GB2241236A - Propenoic acid derivatives - Google Patents

Propenoic acid derivatives Download PDF

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Publication number
GB2241236A
GB2241236A GB9105678A GB9105678A GB2241236A GB 2241236 A GB2241236 A GB 2241236A GB 9105678 A GB9105678 A GB 9105678A GB 9105678 A GB9105678 A GB 9105678A GB 2241236 A GB2241236 A GB 2241236A
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United Kingdom
Prior art keywords
ppm
gum
methyl
compound
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
GB9105678A
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GB2241236B (en
GB9105678D0 (en
Inventor
Vivienne Margaret Anthony
Stephen Paul Heaney
Kevin Beautement
John Martin Clough
Patrick Jelf Crowley
Christopher Richard Ay Godfrey
Paul John De Fraine
Alan John Buckley
Michael Gorden Hutchings
Ian Ferguson
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Imperial Chemical Industries Ltd
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Imperial Chemical Industries Ltd
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Priority claimed from GB878721221A external-priority patent/GB8721221D0/en
Priority claimed from GB878721706A external-priority patent/GB8721706D0/en
Priority claimed from GB888801485A external-priority patent/GB8801485D0/en
Priority claimed from GB888806317A external-priority patent/GB8806317D0/en
Priority claimed from GB888814734A external-priority patent/GB8814734D0/en
Priority claimed from GB8819878A external-priority patent/GB2210041B/en
Application filed by Imperial Chemical Industries Ltd filed Critical Imperial Chemical Industries Ltd
Publication of GB9105678D0 publication Critical patent/GB9105678D0/en
Publication of GB2241236A publication Critical patent/GB2241236A/en
Publication of GB2241236B publication Critical patent/GB2241236B/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
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    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/36—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
    • A01N37/38—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids having at least one oxygen or sulfur atom attached to an aromatic ring system
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    • A01N37/36—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
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    • 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
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    • A01N43/06—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 five-membered rings
    • A01N43/10—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 five-membered rings with sulfur as the ring hetero atom
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
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    • A01N43/20—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 three- or four-membered rings
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    • 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
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    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
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    • C07C205/38—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. nitrodiphenyl ethers
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Description

PROPENOIC ACID DERIVATIVES This invention relates to derivatives of propenoic acid useful as fungicides, to processes for preparing them, to fungicidal compositions containing them, and to methods of using them to combat fungi, especially fungal infections of plants.
EP-A-0178826 describes fungicidal derivatives of propenoic acid and lists the compound (E)-methyl 2-[2-(3phenoxyphenoxy)phenyl]-3-methoxypropeonate.
The present invention provides a compound having the formula (I)
and stereoisomers thereof, wherein K is oxygen or sulphur; Z is optionally substituted aryl or optionally substituted heteroaryl; X is o, S(O)n, NR4, CR1R2, CHR5, CO, CR1(OR2), C=CR1R2, CHR1CHR2, CR1=CR2, CHR1CR2=CH, C=C, OCHR1, CHR1O, OCHR1O, S(O)nCHRl, S(O)nCHRlO, CHR1S(O)n, CHR1OSO2, NR4CHR1, CHR1NR4, C02, 02C, S020, OS02, CO.CO, COCHR1, COCHR1O, CHR1CO, CHOH.CHR1, CHR1.CHOH,
CONR4,OCONR4, NR4CO, CSNR4, OCS.NR4, SCO.NR4, NR4C02, NR4CS, NR4CSO, NR4COS, NR4CONR4, S(O)nNR4, NR4S(O)n, CS2, S2C, CO.S, SCO, N=N, N=CR1, CR1=N, CHR1CHR2CH(OH), CHR1OCO, CHR1SCO, CHR1NR4CO, CHR1NR4COR4, CHR1CHR2CO, 0.N=CR1, CHR1O.N=CR, CO.OCR1R2, CHR1CHR2CHR3, OCHR1CHR2, (CH2)mO, CHR1OCHR2, CHR1CHR20, OCHR1CHR20, S(O)nCHRlCHR2, CHRlS(O)nCHR2, CHR1CHR2S(O)n, CR1=NNR4, NR4N=CR1, CHR1CONR2, CHR1OCO.NR2, CH=CHCH2O, COCHR1CHR20, or (R5)2p+CHR2Q-; A, B and E, which may be the same or different are H, hydroxy, halo, C1-4 alkyl, C14 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, phenoxy, nitro or cyano, R1, R2 and R3, which may be the same or different, are H, C1-4 alkyl or phenyl;R4 is H, C14 alkyl or COR1; R5 is optionally substituted phenyl; Q- is a halide anion; n is 0, 1 or 2 and m is 3, 4 or 5; except that when Z is unsubstituted phenyl and X and K are oxygen, A, B and E are not all hydrogen.
Of particular interest are those compounds in which X is 0, especially when Z is optionally substituted heteroaryl, S, S02, NH, NCH3, NCOCH3, CH(C6H5), CH(OH), CH=CH, OCH2, CH2O, CH(CH3)0, S(O)CH2, S(0)2CH2, S020, CO.CH2O or C02CH2 and, more particularly, 0, CH2O OCH2, 5020 or CH(OH).
The compounds of the invention contain at least one carbon-carbon double bond, and are sometimes obtained in the form of mixtures of geometric isomers. However, these mixtures can be separated into individual isomers, and this invention embraces such isomers, and mixtures thereof in all proportions including those which consist substantially of the (Z)-isomer and those which consist substantially of the (E)-isomer.
The individual isomers which result from the unsymmetrically substituted double bond of the propenoate group are identified by the commonly used terms "E" and "Z". These terms are defined according to the Cahn Ingold-Prelog system which is fully described in the literature (see, for example, J March, "Advanced Organic Chemistry", 3rd edition, Wiley-Interscience, page 109 et seq).
Usually one isomer is more active fungicidally than the other, the more active isomer usually being the one wherein the groups -C02CH3 and -OCH3 are on opposite sides of the olefinic bond of the propenoate group (the (E)isomer). These (E)-isomers form a preferred embodiment of the invention.
The substituent Z in compound (I) is optionally substituted aryl or optionally substituted heteroaryl.
Where valency allows, each of the optionally substituted groups aryl or heteroaryl can carry up to 5 substitutents.
The term "aryl" includes phenyl in particular, and naphthyl. The term "heteroaryl" includes 5- and 6membered heterocyclic groups containing one or more of each of the heteroatoms 0, S and N (preferably S or N), fused benzenoid and heteroaromatic ring systems, and, in each case, the corresponding N-oxides. Examples of heteroaryl groups which Z may be are pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-, 1,2,4-, and 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, 1,2,3- and 1,2,4triazolyl, thienyl, furyl, pyrrolyl, thiazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothienyl, benzoxazolyl and benzthiazolyl and, where appropriate, the corresponding N-oxides.Substituents which may be present in the optionally substituted aryl and heteroaryl moieties include one or more of the following; halo, hydroxy, mercapto, C14 alkyl (especially methyl and ethyl), C24 alkenyl (especially allyl), C24 alkynyl (especially propargyl), C14 alkoxy (especially methoxy), C24 alkenyloxy (especially allyloxy), C24 alkynyloxy (especially propargyloxy), halo(C14)alkyl (especially trifluoromethyl), halo(C1-4)alkoxy (especially trifluoromethoxy), C14 alkylthio (especially methylthio), hydroxy(C1-4)alkyl, C1-4-alkoxy(C1-4)alkyl, C3-6 cycloalkyl, C36 cycloalkyl(Cl~4)alkyl, optionally substituted aryl (especially optionally substituted phenyl), optionally substituted heteroaryl (especially optionally substituted pyridinyl or pyrimidinyl), optionally substituted aryloxy (especially optionally substituted phenoxy), optionally substituted heteroaryloxy (especially optionally substituted pyridinyloxy or pyrimidinyloxy), optionally substituted aryl(C1-4)alkyl (especially optionally substituted benzyl, optionally substituted phenethyl and optionally substituted phenyl npropyl) in which the alkyl moiety is optionally substituted with hydroxy, optionally substituted heteroaryl(C1-4)alkyl (especially optionally substituted pyridinyl- or pyrimidinyl(C1~4)alkyl), optionally substituted aryl(C2~4)alkenyl (especially optionally substituted phenylethenyl), optionally substituted heteroaryl(C2-4)alkenyl (especially optionally substituted pyridinylethenyl or pyrimidinylethenyl), optionally substituted aryl(C1-4)alkoxy (especially optionally substituted benzyloxy), optionally substituted heteroaryl(C1-4)alkoxy (especially optionally substituted pyridinyl- or pyrimidinyl(C1-4)alkoxy), optionally substituted aryloxy(C1-4)alkyl (especially phenoxymethyl), optionally substituted heteroaryloxy (C14 ) alkyl (especially optionally substituted pyridinyloxy- or pyrimidinyloxy(C1-4)alkyl), acyloxy, including C14 alkanoyloxy (especially acetyloxy) and benzoyloxy, cyano, thiocyanato, nitro, -NR'R", -NHCOR', -NHCONR'R", -CONR'R", -COOR', -OSO2R', -SO2R', -COR', -CR'=NR" or ' " -N=CR R in which R and R" are independently hydrogen, C14 alkyl, C1-4 alkoxy, C1-4 alkylthio, C36 cycloalkyl, C36 cycloalkyl(C1-4)alkyl, phenyl or benzyl, the phenyl and benzyl groups being optionally substituted with halogen, C14 alkyl or C1-4 alkoxy.
Substituents which may be present in the aryl or heteroaryl rings of any of the foregoing substituents and in the phenyl ring of R5 include one or more of the following; halo, hydroxy, mercapto, C14 alkyl, C24 alkenyl, C24 alkynyl, C1-4 alkoxy, C24 alkenyloxy, C24 alkynyloxy, halo(C1-4)alkyl, halo(C1~4)alkoxy, C14- alkylthio, hydroxy(C14)alkyl, C14 alkoxy(C1-4)alkyl, C36 cycloalkyl, C3-6 cycloalkyl(C14)alkyl, alkanoyloxy, benzyloxy, cyano, thiocyanato, nitro, -NR'R", -NHCOR', -NHCONR'R", -CONR'R", -COOR', -OS02R', -SO2R', -COR', -CR'=NR" or -N=CR'R" in which R' and R" have the meanings given above.
When any of the substituents A, B and E are C14- alkyl or C14 alkoxy, the alkyl moiety can be in the form of straight or branched chains, that is, the moiety may be methyl, ethyl, n- or iso-propyl, or n-, sec-, iso- or tbutyl. Other references herein to C1-4 alkyl and C1-4 alkoxy carry the same meaning. C24 Alkenyl groups can be in the form of straight or branched chains and, where appropriate, may have either the (E)- or (Z)configuration. Examples of such groups are vinyl, allyl, -C(CH3):CH2, and (E)- and (Z)-crotyl.
The substituents A and B are preferably in the 4- and 5-positions of the phenyl ring, and the substituent E is preferably a small group or a single atom such as hydrogen or halogen. Usually, E and one or both of A and B will be hydrogen.
In one aspect, the invention includes a compound having the formula (Ia)
wherein X is 0, S(O)n in which n is 0, 1 or 2, NH, NCH3, NCH2CH3, NCOCH3, NCH(CH3)2, CH2, CH(CH3), C(CH3)2, CO, C=CH2, C=C(CH3)2, CH2CH2, CH(CH3)CH2, CH2CH(CH3), (E) CH=CH, (Z)-CH=CH, (E)-C(CH3)=C(CH3), C=C, OCH2, OCH(CH3), (CH2)pO in which p is an integer of 1 to 5, CH(CH3)0, SCH2, SCH(CH3), S(O)CH2, S(O)CH(CH3), S(0)2CH2, S(0)2CH(CH3), CH2S, CH(CH3)S, CH2S(O), CH(CH3)S(O), CH2S(0)2, CH(CH3)S(0)2, NHCH2, N(CH3)CH2, N(COCH3)CH21 NHCH(CH3), N(CH3)CH(CH3), N(COCH3)CH(CH3), CH2NH, CH2N(CH3), CH2N(COCH3), CH(CH3)NH, CH(CH3)N(CH3), CH(CH3)N(COCH3), CO2, 02C, S020, OS02, CO.CO, COCH2, COCH(CH3), CH2CO, CH(CH3)CO, CH(OH)CH2, CH(OH)CH(CH3), CH2CH(OH), CH(CH3)CH(OH), CONH, CON(CH3), CON(CH2CH2CH3), CON(CHO), CON(COCH3), NHCO, N(CH3)CO, N(CH2CH3)CO, N(CHO)CO, N(COCH3)CO, CSN(CH3), CSNH, NHCS, N(CH3)CS, S02NH, SO2N(CH3), NHS02, N(CH3)SO2, N(CH2CH3)S02, CS2, S2C, COS, SCO, (E)-N=N, (E)-N=CH, (E)-N=C(CH3), (E)-CH2=N, (E)-C(CH3)=N, CH2CH2CH2, CH(CH3)CH2CH2, CH2CH(CH3)CH2, CH2CH2CH(CH3), OCH2CH2, CH2OCH2, SCH2CH2, S(O)CH2CH2, S(0)2CH2CH2, CH2SCH2, CH2S(O)CH2, CH2S(O)CH2, CH2CH2S, CH2CH2S(O), CH2CH2S( )2, (E)-CH=NNH, (E)-C(CH3)=NNH, (E) CH=NN(CH3), (E)-NHN=CH, (E)-NHN=C(CH3), (E)-N(CH3)N=CH, CH2CONH, CH(CH3)CON(CH3), CH(CH3)CON(CH3), (E)-CH=CHCH2O, COCH2CH2O, trans
trans
CH(C6H5), COCH2O, CH(OH), C02CH2, (C6H5)2P+CH2Br-, CH2OCO, CH2NHCO, CH2SCO, OCH20, OCH2CH2O, S(O)CH2O, COCH(CH3)0, (E)-CH2ON=CH, (Z)-CH2ON=CH, CH2CH2CH(OH), (E)-CH2CH=CH, C(CH3)(OH), CH2OSO2, CH2NHCO.NH, OCO.NH, NHCO.NH or CH2OCO.NH; A is H, hydroxy, halo, C1-4 alkyl, C1-4 alkoxy, trifluoromethyl, nitro, cyano, acetyl or phenoxy;B and E are H or halot D is H, hydroxy, halo, C1-4 alkyl, C1-4 alkoxy, nitro, cyano, halo(C1-4)alkyl (especially trifluoromethyl), halo(C1-4)alkoxy (especially trifluoromethoxy), phenyl, phenoxy, NHCOR6, NHS02R6, NR7R8, C02R71 wherein R6 is C1-4 alkyl (especially methyl) or phenyl and R7 and R8 are independently H or C14 alkyl, or CH302C.C=CH.OCH3; and G is H, halo, C1-4 alkyl, C1-4 alkoxy or nitro; or D and G, when they are adjacent, join to form a benzene or pyridine ring; provided that when A, B, D, E and G are all H, X is not 0.More particularly, it includes a compound having the formula (Ia) wherein X is 0, S(O)n in which n is 0, 1 or 2, CH2, CH2CH2, OCH2, (CH2)pO in which p is an integer of 1 to 5, OCH20, OCH2CH20, CH(OH), CO, CO2, 02C, COS, SCO, C02CH2, S020, (E)-CH=CH, (Z)-CH=CH, (E)-CH=CHCH20, CH(CH3)0, SCH2, SCH2O, S(O)CH2, S(O)CH20, S(0)2CH2, CONH, NH, NCH3, CH2NH, N(CH3)CH2, NHCO, CH2OCO.NH, NCOCH3, NHS02, (E)-N=N, (Z) N=N, (E)-N=CH, (E)-N(CH3)N=CH, (E)-CH20N=N, (Z)-CH20N=CH, CH(C6H5), COCH20, COCH(CH3)0, CH20CO, CH2NHCO, CH2SCO or (C6H5)2P+CH2Br-; A is H, hydroxy, halo, C1-4 alkyl, C14 alkoxy, acetyl or phenoxy; B and E are both H;D is H, hydroxy, halo, C14 alkyl, C14 alkoxy, nitro, cyano, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, amino or CH3O2C.C=CH.OCH3; and G is H, halo, C14 methyl, nitro; or D and G, when they are adjacent, join to form a benzene or pyridine ring; provided that when A, B, D, E and G are all H, X is not 0.
