yl)-phenyl-methanol (0. 8g, 51%). tH NhIR: 8.75(s,2H); 8.4(m,2H); 7.5-7.3(m,9H); 6.9(s,lH).
- 24 -
PREPARATION 12
This Preparation illustrates the preparation of (4-chlorophenyl)-2-(4chlorophenyl)-4.6 di rnethYl-pvrimidin-5 -Yl l-methane.
4-Chlorobenzylidene acetylacetone (22.25g) was dissolved in glacial acetic acid (120cm3) 5 containing ammonium acetate (9Og), and the mixture warmed to 60 C. After 10 minutes, 4-chlorobenzaldehyde (15.5g) was added portionwise, and heating continued for 30 minutes.
The solution was cooled to 12 C and stirred for two hours at this temperature. The resulting thick slurry was collected at the pump, washed with 50% aqueous methanol, followed by water, and air-dried to give (4whlorophenyl)-[2-(4-chlorophenyl)4,6-dimethyl-pyrimidin-5 o yl]methanone (18.3g). 'H Now: 8.4(m,2H); 7.45(m,2H); 7.25(d,2H); 6.95(d,2H); 4.05(s,2H); 2.50(s,6H).
PREPARATION 13
This Preparation illustrates the preparation of 5-(4-chlorobenzvl)-2-(4chlorophenvl)-4,6 distyryl-pyrimidne. 15 (4-Chlorophenyl)-12-(4chlorophenyl)4,6-dimethyl-pyr midin-5-yl]-methane (13.72g, Preparation 12) , benzaldehyde (40cm3) and anhydrous zinc chloride (3.2g) were stirred together, and heated to 150 C under nitrogen for 4 hours. On cooling to the ambient temperature, the resulting dark brown oil solidified. This solid was transferred, after breaking up under ethyl acetate, to a ll flask and stirred vigorously with water (lOOcm3) and a mixture 20 of 1:1 by volume of diethyl ether and hexane. The resulting slurry was filtered, washed with water and hexane, collected at the pump and air-dried to give 5-(4-Chlorobenzyl)-2-(4- -
chlorophenyl)4,6-distyryl-pyrimidine (16.1g, 78%). 'H NMR: 8.7(d,2H); (d, 2H); 8.3(d,2H); 7.2-7.7(m,16H); 4.4(s,2H).
PREPARATION 14
25 This Preparation illustrates the preparation of 5-(4-chlorobenzyl)-2(4-chlorophenvl) pyrirnidine. 5-(4-Chlorobenzyl)-2-(4-chlorophenyl)4,6distyryl-pyrimidine (12.0g, Preparation 13) was added to pyndine(250cm3) at 200C, and potassium permanganate (22g) and water (40cm3) added alternatively portionwise over 15 minutes: the resulting exotherm was held to 27 C 30 maximum by application of a cooling bath. On completion of addition, the dark solution/sluny was stirred for a further three hours at 20 C, then filtered, the filtrate decolourised wth saturated aqueous sodium metabisulphite, and the resulting solution taken to dryness by evaporation of the the solvent under reduced pressure.
- 25 The crude product was partitioned between dilute hydrochloric acid and ethyl acetate, and the organic layer extracted with saturated aqueous sodium carbonate solution. This was carefully acidified with concentrated hydrochloric acid to precipitate a white oily product, which gradually solidifying on stirring. The cooled solution was stirred for 30 minutes, and 5 the solid so formed collected at the pump and air dried to give a mixture of benzoic acid together with the required pyrirnidine diacid (3. 7g).
The mixture was suspended in anisole (50cm3), the vessel purged with nitrogen, and the solution refluxed for 1.5 hours after which time evolution of CO2 had ceased. The anisole was then removed by evaporation under reduced pressure, and the crude product partitioned lo between ethyl acetate and water. The organic phase was extracted with aqueous sodium carbonate solution (to remove benzoic acid), then washed with brine, and dried (MgSO4).
Filtration, followed by removal of the solvent by evaporation under reduced pressure, gave 5-
(4-chlorobenzyl)-2-(4-chlorophenyl)-pyrimidine (1.61g). OH NMR: 8.55(s,2H) ; 8.25(d,2H); 7.35(d,2H); 7.2(d,2H); 7.05(d,2H); 3.9(s,2H).
15 PREPARATION 15
This Preparation illustrates the preparation of (4-chlorophenvl)-2-(4chlorophenyl) pyrimidin-5-vll-methanol. 5-(4-Chlorobenzyl)-2-(4chlorophenyl)-pyiTrudine ( 1.61 g, Preparation 14), N-bromosuccinimide (0. 9lg) and benzoyl peroxide (few mgs, catalytic amount) were added 20 to carbon tetrachloride (25cm3), and the solution heated at the reflux temperature for three hours. On cooling, the reaction mixture was filtered, the residual succinude washed with carbon tetrachloride, and the filtrate taken to dryness by evaporation of the solvent under reduced pressure. The residue was partitioned between ethyl acetate and brine, the organic phase dried (MgSO4), filtered and the solvent removed by evaporation under reduced 2s pressure. Trituration with hexane gave the benzyl bromide as a pale yellow solid (1.75g).
This intermediate bromide product was dissolved in glacial acetic acid (lOcm3), and sodium acetate (0.73g) added. The mixture was heated to the reflex temperature for 10 minutes, where upon a precipitate formed. The reaction mixture was allowed to cool to the ambient temperature at which point the solvent was removed by evaporation under reduced pressure, 30 and the product partitioned between ethyl acetate and water. The organic phase was extracted with aqueous sodium bicarbonate solution, washed with brine, dried (MgSC)4), filtered and solvent again removed by evaporation under reduced pressure. Trituration with hexane gave the required intermediate acetoxy compound (1.02), which was hydrolysed to _.
- - 26 the desired secondary alcohol by adding to isopropanol (lOcm3) containing sodium hydroxide (0.22g) and refluxing for one hour. The i_propanol was removed by evaporation under reduced pressure, the residue partitioned between dilute hydrochloric acid and ethyl acetate, the organic phase washed with brine, dried ((MgS04) and filtered. Following 5 removal of the solvent by evaporation under reduced pressure, trituration with hexane: diethyl ether gave (4-chlorophenyl)-[2-(4chlorophenyl)-pyrimidin-5-yl]-methanol as a white solid (0.61g). OH NMR: 8.70(s,2H); 8.35(d,2H); 7.45(d,2H); 7.35(dd,4H); 5.85(s,1H); 2.8(br.s,1H). PREPARATION 16
lo This Preparation illustrates the preparation of 5-bromo-2chloropvrirnidine.
2-Amino-5-bromopyrimidine (25g) was added to concentrated hydrochloric acid (250cm3), and cooled to 0-2 C in an ice/salt bath, thus precipitating out the hydrochloride salt. Sodium nitrite (25g) was added portionwise, with frothing. On completion of the degassing at 0 C, the temperature was allowed to rise to 20 C, and stimug continued for 30 minutes, at which 5 time the reaction mixture was drowned out into water (11) and extracted with ethyl acetate.
The organic phase was washed with brine, dried ((MgSO4) and filtered. Removal of the solvent by evaporation under reduced pressure gave 5-bromo2-chloropynmidine (9.6g).
This material was carried on to Preparation 17 without further purification.
PREPARATION 17
20 This Preparation illustrates the preparation of 5-bromo-2phenoxypyrimidine.
To a suspension of anhydrous potassium carbonate (5.0g) in methyl sobutyl ketone (50cm3) was added phenol (1.9g), and the mixture stirred at 60 C for 10 minutes. A solution of 5-bromo-2-chloropyTimidine (3.87g, Preparation 16) in methyl iso-butyl ketone (40cm3) was added over a period of five minutes and the stirred reaction nxture was heated to 80 C for a 25 period of seven hours and then at the reflux temperature for a further period of three hours.
After cooling to the ambient temperature, ovemight, the crude reaction mixture was partitioned between ethyl acetate and water, the organic phase washed with aqueous sodium carbonate solution followed by brine and dried (MgSO4). After filtration, removal of the solvent by evaporation under reduced pressure gave 5-bromo-2-phenoxypyrimidine (3.1g).
30 lH NMR: 8.7(s,2H); 7.65-7.25 (m,SH).
PREPARATION 18
This Preparation illustrates the preparation of (4-chlorophenyl)-(2phenoxy-pvrimidin-5-yl) methanol.
- - 27 -
S-Bromo-2-phenoxypyrimidine (1.2g, Preparation 17) was dissolved in dry tetrahydrofuran (9Ocm3) under nitrogen and cooled to a -90 C (liquid N2/hexane bath). n-Butyl lithium (3ml of 1.6M solution in hexane) was added slowly ensuring the internal temperature did not exceed -90 C. After 45 minutes at this temperature, 4-chlorobenzaldehyde (0.672g) in dry 5 tetrahydrofuran (lOcm3) was added again keeping the temperature below -85 C. After 2 hours at -90 C the reaction mixture was allowed to slowly warm to room temperature before quenching with saturated aqueous annnonium chloride solution. The reaction mixture was partitioned between ethyl acetate and water, and the organic phase washed with brine, dried (Na2SO4), filtered and the solvent removed by evaporation under reduced pressure to give an 0 orange gum (1.5g). Column chromatography (silica gel, using 35% ethyl acetate by volume in hexane as eluent) gave (4chlorophenyl)-2-phenoxy-pyrimidin-S-yl)-methanol as a white solid (0.760g, 50% yield). OH Now: 8.7(s,2H); 7.5-7.1(m,9H); 6.00(d,1H); 58(d,1H, D2O exchangable). PREPARATION 19
IS This Preparation illustrates the preparation of 2-(4-chlorophenvl)-3dimethylamino oropan-2-enal. N,N-dimethylformamide (40.2g) was added to phosphonyl chloride (69g) with cooling (ice-bath) ensuring the temperature did not exceed 30 C. The viscous solution was stirred at room temperature for cat five minutes before a heating bath was applied. A solution of 20 4-chlorophenyl acetic acid in N,N-dimethylfonnamide (25.6g in 75cm3) was added over ten minutes ensuring the internal temperature did not exceed 72 C. The reaction was then heated at 70 C for 14 hours before being allowed to stand at the ambient temperature overnight. The reaction mixture was poured onto ice (SOOg) and neutralized with potassium carbonate. The mixture was then heated to 50 C (oil-bath) and treated with 50% sodium 25 hydroxide solution (lSOcm3) over_ ten minutes, keeping the temperature below 55 C. The reaction mixture was then cooled (ice-bath) and the resultant solid collected by filtration at the pump, washed with water and air dried to give 2-(4-chlorophenyl)-3- dimethylamino propan-2-enal (25.1g, 80%). OH NMR: 9.2(s,1H); 7.4(d,2H); 7. 2(d,2H); 6.9(br.s,1H); 3.0(br.s,6H). 30 PREPARATION 20
This Preparation illustrates the preparation of 5-(4-chlorophenyl)-2methylthio pyrimidine. _
- 28 2-Methyl-2-thiopseudourea sulphate (10.3g), sodium methoxide (5.35g) and 2-(4 chlorophenyl)-3-dimethylamino-propan-2-enal (5.187g, Preparation 19) were suspended in dry ethanol (25cm3) and heated to the reflex temperature (oil-bath 100 C) [CARE! methanethiol containing exhaust gases scrubbed with chloros]. After l hour a thick s suspension resulted, which hampered stirring. The reaction allowed to cool to the ambient temperature, neutralised with dilute aqueous hydrochloric acid and then partitioned between ethyl acetate and water. The aqueous washings were extracted (x2) with ethyl acetate and the combined organic phases dried (Na2SO4), filtered and the solvent removed by evaporation under reduced pressure to yield Sg of a solid. The crude product was purified by column 0 chromatograpy (silica gel, eluting with 20% by volume ethyl acetate in hexane followed by 50% by volume ethyl acetate in hexane) to give 5-(4chlorophenyl)-2-methylthimpyrimidine (3g, 50% yield). OH Nl: 0 8.7(s,2H); 7.5 (s,4H); 2.6 (s,3H).