In another aspect, the invention includes a compound having the formula (Ib)
wherein D and G are independently halo, C1-4 alkyl, C1-4 alkoxy, trifluoromethyl, nitro, cyano, phenyl, phenoxy, NHCOR6, NHSO2R6 and NR7R8, in which R6 to R8 have the meanings given above; and A is halo, C1-4 alkyl, C1-4 alkoxy, trifluoromethyl, nitro, cyano, acetyl or phenoxy.
Particularly favoured compounds of the formula (Ib) are those in which D is hydrogen, G is 2- or 3-chloro, 3 bromo, 2- or 4-methoxy, 3- or nitro, 2- or 3-cyano or 3or 4-phenoxy and A is hydrogen or D and G are both hydrogen and A is 4- or 6-bromo or 4- or 6-acetyl.
In yet another aspect, the.invention includes a compound having the formula (Ic)
wherein Z is pyridinyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl, quinolinyl, benzoxazolyl, benzthiazolyl, thienyl, quinoxalinyl, thiazolyl, isoquinolinyl, quinazolinyl, purinyl, oxazolyl, thiadiazolyl, oxadiazolyl, furyl, pyrrolyl or thienopyrimidinyl, each optionally substituted with halo, C14 alkyl, C14 alkoxy, C14 alkylthio, halo(C1-4)alkyl (especially trifluoromethyl), cyano, nitro, COOR7, phenyl, phenoxy, C14 alkanoyl and CONR7R8 in which R7 and R8 are independently H or C14 alkyl; and N-oxides thereof; X is 0, S, NH, N(CH3), S020, CH2, CH2CH2, OCH2, CH2O, CH(OH), CONH or CO; A and B are independently H, halo, C14 alkyl, C14 alkoxy, cyano, nitro, halo(C1-4)alkyl (especially trifluoromethyl) or halo(C1-4)alkoxy (especially trifluoromethoxy); and E is H or halo.
More particularly, it includes a compound having the formula (Ic) wherein X is 0, S, OCH2, S020, CH2, CH20, CONH or CON(CH3); Z is pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyridazin-3yl, 1,3,5-triazin-2-yl, thien-2-yl, pyrrol-2-yl, quinolin2-yl, quinoxalin-2-yl, 1,2,4-triazol-1-yl, thiazol-4-yl, benzthiazol-2-yl, or benzoxazol-2-yl, each optionally substituted with halogen, trifluoromethyl, C14 alkyl, C14 alkoxy, cyano or nitro, and N-oxides thereof and A, B and E are all H.
In still yet another aspect, the invention includes a compound having the formula (Id)
wherein X, A, B, D, E and G have the meanings given for the compound (Ia) and also wherein X is 0 and A, B, D and E are all H.
Compounds having the formula (Id) of particular interest are those wherein X is 0, CH20 or S020 and A, B, D, E and G are all H or D is 2- or 4-nitro.
In still yet another aspect, the invention includes a compound having the formula (lie)
wherein Z, X, A, B and E have the meanings given for the compound (Ic). Compounds having the formula (Ie) of particular interest are those wherein Z is pyrimidin-2-yl or pyrimidin-5-yl, X is 0 and A, B and E are all H.
The invention is illustrated by the compounds listed in Tables I, II, III and IV which follow. Throughout Tables I, II, III and IV the methyl 3-methoxypropenoate group has the (E)-configuration.
TABLE I
Compound Melting No. x D G A B E Olefinic+ Point (0C) 1 S H H H H H 7.42 Gum 2 SO H H H H H Obscured Gum 3 SO2 H H H H H Obscured Wax 4 NH H H H H H 7.44 Wax 5 NCH3 H H H H H 7.44 Gum 6 NCH2CH3 H H H H H 7 NCCCH3 H H H H H 7.39 50-54 8 NCR(CH3)2 H H H H H 9 CH2 H H H H H 7.47 Gum 10 CH(CH3) H H H H H 11 C(CH3)2 H H H H H 12 CO H H H H H 7.47 Gum 13 C:CH2 H H H H H 14 C:C(CH3)2 H H H H H 15 CH2CH2 H H H H H 7.49 Gum 16 CH(CH3)CH2 H H H H H 17 CH2CH(CH3) H H H H H 18 (E)-CH:CH H H H H H 7.49 Gum TABLE I (CONT/D)
Compound Melting No. X D G A B E Olefinic+ Point ( C) 19 (E)-C(CH3):C(CH3) H H H H H 20 C:C H H H H H 21 OCH2 H H H H H 7.46 Gum 22 OCH(CH3) H H H H H 23 CH20 H H H H H 7.44 84 24 CH(CH3)O H H H H H 7.39 99-102 25 SCH2 H H H H H 7.47 Gum 26 SCH(CH3) H H H H H 27 S(O)CH2 H H H H H 7.48 82-86 28 S(O)CH(CH3) H H H H H 29 S(O)2CH2 H H H H H 7.48 140-144 30 S(O)2CH(CH3) H H H H H 31 CH2S H | H H H H 32 CH(CH3)S H H H H H 33 CH2S(O) H H H H H 34 CH(CH3)S(O) H H H H H 35 CH2S(O)2 H H H H H 36 CH(CH3)S(O)2 H H H H H 37 NHCH2 H H H H H 38 N(CH3)CH2 H H H H H 7.44 Gum 39 N(COCH3)CH2 H H H H H 40 NHCH(CH3) H H H H H 41 N(CH3)CH(CH3) H H H H H H 42 N(C0CH3)CH(CH3) HH H H H 43 CH2NH H H H H H 44 CH2N(CH3) H H H H H 45 CH2N(COCH3) H H H H H 46 CH(CH3)NH H H | H | H | H 47 CH(CH3)N(CH3) H H H H H TABLE I (CONT/D)
Compound Melting No. X D G IA B E Olefinic+ Point ( C) 48 CH(CH3)N(COCH3) H H |H H H H 49 CO2 H H H H H 7.46 94-95 50 O2C H H H H H 7.47 Oil 51 SO2O H H H H H 7.40 Gum 52 | OSO2 | H | H | H | H | H 53 CO.CO H H H H H 54 COCH2 H H H H H 55 | COCH(CH3) | H | H | H | H | H 56 CH2CO H H H H H 57 CH(CH3)C0 H H H H H 58 CH(OH)CH2 H H H H H 59 CH(OH)CH(CH3) H H H H H 60 | CH2CH(OH) | H | H | H | H | H 61 CH(CH3)CH(OH) H H H H H 62 CONH H H H H H 7.46 Gum 63 CON(CH3) H H H H H 64 CON(CH2CH2CH3) H H H H H 65 CON(CHO) H H H H H 66 | CON(COCH3) H H H H H 67 NHCO H H H H H 7.40 Gum 68 N(CH3)CO H H H H H 69 N(CH2CH3)Co H H H H H 70 N(CHO)CO H H H H H 71 | N(COCH3)CO H H H H H 72 CSN(CH3) H H 1H H H 73 CSNH | H H t H H H TABLE I (CONT/D)
Compound | | | | | | | Melting No. X D G A B E Olefinic+ Point ( C) 74 NHCS H H H H H 75 N(CH3)CS H H H H H 76 S02NH H H H H H 77 SO2N(CH3) H H H H H 78 NHSO2 H H H H H 7.43 Oil 79 N(CH3)SO2 H H H H H 80 N(CH2CH3)S02 H H H H H 81 CS2 H H H H H 82 S2C H H H H H 83 COS H H H H H 7.38 87-91 84 SCO H H H H H 7.50 Gum 85 (E)-N:N H H H H H 86 (E)-N:CH H H H H H 7.49 or Gum 7.50 87 (E)-N:C(CH3) H H H H H 88 (E)-CH:N H H H H H 89 (E)-C(CH3)::N H H H H H 90 CH2CH2CH2 H H H H H 91 CH(CH3)CH2CH2 H H H H H 92 CH2CH(CH3)CH2 H H H H H 93 CH2CH2CH(CH3) H H H H H 94 OCH2CH2 H H H H H 95 | CH2OCH2 | H | H | H | H | H | | | 96 CH2CH2O H H H H H 7.48 Oil 97 SCH2CH2 H H H H H 98 S(O)CH2CH2 H H H H H 99 S(0)2CH2CH2 H H H H H ,l H TABLE I (CONT/D)
Compound r Melting No. X D G A B E Olefinic+ Point (0C) 100 CH2SCH2 H H H H H 101 CH2S(O)CH2 H H H H H 102 CH2S(O)2CH2 H H H H H 103 CH2CH2S H H H H H 104 CH2CH2S(O) H H H H H 105 CH2CH2S( )2 H H H H H 106 (E):NNH H H H H H 107 (E)-C(CH3)::NNH H H H H H 108 (E)-QI:NN(CH3) H H H ; H H 109 (E)- NHN:CH H H H H H 110 (E)NHN:C(CH3) H H H H H 111 (E)&num;N(CH3)N:CH H H H H H 7.50 121.5 123.5 112 CH2CCSH H H H H H 113 CH(CH3)CON(CH3) H H H H H 114 CH(CH3)CON(CE3) H H H H H 115 (E)-CH::CHCH20 H H H H H 1 7.47 Gum 116 oOCH2CH20 H H H H H 117 /CH2 trans CH CH H H H H H 118 Irans CH'0 1 118 trans CH CH H H H H H 119 0 2-C1 H H H H 7.48 51-54 120 0 3-C1 H H H H 7.48 Gum 121 0 4-C1 H H H H 122 0 2-F H H H H 7.50 Gum TABLE I (CONT/D)
Compound Melting No. X D G A B E Olefinic+ Point ( C) 123 O 3-F H H H H 7.51 Gum 124 O 4-F H H H H 7.35 Gum 125 O | 2-CH3 H H H H 7.51 Gum 126 0 3-CH3 H H H H 7.49 Gum 127 0 4-CH3 H H H H 7.49 Gum 128 0 2-CH3O H H H H 7.46 Gum 129 0 3-CH30 H H H H 7.48 Gum 130 0 4-CH30 H H H H 7.48 Gum 131 0 2-N02 H H H H 7.47 Gum 132 0 3-N02 H H H H 7.49 Gum 133 0 4-N02 H H H H 7.44 67-71 134 0 2-CN H H H H 7.51 108-110 135 0 3-CN H H H H 7.51 Gum 136 O 4-CN H H H H 137 0 2-Br H H H H 138 0 3-Br H H H H 7.48 Gum 139 0 4-Br H H H H 140 0 2-CF3 H H H H 141 0 3-CF3 H H H H | 7.49 Oil 142 0 4-CF3 H H H H H 143 O 2-C6H5O H H H H | 7.46 Gum 144 O 3-C6H5O H H H H 7.48 Gum 145 O 4-C6H5O H H H H 7.50 Gum 146 O 2-CH3CH2O H H H H 147 O 3-CH3CH2O H H H H 148 0 | 4-CH3CH2O H H H H | | | | | | | TABLE I (CONT/D)
Compound Melting No. X D G A B E Olefinic+ Point ( C) 149 O 2-C6H5 H H H H 150 O 3-C6H5 H H H H 7.50 Gum 151 0 4-C6H5 H H H H 152 | O | 2-Cl | 3-Cl | H | H | H 153 0 2-C1 4-Cl H H H 154 0 2-Cl 5-C1 H H H 155 0 2-C1 6-Cl H H H 156 0 3-C1 4-C1 H H H 157 0 3-C1 5-Cl H H H 7.53 Gum 158 0 2-C1 3-CH3O H H H 159 0 2-C1 4-CH3O H H H 160 0 2-C1 5-CH3O H H H 161 0 2-C1 6-CH3O H H H 162 0 3-C1 4-CH30 H H H 163 0 3-Cl | 5-CH3O H H H 164 O 2-CH3O 3-Cl H H H 165 O 2-CH3O 4-Cl H H H 166 0 2-CH30 5-C1 H H H 167 | O | 3-CH3O | 4-Cl | H | H | H 168 0 + + H H H 169 0 + + H H H 170 0 H H 2-F H H 171 0 H H 4-F H H 7.51 Gum 172 0 H H 5-F H H 173 0 H H 6-F H H 174 O H H 4-Cl H H TABLE I (CONT/D)
Compound | | | | Melting No. X D G A B E Olefinic+ Point ( C) 175 0 H H 5-C1 H - H 7.41 Gum 176 0 H H 4-CH3 H H 177 | O | H | H | 5-CH3 | H | H | 7.47 | Gum 178 0 H H 4-CH2O | H | H 179 O O H H 5-CH3O H H 7.42 Gum 180* 0 H H 4-Br H H 7.47 Gum 181 0 H H 5-Br H H 182 | O | H | H | 4-CF3 | H | H 183 0 H H 5-CF3 H H 184 0 H H 4-NO2 H H 185 0 H H 5-NO2 H H 186 0 H H 4-CN H H 187 0 H H 5-CN H H 188 0 H H 4-F 5-F H 189 | O | H | H | 4-Cl | 5-Cl | H 190 0 H H 4-F 5-C1 H 191 0 H H 4-C1 5-F H 192 0 H H 4-CH30 5-C1 H 193 0 H H | 4-CH30 5-F H 194 0 H H H H H 5-F 195 | O | H | H | H | H | 6-Cl 196 (E)-N:N H H | 4-CH3O H H 197 | (E)-N:N H H |4-CH3CH2O H H 198 CH20 2-C1 H ! H H H 199 1 CH20 3-Cl H i H H H 200 CH2O 4-Cl H H H H TABLE I (CONT/D)
Compound Melting No. X D G A B E Olefinic+ Point ( C) 201 CH20 2-F H H H H 202 CH2O 3-F H H H H 203 CH2O 4-F H H H H 204 CH20 2-CH3 H H H H 7.25 108-11 205 CH2O 3-CH3 H H H H 7.24 Gum 206 CH2O 4-CH3 H H H H 7.40 88-90 207 CH20 2-CH30 H H H H 208 | CH2O | 3-CH3O | H | H | H | H | 7.39 | Gum 209 CH2O | 4-CH3O H H H H 210 CH20 2-N02 H H H H 211 CH20 3-NO2 H H H H 212 CH2O 4-NO2 H H H H 7.42 109 213 CH20 2-CN H H H H 214 CH20 3-CN H H H H 7.41 89-92.5 215 CH2O 4-CN H H H H 216 CH2O 2-Br H H H H 7.41 78-80 217 CH2O 3-Br H H H H 7.45 Gum 218 CH2O 4-Br H H H H 7.4 86-88.5 219 | CH2O | 2-CF3 | H | H | H | H 220 CH@O 3-CF3 H H H H obscured Gum 221 CH2O 4-CF3 H H H H 222 CH2O 2-C6H5O H H H H 223 CH2O 3-C6H50 H H H H 224 CH2O 4-C6H5O H H H H 225 CH2O 2-CH3CH2O H H H H TABLE I (CONT/D)
Compound Melting No. X D G A B E Olefinic+ Point ( C) 226 CH20 3-CH3CH2O H H H H 227 CH20 4-CH3CH2O H H H H 228 CH20 2-C6H5 | H H H H 229 CH20 3-C6H5 H H H H 230 CH20 4-C6H5 H H H H obscured Gum 231 CH20 2-Cl 3-C1 H H H 232 | CH2O | 2-Cl | 4-Cl | H | H | H 233 CH20 2-Cl 5-C1 H H H 234 CH20 2-C1 6-C1 H H H 235 | CH2O | 3-Cl | 4-Cl | H | H | H 236 CH20 3-C1 5-C1 H H H 237 CH2O 2-Cl 3-CH3O H H H 238 CH2O 2-Cl 4-CH3O H H H 239 CH20 2-Cl | 5-CH3O H H H 240 CH2O 2-Cl 6-CH3O H H H 241 CH2O 3-Cl 4-CH3O H H H 242 CH20 3-C1 5-CH3O H H H 243 CH2O 2-CH3O 3-Cl H H H 244 CH2O 2-CH3O 4-Cl H H H 245 CH2O 2-CH3O 5-Cl H H H 246 CH2O | 3-CH3O 4-C1 H H H 247 CH2O + F H H H 7.42 100-102.5 248 CH2O | # | # | H H H 7.42 102-106 249 CH2O H H 2-F H H 250 CH2O H H 4-F H H TABLE I (CCOT/D)
Compound Melting No. X D G A B E Olefinic+ Point ( C) 251 CH20 H H 5-F H H 252 CH20 H H 6-F H H 253 CH20 H H 4-C1 H H 254 CH20 H H 5-C1 H H 255 CH20 H H 4-CH3 H H 256 CH20 H H 5-CH3 H H 257 CH20 H H 4-CH30 H H 258 CH20 H H 530 H H 259 CH20 H H 4-Br H H 260 CH20 H H 5-Br H H 261 CH20 H H 4-CF3 H H 262 | CH2O | H | H | 5-CF3 | H | H 263 CH20 H H 4-NO2 H H 264 | CH2O | H | H | 5-NO2 | H | H 265 CH20 H H 4-CN H H 266 CH20 H H 5-CN H H 267 CH20 H H 4-F 5-F H 268 CH20 H H 4-Cl | 5-Cl | H 269 CH20 H H 4-F 5-Cl H 270 CH20 H H 4-C1 5-F H 271 CH20 | H H 4-CH3O 5-C1 H 272 | CH2O | H | H | 4-CH3O | 5-F | H 273 CH20 | H H H H 5-F 274 CH2O H H H H 6-Cl 275 O 4-NH.COCH3 H H H H TABLE I (CONT/D)
Compound Melting No. X D G A B | E Olef ini c+ Point ( C) 276 O |4-NH.SO2C6H5 H H H H 277 o |4-NH.COC6H5 H H H H 278 | O | 4-NH.SO2CH3 | H | H | H | H 279 O 4-N(CH3)2 H H H H 280 SO2O | 4-NH.COCH3 H H H H 281 5020 3-NO2 4-C1 H H H 282 (E)-N::N 4-Cl H 4-HO H H 7.38 143-144 283 SO2O 2-C1 H H H H 7.37 Gum 284 5020 3-C1 H H H H 7.45 Gum 285 SO2O 4-C1 H H H H 7.45 53-59 286 SO2O I 2-F H H H H 287 | 5020 3-F H H H H 288 SO2O 4-F H H H H 7.45 Gum 289 SO2O 2-CH3 H H H H 290 SO2O 3-CH3 H H H H 7.34 Gum 291 | SO2O | 4-CH3 | H | H | H | H | 7.38 | 70-76 292 5020 2-CH30 H H H H 293 | SO2O | 3-CH3O | H | H | H | H 294 SO2O 4-CH3O H H H H 7.39 96-97 295 5020 2-N02 H H H H 7.40 Gum 296 | SO2O | 3-NO2 | H | H | H | H | 7.41 | 90-93.5 297 SO2O | 4-NO2 H H H H 298 SO2O 2-CN H H H H 299 SO2O 3-CN H H H H 300 SO2O 4-CN H H H H 301 5020 ! 2-Br H H H H TABLE I (CONT/D)
Compound Melting No. X D G A B E Olefinic+ Point ( C) 302 SO2O 3-Br H H H H 303 5020 4-Br H H H H 304 5020 2-CF3 H H H H 305 | SO2O | 3-CF3 | H | H | H | H 306 SO2O 4-CF3 H H H H 307 5020 2-C6H5O H H H H 308 | SO2O | 3-C6H5O | H | H | H | H 309 5020 4-C6H5O H H H H 310 | SO2O | 2-CH3CH2O | H | H | H | H 311 5020 | 3-CH3CH2O H H H H 312 | SO2O | 4-CH3CH2O | H | H | H | H 313 SO2O 2-C6H5 H H H H 314 SO2O # 3-C6H5 H H H H 315 SO2O 4-C6H5 H H H H 316 | SO2O | 2-Cl | 3-Cl | H | H | H 317 SO2O 2-C1 4-C1 H H H 318 5020 2-C1 5-Cl H H H 7.53 Gum 319 SO2O 2-Cl 6-Cl H H H 320 5020 3-Cl 4-C1 H H H 321 SO2O 3-Cl 5-Cl H H ; H 322 SO2O 2-Cl 3-CH3O H H H 323 SO2O 2-Cl 4-CH3O H H H 324 SO2O 2-Cl 5-CH3O H H H 325 SO2O 2-Cl 6-CH3O H H H 326 SO2O 3-Cl 4-CH3O H H H 327 5020 | 3 3-Cl 5-CH30 H H H 328 S020 | 2-CH3O 3-C1 H H H TABLE I (CCNT/D)
Compound Melting No. X D G A B E Olefinic+ point ( C) 329 SO2O 2-CH3O 4-Cl H H H 330 SO2O 2-CH3O 5-Cl H H H 331 SO2O 3-CH3O 4-Cl H H H 332 SO2O # # H H H 7.34 Gum 333 5020 + + H H H 7.35 98-100 334 | SO2O | H | H | 2-F |H |H 335 SO20 H H 4-F H H 336 SO2O H H 5-F H H 337 SO2O H H 6-F H H 338 SO2O H H 4-C1 H H 339 5020 H H 5-Cl H H 340 5020 H H 4-CH3 H H 341 5020 H H 5-CH3 H H 342 5020 H H 4-CH3 H H 343 SO2O H H 5-CH3 H H 344 SO2O H H 4-Br H H 345 SO2O H H 5-Br H H 346 5020 H H 4-CF3 |H H 347 SO2O H H 5-CF3 H H 348 SO2O H H 4-NO2 H H 349 SO2O H H 5-NO2 H H 350 SO2O H H 4-CN H H 351 5020 H H 5-CN H H 352 5020 H H 4-F 5-F H 353 5020 H ss H 4-Cl 5-C1 H 354 | SO2O | H | H | 4-F |5-Cl |H TABLE I (CONT/D)
| Compound | | | | Melting No. X D G A B | E | Olefinic+ | Point 355 5020 H H 4-C1 5-F | H 356 5020 H H 4-CH30 5-Cl H 357 5020 H H 3-CH30 5-F H 358 SO2O H H H H 5-F 359 | SO2O | H | H | H | H |6-Cl 360 CH(C6H5) H H H H H 7.44 Gum 361 0 | 3-C1 H 4-C1 H H 362 0 3-CH30 4-Cl 5-F H H 363 CH20 4-F H 5-CH3O H H 364 | SO2O | 3-CH3 | H | 4-F | H | H 365) O H H 4-CH3CO H H 7.43 90-92 366+ | O | H | H | 6-CH3CO | H | H | 7.48 | 82-85 367* O H | H 6-Br H H 7.45 Gum 368 0 H H 5-C6H5O H H 7.46 Gum 369 SO2O 3-NH2 H H H H 7.43 88-92 370 COCH20 H H H H H 7.47 49-52 371 OCH2 4-CH3O H H H H 7.49 66-69 372 OCH2 3-CH3O H H H H 7.47 Gum 373 | OCH2 | 3-CN | H | H | H | H | 7.48 | 71-75 374 OCH2 4-CN H H H H 7.48 1 Gum 375 OCH2 4-NO2 H H H H 7.48 |108-110 376 OCH2 2-C1 H H H H 7.46 | 83-87 377 OCH2 2-CH30 H H H H 7.48 t Gum 378 OCH2 2-CN H H jH H 7.47 , 95-10 379 (E)-N: :N 4-Cl H 4-CH3O H H obscured 61 380 CH(OH) H H H H H 7.45 Gu TABLE I (CONT/D)
Compound Melting No. X D G A B E Olefinic+ Point ( C) 381 OCH2 2-NO2 H H H H 7.48 Gum 382 OCH2 3-NO2 H H H H 7.48 Gum 383 OCH2 3-Br H H H H 7.47 Oil 384 | OCH2 3-Cl H H H H 7.40 Oil 385 | OCH2 | 3-C6H5O | H | H | H | H | 7.47 | Oil 386 OCH2 4-Cl H H H H 7.47 | 72-76 387 S(O)CH2 4-Cl H H H H 7.42 , 105-11 388 S(0)2CH2 | 4-C1 H H H H 7.47 126-130.5 389 | OCH2 2-Br H H H H 7.46 87.5-9 | 390 | O | 2-NO2 | 4-NO2 | H | H | H | 7.46 | 54-57 391 1 0 2-Me 3-Me H H H 7.50 Gum 392 0 2-Me 4-Me H H H 7.51 Gum 393 0 2-Me 5-Me H H H 7.50 Gum 394 0 2-Me 6-Me H H H 7.50 Gum 395 0 3-Me 4-Me H H H 7.50 Gun 396 0 3-Me 5-Me H H H 7.51 Wax 397 | OCH2 4-Br H H H H 7.47 Oil 398 CO2CH2 H H H H H 7.47 Gum 399 SCCH2 2-Cl H H H H 7.47 74-78 400 SCH2 4-NO2 H H H H 7.48 Gum 401 S(O)CH2 2-Cl H H H H 7.60 Gum 402 |S(O)2CH2 2-Cl H H H H 7.59 Gum 403 (E/Z)-CH=CH# 4-NO2 H H H H 7.49 Gum 404 Ph2+PCH2Br- H H H H H 7.40 176-177 405 CH2O 4-tert-C4H9 H H H H 7.31 Gum 406 CH2OCO H H H H H 7.46 Gum TABLE I (CCNT/D)
Compound Melting No. X D G A B E Olefinic+ Point ( C) 407 CH2NHCO H H H H H 7.41 Gum 408 CH2SCO H H H H H 7.45 Gum 409 02C 3-N02 H H H H 7.50 Gum 410 OCH20 4-Cl H H H H 7.47 Oil 411 S(O)CH2O H H H H H 7.47 Oil 412 COCH(CH3)O H H H H H 7.45 Oil 413 (E)-CH2ON:CH H H H H H 7.49 Gum 414 (Z)-CH2ON::CH H H H H H 7.46 Gum 415 (CH2)3O H H H H H 7.48 Oil 416 (CH2)4O H H H H H 7.47 Oil 417 (CCH2)5O 5O H H H H H 7.48 Oil 418 (E)-N:N 4-OH H H H H 7.50 Oil 419 (E)-N::N 4-CH3O H H H H 7.49 Gum 420 CO.NH 2-Br H H H H 7.49 421 CO.NH 3-Br H H H H 7.47 FDam 422 CO.NH 3-CH30 H H H H 7.48 423 OCH2CH2O H H H H H 7.45 Gum 424 9020 t # H H H 7.29 Gum 425 SCH2O H H H H H 7.47 Oil 426 CH2O 2-(CH3O2C- H H H H 7.40 or Gum C=CH.OCH3) 7.52 427 SO2O 4-CF3O H H H H obscured Gum 428 socp 2-CH3O2C H H H H 7.41 429 CH2CH2CH(OH) H H H H H 430 (E)-CH2CH=CH H H H H H TABLE I (CONT/D)
| Compound Melting | No. X X D G A B E Olefinic+ Point | | | | | | | | ( C) 431 | C(CH3)(OH) H H H H H 432 i CH(OH) 2-Cl H H H H 433 j CH(OH) 4-C1 H H H H 434 | CH(OH) 2-CH3O H H H H 435 , CH(OH) 3-CF3 H H H H 436 CH(OH) 3-CN H H H H 1437 CH(OH) 4-N02 H H H H 438 CH2OSO2 H H H H H 439 CH2NHCO.NH H H H H H 440 CH2NH H H H H H 441 OCO.NH H H H H H 442 NHCO.NH H H H H H 443 | CH2OCO.NH H H H H H 7.47 Gum 444 SO2NH 4-Br H H H H 445 CH2NH 3-CH3 H H H H TABLE I - FOOTNOTES:: + Chemical shift of singlet from olefinic proton on beta methoxypropenoate group (p.p.m from tetramethylsilane).