PREPARATION 21
This Preparation illustrates the preparation of 5-(4-chlorophenvl)-2methylsulfonvl 15 pvrimidine. 5-(4-Chlorophenyl)-2-methylthio-pyrirnidine (3.43g, Preparation 20) was dissolved in chloroform (80cm3) and stirred at 0 C (ice/water bath). 50qo m-Chloroperbenzoic acid (l S.lg) was then dissolved in chloroform (320cm3) and added dropwise to the pyrimidine.
The reaction mixture was allowed to stir at the ambient temperature for a period of six hours, 20 and then to stand overnight. The reaction mixture was then diluted with chloroform and washed successively with saturated aqueous sodium metabisulphite solution, saturated aqueous sodium bicarbonate solution and saturated brine. After drying (Na2SO4) and filtration, removal of the solvent by evaporation under reduced pressure gave 5-(4 chlorophenyl)-2-methylsulfonyl-pyrimidine as a white solid (4g). This was used without 25 purification in Preparation 22. 'H NMR: o 9. l(s,2H); 7.6(s,4H); 3.4(s,3H).
PREPARATION 22
This Preparation illustrates the preparation of 5-(4-chlorophenvl)pvrimidine-2-carbonitrile.
5-(4-Chlorophenyl)-2-methylsulfonyl-pyrimidine ( 4.2g, Preparation 22) and sodium cyanide (2.3g) were heated in N,N-dimethylformamide (lOOcm3) at 50 C (oil-bath) for a period of 30 30 minutes. The cooled reaction mixture was then diluted with water (SOOcm3) and extracted (4 x 80cm3) with diethyl ether. The combined organic phases were washed with water, then brine, and the solvent removed by evaporation under reduced pressure giving a dark brown solid. This was subjected to column chromatograpy (silica gel, eluting with
- 29 dichloromethane) to give 5-(4-chlorophenyl)-pyrimidine-2carbonitrile as an orange solid (2.9g). OH NOR: 9.05(s,2H); 7.55(s,4H).
PREPARATION 23
This Preparation illustrates the preparation of (4-chlorophenvll-5-(4chlorophenvl) 5 pyrimidin-2-yll-methanone. A solution of 5-(4chlorophenyl)-pyrimidine-2-carbonitrile (0.13g, Preparation 22) in anhydrous tetrahydrofuran (5cm3) was cooled to 0 C (ice/water bath) under N2. A solution of p-chlorophenyl magnesium bromide (9001 of 1M solution in diethyl ether) was added dropwise giving a dark brown solution. The reaction mixture was taken to pH2 with dilute 0 hydrochloric acid and stirred for 15 minutes. The yellowish suspension was partitioned between with water and ethyl acetate and the aqueous layer extracted (x2) with ethyl acetate.
The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered and the solvent removed by evaporation under reduced pressure to give (4-chlorophenyl)-[5(4-chlorophenyl)-pyrimidin-2-yl]-methanone as 5 an orange solid (0.23g), which was used in Preparation 24 without further purification. OH NMR: 9. 1(s,2H); 8.1(d,2); 7.7-7.5(m,6H).
PREPARATION 24
This Preparation illustrates the preparation of (4-chlorophenyl)-5-(4chlorophenyl) pvrimidin-2-YIl-methanol. 20 (4-Chlorophenyl)-[5-(4chlorophenyl)-pyrirnidin-2-yl]-methanone (0.20g, Preparation 23) was suspended in a mixture of tetrahydrofuran (5cm3) and sopropanol (2cm3) and the stirred suspension cooled to 0 C (icelwater bath). Sodium borohydride (0.030g) was added and the reaction allowed to stir at the ambient temperature for a period of one hour. Excess acetone was added (to quench the excess borohydride) and after 30 minutes the solvent was removed 25 by evaporation under reduced pressure. The residue was partitioned between ethyl acetate and brine and the brine re-extracted with ethyl acetate. The combined organic phases were dried (Na:SOJ,), filtered and the solvent was removed by evaporation under reduced pressure. Punfication of the residue was achieved by column chromatography (silica gel, using 35% by volume ethyl acetate in hexane as eluent) to give gave (4-chlorophenyl)-[5-(4 ao chlorophenyl)-pyrimidin- 2-yl]-methanol (0.120g). OH NMR: o 8.9(s,2H); 7.3-7.55(m,8H); 5.9(s,lH); 4.8-5.0 (br.s, D2O exchangeable).
PREPARATION 25
This Preparation illustrates the preparation of 5-chloro-2-cvanopyrimidine.
(A - 30
A solution of 2,5-dichloropyrimidine (14.9g) was slowly added at 0-2 C to a two-phase, vigorously stirred mixture of toluene (40cm3), water (20cm3), and 45% aqueous trimethylarnine (16.5cm3). The mixture was allowed to warm slowly to SAC, then stirred for 22 hours. The phases were then separated, the organic phase water-washed, and the 5 combined aqueous phases replaced in the reaction flask. Toluene (40cm3) was added and a solution of potassium cyanide (6.6g) in water (20cm3) added over 5 minutes at 2-5 C. The reaction mixture was then was allowed to warm to 20 C, and stirred for a further 20 hours.
The reaction mixture was then filtered, and the separated organic phase washed with: brine, dried (MgSO4) and decolourised (charcoal). After filtration, the solvent was removed lo by evaporation under reduced pressure to give 5-chloro-2-cyano pyrimidine (7.7g). 'H NMR: o 8.95(s,2H).
PREPARATION 26
This Preparation illustrates the preparation of 2-cyanoRvrimidine.
2-Chloropyirnidine was reacted in a similar manner to that described in Preparation 25, to 5 give, after purification by column chromatography (silica gel, using a 1:1 by volume ethyl acetate/hexanes mixture as eluent), 2-cyano-pyrirnidine as a light brown oil which crystallized on standing (50%). OH NMR: o 8.7(d,2H); 7.35 (I, 1H).
PREPARATION 27
This Preparation illustrates the preparation of biphenyl-4-yl-pyimidm-2vl-methanone.
20 To magnesium turnings (0.286g) and a crystal of I2 in dry THE (lOcm3), under nitrogen, was added a solution of 4-bromobiphenyl in dry tetrahydrofuran (2.77g in 20cm3). The mixture was heated to vigorous reflex by means of an air-gun until the purple coloration had dispersed. The clear mixture was then heated at 55 C (oil-bath) for two hours at which stage most of the magnesium had dissolved to give a greenish solution. This was cooled to 0 C 25 (ice/water bath) and treated with 2cyanopyrimidine (1.Og, Preparation 26) in dry THE (lOcm3) to give a dark brown solution. The reaction mixture then was stirred at the ambient temperature for two hours. The mixture was taken to pH1, with dilute hydrochloric acid, and stirred at the ambient temperature for 30 minutes before being partitioned between ethyl acetate and waten The aqueous layer was extracted (x3) with ethyl acetate and the 30 combined organic phases washed with aqueous saturated sodium bicarbonate solution and brine. After drying (Na2SO4), the solution was filtered and the solvent removed by evaporation under reduced pressure. The crude solid product was subjected to column chromatography (silica gel using a 3:2 by volume mixture of ethyl acetate and hexanes as
- 31 eluent) to give biphenyl-4-yl-pyrimidin-2-yl-methanone (2.84g, 86%). lH NMR: 9.0(d,2H); 8.1(d,2H); 7.75(d,2H);7.65(d,2H); 7.35-7.55(m.,4H).
PREPARATION 28
This Preparation illustrates the preparation of (4'-bromo-biphenvl4-yl-(5chloro 5 pyrimidin-2-yl)-methanone.
5-Chloro-2-cyano-pyrirnidine was reacted with the Grignard reagent from 4, 4' dibromobiphenyl in a similar manner to that described in Preparation 27 to give (4'-bromo biphenyl-4-yl-(5-chloro-pyrimidin-2-yl)-methanone (35%). OH NMR: o 8.9(s, 2H);: 8.1 (d,2H); 7.75-7.40(m,bH).
lo PREPARATION 29 This Preparation illustrates the preparation of biphenyl4-vl-pvrimidin-2-vl-methanol. Biphenyl-4-yl-pyrimidin-2-yl-methanone (2.13g, Preparation 27) was
dissolved in a mixture of tetrahydrofuran and i_propanol (5:2 by volume, lOOcm3) and stirred at the ambient temperature. Sodium borohydride (0. 372g) was added in one portion. After 45 minutes, 5 excess borohydride was quenched by the addition of acetone and the reaction mixture was taken to dryness by evaporation of the solvent under reduced pressure. The residue was partitioned between ethyl acetate (lOOcn3) and brine (lOOcm3) and the organic layer dried (Na2SO4), filtered and again taken to dryness by evaporation of the solvent under reduced pressure. The residue was taken up in chloroform and passed through a thin bed of silica gel.
20 After removal of the solvent by evaporation under reduced pressure, the resultant solid was recrystallized from a mixture of ethyl acetate and hexanes to give, after air-drying, biphenyl-
4-yl-pyrimidin-2-yl-methanol (1.66g, 77% yield). 'H Now: 8.75(d,2H); 7.67.2(m,10H); 5.9(d,1H); 4.9(d,1H, D20 exchangeable).
- 32 -
PREPARATION 30
This Preparation illustrates the preparation of t4'-bromo-biphenvl4-yl)(5-chloro pyrimidin-2-vl)-methanol. (4'-Bromo-biphenyl-4-yl-(5-chloropyrimidin-2-yl)-methanone (Preparation 28) was reacted 5 in a similar manner to that illustrated in Preparation 29 to give (4'-bromo-biphenyl-4yl-(5 chloro-pyrirnidin-2-yl-methanol (90%). 'H NMR: 8.7(d,2H); 7.7-7.4(m, 8H); S.95(d,1H); 4.6(d,1H,D2O exchangeable).
PREPARATION 3 1
This Preparation illustrates the preparation of biphenyl4-vl-(2methylthio-pyrimidin 0 S-yl)-methanol. To a solution of 2-methylthio-Sbromopyrimidine (1.00Sg) in dry tetrahydrofuran (80cm3) under nitrogen at -9O0C (liquid N2/IPA bath) was added n-butyl lithium (3.06cm3 of a 1.6M solution in hexanes) ensuring the internal temperature did not exceed 88 C. The resultant orange solution was stirred at this temperature for 45 minutes before a solution of 5 4-biphenylcarboxaldehyde in dry tetrahydrofuran (0.892g in lOcm3) was added slowly, keeping the temperature below 85 C. After two hours at this temperature the reaction mixture was allowed to warm to -5 C before quenching with saturated ammonium chloride solution. The reaction mixture was then partitioned between ethyl acetate and water, the ethyl acetate layer washed with bane, dried (Na2SO4), filtered and the solvent removed by 20 evaporation under reduced pressure to give a pale brown oil (1.523g). This was purified by column chromatography (silica gel using a mixture of ethyl acetate and hexanes, 25% to 40% by volume' in 5% graduations, as eluent) to give biphenyl4-yl-(2-methylthio-pyrimidin-S yl)-methanol (0.440g, 29%). 'H NMR: o 9.55(s,2H); 7.65-7.5(m,4H); 7.5-7.3(m,5H); 5.9(s,1H); 2.5(s,3H). MS: (EVCI): MH+ 309.
25 PREPARATION 32
This Preparation illustrates the preparation of (biphenvl-4-vl)-pYridin-2Yl-methanol.
The Grignard reagent derived from 4-bromobiphenyl (3.01g) in dry THF (25cm3) was prepared as previously described (Preparation 27), and cooled to -78 C.
Pyridine-2-carboxaldehyde (1.38g) was slowly added, giving a brown solution. After a period 30 of five minutes, the reaction was carefully quenched with saturated aqueous ammonium chloride, then partitioned between ethyl acetate and water. The organic phase, together with further ethyl acetate extracts were washed with brine, dried (Na2SO4), filtered and the solvent removed by evaporation under reduced pressure to give a dark brown oil. Column
f - 33 chronatography (silica gel, using hexane to dichloromethane, in increments, followed by dichloromethane containing ethyl acetate, 5% by volume as eluent) gave (biphenyl-4-yl pyndin-2-yl-methanol (1.375g, 41%). OH NMR: 8.6(dd,1H); 7.7-7.5(m,5H); 7 45-7.3(m,5H); 7.25-7.15(m,2H); 5.8(s, 1H).
5 PREPARATION 33
This Preparation illustrates the preparation of (4'-bromo-biphenvl-4-vl)pyridin-2-vl methanol. Pyridine-2-carboxaldehyde was reacted with the Grignard reagent of 4,4'-dibromobiphenyl, in a similar manner to that illustrated in Preparation 32, to give (4'-bromo-biphenyl4-yl) 10 pyridin2-yl-methanol (26%). OH NMR (CDCl3): 8.6(dd,1H); 7.6-7.4(m,5H); 7.2(m,2H); 5.8 (br.d,lH); 5.3(br.d, 1H, D2O exchangeable).
PREPARATION 34
This Preparation illustrates the preparation of (4'-bromo-biphenyl-4-vl)pvridin-4-yl methanol. is Pyridine4-carboxaldehyde was reacted with the Grignard reagent of 4,4'-dibromobiphenyl, in a similar manner to that illustrated in Preparation 32, to give (4'-bromo-biphenyl-4-yl) pyridin-4yl-methanol (52%). tH NOR (d6-DMSO): 0 8.5 (d,2H); 7.5-7.3(m,10H); 6.1(d, 1H); 5.75(d, D2O exchangeable, 1H).
PREPARATION 35
20 This Preparation illustrates the preparation of biphenYl4-Yl-(lHimidazol-2-Ylt methanone. ltnidazole (0.805g) was dissolved in dry pyridine (30cm3) under nitrogen and treated with dry trimethylamine (3. 3cm3). The resultant solution was cooled in ice and treated with a solution of 4-biphenylcarbonyl chloride in dry dichloromethane (5.488g in 40cm3) giving rise 25 to a cloudy orange-brown reaction mixture. This was stirred at the ambient temperature for two hours before treatment with 7M sodium hydroxide solution (15cm3). The resultant mixture was heated to at the reflex temperature for 40 minutes before being allowed to stand at the ambient temperature overnight. The reaction mixture was than filtered and the filtrate partitioned with ethyl acetate. The layers were separated and the aqueous phase re-extracted 30 with ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4), filtered and the solvent removed by evaporation under reduced pressure to give a brown solid (2.33g). This was purified by column chromatography (silica using a 1:1 by volume mixture of ethyl acetate and hexane as eluent) to give biphenyl4-yl-(lH-imidazol-2-yl)-methanone as
- 34 an off-white solid (1.548g, 52%). OH NMR: 613.0(s,1H); 8.6(d,2H); 7. 8-7.6(m,4H); 7.55 7.2(m,5H). MS EVCI: M+ 248.
PREPARATION 36
This Preparation illustrates the preparation of biphenvl4-Yl-(lH-imidazol2-YI) methanol. Biphenyl-4-yl-(lH-imidazol-2-yl)-methanone (1.266g, Preparation 35) was dissolved in a rnxture of tetrahydrofuran (400cm3) and sopropanol (lOOcm3) and cooled in ice.
Sodium borohydride (0.385g) was added and the mixture allowed to stir at the ambient temperature for a period of one hour. Acetone (lOcm3) was then added and the reaction 0 mixture was stirred for 30 minutes before removal of the solvent by evaporation under reduced pressure. The solid residue was collected at the pump, washed with iced water, then dry diethyl ether, and air dried to give 1.1 82g of a cream solid. This was used in Example 14 without purification. OH Now (d6-DMSO): o 12.1(br.s,1H- D2O exchangeable); 7.8 7.4(m,9H); 7.1(s,1H); 6.9(s,1H); 6.35(d,1H-D20 exchangeable); 5.9(d,1H). MS (EI/CI): My 5 250 PREPARATION 37
This Preparation illustrates the preparation of (4'-bromo-biphenvl-4-vl?oxazol-2-vl methanol. Oxazole (0.870g) in dry tetrahydrofuran (lOcm3) was cooled to -780C (dry ice/acetone) So under nitrogen and treated dropwise with sec butyl lithium ( 1 1.5cm3 of 1.1 M solution in hexanes). The orange solution was stirred at -78 C for 15 minutes before treatment with 4-bromo-4'-biphenylcarboxaldehyde (3.293g) in dry tetrahydrofuran (30nd). After 30 nunutes the reaction mixture was quenched with saturated aqueous ammonium chloride solution and allowed to warm to the ambient temperature. The reaction mixture was 25 partitioned between ethyl acetate and water and the organic phase washed with saturated sodium bicarbonate solution then brine, dried (Na2SO4) and filtered. Removal of the solvent by evaporation under reduced pressure gave a brown foam (4.292g) which was purified by column chromatography (silica gel, eluting with hexane, then 35% ethyl acetate by volume in hexane and finally ethyl acetate). (4'Bromo-biphenyl-4-yl)-oxazol-2-yl-methanol was 30 obtained as a light brown foam (1.854g, 45%). OH NMR: 7.9(s,1H); 7.6-7.4(m,9H); 5.85(s,1H). PREPARATION 38
f - 35 This Preparation illustrates the preparation of biphenyl-4-vl-(4.5dimethYl-thiazol-2 Yl)-methanone, 4,5-Dimethylthiazole (2.4g) and 4biphenylcarboxaldehyde (11.64g) were treated with 2M sulphuric acid (10. 6cm3) and then dissolved in glacial acetic acid (80cm3). Iron (II) 5 sulphate heptahydrate (17.7g) was dissolved in hot water (60cm3) and this solution cooled in ice before adding to the cooled reaction mixture (ice/bath). At the same time t-butyl hydroperoxide (21cm3 of 3M solution in iso-octane) was added. The reaction mixture was dark brown, and over time a geleatinous solid separated. The mixture was filtered and the sticky orange solid cake washed with water and saturated aqueous sodium bicarbonate lo solution. The filtrate was extracted (x2) with chloroform filtered through 'thi-flo" and washed with aqueous sodium bicarbonate solution and brine before combining with the filtrate cake. Removal of the solvent by evaporation under reduced pressure gave a sticky brown solid (13.8g) which was further purified by chromatography (silica gel, using 15% by volume diethyl ether in hexane as eluent) to give, after removal of the solvent under reduced is pressure, an orange oil (6.5g) which was then stirred in ethanol at room temperature. The precipitate so formed was collected at the pump, washed well with iced ethanol and air- dried to give biphenyl4-yl-(4,5-dimethyl-thiazol-2-yl)-methanone as a white solid (1.29g). 'H NMR: 8.5(d,2H); 7.8-7.65(2xd,4H); 7.5-7.4(m,3H); 2.5(2xs,6H).
PREPARATION 39
20 This Preparation illustrates the preparation of biphenyl-4-vl-(4,5dimethvl-thiazol-2 vl)-methanol. Biphenyl-4-yl-(4,5-dimethyl-thiazol-2-yl) -methanone (1.29g, Preparation 38) was dissolved in tetrahydrofuran (20cm3) and i_propanol (30cm3) and this solution cooled in ice.
Sodium borohydride (0.333g) was added in one portion. After 15 minutes the reaction 2s mixture was treated with 2M hydrochloric acid (CARE! bubbling) to pH7 before removal of the solvent under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer washed with brine, dried (Na2SO4), filtered and the solvent removed by evaporation under reduced pressure to give biphenyl4-yl-(4,5dmethyl-thiazol 2-yl)-methanol as a white foam ( 1.3 la). This was used without purification in the next step.
30 tH NMR: 67.65(m,9H); 6.0(s, 1H); 2.3(s,6H).
PREPARATION 40
Am. - 36 This Preparation illustrates the preparation of 3-(4'-bromobiphenvl-4-Yl)-thiazol-2-yl methanol. 2-Bromothiazole (1.365g) was added to n-butyl lithium (5.2cm3 of 1.6M solution in hexane) in anhydrous tetrahydrofuran (20cm3) at -78 C (dry ice/acetone) under nitrogen.
5 After 30 minutes at -78 C, a solution of 4-bromo4'biphenylcarboxaldehyde in dry tetrahydrofuran (2.17g in 20cm3) was added dropwise. The reaction mixture was allowed to warm to the ambient temperature and quenched with saturated aqueous ammonium chloride solution. The mixture was then partitioned between ethyl acetate and water and the aqueous phase extracted with ethyl acetate. The combined organic phases were thoroughly washed 0 with brine, dried (Na2SO4) and filtered through a thin bed of silica to give, after re novel of the solvent by evaporation under reduced pressure, a dark brown oil (2.826g).