Solvent: CDC13 unless otherwise stated.
+ Substituents D and G join to form a fused ring. Thus compound numbers 168, 169, 247, 248, 332 and 333 are:
X COMPOUND NO 0 168 CHO 247 S020 332
X COMPOUND NO 0 169 CH20 248 S020 333 And Compound No. 424 is
*, + Indicate, in each case, that structural assignment may be reversed. Thus the characterising data attributed to Compound No. 180 may, in fact, be that for Compound No. 367 and vice versa. The same applies to Compound Nos. 365 and 366.
# (E):(Z) ratio = 85:15 (see Example 20).
Ph is phenyl.
TABLE II
Compound Melting No. | Z | X | A | B | E | Olefinic+ | Point ( C) 1 Pyridin-2-yl O H H H 7.48 Gum 2 Pyridin-2-yl S H H H 3 Pyridin-2-yl N(CH3) H H H 4 Pyridin-2-yl SO2O H H H 5 Pyridin-2-yl CH2CH2 H H H 6 Pyridin-2-yl OCH2 H H H 7.48 Gum 7 Pyridin-2-yl CH20 H H H 8 Pyridin-3-yl 0 H H H 7.48 Gum.
9 Pyridin-3-yl S H H H 10 Pyridin-3-yl N(CH3) H H H 11 Pyridin-3-yl SO2O H H H 12 Pyridin-3-yl CH2CH2 H H H 13 Pyridin-3-yl OCH2 H H H 14 Pyridin-3-yl CH2O H H H 15 Pyridin-4-yl 0 H H H 7.48 16 |Pyridin-4-yl S H H H 17 Pyridin-4-yl N(CH3) H H H | 18 |Pyridin-4-yl | SO2O | H | H | H 19 Pyridin-4-yl CH2CH2 H H H TABLE II (CONT/D)
Compound Melting No. Z X A B E Olefinic+ Point ( C) 20 Pyridin-4-yl OCH2 H H H 21 Pyridin-4-yl CH20 H H H 22 Pyrimidin-2-yl 0 H H H 7.38 Gum 23 Pyrimidin-2-yl S H H H 7.49 Gum 24 Pyrimidin-4-yl N(CH3) H H H 25 Pyrimidin-4-yl SO2O H H H 26 Pyrimidin-5-yl CH2CH2 H H H 27 Pyrimidin-5-yl CH20 H H H 28 1,2,4-Triazin-3-yl OCH2 H H H 29 1,3,5-Triazin-2-yl 0 H H H 30 Pyrazin-2-yl 0 H H H 7.49 Gum 131 Pyrazin-2-yl S H H H 32 Pyrazin-2-yl N(CH3) H H H 33 Pyrazin-2-yl S020 H H H 34 Pyrazin-2-yl CH20 H H H 35 Pyridazin-3-yl 0 H H H 7.49 Gum 36 Pyridazin-3-yl S H H H 37 Pyridazin-3-y1 S020 H H H 38 Quinolin-2-yl O H H | H 7.43 109-110 39 Quinolin-2-yl CH20 H H H 40 Quinolin-3-yl 0 H H H 41 |Quinolin-3-yl | SO2O | H | H | H 42 Benzoxazol-2-yl O H H H 43 Benzoxazol-2-yl S H H H 44 |Benzoaxol-2-yl N(CH3) H H H 45 Benzoaxol-2-yl SO2O H H H TABLE II (CONT/D)
Compound Melting No. Z X A B E Olefinic+ Point ( C) 46 |Benzthiazol-2-yl |CH2CH2 | H | H | H 47 Benzthiazol-2-yl |OCH2 H H H 7.49 Gum 48 Benzthiazol-2-yl ::CH20 H H H 49 Thien-2-yl CH2O H H H 50 Thien-2-yl CH2CH2 H H H 51 Dien-3-yl 1 O H H H 52 Thien-2-yl |SO2O H H H 7.40 Gum 53 5-CF3-Pyridin-2-yl O H H H 7.49 Oil 54 -CF3-Pyridin-2-yl S H H H 55 5-CF3-Pyridin-2-yl |CH2O H H H 56 3-F-Pyridin-2-yl O H H H 57 3-Cl-Pyridin-2-yl O H H H 58 4-Br-Pyridin-2-yl O H H H 59 5-CH3-Pyridin-2-yl 0 H H H 60 6-CH3O-Pyridin-2-yl O H H H 61 2-F-Pyridin-3-yl O H H H 62 3-CF3-Pyridin-4-yl O H H H 63 4,6-di-F-Pyridin-2-yl 0 H H H 64 3-NO2-5-CF3- O H H H Pyridin-2-yl 65 5-(CH3O2C)- O H H H Pyridin-2-yl | | | | | | | 66 |3-CH3-Pyridin-2-yl 0 H H H 67 v H3-Pyridin-2-yl O H H H H 68 w H3-Pyridin-2-yl O H H H 69 5-(CN)-Pyridin-2-yl O H H H 7.49 Gum TABLE II (CCOT/D)
Compound Melting No. Z X A B E Olefinic+ Point ( C) 70 3-Cl-5-(C6H50)-l, O H H H |3,5-triazin-2-yl | | 71 Pyridin-2-yl 0 2-F H H 72 Pyridin-2-yl 0 4-Cl H H 73 Pyridin-4-yl O 5-CH3 H H 74 Pyridin-4-yl 0 4-CH30 H H 75 |5-CF3-Pyridin-2-yl | O |5-CN |H | H 76 5-CF3-Pyridin-2-yl O 4-F 5-CH30 H 77 |Pyrimidin-2-yl | O |H |H | 5-Cl 78 Pyrimidin-2-yl 0 H H 6-F 79 Benzoxazol-2-yl O 4-CF30 H 5-F 80 |Benzoaxol-2-yl | O |5-NO2 |H | H 81 1,2,4-Triazol-1-yl CH2 H H H 7.48 Gum 82 1,2,3-Triazol-1-yl CH2 H H H 83 Benzthiazol-2-yl O H H H 7.38 Gum 84 3-Chloroquinoxalin-2-yl 0 H H H 7.50 117-119| 85 Pyrimidin-2-yl OCH2 H H H 7.49 Oil 86 3,5-di-Cl-1,3,5- 0 H H H 7.52 Gum triazin-2-yl 87 Pyrimidin-5-yl 0 H H H 7.47 Oil 88 3-Cl,5-(CH3O)-1,3,5- 0 H H H 7.50 Gum triazin-2-yl 89 6-Cl-Pyrimidin-4-yl 0 H H H 7.49 oil 90 5-Br-Pyrimidin-2-yl 0 H H H 7.48 Gum 91 5-Cl-Pyrimidin-2-yl 0 H H H 7.48 | Oil 92 Pyrimidin-4-yl 0 H H H 7.48 Oil 93 2,6-Di-CH3O- O H H H 7.48 Oil Pyrimidin-4-yl TABLE II (CONT/D)
CcmFoundij Melting No. | Z X A B E Olefinic+ Point ( C) 94 2-Cl-6-CH3-Pyrimidin- O H H H 7.50 113-118 4-yl 95 2,6-Di-Cl-Pyrimidin- O H H H 7.50 113-115 4-yl 96 2,5,6-Tri-Cl- 0 H H H 7.49 Gum Pyrimidin-4-yl 97 2-C1-Pyrimidin-4-yl O H H H * Oil 98 2-CH3-Thiazol-4-yl CH2O H H H 7.48 Oil 99 Benzoxazol-2-yl OCH2 H H H 7.50 Gum 100 Pyrazin-2-yl OCH2 H H H 7.49 Gum 101 6-C1-Pyrazin-2-yl OCH2 H H H 7.49 Gum 102 Ouinolin-2-yl OCH2 H H H 7.49 Gum 103 6-Cl-Pyridazin-3-yl OCH2 H H H | 7.49 Gum 104 Pyridin-4-yl, N-oxide OCH2 H H H 7.49 Foam 105 5-CF3-Pyridin-2-yl OCH2 H H H 7.48 Gum 106 3-Cyanopyridin-2-yl 0 H H H 7.48 Gum 107 5-N02-Pyridin-2-yl O H H H 7.49 Gum 108 Pyridin-2-yl CHO H H H 109 Pyrimidin-2-yl SO2O H H H 110 Pyrimidin-2-yl NH H H H 111 Pyrimidin-2-yl N(CH3) H H H 112 Pyrimidin-2-yl CH2 H H H 113 Pyrimidin-2-yl CH(OH) H H H 114 Pyrimidin-2-yl CH2CH2 H H H 115 Pyrimidin-4-yl 0 H H H 116 Pyrimidin-4-yl CH2O H H H 117 Pyrimidin-4-yl OCH2 H H H 118 Pyrimidin-4-yl NH H H H TABLE II (CONT/D)
Compound Melting No. Z X A B E Olefinic+ Point ( C)| 119 Pyrimidin-4-yl S H H H 120 Pyrimidin-4-yl CH2 H H H 121 Pyrimidin-4-yl CH(OH) H H H 122 Pyrimidin-4-yl CH2CH2 H H H 123 Pyrimidin-5-yl SO2O H H H 124 Pyrimidin-5-yl OCH2 H H H 125 |Pyrimidin-5-yl | NH |H | H | H 126 Pyrimidin-5-yl N(CH3) H H H 127 Pyrimidin-5-yl S H H H 128 Pyrimidin-5-yl CH2 H H H 129 Pyrimidin-5-yl CH(OH) H H H 130 6-Chloropyridazin- 0 H H H 7.50 Gum 3-yl 131 6-Chloropyridazin- CH20 H H H 3-yl 132 |6-Chloropyridazin- | NH |H | H | H 3-yl 133 6-Chloropyridazin- N(CH3) H H H 3-yl 134 6-Chloropyridazin- CH(OH) H H H 3-yl 135 Pyridazin-4-yl 0 H H H 136 |Pyridazin-4-yl | OCH2 |H | H | H 137 Pyridazin-4-yl NH H H H 138 Pyridazin-4-yl SO2O H H H 139 1,3,5-Triazin-2-yl NH H H H 140 1,3,5-Triazin-2-yl N(CH3) H H H 141 |1,2,4-Triazin-3-yl | O |H | H | H TABLE II (CONT/D)
Compound Melting No. Z X A B E Olefinic+ Point ( C) 142 1,2,4-Triazin-3-yl NH H H H 143 1,2,4-Triazin-3-yl N(CH3) H H H 144 1,2,4-Triazin-5-yl 0 H H H 145 1,2,4-Triazin-5-yl NH H H H 146 1,2,4-Triazin-6-yl 0 H H H 147 1,2,4-Triazin-6-yl N(CH3) H H H 148 Pyrimidin-2-yl, O H H H N-oxide 149 Pyrimidin-4-yl, 1- O H H H N-oxide 150 Pyrimidin-4-yl, 3- 0 H H H N-oxide 151 Pyridin-2-yl, N-oxide O H H H 152 Pyridin-3-yl, N-oxide O H H H 153 Pyrazin-2-y1, 1N-oxide 0 H H H 154 Pyrazin-2-yl, 4-N-oxide 0 H H H 155 Pyridazin-3-yl, 1-N- O H H H oxide 156 Pyridazin-3-yl, 2-N- O H H H oxide 157 Isoquinolin-l-yl O H H H 158 Isoquinolin-1-yl NH H H H 159 Isoquinolin-l-yl CHO H H H 160 Isoquinolin-l-yl OCH2 H H H 161 IsoqLiinolin-1-yl CH(OH) H H H 162 Isoquinolin-l-yl S H H H 163 Isoquinolin-l-yl 5020 H H H 164 Quinolin-4-yl O H H H TABLE II (CONT/D)
Compound Melting No. Z X A B E Olefinic+ Point ( ) 165 Quinolin-4-yl NH H H H 166 Quinolin-4-yl CH20 H H H 167 Quinolin,4-yl OCH2 H H H 168 Quinolin-4-yl CH(OH) H H H 169 Quinolin-4-yl S H H H 170 Quinolin-4-yl SO2O H H H 171 Quinazolin-4-yl 0 H H H 172 Quinazolin-4-yl NH H H H 173 Quinazolin-4-yl CH20 H H H 174 Quinazolin-4-yl OCH2 H H H 175 Quinazolin-4-yl CH(OH) H H H 176 Quinazolin-4-yl S H H H 177 |Quinazolin-4-yl | SO2O | H | H | H 178 7-Chloroquinolin-4-yl O H H H 179 7-Chloroquinolin-4-yl S H H H 180 7-Chloroquinolin-4-yl NH H H H 181 Purin-6-yl O H H H 182 2-Chloropurin-6-yl S H H H 183 2-Chloropurin-6-yl NH H H H 184 5-NO2-Thien-2-yl OCH2 H H H 185 5-NO2-Thien-2-yl O H H H 186 Thiazo1-2-y1 CH2O H H H 187 ThiaaD1-2-yl O H H H 188 Thiazol-2-yl NH H H H 189 Thiazol-4-yl CHO H H H 190 Thiazol-4-yl 0 H H H 191 Thiazol-4-yl NH H H H 192 |Thiazol-5-yl | CH2O | H | H | H 193 Thiazol-5-yl 0 H H H 194 |Thiazol-5-yl | NH | H | H | H TABLE II (CONT/D)
Compound i i Melting No Z X A | B | E - Olefinic+ Point ("C) 195 OgA7n1-2-yl CE20 H | H H 196 OxA7nl 4-yl O H | H H 197 OxA - 1-5-yl NH2 H | H H 198 5-CF3-1,3,4-Thia- O H H H diAzol-2-yl 199 5-CF3-1,3,4 > Thia- O H H H di^nl-2-yl 200 4-C1-1,2,5lRhia- O H H H di^l-3-yl l 201 < ?S O 0 H H | H 7.49 115-116 l N H | H I ! 202 ; NH H H { H 202 MI 203 | z N z N(CH3) H H H I 204 -Pyrimiain-2-r .