Chromatography (silica using a 1:1 by volume Fixture of ethyl acetate and hexane as eluent) gave 3-[(4'-bromo-biphenyl4-yl)-thiazol-2-yl-methanol as a brown solid (0.866g, 32%). lH NMR (CDCl3): S 8.75(s,1H); 8.55(m?6H); 7.3(d,1H); 6.1(d,1H); 2.4(m,2H); 5 3.6(d,1H-D2O exchangeable).
PREPARATION 41
Preparation illustrates the preparation of (4'-bromo-biphenvl-4-YI)pvrazin-2-yl methanone. 5-(4'-Bromo-biphenyl4-carbonyl)-pyrazine-2carboxylic acid was prepared from 4 20 bromo4'-biphenyl-carboxaldehyde and pyrazine-2-carboxylic acid according to the method described in Preparation 38. The acid so formed was then heated at the reflux temperature in anisole, overnight, to effect decarboxylation. The crude reaction mixture was contaminated with 4'-bromo4-biphenylcarboxylic acid which was removed by washing the crude reaction mixture with aqueous sodium carbonate solution. The organic phase was thoroughly washed 25 with brine, dried (Na2SO4), filtered and the solvent removed by evaporation under reduced pressure The product was obtained pure by column chromatography of the residue (silica, using a mixture of 10% by volume ethyl acetate in dichloromethane as eluent) to give (4' bromobiphenyl4-yl3-pyrazin-2-yl-methanone. The yield over two steps was 5%. 'H NMR: 9.3(s,1H); 8.8(d,1H); 8.7(d,1H); 8.2(d,2H); 7.75^7.45(m,6H).
PREPARATION 42
:: - 37
This Preparation illustrates the preparation of (4'-bromo-biphenvl-4-yl)pYrazn-2-YI methanol. (4'-Bromo-biphenyl4-yl)-pyrazin-2-yl-methanone (0. 145g, Preparation 42) was dissolved in a mixture of ethanol (5cm3) and tetrahydrofuran (lcm3) and treated with sodium 5 borohydride (0.020g). After 24 hours the excess borohydride was quenched with acetone and the solvent removed by evaporation under reduced pressure. The residue was partitioned between ethyl acetate and brine and the organic layer dried (Na2SO4), filtered, and the solvent removed by evaporation under reduced pressure to give (4'-bromo-biphenyl-4-yl) pyrazin-2-yl-methanol as an oily solid (0.145g). This was used without purification in the lo next step (Example 18). 'H Now: o 8.55(s,1H); 8.4(d,1H); 8.35(d,1H); 7.5-7. 25(m,8H), 5.(s,1H). EXAMPLE 1
This Example illustrates the preparation of 3-(4'-bromo-biphenyl4-vl)furan-2-vl methvll-4-hydroxvcoumarin (compound 17 in Table 1).
5 A mixture of 4-hydroxycoumarin (1.29g) and (4'-bromo-biphenyl-4-yl)furan-2-yl methanol (2.63g, Preparation 5) in toluene (50cm3) was heated at the reflux temperature for a total of eight hours. After being allowed to cool to the ambient temperature, the solvent was removed by evaporation under reduced pressure, and the residue was triturated with a mixture of ethyl acetate and hexane. The solid so fanned was collected at the pump and 20 again triturated with ethyl acetate. This process was repeated several times to give 3-[(4' bromo-biphenyl-4-yl)-furan-2-ylmethyl]-4-hydroxycoumarin as a pale pink coloured solid (1.42g) with mp 193-6OC. OH NMR: 7.83(d,1H); 7.6-7.25(m,14H); 6.45(m,1H); 6.35(d,1H); 6. 09(s, 1H).
EXAMPLE 2
2s Eample illustrates the preparation of 3-1 (4'-bromo-biphenvl4-yl)-(5bromo-furan 2 vl)-methyll4-hydroxYcoumarin (compound 18 in Table 1).
A mixture of 4-hydroxycoumarin (0.810g) and (4'-bromo-biphenyl-4-yl)-(5bromo furan-2-yl)-methanol (2.04g, Preparation 3), in toluene (50cm3), was heated at 100 C for three hours. After being allowed to cool to the ambient temperature, the solvent was 30 removed by evaporation under reduced pressure, and the solid so formed collected at the pump and washed with toluene. The crude product was triturated with ethanol, collected at the pump, washed with more ethanol and air dried to give 3[(4'-bromo-biphenyl4-yl)-(5
- 38 bromo-furan-2-yl)-methyl]-4-hydroxycoumann (2.41g) as a white solid with mp 207 C. 'H NMR: 1.82(d,1H); 7.6-7.19(m,1 1H); 6.88(s,1H); 6.34(d, 1H); 6.29(d,1H); 6.03(s, 1H).
EXAMPLE 3
This Example illustrates the preparation of 3-(4'-bromo-biphenvl-4-vl)-(5chloro s thiophen-2-yll-methvll4-hydroxYcoumarin (compound 19 in Table 1).
A mixture of 4-hydroxycoumarin (0.810g) and (4'bromo-biphenyl4-yl)-(5chloro thiophene-2-yl)-methanol (3.80g,, Preparation 7), in xylene (120cm3), was heated to the reflex temperature for six hours in a Dean and Stark apparatus. After being allowed to cool to the ambient temperature overnight, the solid so formed was collected at the pump and 0 washed with toluene. The crude product was triturated with ethanol, collected at the pump, recrystallized from ethanol and air dried to give 3-1(4'-bromo-biphenyl4-yl)-(5-chloro thiophene-2-yl)-methyl]4hydroxycoumann (2.21g) as a white solid with mp 2124 C. OH Now: 7.80(d,1; 7.62-7.52(m,5H); 7.46-7.38(m,4H); 7.35-7.25(m,2H); 6.82(m,2H); 6.70(d,1H); 6.06(s, 1H) 5 EXAMPLE 4
Example illustrates the preparation of 3-henyl-(2-phenvl-pvrimin-5-vl)methvll4 hydroxvcoumarn (compound 1 in Table 1).
(2-Phenyl-pyrimidin-5-yl)-phenyl-methanol (0.75g, Preparation 11) was dissolved in dry xylene (Scm3) under reflux, the mixture cooled and 4hydroxycoumarin (0.46g) and 20 p-toluene sulphonic acid (few mgs, catalytic) added. After heating at the reflux temperature for eight hours, the reaction was cooled and allowed to stand at 20 C for several days, to give a buff precipitate. This was collected at the pump and recrystallization from ethyl acetate-hexane gave 3-[(phenyl-(2-phenylpyrimin-5-yl)-methyl]-4-hydroxycoumarin. mp 145 C. NMR(d6-DMSO): 8.8(s,2H) ; 8.5(m,2H); 8.2(d,1H); 7.35-7.8(m,1 1H); 6.1(s,1H).
25 EXAMPLE 5
This Example illustrates the preparation of 3-(4-chlorophenvl)-2-(4chlorophenvl) pyrimidin-S-yll-methYI I-4-hvdroxycoumarin (compound 2 in Table 1) (4-Chlorophenyl)- [2-(4-chlorophenyl)-pynrnidin-5-yl]-methanol (0.331 g, Preparation 15), 4-hydroxycoumarin (0.162g) and ptoluenesulphonic acid (few mgs, catalytic) were 30 added to xylene (5cm3), the flask flushed with nitrogen, and the solution heated at the reflex temperature for three hours. On stand ng at 20 C overnight, an oil settled out, which solidified on scratching. The solvent was removed by evaporation under reduced pressure, and the residue was partitioned between ethyl acetate and water, washed with brine, dried
i\ over magnesium sulphate and taken to dryness by evaporation under reduced pressure.
Crystallisation of the so formed solid from diethyl ether gave 3-{ (4chlorophenyl)-[2-(4 chlorophenyl)-pyrimidin-5-yl]-methyl}-4hydroxycoumarin, mp 21 5-6OC. OH NMR (d6 DMSO): 8.65(s,2H); 8.3(d,2H); 8. 0(dd,1H); 7.25-7.6(m,9H); 5.(s,1H). 3 5 EXAMPLE 6
This Example illustrates the preparation of 3-(4-chlorophenyl)-(2-phenoxY pyrimidin-5-Yl)-methY11-4-hydroxvcoumarin (compound 3 in Table 1).
(4-Chlorophenyl)-(2-phenoxy-pyrimidin-5-yl)-methanol (0.747g, Preparation 18), 4-hydroxycoumarin (0.775g), sodium sulphate ( l.Og) and ptoluenesulphonic acid (O.OSOg) 10 were heated at the reflux temperature in dry xylene (30cm3) for five hours. The cooled reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic phase washed with brine, dried (Na2SO4), filtered and the solvent removed by evaporation under reduced pressure. The crude product was purified by column chromatography (silica gel, using 2.5% by volume methanol in dichloromethane as 5 eluent) to give 3[(4-chlorophenyl)-(2-phenoxy-pyrimidin-5-yl)-methyl]-4-hydroxycoumarin as an off-white solid (0.615g, 57%). OH NMR: o 8.5(s,2H); 8.0(d,1H); 7.55(t, 1H); 7.5-7.1(m,11H); 5.9(s,1H). MS (FAB): M+ 457.
EXAMPLE 7
Example illustrates the preparation of 3-4-chlorophenvl)-5-(4chlorophenyl) 20 pvrimidin-2-yll-methyll-4-hydroxvcoumarin (compound 4 in Table 1).
(4-Chlorophenyl)-[5-(4-chlorophenyl)-pyrimidin-2-yl]-methanol (0.84g, Preparation 24), 4-hydroxycoumarin (1.24g), p-toluenesulphonic acid (O. OSg, catalytic) were suspended in dry xylene (40cm3) under nitrogen and heated at the reflux temperature (oil-bath 175 C) for a period of 18 hours. The bulk of the xylene was removed by evaporation under reduced 25 pressure (evaporator bath at 80 C) and the residue subjected to chromatography (silica gel, using dichloromethane followed by dichloromethane containing up to 5% by volume ethyl acetate, in 1% increments, as eluent) to give 3-(4-chlorophenyl)-5[4-chlorophenyl)- I pyrimidin-2-yl] methyl}4-hydroxycoumarin as a light brown foam (0.938g). OH NMR: o 14.4(br.s,lH); 9.0(s,2H); 8.O(d,lH); 7.2-7.7(m,1lH); 6.5(s,lH). MS (El/CT): M+ 474/476.
Go: r EXAMPLE 8
Example illustrates the preparation of 3-(4'-bromo-biphenyl-4-yl)-(5chloro pymidin-2-Yl)-methYll-4-hYdroxvcoumarin (compound 5 in Table 1).
(4'-Bromo-biphenyl-4-yl)-(5-chloro-pyrimidin-2-yl)-methanol (0.830g, Preparation 3 5 30), 4-hydroxycoumarin (0.361g) and p-toluenesulphuric acid (0.120g) were suspended in dry xylene (35cm3) and heated at the reflux temperature for a period of three hours (oil-bath at 175 C). The bulk of the xylene was removed by evaporation under reduced pressure (evaporator bath at 70 C) and the residue subjected to chromatography (silica gel, eluting with a 45:55 by volume mixture of ethyl acetate and hexane) to give the 3-[(4'-bromo 0 biphenyl4-yl)-(5-chloro-pyrimidin-2-yl) -methyl]-4-hydroxycoumarin as a foam (0.946g, 82%). HNMR: 613.5(bs,1H); 8. 8(s,2H); 7.95(dd,1H); 7.6-7.2(m,11H); 6.5(s,1H): M+ 518/520.
EXAMPLE 9
This Example illustrates the preparation of 3-(biphenvl-4-yl-pvimidin-2Yl-metEvl)-4 5 hydroxvcoumarin (compound 6 in Table 1).
Biphenyl-4-yl-pyrimidin-2-yl-methanol (Preparation 29) was reacted with 4 hydroxycoumarin in a similar manner to that illustrated in Example 8, save that the reaction mixture was heated for a total of 72 hours, to give 3-(biphenyl-4-yl-pyrimidin-2-yl-nethyl) 4-hydroxycoumarin (35%). OH NMR: 14.8(br.s,1H); 8.9(d,2H); 8.0(dd,1H); 20 7.6-7.2(m,13H); 6.5(s,1H): M+ 407.
EXAMPLE 10
This Example illustrates the preparation of 3-[biphenvl-4-vl-(2methylthio-pyrimidin 5-vl)-methyll-4-hvdroxvcoumarin (compound 7 in Table 1).
Biphenyl4-yl-(2-methylthio-pyrimidin-5-yl)-methanol (0.430g, Preparation 31), 25 4-hydroxycoumarin (0.679g), sodium sulphate (O.SOOg) and ptoluenesulphonic acid (0.030g, catalytic amount) in dry xylene (30cm3) were heated at the reflex temperature under nitrogen (oil-bath at 178 C). After one hour the solvent was removed by evaporation under reduced pressure and the residue was subjected to column chromatography (silica gel, using 0.5% by volume methanol in dichloromethane as eluent) to give 3-[biphenyl4-yl-(2-methylthio 30 pyrimidin-5-yl)-methyl]-4hydroxycoumarin as a brown foam (0.50g, 79% yield). 'H NMR: 8.6(d,2H); 7. 8(d,1H); 7.2-7.6(m,12H); 5.9(s,1H); 2.55(s,3H). MS (FAB): M+ 453.
- 41 EXAMPLE 11
This Example illustrates the preparation of 3-(4'-brornobiphenyl-4-YI)pyridin-2-yl methyll-4-hydroxycoumarin (compound 10 in Table 1).
(4'-Bromo-biphenyl-4-yl)-pyridin-2-yl-methanol (l.OOg, Preparation 33) was reacted 5 with 4-hydroxycoumarin (0.953g) in a similar manner to that illustrated in Example 10 to give, following chromatography (silica gel, hexane to dichloromethane, in steps, and dichloromethane containing ethyl acetate, 5Yo by volume, as eluent), 3-[(4'-bromobiphenyl4 yl)-pyridin-2yl-methyl] 4-hydroxycoumarin. OH NMR: o 8.6(dd,1H); 8.0-7.9(m,2H); 7.7(dd, 1H); 7.55-7.2(m,12H); 6.2(s,1H).
10 EXAMPLE 12
This Example illustrates the preparation of 3-(biphenyl-4-vl-pvridin-2-YImethyl)-4 hvdroxvcoumarin (compound 9 in Table 1).
Biphenyl-4-yl-pyridin-2-yl-methanol (Preparation 32) was reacted with 4 hydroxycoumarin in a similar manner to that illustrated in Example 10 to give, following 15 chromatograpy 3-(biphenyl-4-yl-pyridin-2-yl-methyl)-4hydroxycoumarin. 'H Now (CDCI3): 8.6(dd,1H); 8.0-7.9(m, 2H); 7.7(dd,1H); 7.55-7.2(m,13H);6.2(s,1H). M+ 406.
EXAMPLE 13
This Example illustrates the preparation of 3-(4'-bromobiphenvl-4-vl)pYridin-4-YI methvl)-4-hYdroxycoumarin (compound 8 in Table 1).
20 (4'-Bromo-biphenyl-4-yl)-pyridin4-yl-methanol (Preparation 34) was reacted with 4 hydroxycoumarin in a similar manner to that illustrated in Example 10 to give, following chromatography 3-[(4'-bromobiphenyl-4-yl)pyridin4-yl-methyl]-4-hydroxycoumarin. OH NMR (d6-DMSO): 0 8.45(d,2H); 8. 05(d,1H); 7.6-7.2(m,13H); 6.0(s,1H). MA 484/486.; EXAMPLE 14
2s This Example illustrates the preparation of 3-[biphenyl-4-yl-(lHirnidazol-2-vl) methyll-4-hYdroxvcoumarin (compound 11 in Table 1).
Biphenyl-4-yl-(lH-imidazol-2-yl)-methanol (Preparation 36) was reacted with 4- 1 hydroxycoumarin in a similar manner to that illustrated in Example 10' save that in this Example the reaction mixture was heated at the reflex temperature for a period of 90 30 minutes. After cooling to the ambient temperature, the solvent was removed by evaporation under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was washed with dilute aqueous sodium bicarbonate solution, followed by brine, dried (Na2SO4) and filtered. Following removal of the solvent under reduced pressure,
:> - 42
the residue was purified by column chromatography (silica gel, using dichloromethane containing methanol, 1% by volume, as eluent) to give 3[biphenyl-4-yl-(lH-imidazol-2-yl) methyl]-hydroxycoumarin, mp 275 C. OH NMR (d6-DMSO): 7.85(s,1H); 7.6-
7.1(d,14H); 5.00(s,1H). MS: M+394. l s EXAMPLE 15
This Example illustrates the preparation of 3-(4'-bromo-biphenvl-4-yl)oxazol-2-vl-
methyll-4-hYdroxycoumarin (compound 12 in Table 1).
4'-Bromo-biphenyl4-yl-oxazol-2-yl-methanol (Preparation 37) was reacted with 4-hydroxycoumarin in a similar manner to that described in Example 10. The crude product 0 was purified by chromatography (silica, elating with dichloromethane) to give 3-[(4'-bromo-
biphenyl-4-yl)^oxazol-2-yl-methyll-4-hydroxycoumarin as a light brown foam (73% yield).
OH NMR: 8.1(s,1H); 7.95(d,1H); 7.9(s,1H); 7.55-7.2(m,11H); 6.1(s,1H). MS (FAB): M+ 474t476. EXAMPLE 16
15 This Example illustrates the preparation of 3-[biphenyl4-yl-(4.5dimethyl-thiazol-2 yli-methvll-4-hydroxycoumarin (compound 13 in Table 1).
Biphenyl-4-yl-(4,5-dimethyl-thiazol-2-yl-methanol (Preparation 39) was reacted with 4-hydroxycoumarin in a similar manner to that described in Example 10. The crude product was purified by chromatography (silica gel, eluting with a 9:1 by volume mixture of 20 dichloromethane and hexane followed by dichloromethane) to give 3-[biphenyl4-yl-(4,5 dimethyl-thazol2-yl)-methyl]-hydroxycoumarin as a white foam (83%). 'H NMR: o 8.0(dd,1H); 7.55-7.2(m,12H); 6.3(s,1H); 2.4(s,3H); 2.35(s,3H). MS: M+ 439.
EXAMPLE 17
This Example illustrates the preparation of 3-f(4'-bromo-biphenyl-4-Yl)thiazol-2-vl 2s methYll4-hydroxycouma,rin (compound 14 in Table 1).
3-[(4'-Bromo-biphenyl-4-yl)-thiazol-2-yl-methanol (Preparation 40) was reacted with 4-hydroxycoumarin in a similar manner to that described in Example 10. The crude product was purified by chromatography (silica gel, eluting with dichloromethane) to give 3-[(4'-. l bromo-biphenyl-yl)thiazol-2-yl-methyl]-4-hydroxycoumarin as a pale brown foam (73%).
30 lH NMR: 8: 8.0(dd,1H); 7.85(d,1H); 7.55-7.2(m,12H); 6.5(s,1H). MS (EI/CI) (pos): M' 489/491.
:: - 43
EXAMPLE 18
This Example illustrates the preparation of 3-(4-bromo-biphenyl-4-Yl)pYrazin-2-Yl methvll-4-hvdroxycoumarin (compound 15 in Table 1).
(4-bromo-biphenyl-4-yl)-pyrazin-2-yl-methanol (0.145g, Preparation 42), was reacted 5 with 4-hydroxycoumarin in a similar manner to that described in Example 10. The crude product was purified by chromatography (silica gel, eluting with 5% by volume ethyl acetate in dichloromethane). The chromatograpy was repeated (silica gel, using 10% by volume acetone in hexane as eluent) to give 3-[(4'-bromo-biphenyl4-yl)-pyrazin-2-ylmethyl]4-
hydroxycoumarin as a light brown solid (0.065g, 31%). OH NMR: 9.0(d,1H); 8.75(d,1H); 0 8.55(t,1H) 7.95(dd,1H); 7.2-7.6(m,11H); 6.3(s,1H). MS (FAB) : M+ 484.
EXAMPLE 19 i
This example illustrates the preparation of compound No. 1 of Table II.
Step a Aluminium chloride (46g) was added to a solution of benzoyl chloride (40cm), in lS dichloromethane (150cm), at such a rate to maintain reflux. After the addition was complete, the stirred reaction mixture was heated to reflux for a further 45 rrunutes, at which time was added a solution of 4-bromobiphenyl (80.4g) in dichloromethane (200cm), dropwise, over a period of 1 hour. The majority of the solvent was then removed by distillation, at atmospheric pressure, yielding a sticky green solid. The solid was then added o cautiously to a cooled (ice) solution of concentrated hydrochloric acid (40cm) in water (400cm). The beige precipitate so fonned was sti'Ted vigorously, collected by filtration at the pump, and washed with water, followed by diethyl ether. The crudesolid was triturated in diethyl ether (400cm), collected once more at the pump, and dried to give 4-(4' bromophenyl)-benzophenone as a white powder (98.6g).
25 H NMR (CDCl3): 7.90-7.80 (complex, 4H), 7.70-7.45 (complex, 4H) Melting point: 156.5-157.3 C.
Infra red: 1642cm-1 (nujol mull).
step b Sodium borohydride (0.335g) was added to a stirred suspension of the benzophenone from 30 Step a (3g) in ethanol (35cm). After stirring at the ambient temperature until TLC (silica plates, ethyl acetate/hexane, 1:9 as eluent) showed the absence of starting material. The
A\ - 44
reaction mixture was then poured into water (50cm), and extracted into dichloromethane (2x 50cm). The combined organic layers were washed with water (50cm), dried over anhydrous magnesium sulphate, filtered, and the solvent removed by evaporation under reduced pressure to give (4'bromobiphenyl4-yl)benzyl alcohol as a white solid (2.95g).