204 0 Hi H H 205 4-Br-eyrimidin-2-yl | O H t H | H 206 4-Fimidir21 0 O H I H 207 4-CH3-Pyrimidin-2-yl i 0 H H I H 208 4-CH30-Pyrimidin-2-yl O O H j H i H 209 209 4-CH3CH20iPyrimidinr ', O H | H , H 2-yl 210 49N02-Pyrimidin-2-yl 0 H H H ! H ! 211 4-Cyano-qimidin-2-y 0 H H ! H 212 4-CF3-PyrImidin-2-yl O H H H H 213 4-C6H5-Thrrmidin-2-y1 O 1H H ; ; 214 4 P imid m -2-yl 0 H H H TABLE II (CONT/D)
Compound Melting No. Z X A B E Olefinic+ Point ( C) 215 5-F-Pyrimidin-2-yl O H H H 216 5-CH3-Pyrimidin-2-yl O H H H 217 5-CH3O-Pyrimidin-2-yl O H H H 218 5-CH3CH2O-Pyrimidin- O H H H 2-yl 219 |5-NO2-Pyrimidin-2-yl | O | H | H | H 220 |5-Cyano-Pyrimidin-2-yl 0 H H H 221 |5-CF3-Pyrimidin-2-yl O H H H 222 5-C6H5-Pyrimidin-2-yl O H H H 223 5-C6H5O-Pyrimidin-2-yl O H H H 224 |4,5-Di-Cl-Pyrimidin- O H H H 2-yl 225 |4,6-Di-Cl-Pyrimidin- O H H H 2-yl 226 4-Cl-6-CH3-Pyrimidin- O H H H 2-yl 227 4-Cl-5-CH3O-Pyrimidin- O H H H 2-yl 228 2-F-Pyrimidin-4-yl O H H H 229 2-Br-Pyrimidin-4-yl O H H H 230 2-CH3-Pyrimidin-4-yl O H H H 231 2-CH3O-Pyrimidin-4-yl O H H H 232 2-CH3CH2O-Pyrimidin- O H H H 4-yl 233 2-NO2-Pyrimidin-4-yl O H H H 234 |2-CH3S-Pyrimidin-4-yl | O | H | H | H 235 2-Cyano-Pyrimidin-4-yl O H H H 236 2-CF3-Pyrimidin-4-yl O H H H 237 2-C6H5O-Pyrimidin-4-yl O H H H I: TABLE II (CONT/D)
Compound Melting No. Z X A B E Olefinic+ Point ( C)| 238 2-C6H5-Pyrimidin-4-yl O H H H 239 6-F-Pyrimidin-4-yl O H H H 240 6-Br-Pyrimidin-4-yl O H H H 241 |6-CH3-Pyrimidin-4-yl O H H H 242 6-CH3O-Pyrimidin-4-yl O H H H 4-yl 244 |6-NO2-Pyrimidin-4-yl O H H H 245 6-Cyano-Pyrimidin-4-yl 0 H H H 246 |6-CF3-Pyrimidin-4-yl | O | H | H | H 247 6-C6H5O-Pyrimidin-4-yl O H H H 248 6-C6H5-Pyrimidin-4-yl O H H H 249 5-F-Pyrimidin-4-yl O H H H 250 5-Cl-Pyrimidin-4-yl 0 H H H 251 5-Br-Pyrimidin-4-yl O H H H 252 5-CH3-Pyrimidin-4-yl O H H H 253 5-CH3O-Pyrimidin-4-yl O H H H 254 5-CH3CH2O-Pyrimidin- O H H H 4-yl 255 5-NO2-Pyrimidin-4-yl O H H H 257 5-CF3-Pyrimidin-4-yl O H H H 258 5-C6H5O-Pyrimidin- O H H H 4yl 259 |5-C6H5-Pyrimidin-4-yl | O | H | H | H 260 2-Cl-Pyrimidin-5-yl 0 H H H 261 2-CH3-Pyrimidin-5-yl O H H H 262 - 2-F-Pyrimidin-5-yl O H | H H | 263 |2-CH3O-Pyrimidin-5-yl | O | H | H | H 264 2-Cyano-Pyrimidin-5-yl O H H H TABLE II (CONT/D)
Compound Melting No. Z X A B E Olefinic+ Point ( C) 265 4-CH3-Pyrimidin-5-yl O H H H 266 4-CH3O-Pyrimidin-5-yl O H H H 267 4-CF3-Pyrimidin-5-yl O H H H 268 2,4-CH3-Pyrimidin- O H H H 5-yl 269 2-CH3S-4-CH3O- O H H H Pyrimidin-5-yl 270 Pyrrol-2-yl CONH H H H 7.48 Fbam 271 6-Cl-3-NO2-Pyridin- 0 H H H 7.50 Gum 2-yl and 6-Cl-5-NO2-Pyridin 2-yl, 1::1 mixture 272 3,6-Di-CH3-Pyrazin-2- O H H H 7.49 Gum yl 273 6-Cl-Pyrazin-2-yl O H H H 7.50 Gum 274 6-CH3O-Pyridazin-3-yl O H H H 7.50 Gum 275 6-Cl-4-CH3-Pyridazin- O H H H 3-yl 276 6-Cl-5-CH3-Pyridazin- O H H H 3-yl 277 4-CF3-Pyridin-2-yl O H H H 278 6-Cyanopyridin-2-yl 0 H H H 279 4-Cyanopyridin-2-yl O H H H 280 4-Acetytpyridin-2-yl O H H H 281 6-C6H5-Pyridazin-3-yl O H H H 282 2-(CH302C)-Pyridin-2-yl 0 H H H 283 5-(CH3O2C)-Pyridin-3- O H H H yl 284 4-CF2C1-Pyridin-2-yl O H H H TABLE II (CONT/D)
Compound Melting No. Z X A B E Olefinic+ Point ( C) 285 3,5-Di-CF3-Pyridin-2- O H H H yl 286 6-CF3-Pyridin-2-yl O H -H H 287 5-CF3-Pyridin-3-yl O H H H 288 2-Cl-Pyridin-3-yl O H H H 289 2-CH30-Pyridin-3-yl O H H H 290 |2-Cl-Pyridin-4-yl 0 H H H 291 |2-CH3O-Pyridin-4-yl O H H H 292 2-Cl-Pyridin-5-yl 0 H H H 293 2-CH3O-Pyridin-5-yl O H H H 294 3-CH3S-Pyridin-2-yl O H H H 295 4-CF30-Pyridin-2-yl O H H | H 296 4-CON(CH3)2-Pyridin- O H H H 2-yl 297 3-Cl-1,2,4-Oxa- O H H H diazol-5-yl 298 3-Cl-1,2,4-Oxa- S H H H diazol-5-yl 299 5-CH3S-1,2,4-Oxa- 0 H H H diazol-3-yl 300 Pyridin-2-yl CH(OH) H H H 301 |Pyridin-3-yl |CH(OH) |H | H | H 302 Pyridin-4-yl CH(OH) H H H 303 Pyridln-2-yl Co H H H 304 Pyridin-3-yl CO H H H 305 Pyridin-4-yl CO H H H 306 Thien-2-yl CH(OH) H H H 307 Furan-2-yl CH(OH) H H H 308 N-CH3-Pyrrol-2-yl CH(OH) H H H TABLE II (CONT/D)
Compound Melting No. Z X | A B E Olefinic+ Point ( C) 309 |N-CH3-Pyrrol-2-yl Co H H H 310 6-Br-Pyridin-2-yl OCH2 H H H 7.49 Oil 311 4-Cl-Pyrimidin-2-yl |OCH2 H H H 7.49 Oil and 2-Cl-Pyrimidin- I r-4yl (3::1 mixture, not necessarily respectively) 312 |2,6-Di-F-Pyridimin-4-yl| 0 H H H 313 2-CH3S-6-CH3- O H H H 7.48 Gum Pyrimidin-4-yl 314 2-CH3S-Pyrimidin-4-yl O H H H 315 N-CH3-Pyrrol-2-yl CON- H H H 7.47 Gum (CH3) 316 |5-CF3-Pyridin-2-yl NH H H H 317 2-Cl-Pyrimidin-4-yl NH H H H 318 4-Cl-Pyrimidin-2-yl NH H H H 319 |5-NO2-6-(CH3)2N- | O o H H H 7.48 Gum | Pyridin-2-yl 320 |6-Cl-4-CH3-Pyridazin- | O H H H 7.50 Gum 3-yl and 6-Cl-5-CH3-Pyridazin-3-yl (3:2 mixture, not necessarily respectively) FOOTNOTES : + Chemical shift of singlet from olefinic proton on beta-methoxypropenoate group (p.p.m fran tetramethylsilane).
Solvent: CDC13 unless otherwise stated.
* See Table V for carbon-13 n.m.r. data.
TABLE III
Table III comprises 446 compounds of the general structure above. The first 445 of these have all the values of X, D, G, A, B and E listed in Table I. That is, Compound Nos. 1 to 445 of Table III are the same as those of Table I except that the value of K is oxygen in Table I and sulphur in Table III. Compound No. 446 has the above structure wherein X is oxygen and A, B, D, E and G are all hydrogen. A description of the preparation of Compound No. 446 is given in Example 11.
TABLE III
Compound Melting No. X D G A B E Olefinic Point ( C) 23 CH20 H H H H H 7.49 Gum 51 SO2O H H H H H 7.46 Gum 131 0 2-N02 H H H H 7.48 Gum 212 CH20 4-N02 H H H H 7.49 Gum 446 0 H H H H H 7.48 48-51.5 TABLE IV
Table IV comprises 320 compounds of the general structure above with all the values of Z, X, A, B and E listed in Table II.That is, compounds Nos. 1 to 320 of Table IV are the same as those of Table II except that the value of K is oxygen in Table II and sulphur in Table IV.
I Compound Melting No. Z X A B E Olefinic+ Point ( C) 22 Pyrimidin-2-yl O H H H 7.49 Gum 87 Pyrimidin-5-yl 0 | H H H 7.48 Gum | | TABLE V : SELECTED PROTON NMR DATA Table V snows selected proton n.m.r data for certain compounds described in Tables I, II, III and IV. Chemical shifts are measured in p.p.m from tetramethylsilane, and deuterochloroform was used as solvent throughout.The column headed 'frequency' refers to the operating frequency of the n.m.r spectrometer. The following abbreviations are used br = broad s = singlet d = doublet t = triplet q = quartet m = multiplet
TABLE COMPOUND FREQUENCY NO. NO. (MHz) I 2 60 3.36 (3H, s), 3.46 (3H, s), 6.6-7.6 (14H, m) ppm.
I 7 60 1.98 (3H, s), 3.48 (3H, s), 3.59 (3H, s), 6.6-7.3 (13H, m), 7.39 (1H, s) ppm.
I I 15 270 2.88 (4H, s), 3.60 (3H, s) 3.77 (3H, s), 6.76-3.93 (4H, m), 7.07-7.33 (9H, m), 7.49 (1H, s) ppm I | 25 270 3.59 (3H, s), 3.74 (3H, s), 4.05 (2H, s), 6.80-7.32 (13H, m), 7.47 (1H, s) ppm.
I 27 270 3.60 (3H, s), 3.77 (3H, s), 3.98 (2H, q), 6.60-6.90 (4H, m), 7.10-7.30 (4H, m), 7.39-7.50 (5H, m), 7.48 (1H, s) ppm.
I 29 400 3.59 (3H, s), 3.77 (3H, s), 4.26 (2H, s), 6.70-6.90 (4H, m), 7.10-7.30 (5H, m), 7.45-7.52 (1H, m), 7.48 (1H, s), 7.60-7.70 (3H, m) ppm.
I 38 270 2.99 (3H, s), 3.56 (3H, s), 3.69 (3H, s), 4.46 (2H, s),
TABLE COMPOUND FREQUENCY NO. NO. (MHz) 6.65-6.73 (3H, t), 6.79 (1H, d), 6.85-6.95 (3H, t), 7.10 (1H, t), 7.16-7.29 | | | (5H, m), 7.44 (1H, s) ppm.
I 62 270 3.61 (3H, s), 3.78 (3H, s), 6.7-7.6 (11H, m), 7.46 (1H, s), 7.8 (3H, m) ppm.
I | 67 270 3.59 (3H, s), 3.79 (3H, s), 7.02-7.40 (10H, m), 7.40 (1H, s), 7.70 (2H, d), 8.32 (1H, s) ppm.
I | 84 | 270 | 3.60 (3H, s), 3.75 (3H, s), 6.97 (1H, d), 7.14-7.53 (11H, m), 7.50 (1H, s), 7.59 (1H, d), 7.70 (1H, d) ppm.
I | 86 400 3.60 (3H, s), 3.74 (3H, s), 6.99 (1H, d), 7.09 (1H, d), 7.12-7.41 (9H, m), 7.49 (1H, s), 7.50 (1H, s), 7.59 (1H, d), 8.38 (1H, s) ppm.
I | 96 400 3.07 (2H, t), 3.60 (3H, s), 3.75 (3H, 3H, 4.10 (2H, t), (1H, s) ppm.
TABLE COMPOUND FREQUENCY NO. NO. (MHz) | I | 115 270 3.60 (3H, s), 3.75 (3H, s), 4.63 (2H, d), 6.3-7.4 (15H, m), 7.47 (1H, s) ppm.
I 119 270 3.60 (3H, s), 3.76 (3H, s), 6.58-6.72 (3H, m), 6.96 7.32 (8H, m), 7.41-7.50 (1H, m), 7.48 (1H, s) ppm.
I 120 270 3.60 (3H, s), 3.76 (3H, s), 6.62-7.36 (12H, m), 7.48 (1H, s) ppm.
I 122 90 3.61 (3H, s), 3.77 (3H, s), 6.5-6.8 (3H, m), 6.9-7.4 (9H, m), 7.50 (1H, s) ppm.
I 123 90 3.64 (3H, s), 3.79 (3H, s), 6.6-6.9 (2H, m), 6.9-7.5 (10H, m), 7.51 (1H, s) ppm.
I 125 90 2.23 (3H, s), 3.61 (3H, s), 3.77 (3H, s), 6.5-6.8 (3H, m) 6.8 (3H, m), 6.8-7.5 (9H,m) 7.51 (1H, s) ppm.