5 'H NMR (CDC13): 7.55-7.25 (complex, 13H),5.90 (d, 1H), 2.25 (d, 1H).
Infrared: 3551cm1.
Step c A solution of the benzhydrol from Step b (1.70g),4-hydroxycoumarin (0.810g), and p 10 toluenesulphonic acid (lOmg, catalytic), in xylene (50cm) was heated to reflux under Dean Stark conditions for a period of six hours. After cooling to the ambient temperature, the solvent was removed by evaporation under reduced pressure, the residue dissolved in ethyl acetate and washed with aqueous sodium bicarbonate solution. The organic phase was then dried over anhydrous magnesium sulphate, filtered, and the solvent removed by evaporation 5 under reduced pressure to give a sticky pink solid. Recrystallization from a nuxture of toluene and ethyl acetate gave 3-[(4'-bromobiphenyl-4-yl)-tolyl]-4-hydroxycoumarin as a white solid (2.42g), mp 139-141 C.
H NMR (CDCI3): 7.95 (d, IH); 7.55-7.15 (complex, 16H); 6.05 (s, 1H).
M+: 482/484
20 EXAMPLE 20
This example illustrates the preparation of compound 4 in Table II.
Step a Aluminium chloride (7.35g) in dichloromethane (75cm) was added, portionwise, to a cooled solution of 4-bromobiphenyl (11.65g) and 4chlorobenzoyl chlorde (13.125g) in 25 dichloromethane (45cm). The reaction mixture was stirred at the ambient temperature overnight, whereupon a further portion of aluminium chloride (1.817g) was added, and the reaction stirred for a further 24 hours. The reaction mixture was then carefully poured into water, acidified with dilute hydrochloric acid, and extracted into dichloromethane (lSOcm).
Filtration gave a yellow solid (6g), which was later combined with the solid (7.8g) obtained 30 after the organic phase was separated, dried over anhydrous magnesium sulphate, filtered.
and the solvent removed by evaporation under reduced pressure. The crude reaction product was then passed through a plug of silica, using dichloromethane, ethyl acetate, acetone and
- 45 -
methanol as solvents - the relevant fractions being combined to give 4-(4bromophenyl)-4' chlorobenzophenone as a solid.
tH NMR (CDCI3): 7.90-7.75 (complex, 4H), 7.70-7.55 (complex, 4H), 7.50-7. 45 (complex, 4H) 5 Infra red: 1682cm 1 Stegb A total of 400mg of sodium borohydride was added to a solution of the benzophenone generated in Step a (2g) in ethanol (35cm). The stirred reaction mixture was heated to 60 C until GLC showed the absence of starting material. The reaction mixture was then poured lo into cooled water, and extracted into dichloromethane (2xSOcm). The combined organic phases were washed with water, dried over anhydrous magnesium sulphate, filtered, and the solvent removed by evaporation under reduced pressure to give (4'-bromobiphenyl- yl)4 chlorobenzyl alcohol as a white solid (1.61g).
OH NMR (CDCI3): 7.60-7.30 (complex, 12H), 5.85 (d, IH), 2.25 (d, IH) 5 Infra red: 331 lcm Step c A solution of the benzhydrol from Step b (3. 74g), 4-hydroxycoumarin (1.62g), and p toluenesulphonic acid (30mg, catalytic), in xylene (lOOcm) was heated to reflux under Dean-Stark conditions for a period of five hours. ARer cooling to the ambient temperature 20 the solution was washed with aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulphate, filtered, and the solvent removed by evaporation under reduced pressure to give a pale yellow foam. The crude product was triturated with hot ethanol to give a white solid which was collected at the pump, washed with ethanol and dried under vacuum to give 3-[(4'-bromobiphenyl-4-yl)-4chlorophenylmethyl]-4-hydroxycoumarin 2s (2.74g), mp 202-204 C.
H N (CDCI3): 7.75 (d, 1H); 7.60-7.20 (complex, 15H); 6.30 (bs, 1); 5.96 (s, 1H); M+: 5 18
EXAMPLE 21
This example illustrates the preparation of compound No. 72 of Table II.
( - 46
Step a A suspension of 4-nitrobiphenyl-4'-carboxylic acid (20.0g) in thionyl chloride (60cm) was cautiously heated {o reflux in the presence of 1-2 drops of dimethylformamide, and allowed to continue refluxing for a period of 24 hours. The reaction mixture was then allowed to 5 cool to the ambient temperature, and residual thionyl chloride was removed, by evaporation under reduced pressure, to give the acid chloride as a pale yellow crystalline solid, which was used without further purification.
Afro red: 1775cm Step b lo A solution of the acid chloride generated in Step a (S.Og) in warm nitrobenzene (40cm) was added to a solution of aluminium chloride (3.06g) in nitrobenzene (20cm). After stirring the mixture for a period of one hour, chlorobenzene (3.22g) was added dropwise, over a brief period. After heating to 50-60 C for a period of 24 hours, a further sample of chlorobenzene (3.22g) was added dropwise, and the stirred reaction mixture was heated to 100-110 C for a 5 period of 2.5 hours. The reaction mixture was allowed to cool to the ambient temperature, and poured carefully into 2M HCI (lOOcm), with cooling by the addition of ice. The reaction mixture was then extracted into dichloromethane (lOOcm) and filtered through a; pad of celite. The pad was washed with water and acetone, the combined filtrate and l washings were separated, and the organic layer re-extracted with dichloromethane. The 20 combined organic phases were washed with saturated aqueous sodium bicarbonate solution followed by water, dried over magnesium sulphate, filtered, and the solvent removed by evaporation under reduced pressure. Excess chlorobenzene and nitrobenzene solvent were then removed, again by evaporation under reduced pressure (ca 1.47 kPa), to give the crude I product as a sticky brown solid. Trituration of the solid with boiling ethyl acetate (30cm) 25 gave 4-chloro-4-(4-nitrophenyl)benzophenone as a greenish-brown solid (1.366g) which was used without further purification.
1H NMR (CDC13): 8.40-8.30 (complex, 2H), 7.95-7.80 (d, 2H), 7.80-7.70 (compex, 6H), 7.50 (d, 2H). Infra red: 1645cm 1.
* step c 30 The benzophenone generated in Step b (0.87g) was reacted with sodium borohydride in a manner similar the that illustrated in Example 2O, Step b, to give, after chromatography on
- 47 silica gel using dichloromethane as eluent, 4-chloro-(4'nitrobiphenyl-4-yl)-benzyl alcohol (0.551g) as a pale yellow solid.
lH NMR (CDCI3): 8.28 (d, 2H), 7.73 (d, 2H), 7.60 (d, 2H), 7.50 (d, 2H), 7. 35 (bs, 4H), 5.90 (s, 1H). Infra red: 3260 cm 1 5 Step d The alcohol prepared in Step c was then reacted with 4-hydroxycoumarin in a manner analogous to that illustrated in Example 20, Step c. The crude product was then triturated with hot methanol (Scary), to give 3-[4-chlorophenyl(4'-nitrobiphenyl-4-yl)-methyl]-4 hydroxycoumarin (0.534g) as an orange brown crystalline solid.! 0 lH Now (d6 DMSO): 8.45 (d, 2H), 8.19 (d, 1H), 8.08 (d, 2H), 7.88 (d, 2H), 7.78 (I, 1H), 7.55-7.40 (complex, 8H), 6.05 (s, 1H).
Infra red: 3300, 1665, 1620cml. Melting point: 265-267 C.
EXAMPLE 22
This Example illustrates the preparation of Compound No. 71 of Table n.
5 Step a 4-(4-Chlorophenyl)-4'-nitrobenzophenone (Example 21, Step b) (4. 53g) was added portion wise to a stirred solution of tin (II) chloride (8. 89g) in concentrated hydrochloric acid (20cm). The vigorously stirred suspension was then heated to reflux for a period of 2 hours, I allowed to cool to the ambient temperature, and poured carefully into water (lOOcm). Solid 20 sodium bicarbonate was then added portion-wise (care) to bring the pH of the reaction mixture to cat 8, whereupon it was extracted into ethyl acetate (3 x SOcm). The aqueous phase was then further extracted with chloroform (3 x SOcm), and the combined chloroform layers were washed with water (50cm), dried over anhydrous magnesium sulphate, filtered, and the solvent removed by evaporation under reduced pressure to give 4-(4-aminophenyl) 25 4'-chlorobenzophenone as a brownish yellow solid (1.82g) OH NMR (CDCI3): 7.85-7.75 (complex, 4H), 7.65 (d, 2H) , 7.48 (q, 4H), 6.80 (d, 2H), 3.85 (bs, 2H) Step b A solution of tertiary butyl nitrite (2.04g) in dry tetrahydofuran (lOcm) was added 30 dropwise to a solution of 4-(4-aminophenyl)-4'-chlorobenzophenone (Step a) (3.04g) in tetrahydrofuran (30cm). The reaction mixture was allowed to stir overnight, whereupon it
(A - 48
was poured into water (120cm), and extracted into dichloromethane (3 x 50cm). The combined chloroform layers were washed with water (SOcm), dried over anhydrous magnesium sulphate, filtered, and the solvent removed by evaporation under reduced pressure to give 4-phenyl-4'- chlorobenzophenone as a red solid (.62g) which was used in 5 Step c without further purification.
OH AIR (CDC13): 7.98-7.76 (complex, 88), 7.74-7.70 (d, 2H), 7.60-7.45 (complex, 3H) Infrared: 1645cm1 Step c The benzophenone generated in Step b (.48g) was reacted with sodium borohydride! lo in a manner similar to that illustrated in Example 20, Step b, to give, after chromatography on silica gel using dichloromethane as eluent, biphenyl-(4-chlorophenyl)methanol (0.551g) as a pale yellow solid.
lH AIR (CDC13): 7.55 (d,2H; 7.48-7.30 (complex 10H), 5.85 (s, lH).
Step d Is The alcohol prepared in Step c was then reacted with 4hydroxycoumarin in a manner analogous to that illustrated in Example 2O, Step c. The crude product was then recrystallized from a mixture of toluene and cyclohexane (7:3), to give 3 -[(biphenyl4-yl)-4 chlorophenylmethyl]4-hydroxycoumarin as a brown crystalline solid. I IH NMR (CDC13): 8.18 (d, lH), 7.80-7.70 (complex, 4H), 7.65-7.40 (complex, 14H). Infra 20 red: 340O, 3200, 166O, 1620cml. Melting point 199-203 C (decomp).
EXAMPLE 23
This Example illustrates the preparation of 4-hydroxy-3-{ [4-(5chloropyrirrudin-2 yloxy)-phenyl]-phenyl-methyl}-coumarin, compound No. 3 in Table m.
Stage 1. Preparation of 4-(5-chloropvrimidin-2-yloxy)-benzophenone.
25 Potassium carbonate (2.76g) was added to a solution of 4hydroxybenzophenone (3.96g) and 2,5-dichloropyrimidine (2.76g) in dry dimethylacetamide (50cm). The reaction mixture was then heated to 100 C for a period of two hours. Further 2,5-dichloropyrimidine (0.3g) was added, and the reaction mixture was heated for a further one hour. After cooling to the ambient temperature, the reaction mixture was poured mto an ice/water slurry, together with 30 a few drops of detergent. The solid so formed was collected at the pump, washed with water,
- 49 and dried under air. Recrystallisation from ethanol then gave 4-(Schloropyrimidin-2 yloxy)benzophenone as white crystals (4.66g) with mp 113-116 C.
1H NMR (CDC13): 8.52 (s., 2H), 7.92 (d., 2H), 7.82 (d., 2H), 7.58 (m, 1H), 7.50 (m., 2H)., 7.30 (d., 2H) s Stage 2. Preparation of 14-(SchloropYrimidin-2-yloxv)-phenyll-phenyl-methanol.
4-(5-Chloropyrimidin-2-yloxy)benzophenone (3.10g) (stage 1) was suspended in Isopropanol (lOOcm) and alurninium isopropoxide (6.12g) was added. The stirred reaction mixture was then heated to reflex for a period of 6 hours under an atmosphere of nitrogen. The solvent was then removed by evaporation under atmospheric pressure, and the residue dissloved in! 0 ethyl acetate and filtered. The filtrate was washed with aqueous annonium chloride solution, dried over anhydrous magnesium sulphate, filtered and the solvent removed, by evaporation under reduced pressure, to give a pale yellow oil. Tnturation and crystallization gave an off- white solid which was recrystallized from a mixture of ethyl acetate and hexane to give [4-(S-chloropyrimidin-2-yloxy)-phenyl]-phenyl-methanol as a white solid (2.90g) 15 with mp 120-123 C.
1H NMR (COC13): 8.45 (s., 2H), 7.50-7.25 (m., 7H), 7.14 (d., 2H), 5.88 (d. , 1H), 2,45 (d., 1H). Stage 3. Preparation of 4-hvdroxv-3- I r4-(Schloropyrimidin-2-vloxy)-phenvll-phenyl- I methyl I-coumarin.
20 4-Hydroxycoumarin (1.30g) and [4-(5-chloropyrimidin-2-yloxy)-phenyl]phenyl-methanol l (stage 2) (2.50g) were suspended in xylene (lOOcm). pToluenesulphonic acid (20mg) was added and the reaction mixture was heated to 120 C for a period of 2 hours. The reaction mixture was allowed to cool to the ambient temperature and the solvent was removed under I reduced pressure yielding a yellow gum. Trituration with hexane followed by ethanol gave 25 4-hydroxy-3-t 14-(5-chloroPyrimidin-2-yloxy)-phenyl]phenyl-methyl}-coumarin as a white solid (3.21) with m.pt 72-76 C.
1H NMR (CDC13): 8.48 (s., 2H), 7.76 (d., 1H), 7.55 (t., 1H), 7.45-7.15 (m. , 11H), 6.30 (b, 1H), 6.02 (s., 1H) EXAMPLE 24
30 This Example illustrates the preparation of 4-hydroxy-3-{phenyl-[4pyrimidin-2 yloxyphenyl]-methyl)-coumarin, compound No. 7 in Table m.
Staze 1. Preparation of 4-pvrmidin-2-vloxvbenzophenone.
- 50 4-Hydroxybenzophenone (7.92g) was reacted with 2-chloropyrimidine (4. 58g) in similar manner to that illustrated in Example 23, stage 1 to give 4-pyrimidin-2-yloxybenzophenone as pale yellow prisms (8.72g) with mp 143145 C.
1H NMR (CDC13): 8.60 (d., 2H), 7.95 (d., 2H), 7.85 (d., 2H), 7.60 (t., 1H) , 7.52 (t., 2H), 5 7.35(d,2H),7.12 (t., 1H).
Stage 2. Preparation of phenvl-4-pYrimidin-2-vloxyphenYl)-methanol.
4-(5-Pyrimidin-2-yloxy)benzophenone (7.59g) (stage 1) was suspended in ethanol (lOOcm3) and sodium borohydride (1.57g) was added portionwise over 5 minutes. The reaction mixture was then stirred at the ambient temperature for a period of 1 hour, and allowed to! 0 stand ovemight. The reaction mixture was then poured into an ice/water slurry and the buff solid so formed was collected and water washed at the pump. Recrystallisation from ethanol gave phenyl-(4-pyrmidin-2-yloxyphenyl)methanol as an off-white solid (6.62g) with mp 1 67- 1 69 C.
1H NMR (CDC13): S.55 (d., 2H), 7.50-7.20 (m., 7H), 7.14 (d., 2H), 7.05 (t. , 1H), 5.85 (d., 5 1H), 4.24 (d., 1H).
Stage 3 The preparation of 4-hvdroxy-3-Iphenyl-(4-pYrirnidin-2Yloxvphenyl)-methylI coumarln. 4-Hydroxy-coumarin (2.43g) and phenyl-(4pyrimidin-2-yloxyphenyl)-methanol (stage 3) 1 (4.17g) were reacted together in a similar manner to that described in Example 23, stage 3.
20 The crude product was purified by trituration in hexane to give 4hydroxy-3-{phenyl-4 pyrimidin-2-yloxyphenyl]-methyl)coumarin an off white solid (4012g) with mp 90-92 C (decomp). H NMR (CDC13): 8.56 (d., 2H), 7. 75 (d., 1H), 7.55 (t., 1H), 7.45-7.20 (m., 11H), 7.07 (t., 1 1H), 6.30 (b, IH), 6.02 (s., 1H).
25 EXAMPLE 25
This Example illustrates the preparation of 4-hydroxy-3-{ [4-(Smethylpymidin-2 yloxy)-phenyl]-phenyl-methyl}-coumarin, compound No. 5 in Table m.
Stage 1. Preparation of 4-(5-methvlpvrimidin-2-YloxY)benzophenone.
4-Hydroxybenzophenone (1.38g) was reacted wth 2-chloro-5-methylpyrimidine (0.9Og) in 30 similar manner to that illustrated in Example 23, stage 1 to give 4-(5-methylpyrimidin-2 yloxy)benzophenone as a solid (1.75g) with mp 111-114 C.
< - 51
1H Now o (CDC13: 8.45 (s., 2H), 7.92 (d., 1H), 7.82 (d., 2H), 7.60 (I., 1H), 7.52 (t., 2H), 7.30 (d, 2H), 2.30 (s., 3H).
Stage 2. Preparation of r4-(S-methylpvrirnidin-2-yloxy)-phenvll-phenylmethanol.
4-(5-Methylpyrimidin-2-yloxy)benzophenone (5.80g) (stage 1) was reacted with isopropanol 5 and aluminium isopropoxide in a similar manner to that illustrated in Example 23, stage 2, to give [4-(S-methylpyrimidin-2-yloxy) -phenyll-phenyl-methanol as a pale yellow solid (4.57g) with mp 149-152 C.
1H NMR (CDC13): 8.32 (s., 2H), 7.45-7.25 (m., 7H), 7.14 (d., 2H), 5.84 (d. , 1H), 2,63 (s., 1H) 2.24 (s., 3H).
10 Stage 3. The preparation of 4-hvdroxv-3-4-(5-methvlpYrimidin-2-yloxy)phenYIl-phenyl rnethyl t-coumarin.
4-Hydroxycoumarin (1.46g) and [4-(5-methylpyrimidin-2-yloxy)-phenyl]phenyl-methanol (stage 3) (2.63g) were reacted together in a similar manner to that described in Example 23, stage 3, except that in this example toluene was used as solvent. The crude product was 15 purified by column chromatography on silica gel using a 1:1 mixture of ethyl acetate and hexane to pure ethyl acetate as eluent, to give 4-hydroxy-3-{ [4-(5methylpyrimidin-2-ylaxy) phenyl]-phenyl-methyl}-coumarin as pale yellow solid (2.05g) with mp 81-85 C.
1H NMR S (CDC13): 8.38 (s., 2H), 7.75 (d., 1H), 7.55 (I., 1H), 7.45-7.20 (m., 1 IH), 6.30 (b, 1 1H), 6.00 (s., 1H), 2.27 (s.,3H).
20 EXAMPLE 26
This example illustrates a number of different bait formulations.
Ingredients Wt% ( A. This composition may be used as a powder or may be compressed into pellets.
25 Active ingredient 0.00005 to 0.2 Preserving agent 0.005% Hydrophobic agent (wax) 5.0 Rodent attractant 2.5 Powdered solid 4.5 30 Moisture retaining agent 0.5 Visible dye 0.25 Cereal flour up to 100.0
(- - 52
B. Active ingredient 0.005 toO.05 Inert ingredients 5.0! Cereal flour 90. 0 s Rodent attractant up to 100.0 C. This composition is formulated into a wax block.
Active ingredient 0.001 to 0.1 Moisture retaining agent 0.05 lo Cereal flour 55.0 Rodent Attractant 5.0 Visible dye 0.25 Hydrophobic agent (wax) up to 100.0 5 D. This composition is a liquid concentrate.
Active ingredient up to 4.0 Oil up to 100.0 E. This composition is a powder concentrate.
20 Active ingredient up to 0.1 Mineral oil 10 0 Kaolin up to 100.0 EXAMPLE 27
25 This example demonstrates a range of bait formulations suitable for use in the method of the present invention.
Ingredients Wt % A. Active ingredient 0.005 30 Chlorinated phenols 0.005% (preserving agent) Synthetic wax 5.0 (hydrophobic agent)
:> - 53
Protein hydrolysate 2.5 (rodent attractant) Powdered chalk 45! Polyethylene glycol 0.5 5 (moisture retaining agent) Prussian blue 0.25 (visible dye) Wheat meal up to 100.0 lo B. Active ingredient 0.05 Vegetable oil S.O Maize meal/oat meal 90.0 mixture (3:1) Sucrose up to 100.0 C. Active ingredient 0.015 Monosodium glutamate 0.5 Sugar 2.0 Kaolin 2.0 20 Rubine toner trace Wheatmeal up to 100 D. Active ingredient 0.02 Polyethylene glycol 0.05 25 Maize meal 55.0 Sucrose S.O Prussian Blue 0.25 Paraffin wax up to 100.0 30 E. Active ingredient 1.0 Vegetable oil up to 100.0 F. Active ingredient 0.1
- 54 Mineral oil 10.0 Kaolin up to 100.0 EXAMPLE 28
s This example illustrates the rodenticidal activity of compounds according to the invention. Test animals of the strain Rattus not vegicus were acclimatsed in solid bottomed cages under hygienic conditions with free access to food and water for seven days prior to treatment, at a temperature of 20 2 C and ambient humidity and under controlled airflow.
lo Lighting was controlled to provide a 12 hour light/dark cycle. Test animals were chosen within an age range of 6-10 weeks and a weight range of 150-300g. Following the acclimatization period, the test subjects were marked for individual identification and provided with a laboratory diet for a 6 day conditioning period.