I 126 400 2.33 (3H, s), 3.61 (3H, s), 3.76 (3H, s), 6.62-7.3 (12H, m), 7.49 (1H, s) ppm.
TABLE COMPOUND FREQUENCY NO. NO. (MHz) I 127 90 2.32 (3H, s), 3.60 (3H, s), 3.75 (3H, s), 6.62-7.40 | - (12H, m), 7.49 (1H, s) ppm.
I 128 270 3.58 (3H, s), 3.74 (3H, s), 3.82 (3H, s), 6.56-6.65 (3H, m), 6.84-7.00 (4H, m), 7.06-7.28 (5H. m), 7.46 (1H, s) ppm.
I 130 60 3.6 (3H, s), 3.75 (3H, s), 3.8 (3H, s), 6.57-7.3 (12H, m), 7.48 (1H, s) ppm.
I 131 270 3.61 (3H, s), 3.76 (3H, s), 6.62-6.79 (3H, m), 6.97 7.34 (7H, m), 7.47 (1H, s), 7.48-7.56 (1H, m), 7.94 (1H, d) ppm.
I 135 90 3.62 (3H, s), 3.78 (3H, s), 6.6-6.9 (3H, m), 6.9-7.6 (9H, m), 7.51 (1H, s) ppm.
I 138 270 3.60 (3H, s), 3.76 (3H, s), 6.62-6.76 (3H, m), 6.90 7.02 (2H, m), 7.12-7.38 (7H, m), 7.48 (1H, s) ppm.
| TABLE | COMPOUND| FREQUENCY NO. | NO. (MHz) I 141 250 3.59 (3H, s), 3.70 (3H, s), 6.6-6.8 (3H, m), 6.9-7.1 (1H, m), 7.1-7.5 (8H, m), 7.49 (1H,s) ppm.
I 143 90 3.56 (3H, s), 3.68 (3H, s), 6.54-7.36 (17H, m), 7.46 (1H, s) ppm.
I 144 400 3.60 (3H, s), 3.75 (3H, s), 6.65-6.76 (5H, m), 6.97 (1H, d), 7.02 (2H, d), 7.10-7.3 (9H, m), 7.48 (1H, s).
I 145 90 3.62 (3H, s), 3.77 (3H, s), 6.64-7.49 (17H, m), 7.50 (1H, s) ppm I 150 90 3.59 (3H, s), 3.74 (3H,- s), 6.6-6.9 (3H, m), 6.9-7.7 (14H, m), 7.50 (1H, s) ppm.
I 157 90 3.64 (3H, s), 3.79 (3H, s), 6.6-7.5 (11H, m), 7.53 (1H, s) ppm I | 171 90 3.61 (3H, s), 3.76 (3H, s), 6.6-6.8 (2H, m), 6.8-7.5 (10H, m), 7.51 (1H, s) ppm.
TABLE COMPOUND FREQUENCY NO. NO. (MHz) I 175 90 3.57 (3H, s), 3.73 (3H, s), 6.50 (1H, t), 6.58 (2H, d), 6.9-7.4 (9H, m), 7.41 (1H, s) ppm.
I 177 90 2.25 (3H, s), 3.60 (3H, s), 3.76 (3H, s), 6.4-6.6 (3H, m), 6.9-7.4 (9H, m), 7.47 (1H, s) ppm.
I 179 90 3.57 (3H, s), 3.68 (3H, s), 3.72 (3H, s), 6.20 (3H, m), 6.8-7.4 (9H, m), 7.42 (1H, s) ppm.
I 180 250 3.61 (3H, s), 3.76 (3H, s), 6.4-6.6 (2H, m), 6.9-7.0 (3H, m), 7.07 (1H, t), 7.16 (1H, t), 7.2-7.4 (4H, m), 7.46 (1H, d), 7.47 (1H, s) ppm.
I 205 60 2.11 (3H, s), 3.35 (3H, s), 3.40 (3H, s), 4.71 (2H, s), 6.2-7.2 (12H, m), 7.24 (1H, s) ppm.
I 206 90 2.32 (3H, s), 3.55 (3H, s), 3.7 (3H, s), 4.9 (2H, s), 6.45-7.28 (12H, m), 7.40 (1H, s) ppm.
TABLE COMPOUND FREQUENCY NO. NO. (MHz) I 208 90 3.54 (3H, s), 3.7 (3H, s), 3.77 (3H, s), 6.44-7.3 (12H, m), 7.39 (1H, s) ppm.
I 214 90 3.56 (3H, s),3.73 (3H, s), 5.0 (2H, s), 6.5-7.65 (12H, m), 7.41 (1@ s) ppm.
I | 216 | 90 | 3.56 (3H, s), 3.69 (3H, s) 5.04 (2H, s), 6.49-7.57 (12H, m), 7.41 (1H, s) ppm.
I 217 60 3.55 (3H, s), 3.65 (3H, s), 4.90 (2H, s), 7.45 (1H, s), 6.4-7.5 (12H, m) ppm.
I 218 90 3.54 (3H, s) 3.7 (3H, s) 4.9 (2H, s), 6.42-7.48 (12H, m), 7.4 (1H, s) ppm.
I 220 60 3.40 (3H, s), 3.49 (3H, s), 4.85 (2H, s) 6.2-7.5 (13H, m) ppm.
I 230 60 3.44 (3H, s), 3.52 (3H, s), 4.87 (2H, s), 6.3-7.6 (18H, m) ppm.
TABLE COMPOUND | FREQUENCY NO NO | (MHz) I 247 90 I 3.5 (3H, s), 3.61 (3H, s), 5.07 (2H, s), 6.41-7.79 (15H, m), 7.42 (1H, s) ppm.
I 248 90 | 3.56 (3H, s), 3.7 (3H, s), 5.4 (2H, s), 6.5-8.4 (15H, m), 7.42 (1H, s) ppm.
I 283 60 3.45 (3H, s), 3.59 (3H, s), 6.5-8.0 (13H, m) ppm.
1 I 284 60 3.45 (3H, s), 3.57 (3H, s), 6.3-7.8 (13H, m) ppm.
1 I 285 250 3.57 (3H, s), 3.72 (3H, s), 6.55-7.78 (12H, m), 7.45 (1H, s) ppm.
I 288 | 60 3.39 (3H, 5), 3.52 (3H, s),| 6.4-7.4 (10H, m), 7.45 (1H,| s), 7.7-8.0 (2H, m) ppm.
I 290 | 60 2.25 (3H, s), 3.43 (3H, s),| 3.55 (3H, s), 6.4-7.7 (13H,| m) ppm.
I 291 90 2.43 (3H, s), 3.54 (3H, s) i i 3.71 (3H, s), 6.5-7.68 | (12H, m), 7.38 (1H, s) ppm
TABLE COMPOUND FREQUENCY NO NO (MHz) I I 295 60 3.52 (3H, s), 3.67 (3H, s), 6.6-8.0 (13H, m) ppm.
I 296 90 3.54 (3H, s), 3.72 (3H, s), 6.48-8.69 (12H, m), 7.41 (1H, s) ppm.
I 318 60 3.59 (3H, s), 3.72 (3H, s), 6.7-8.0 (12H, m) ppm.
I 332 90 3.48 (3H, s), 3.63 (3H, s), 6.48-8.3 (15H, m), 7.43 (1H, s) ppm.
1 I 333 90 3.44 (3H, s), 3.61 (3H, s), 6.41-8.7 (15H, m), 7.35 (1H, s) ppm.
I 360 250 3.55 (3H, s), 3.71 (3H, s), 6.15 (1H, s), 6.48-7.39 (14H, m), 7.44 (1H, s) ppm.
I 367 250 3.56 (3H, s), 3.70 (3H, s), 6.5-6.7 (2H, m), 6.95 (3H, t), 7.12 (2H, q), 7.2-7.4 (4H, m), 7.45 (1H, s), 7.48 (1H, d) ppm.
TABLE COMPOUND FREQUENCY NO NO (MHz) I 368 90 3.57 (3H, s), 3.73 (3H, s), 6.33 (3H, s), 6.9-7.5 (14H, m), 7.46 (1H, s) ppm.
I 369 60 3.5 (3H, s), 3.6 (3H,s ), 4.1 @ (2 br s), 6.6-7.3 (12H, m), 7.43 (1H, s) pp I 370 90 3.6 (3H, S), , 3.76 (3H, s 5.24 (2H, s), , 6.51-8.04 (13H, m), 7.47 (1H, s) ppm.
I 371 400 3.60 (3H, s), 3.75 (3H, s), 3.76 (3H, s), 4.95 (2H, | 6.80-6.94 (6H, m), 7.03 (1H, s), 7.08-7.16 (2H, q), 7.24-7.30 (3H, m), 7.49 (1H, s) ppm.
I 373 270 3.60 (3H, s), 3.76 (3H, s), 5.02 (2H, s), 6.88-6.96 (2H, d), 6.98-7.40 (10H, m), 7.48 (1H, s) ppm.
I 374 270 3.61 (3H, s), 3.76 (3H, s), 5.05 (2H, s), 6.76-7.60 (m), 7.48 (s) ppm.
TABLE COMPOUND FREQUENCY NO. NO.
I 376 270 3.59 (3H, s), 3.73 (3H, s), 5.08 (2H, s), 6.84-6.96 (4H, m), 7.04-7.40 (8H, m), 7.46 (1H, s) ppm.
I 377 400 3.59 (3H, s), 3.75 (3H, s), 3.87 (3H, s), 5.10 (2H, s), 6.8-6.95 (6H, m), 7.05-7.15 (3H, m), 7.22-7.30 (3H, m), 7.48 (1H s) ppm.
378 400 3.60 (3H, s), 3.75 (3H, s) 5.14 (2H, s), 6.90-7.04 (5H, m), 7.13-7.19 (2H m), 7.24-7.32 (3H, m), 7.47 (1H, s), 7.48-7.60 (2H, m) ppm.
I 381 270 3.59 (3H, s), 3.75 (3H, s), 5.17 (2H, s), 6.75 (1H, d), 6.88-7.35 (11H, m), 7.48 (1H, s), 7.50 (1H, m), 7.85 (1H, d) ppm.
I 382 400 3.60 (3H, s), 3.77 (3H, s), 5.10 (2H, s) 6.94 (2H, d), 7.50 (1H, s), 7.10-7.18 (2H, m), 7.40-7.33 (4H, m), (2H, m), 7.40-7.33 (4H, m), 7.42 (1H t), 7.48 (1H, s), 7.78 (1H, s), 7.84 (1H, d) ppm.
TABLE COMPOUND FREQUENCY NO NO (MHz) I 383 270 3.60 (3H, s), 3.72 (3H, s), 4.97 (2H, s), 6.84-7.36 (12H, m), 7.47 (1H, s) ppm.
1 384 400 3.53 (3H, s), 3.68 (3H, s), 4.91 (2H, s), 6.73-7.26 (12H, m), 7.40 (1H, s), ppm I 385 270 3.58 (3H, s), 3,73 (3H, s), 4.95 (2H, m), 6.58 (2H, m), 6.66 (1H, d), 6.86-7.35 (14H, m) ppm.
I 386 270 3.59 (3H, s), 3.73 (3H, s), 4.97 (2H, s), 6.80-6.92 (4H, m), 7.0-7.32 (8H, m), 7.47 (1H, s) ppm I 387 270 3.60 (3H, s), 3.77 (3H, d), 3.96 (2H, s), 6.60 (1H, s), 6.70-6.90 (3H, m), 7.18 (2H, q), 7.24-7.36 (3H, m), 7.27 (1H, s), 7.40-7.48 (3H, m) ppm.
I 388 400 3.60 (3H, s), 3.78 (3H, s), 4.25 (2H, d), 6.68 (1H, s), 6.75 (1H, d), 6.82 (1H, d),| 6.90 (1H, d), 7.13 (4H, m) 7.27 (1H, s), 7.42-7.48 (3H, m), 7.57 (2H, d) ppm
TABLE COMPOUND FREQUENCY NO NO I 389 270 3.58 (3H, s), 3.72 (3H, s), 5.08 (2H, s), 6.80-6.96 (4H| m), 7.08-7.32 (7H, m), 7.46 (1H, s), 7.54 (1H, d) ppm.
I 391 | 250 2.22 (6H, s), 3.65 (3H, s), ! 3.75 (3H, s), 6.60-7.30 | | (11H, m), 7.50 (1H, s), ppm I 392 90 2.17 (3H, s), 2.34 (3H, s), 3.55 (3H, s) 3.70 (3H s), 6.50-7.24 (llH, m), 7.51 | | | (1H, s) ppm I j 393 90 2.14 (3H, s), 2.27 (3H, s), 3.59 (3h, s), 3.76 (3H, s), 6.53-7.28 (11H, m), 7.50 | | | (1H, s) ppm I 394 250 2.08 (6H, s), 3.52 (3H, s), 3.75 (3H, s), 6.40-7.20 | | (11H, m), 7.50 (1H, s) ppm.
I , 395 | 90 2.24 (6H, s), 3.61 (3H, s), | | | 3.77 (3H ,s), 6.63-7.30 (11H, m) 7.50 (1H, s) ppm I 396 90 2.28 (6H, s), 3.60 (3H, s), 3.77 (3H, s), 6.63-7.24 (11H, m), 7.51 (1H s), ppm.
TABLE COMPOUND FREQUENCY NO NO I 397 270 3.58 (3H, s), 3.73 (3H, s), 4.96 (2H, s), 6.80 (2H, d), 6.86-6.92 (2H, m),7.0-7.16 (3H, m), 7.20-7.38 (5H, m), 7.47 (1H, s) ppm.
I | 399 270 3.60 (3H, s), 3.76 (3H, s), 4.08 (2H, s), 6.80-7.58 (12H, m), 7.47 (1H, s), ppm I | 400 400 3.59 (3H, s), 3.75 (3H, s), 4.18 (2H, s), 6.85 (2H, d), 7.00 (1H, s), 7.05 (1H, d), 7.10-7.35 (5H, m), 7.48 (1H, s), 8.10 (2H, d) ppm.
I | 401 400 3.72 (3H, s), 3.88 (3H, s), 4.22 (2H, q), 6.83 (1H, s), 6.88-7.0 (3H, m), 7.21-7.42 (4H, in), 7.50 (3H, d), 7.60 (1H, s), 7.66 (1H, m) ppm.