Each test substance was applied orally by intubation at a rate of 40mg/kg body weight S (except where otherwise indicated) to two male test subjects. Clinical observations were made twice within 24 hours of dosing, then daily. Observed mortalities are recorded in Table V. i
- 55 TABLE V
) Compound No. Table No Observed mortality s 1 I 2/2* 2 I 2/2
4 1 212
5 I 212
6 I 2/2:
10 7 I 2/2*
8 I 212
10 I 2/2 1
12 1 212
13 I 212 1
15 14 I 212 i 16 I 212
17 I 2/2
18 1 212
19 I 2/2
20 1 n 2/2 2 n 2/2 4 2/2
8 n 2/2 10 II 2/2
2s 12 212 63 n 2/2 71 II 2/2*
72 II 212
78 II 1/2*
30 81 II 2/2
82 2/2
f \ - 56 TABLE V
Compound No. Table No Observed mortality s 83 II 2/2 84 II 2/2
88 II 2/2
90 1/2*
91 II 2/2
0 92 2/2*
93 2/2
94 II 2/2* 1
95 2/2
97 2/2 1
5 98 2/2 i 2/2 100 2/2*
102 2/2
104 n 2/2* 20 105 2/2*
106 2/2
107 2/2
108 2/2
1 1 0 II 2/2*
25 1 1 1 II 1/2*
112 2/2
113 1/2*
3 m 2/2 s m 1/2* * Incubation rate of 200mg/kg
_ 57 -
an) '/3_ N:N Rim 2 Ram 'I
:: - 5 8
4 S215 ' 4 \,., S
art R' j S ( Xll) (XIV) (XV) ma 6 1 4 0,,' Ram (XVI) ( XVII) (XV111)
X X HO H(Z)m O (Z)m Ye (XIX) R4 Rs R1: :1 Hal me, 1 | NON
SAC -: RRJ4
(XXI) ZH (XXII)
- s9 -
- S C H E 141 E I
O O 4-Hydroxycoumarin, H 1 A, Y A, H e t 1) Couple 1) Couple 2) H+k NaBH4 0 \ Al(OPisO)3 Ix Li, M9 CHO X I Ll M rsci Am/ 1) Couple Frledel^C rafts Hal X X COCI CN CHO |
g+ FeSO4, SuOOH 63 O c'; (or reverse) XH
it. - 60 Scheme I I R5 i A} l340R] R +< AlC1, R 4 C1 R
o
- 6 1 Scheme III \Hal | NaH/K2CO1 R2 o z R R R Sche!ne IV o to + CH2n Nan / Kz CO3 o 1 11 O W:]
- 62 !y Scheme V NH R
ERIC, C: //
(R = C, 4 alkyl eg ethyl) 4 R R NOUN N\>N
NH2 (XXII)

Claims (13)

- 63 - CLAIMS
1. A compound of formula (I) OH X R i (Z)K R4 R s or a stereoisomer or salt thereof, wherein: A is oxygen or sulphur; K is CH or N; is a group of formula II to XV; Y is a group of formula XVI to xvm; o each Z is independently oxygen, sulphur, optionally substituted -(CH2)D-, alkenylene, alkynylene, -(C H 2)n- 0 -(C H 2)n-, - O ( C H 2)n, -( C H 2) n O, O ( C H 2)n O, - C O -, - C 0 2-' ( C H 2)n C 0, -S(C H 2)n, -(C H 2) nS-, -S O ( C H 2)n-, -(C H 2)ns O -, -S 0 2( C H 2)n, (C H 2)nS O 2-' SO-, -SO2-, -NH- or-N(alkyl)-; R', R2, R3, R4, Rs and R6 are each independently hydrogen, halogen, cyano, alkyl, 1S alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, haloalkyl, haloalkoxy, haloalkenyl, haloalkynyl, alkenyloxy, alkynyloxy, hydroxy, nitro, amino, alkylamino, dialkylamino, optionally substituted aryl, aryloxy, arylalkoxy, -S-alkyl, -SO-alkyl, -SO2-alkyl, -S-haloalkyl, -SO-haloalkyl, -SO2-haloalkyl, -Salkenyl, -SO-alkeT,yl, -SO2-alkenyl, -S -alkynyl, -SO-alkynyl, -SO2alkynyl, -CO-alkyl, -CO-haloalkyl, -CO2H, -CO2-alkyl, 20 -CO2-haloal kyl, -CO-aryl, -S-aryl, -SO-aryl, -SO2-aryl, -SFs, -CO-amino, -CO-alkylarnino, -CO-dialkylarnino, -CO2-amino, -CO2-alkylamino, -CO2 dialkylarnino, alkoxycarbonyl, alkenyloxycarbonyl or alkenyloxycarbonyl, or when R' and R2 are attached to adjacent carbon atoms in the groups of formulae II, m and V to XV, they may join to form an optionally substituted fused benzene ring; 2s n is 1 or 2; m is 0 or 1; and pisOor 1.
:\ - 64
2. A compound according to claim 1 wherein: A is oxygen or sulphur; K is CH; 5 X is a group of fonnula I1 to XV; Y is a group of formula XVI to xvm; each Z is independently oxygen, sulphur, -(CH2)n-, alkenylene, alkynylene, -(CH2)n-O-(CH2)n-, o(cH2)n-, (cH2)no-, O(CH2)nO, (CH2)nCO' S(CH2)n, -(CH2)nS-, SO(CH2)n7 (cH2)nso-, so2(cH2)n-, (cH2)nso2-, -SO-, or -SO2-; 10 R', R2, R3, R4, R5 and R6 are each independently hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, haloalkyl, haloalkoxy, haloalkenyl, haloalkynyl, alkenyloxy, alkynyloxy, hydroxy, nitro, amino, alkylamino, diallcylarnino, optionally substituted aryl, aryloxy, arylalkoxy, -S-alkyl, -SO-alkyl, -SO2-alkyl, -S-haloalkyl, -SO-haloalkyl, -SO2-haloalkyl, -S -alkenyl, -SO-alkenyl, 5 -SO2-alkenyl, S-alkynyl, -SO-alkynyl, -SO2-alkynyl, -CO-alkyl, -CO2-alkyl, -CO-aryl, -Saryl, -SO-aryl, -SO2-aryl, -SFs, -CO-amino, -CO-alkylarnino, -COdialkylamino, alkoxycarbonyl, alkenylaxycarbonyl or alkenyloxycarbonyl, or when R' and R2 are attached to adjacent carbon atoms in the groups of formulae II, m and V to XV, they may jon to form an optionally substituted fused benzene ring; 20 nis 1 or2; misOor l;and pisOorl.
3. A compound according to claim 2 wherein m+n = 0 or 2.
4. A compound according to claim 2 wherein X is a group of formula (m), (V), (X) or (XI); Ri, R2, R3, Rs and R6 are hydrogen; R4 is -SCH3, -SOCH3, -SO2CH3, Br, Cl, F. CN or hydrogen; m=0, p=O; Y is a group of formula (XVI), and A is oxygen.
30
5. A compound according to claim 1 wherein K is CH; X is the group (II) , Y is the group (XVT); m is O; and p is O or 1.
- 65
6. A compound according to claim 5 wherein R' is hydrogen, cyano or halogen; R2 is hydrogen; R4 is hydrogen, halogen, Cn6 haloalkoxy, nitro or cyano; Rs is hydrogen; R3 and R6 are hydrogen; p is 0 or 1; and Z is oxygen, -OCH2, -CH2- or -(CH2)2- when p is 1.
7. A compound according to claim 5 wherein R' is hydrogen, 4-cyano, 4-chloro, 4-bromo or 4-fluoro; R2 is hydrogen; R4 is hydrogen, 4-chloro, 4-bromo, 4-fluoro, 4-C'.
6haloalkoxy, 4-nitro or 4-cyano; and R3, R. and R6 are all hydrogen.
o
8. A compound according to claim 1 wherein K is N; X is the group (II); Y is the group (XVI); m is 0; p is 1; R. R. R. R and R are each independently hydrogen, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, haloalkyl, haloalkoxy, halo-substituted alkenyl, halo-substituted alkynyl, alkenyloxy, alkynyloxy, hydroxyl, nitro, amino, alkylamino, dialkylarnino, optionally substituted aryl, aryloxy, 5 arylalkoxy,-S-alkyl,-SO-alkyl,-SO2-alkyl,-S-haloakyl,-SOhaloalkyl, -SO2-haloalkyl, -S-alkenyl, -SO-alkenyl, -SO2-alkenyl, -Salkynyl, -SO-alkynyl, -SO2-alkynyl, -CO-alkyl, -CO2-alkyl, -CO-aryl, -S aryl, -SO-aryl, -SO2-aryl, -SFs -CO2-arnino, -CO2-alkylamino, -CO2-di al kyl amino, alkoxycarbonyl, alkenyloxycarbonyl and alkenyloxycarbonyl; 20 R6 is hydrogen, halogen, alkyl, or CF3; Z is oxygen, sulphur, -SO-, SO2-, -CH20-, -CH2S-, -NH- or -N(alkyl)-; and A is oxygen or sulphur.
9. A compound according to claim wherein R is hydrogen7 cyano, carboxy, NH2CO-, 2s or mono- or di-C 6 alkylNCO- or halogen; R is hydrogen, C 6 alkyl, halogen, C, 6 haloalkoxy, nitro, cyano, carboxy, NH2CO- or mono- or di- C' 6 alkylNCO-; R2, R3, Rs and R are all hydrogen; and A and Z are both oxygen.
10. A compound according to claim 8. wherein R' is hydrogen, 4-cyano, 4chloro, 4 30 bromo or 4-fluoro; R4 is hydrogen, 5-chloro, 5-bromo, 5fluoro, 5-C 6 haloalkoxy;
5-nitro, S-cyano, S-carboxy, 5-Cl 6 alkyl, R2, R3, R5 and R6 are hydrogen; A and Z are both oxygen.
11. A process for the prepartion of a compound according to claim 1 which comprises 5 reacting a 4-hydroxycoumarin or thiacoumarin with a compound of formula (XIX): X HO H (Z)q' (Zen K (XIX) I R4
RK5/ wherein K, X, Y. Z. m, p, R4 and Rs have the meanings given in claim 1, under acidic conditions.
12. Rodenticidal composition comprising a rodenticidally effective amount of a compound of formula (I) as defined in claim 1 and an inert carrier or diluent.
13. Method of killing or reducing a population of rodents which comprises supplying to a 5 locus frequented by the rodents a rodenticidally effective amount of a rodenticidal composition comprising an inert diluent or carrier and as active ingredient a rodenticidally effective amount of a compound of formula (I) as defined in claim 1.
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