I | 402 400 3.70 (3H, s), 3.87 (3H, s), 4.70 (2H, s) 6.80 (1H, d), 6.95-7.05 (3H, m), 7.22 7.48 (5H, m), 7.59 (1H, s), 7.65 (2H, s), 7.92 (1H, d) ppm
TABLE COMPOUND FREQUENCY NO NO I | 405 60 1.21 (9H, s), 3.42 (3H, s), 3.46 (3H, s), 4.80 (2H, s), 6.3-7.3 (12H, m), 7.31 (1H, | s) ppm.
406 270 3.57 (3H, s), 3.71 (3H, s), 5.32 (2H, s), 6.92 (1H, d), 7.16 (2H, t), 7.24-7.43 (8H, m), 7.46 (1H, s), 7.66 (1H, d), 7.76 (1H, d) ppm.
I | 407 270 3.51 (3H, s), 3.73 (3H, s), 4.59 (2H, d), 6.70 (1H, t), 6.96 (1H, d), 7.08 (1H, dd), 7.19 (1H, d), 7.22 7.37 (9H, m), 7.41 (1H, s), 7.48 (1H, d) ppm.
I | 408 270 3.59 (3H, s), 3.71 (3H, s), 4.29 (2H, s), 6.94 (1H, d), 7.13-7.38 (10H, m), 7.45 (1H, s), 7.51 (1H, t), 7.63 (1H, d) ppm.
I 409 270 3.61 (3H, s), 3.78 (3H, s), 6.99 (1H, d), 7.15-7.36 (4H, m), 7.44 (1H, t), 7.50 (1H, s), 7.53-7.65 (2H, m), 7.78 (1H, t), 7.89 (1H, d), 8.10-8.19 (2H, m) ppm.
TABLE COMPOUND FREQUENCY NO NO I 410 400 3.60 (3H, s), 3.75 (3H, s), 5.63 (2H, s), 6.6-7.3 (12H, m), 7.47 (1H, s) ppm.
I 411 400 3.60 (3H, s), 3.75 (3H, s), 4.8 (1H, d), 4.94 (1H, d), 6.6-7.7 (13H, m), 7.47 (1H, s) ppm.
I 412 270 1.67 (3H, d), 3.55 (3H, s), 3.70 (3H, s), 5.45 (1H, q), 6.5-8.1 (13H, m), 7.45 (1H, s) ppm.
I 413 270 3.59 (3H, s), 3.73 (3H, s), 5.17 (2H, s), 6.90-6.99 (2H, m), 7.12-7.43 (1H, m), 7.49 (1H, s), 8.08 (1H, s) ppm.
I 414 270 3.55 (3H, s), 3.70 (3H, s), 5.21 (2H, s), 6.91-7.0 (2H, m), 7.10-7.19 (1H, m), 7.21-7.38 (9H, m), 7.46 (1H, s), 7.53-7.60 (2H, m) ppm.
I 415 270 2.05 (2H, m), 2.78 (2H, t), 3.60 (3H, s), 3.75 (3H, s), 3.90 (2H, t), 6.5-7.3 (13H, m), 7.48 (1H, s) ppm.
TABLE COMPOUND FREQUENCY t NO NO I 416 270 1.78 (4H, m), 2.65 (2H, m), 3.60 (3H, s), 3.75 (3H, s), 3.9 (2H, m), 6.5-7.3 (13H m), 7.47 (1H, s) ppm.
I 417 270 1.44-1.85 (6H, m), 2.6 (2H, t), 3.60 (3H, s), 3.75 (3H, s), 3.87 (2H, t), 6.48-7.3 (13H, m), 7.48 (1H, s) ppm.
I 418 270 3.61 (3H, s), 3.76 (3H, s), 5.68 (1H, s), 6.8-7.6 (10H, m), 7.50 (1H, s), 7.8 (2H, m) ppm.
I 419 270 3.60 (3H, s), 3.74 (3H, s), 3.89 (3H,s ), 6.9-7.6 (10H, m), 7.49 (1H, s), 7.9 (2H, m) ppm.
I 420 270 3.62 (3H, s), 3.78 (3H, s), 6.72-7.67 (13H, m), 7.49 (1H, s) ppm.
I 422 270 3.62 (3H,s ), 3.80 (3H, s), 3.87 (3H, s), 6.72-7.48 (12H, m), 7.48 (1H, s), 7.78 (1H, s) ppm.
TABLE COMPOUND FREQUENCY NO | N I 423 270 3.60 (3H, s), 3.70 (3H, s), 4.23 (4H, m), 6.53-7.3 (13H, m), 7.45 (1H, s) ppm.
I 424 60 3.40 (3H, s), 3.50 (3H, s), 6.40-8.4 (15H, m), 8.9 (1H, s) ppm.
I 425 270 3.60 (3H, s), 3.75 (3H, s), 5.40 (2H, s), 6.55-7.5 (13H, m), 7.47 (1H, s) ppm.
I 426 90 3.53 (3H, s), 3.61 (3H, s), 3.63 (3H, s), 3.66 (3H, s), 4.90 (2H, s), 6.40-7.6 (14H, m) ppm.
I 427 90 3.43 (3H, s), 3.61 (3H, s), 6.4-7.4 (1OH, m), 7.32 (1H, s), 7.77 (2H, d) ppm.
I 428 90 3.55 (3H, s), 3.65 (3H, s), 3.85 (3H, s), 6.7-8.0 (13H, m) ppm.
I 443 270 3.59 (3H, s), 3.74 (3H, s), 5.17 (2H, s), 6.6-7.4 (14H, m), 7.47 (1H, s) ppm.
TABLE COMPOUND FREQUENCY NO NO II 23 270 3.63 (3H, s), 3.74 (3H, s), 6.97-7.05 (3H, m), 7.10 (1H, d), 7.22-7.33 (4H, m), 7.48 (1H, d), 7.49 (1H, s), 8.54 (2H, d) ppm.
II 30 270 3.60 (3H, s), 3.74 (3H, s), 6.73-7.35 (8H, m), 7.49 (1H, s), 8.10 (1H, m), 8.25 (1H, m), 8.38 (1H, m) ppm.
II 47 270 3.60 (3H, s), 3.75 (3H, s), 5.52 (2H, s), 6.96 (2H, d), 7.07-7.40 (8H, m), 7.49 (1H, s), 7.61-7.71 (2H, q) ppm.
II 52 60 3.51 (3H, s), 3.64 (3H, s), | 7.40 (1H, s), 6.5-7.8 (11H, m) ppm.
II 53 270 3.60 (3H, s), 3.75 (3H, s), 6.74-7.35 (9H, m), 7.49 (1H, s), 7.88 (1H, m), 8.43 (1H, m) ppm.
II 69 270 3.60 (3H, s), 3.75 (3H, 8), 6.73-7.36 (9H, m), 7.49 (1H, s), 7.89 (1H, m), 8.45 (1H, m).
TABLE COMPOUND FREQUENCY NO II 81 270 3.63 (3H, s), 3.78 (3H, s), 5.32 (2H, s), 6.84-6.92 (4H, m), 7.10-7.30 (4H, m), 7.48 (1H, s), 7.98 8 (1H, s), 8.08 8 (1H, s) ppm.
II 83 90 3.54 (3H, , s), 3.65 (3H, S), 6.76-7.68 (12H, m), 7.38 (1H, s) ppm.
II 86 90 3.62 (3H, s), 3.79 (3H, s), 6.8-7.5 5 (8H, m), 7.52 (1H, s) ppm.
II 87 270 3.61 (3H, s), 3.76 (3H, s), 6.66-6.74 (2H, m), 6.79 (1H, dd), 7.00 (1H, d 7.16 @ (1H, m), 7.24-7.34 (3H, m), 7.47 @ (1H, s), 8.47 (2H, , s), 8.96 (1H, s) ppm.
II 88 90 3.62 (3H, s), 3.76 (3H, s), 4.30 (3H, s), 6.80-7.42 (8H, m), 7.50 (1H, s) ppm.
II 90 270 3.61 (3H, S), 3.76 (3H, , s), 6.77 @ (1H, t), 6.86 (2H, m), 7.04 (1H, d), 7.15 (1H, m), 7.29 (3H, m), 7.48 (1H, s), 8.55 @ (2H, s) ppm.
TABLE COMPOUND FREQUENCY NO NO II 91 270 3.61 (3H, s), 3.75 (3H, s), 6.77 (1H, t), 6.83-6.89 (2H, m), 7.04 (1H, d), 7.15 (1H, t), 7.25-7.35 (3H, m), 7.48 (1H, s), 8.47 (2H, s) ppm.
II 93 270 3.60 (3H, s), 3.75 (3H, s), 3.90 (3H, s), 3.94 (3H, s), 5.67 (1H, s), 6.76 (1H, t), 6.84 (2H, m), 7.00 (1H, d), 7.15 (1H, m), 7.25-7.32 (2H, m), 7.48 (1H, s) ppm.
II 96 270 3.61 (3H, s), 3.75 (3H, s), 6.75 (1H, t), 6.83 (1H, dd), 6.95 (1H, dd), 7.07 dd) 6.95 (1H, dd), 7.07 (1H, d), 7.18 (1H, m), 7.29-7.3 (3H, m), 7.49 (1H, s) ppm.
II 97 Proton-decoupled Carbon 13 n.m.r. at 67.7 MHz : delta 51.25, 61.59, 106.5 delta 51.25, 61.59, 106.54, 107.41, 110.85, 114.96, 115.45, 119.58, 123.72, 125.06, 128.90, 130.05, 132.41, 152.29, 153.57, 158.81, 160.03, 160.13, 160.22, 167.49, 169.95 ppm.
TABLE COMPOUND FREQUENCY NO NO II 98 270 2.72 (3H, s), 3.60 (3H, s), 3.77 (3H, s), 5.08 (2H, s), 3.77 (3H, s s), 5.08 (2H, s), 6.5-7.4 (9H, m), 7.48 (1H, s) ppm.
II 99 270 3.60 (3H, s), 3.74 (3H, s), 5.50 (2H, s), 6.92-7.0 (2H, m), 7.09-7.36 (9H, m), 7.47 (1H, s), 7.50 (1H, d) ppm.
II 100 270 3.60 (3H, s), 3.75 (3H, s), 5.33 (2H, s), 6.90-6.96 (2H, m), 7.06-7.18 (3H, m), (2H, m), 7.06-7.18 (3H, m), 7.24-7.34 (3H, m), 7.49 (1H, s), 8.07 (1H, d), 8.14 (1H, d), 8.28 (1H, s) ppm.
II 101 270 3.60 (3H, s), 3.75 (3H, s), 5.31 (2H, s), 6.90-6.99 (2H, m), 7.06 (1H, s), 7.10-7.18 (2H, m), 7.25 7.34 (3H, m), 7.49 (1H, s), 8.17 (2H, s) ppm.
II 102 270 3.60 (3H, s), 3.75 (3H, s), 5.50 (2H, s), 6.89-6.99 (3H, m), 7.1-7.42 (7H, m), 7.49 (1H, s), 7.62 (1H, t), 7.71 (1H, d), 7.83 (1H, d), 8.0 (1H, d) ppm.
TABLE COMPOUND FREQUENCY NO NO II 103 270 3.60 (3H, s), 3.77 (3H, s), 5.49 (2H, s), 6.90-6.98 (2H, m), 7.0 (1H d), 7.08 7.20 (3H, m), 7.24-7.33 (3H, m), 7.39 (1H, d), 7.49 (1H, s) ppm.
II 104 270 3.44 (3H, s), 3.70 (3H, s), 5.09 (2H, s), 6.82 (2H, d), 6.90 (1H, s), 7.0-7.14 (4H, m), 7.16-7.36 (3H, m), 7.49 (1H, s), 8.05 (2H, d) ppm.
II 105 270 3.60 (3H, s), 3.75 (3H, s), 5.38 (2H, s), 6.82-6.98 (3H, m), 7.05-7.20 (3H, m), 7.20-7.35 (3H, m), 7.48 (1H, s), 7.78 (1H, d), 8.43 (1H, s) ppm.
II 106 270 3.60 (3H, s), 3.76 (3H, s), 6.74-7.38 (9H, m), 7.48 (1H, s), 7.98 (1H, m), 8.30 (1H, m) ppm.
II 107 270 3.60 (3H, s), 3.76 (3H, s), 6.75-7.37 (9H, m), 7.49 (1H, s), 8.45 (1H, m), 9.03 (1H, m) ppm.
TABLE COMPOUND FREQUENCY NO NO II 270 270 3.61 (3H, s), 3.78 (3H, s), 6.28 (1H, m), 6.70 (2H, m), 6.9-7.5 (9H, m), 7.48 (1H, s), 9.55 (1H, br, s) ppm.
II 271 270 3.60 (3H, s), 3.74 (3H, s), 6.74-7.39 (9H, m), 7.50 (1H, s), 8.32 (1H, m) ppm.
II 272 270 2.32 (3H, s), 2.54 (3H, s), 3.60 (3H, s), 3.76 (3H, s), 6.72-7.35 (8H, m), 7.49 (1H, s), 8.00 (1H, s) ppm.
II 273 270 3.60 (3H, s), 3.72 (3H, s), 6.72-7.36 (8H, m), 7.50 (1H, s), 8.26 (2H, m) ppm.
II 274 270 3.60 (3H, s), 3.75 (3H, s), 4.04 (3H, s), 6.74-7.36 (10H, m), 7.50 (1H, s) ppm.
II 310 270 3.60 (3H, s), 3.75 (3H, s), 5.30 (2H, s), 6.72 (1H, d), 6.87-7.35 (9H, m), 7.43 (1H, t), 7.49 (1H, s) ppm.
II 311 270 Data in common for both regioisomers : 3.60 (3H, s), 3.77 (3H, s), 5.38 (2H,
TABLE COMPOUND FREQUENCY NO NO s), 6.90-7.18 (5H, m), 7.23-7.33 (3H, m), 7.49 (1H, s) ppm. Data for major isomer : 6.70 (1H, d), 8.32 (1H, d) ppm. Data for minor isomer : 6.98 (1H, d), 8.38 (1H, d) ppm.
II 315 270 3.39 (3H, S), 3.60 (3H, S), 3.73 (3H, s), 3.84 (3H, s), 5.63 (1H, m), 5.85 (1H, m), 6.59 (1H, m), 6.7-7.3 (8H m), 7.47 (1H, m) ppm.
II 8 270 3.60 (3H, S), 3.75 (3H, S), 6.62-7.36 (10H, m), 7.48 (1H, s), 8.38 (2H, m) ppm.
II 15 270 3.60 (3H, s), 3.74 (3H, s), 6.66-7.37 (10H, m), 7.48 (1H, s), 8.45 (2H, m) ppm.
II 35 270 3.60 (3H, s), 3.74 (3H, s), 6.70-7.50 (10H, m), 7.49 (1H, s), 8.92 (1H, m) ppm.
II 313 270 2.38 (3H, s), 2.41 (3H, s), 3.59 (3H, s), 3.75 (3H, s), 6.29 (1H, s), 6.75 (1H, t), 6.84 (2H, t of d), 6.98 (1H, d), 7.15 (1H, t)
TABLE COMPOUND FREQUENCY NO NO 7.25-7.34 (3H, m), 7.48 (1H, s) ppm.
II 319 270 2.90 (6H, s), 3.60 (3H, s), 3.77 (3H, s), 6.18 (1H, d), 6.75-7.37 (8H, m), 7.48 (1H, s), 8.22 (1H, d) ppm.
II 320 270 Data in common for both regioisomers: 3.61 (3H, s) 3.74 (3H, s), 7.50 (1H, s) ppm. Data for major isomer: 2.35 (3H, s) ppm.
Data for minor isomer: 2.38 (3H, s) ppm III 23 270 3.65 (3H, s), 3.75 (3H, S), 4.97 (2H, s), 6.75-6.87 (3H m), 7.14 (1H, t), 7.21-7.40 (9H, m), 7.49 (1H, s) ppm.
III 51 270 3.61 (3H, a), 3.73 (3H, s) 6.75-6.82 (2H, m), 7.02- 7.17 (2H, m), 7.22-7.38 (3H, m), 7.46 (1H, s), 7.47-7.59 (4H, m), 7.62 7.72 (lH, m), 7.80 (1H, d) ppm.
III 131 270 3.63 (3H, s) 3.74 (3H, s), 6.80 (1H d), 6.86 (1H, s),
TABLE COMPOUND | FREQUENCY NO NO 6.99 (2H, d), 7.15-7.37 (6H, m), 7.48 (1H, s), 7.46 (1H, d), 7.93 (1H, d) ppm.
III 212 270 3.65 (3H, s), , 3.77 (@ s), | 5.08 (2H, s), 6.74-6.80 (2H, m), 6.85-6.89 9 (1 d), 7.16 (1H, t), 7.20-7.38 (4H, m), 7.49 (1H, s), 7.54 (2H, d), 8.21 (2H, d) ppm.
IV 87 270 3.64 (3H, s), 3.75 (3H, s), 6.80 (1H, d), 6.86 (1H, s), 7.03 (1H, d), 7.21-7.38 (4H, m), 7.47 (1H, d), 7.48 (1H, s), 8.44 (2H, s), 8.95 (1H, s) ppm.
The compounds of the invention of formula (I) can be made by a variety of methods, and some of these are illustrated in Schemes I to VIII. Throughout these Schemes, the terms Z, X, A, B, E, K, R1, R2, R3, R4 and R5 are as defined above, R6 is hydrogen or a metal (such as sodium or potassium), R is an alkyl group, and L is a leaving group such as a halide (chloride, bromide or iodide), a CH3S04-anion, or a sulphonyloxy-anion. Each of the transformations described in Schemes I to VIII is performed at a suitable temperature and either in a suitable solvent or in the absence of a solvent.
Scheme I illustrates ways in which the methyl betamethoxypropenoate group can be constructed in the final stages of the preparation of the compounds of the invention from precursors with a preformed framework of 3 aromatic rings. Alternatively, the methyl beta-methoxypropenoate group may be constructed at an earlier stage of the preparation, in which case the final step or steps comprise elaboration of other parts of the compounds of the invention to form the framework of 3 aromatic rings.
Examples of procedures of this kind are shown in Schemes III to VIII.
In whichever order the steps are carried out to prepare the compounds of the invention, the diphenyl ether or thioether linkage which is common to all the compounds of the invention can be prepared by one of the coupling reactions shown in Scheme II. For a review of the Ullmann ether synthesis see A.A. Moroz and M.S. Shrartsberg, Russian Chem.Reviews, 1974, 43, 679. See also D. Hands, H. Marley, S.J. Skittrall, S.H.B. Wright and T. R.
Verhoeven, J.Heterocyclic Chem., 1986, 23, 1333. These couplings are often performed in the presence of a catalyst which consists of a transition metal or a salt or compound of a transition metal, such as copper or a copper salt or compound, or a mixture thereof. In Scheme II, the term W represents either the group Z-X-, wherein Z and X are as defined above, or a group which can be converted by standard procedures described in the chemical literature into the group Z-X-; for example W can be -OH, -SH, or NHR4. The term Y represents either the alpha-linked methyl beta-methoxypropenoate group of the compounds of the invention or a group which can be converted into such a group by standard methods described in the chemical literature and/or described in Scheme I an the following d paragraphs.For example Y can be -CH2COOH, -CH2COOMe or -CHO. In the context of Scheme II, the term L is preferably a halogen. Thus compounds of formula (XI) react with compounds of formula (XII) under the conditions of the Ullmann reaction already described to give the intermediates of formula (VIII). As an example of one of the coupling reactions shown in Scheme II, substituted 3phenoxyphenols, as their salts, undergo coupling with 2bromo- or 2-chlorophenylacetic acid salts to give, after acidification, substituted 2-(3-phenoxyphenoxy)phenylacetic acids (compare, for example, GB 2078-743, Ihara Chem.Ind., 27.06.80). Alternatively, intermediates of formula (VIII) can be made by reacting compounds of formula (IX) with compounds of formula (X) under the conditions of the Ullmann reaction already described.
In one particular aspect, the invention includes a process for the preparation of the compound of formula (I) which comprises reacting a compound of general formula (XIIa) :
wherein Y is halogen with a phenol or thiophenol of general formula (XIa)
in the presence of a base, or with a salt of the phenol or thiophenol (XIa), preferably in the presence of a catalyst which comprises a suitable transition metal, a transition metal salt or compound or a mixture thereof.
The compounds of the invention of formula (I) can be prepared from the phenylacetates of formula (III) or the ketoesters of formula (VI) by the steps shown in Scheme I.
Thus compounds of formula (I) can be prepared by treatment of phenylacetates of formula (III) with a base (such as sodium hydride or sodium methoxide) and methyl formate. If a species of formula CH3L, wherein L is as defined above, is then added to the reaction mixture, compounds of formula (I) may be obtained. If a protic acid is added to the reaction mixture, compounds of formula (II) wherein R6 is hydrogen are obtained.
Alternatively, the species of formula (II) wherein R6 is a metal (such as sodium) may themselves be isolated from the reaction mixture.
Compounds of formula (II) wherein R6 is a metal can be converted into compounds of formula (I) by treatment with a species of formula CH3L, wherein L is as defined above. Compounds of formula (11) wherein R6 is hydrogen can be converted into compounds of formula (I) by successive treatments with a base (such as potassium carbonate) and a species of general formula CH3L.
Alternatively, compounds of formula (I) can be prepared from acetals of formula (IV) by elimination of methanol under either acidic or basic conditions.
Examples of reagents or reagent mixtures which can be used for this transformation are lithium di-isopropylamide potassium hydrogen sulphate (see, for example, T Yamada, H Hagiwara and H Uda, J.Chem.Soc., Chemical Communications, 1980, 838, and references therein); and triethylamine, often in the presence of a Lewis acid such as titanium tetrachloride (see, for example, K Nsunda and L Heresi, J.Chem.Soc., Chemical Communications, 1985, 1000).
Acetals of formula (IV) can be prepared by treatment of methyl silyl ketene acetals of formula (V), wherein R is an alkyl group, with trimethyl orthoformate in the presence of a Lewis acid such as titanium tetrachloride (see, for example, K Saigo, M Osaki and T Mukaiyama, Chemistry Letters, 1976, 769).
Methyl silyl ketene acetals of formula (V) can be prepared from phenylacetates of formula (III) by treatment with a base and a trialkylsilyl halide of formula R3SiCl or R3SiBr, such as trimethylsilyl chloride, or a base (such as triethylamine) and a trialkylsilyl triflate of formula R3Si-OSO2CF3 (see, for example, C Ainsworth, F Chen and Y Kuo, J.Organometallic Chemistry, 1972, 46, 59).
It is not always necessary to isolate the intermediates (IV) and (V)r under appropriate conditions, compounds of formula (I) may be prepared from phenylacetates of formula (III) in "one pot" by the successive addition of suitable reagents listed above.
Alternatively, compounds of formula (I) can be prepared by treatment of ketoesters of formula (VI) with a methoxymethylenating reagent, for example, methoxymethylenetriphenylphosphorane (see, for example, W Steglich, G Schramm, T Anke and F Oberwinkler, EP 0044448, 4.7.1980).
Ketoesters of formula (VI) may be prepared by methods described in the literature. Particularly useful methods include (i) the reaction of appropriate phenylmagnesium halides or phenyl-lithium species with dimethyl oxalate using the method described by L M Weinstock, R B Currie and A V Lovell, Synth.Commun., 1981, 11, 943 and references therein; (ii) oxidation of phenylacetates of formula (III) using selenium dioxide, generally in the absence of a solvent, and generally at a temperature above 100 CC; and (iii) oxidation of mandelic acid esters using, for example, manganese oxide in.a suitable solvent.
Phenylacetates of formula (III) and the corresponding phenylacetic acids of formula (VII) may also be prepared by numerous other methods described in the chemical literature. For example, several useful methods are described by D C Atkinson, K E Godfrey, B Meek, J F Saville and M R Stillings, J.Med.Chem., 1983, 26, 1353 and D C Atkinson, K E Godfrey, P L Meyers, N C Phillips, M R Stillings and A P Welbourn, J.Med.Chem., 1983, 26, 1361.
Furthermore, many of the methods described for the preparation of 2-arylpropionic esters and acids by J-P Rieu, A Boucherle, H Cousse and G Mouzin, Tetrahedron, 1986, 42, 4095, are also applicable to the preparation of phenylacetates of formula (III) and phenylacetic acids of formula (VII) using appropriate precursors wherein the ortho substituted-phenoxy substituent and the substituent E are already present.
Scheme I
Scheme II
Schemes III, IV, V, VI and VII illustrate examples of intermediates containing the methyl beta-methoxypropenoate group and show how they may be converted into certain specific types of compound of the invention (I).
Thus, in scheme III, in the presence of a base, and sometimes in the presence of a transition metal or transition metal salt catalyst, such as a copper or copper salt catalyst, compounds of formula (XIII) react with aromatic or heteroaromatic compounds of formula ZL, wherein Z and L are as defined above, or with iodonium salts of formula Z2I+T-, wherein Z is as defined as above and T is a counter ion, such as a halide ion, or with aryl or heteroarylbismuth species, to give compounds of formula (XIV). In addition, in the presence of a base, compounds of formula (XIII) react with aryl- or heteroarylsulphonyl halides of formula ZS02Q, wherein Z is as defined above and Q is a halogen, to give compounds of formula (XV).Furthermore, and also in the presence of a base, compounds of formula (XIII) react with arylalkyl or heteroarylalkyl species of formula ZCHR1L, wherein Z, R1 and L are as defined above, to give compounds of formula (XVI).
In scheme IV, the thiols of formula (XVII), generally in the presence of a base, react with aromatic or heteroaromatic compounds of formula ZL, or with iodonium salts of formula Z2I+T , or with aryl- or heteroarylbismuth species, to give compounds of formula (XVIII) in ways which are analogous to the reactions of the corresponding phenols of formula (XIII) shown in Scheme III. Similarly, and again in the presence of a base, the thiols of formula (XVII) react with arylalkyl or heteroarylalkyl species of formula ZCHR1L to give compounds of formula (XIX). The sulphides of formula (XVIII) and (XIX) can be oxidised to the corresponding sulphoxides and sulphones by standard methods described in the chemical literature.
In Scheme V, compounds of formula (XX) react with hydroxy-derivatives of aromatic or heteroaromatic compounds of formula ZOH, wherein Z is as defined above, often in the presence of a base; to form compounds of formula (XXI). Furthermore, compounds of formula (XX) react with trialkylphosphites of formula P(OR)3 or with species of formula M+P-(O)(OR)2, wherein R is as defined above in each case and M is a metal such as sodium or lithium, to give phosphonates of formula (XXII).
Phosphonates of formula (XXII), in the presence of a base, react with aldehydes or ketones of formula ZR1C:O, wherein Z and R1 are as defined above, to give olefins of formula (XXIV). In addition, aldehydes or ketones of formula (XXIII), on treatment with phosphonate anions of formula ZR1C P(O)(OR)2M+, wherein Z, R, R1 and M are as defined above, or with the corresponding phosphoranes, also give olefins of formula (XXIV). The olefins of formula (XXIV) can be reduced to the compounds of formula (XXV) by, for example, hydrogenation over an appropriate catalyst.
In Scheme VI, compounds of formula (XXVI), in the presence of a base, react with acid halides of formula ZCOQ, wherein Z and Q are as defined above, or, in the presence of an appropriate dehydrating agent, react with acids of formula ZCO2H, wherein Z is as defined above, to give compounds of formula (XXVII).
Intermediates of formula (XXVI) can also be converted into other types of compound of the invention of formula (I) by methods described in the chemical literature. For example, compounds of formula (XXVI) wherein R4 is hydrogen can be converted, via diazotisation, into the corresponding sulphonyl chlorides (compare Organic Syntheses, 1981, 60, 121) and then, by treatment with alcohols or phenols in the presence of a base, into sulphonic esters.
Compounds of the invention of formula (I) wherein at least one of A and B is hydrogen may be converted into compounds of the invention of fprmula (I) wherein at least one of A and B are certain substituents (such as a halogen or a nitro or acyl group) by electrophilic substitution processes of the kind described in the chemical literature.
The intermediates of formulae (XIII), (XVII), (XX), (XXIII) and (XXVI) can be prepared by processes described in the chemical literature and by processes of the kinds described in Schemes I and II. For example, compounds of formula (XX) where L is bromine can be made from compounds of formula (XX) where L is H, by reaction with Nbromosuccinimide or N,N-dibromo-dimethylhydantoin, in the presence or absence of irradiation by light.
The intermediates of formulae (IX), (X), (XI), (XII), ZL, Z2I+T-, ZCHR1L, ZS02Q, ZOH, ZR1C:O, ZR1C-P(O)(OR)2M+, ZCOQ and ZC02H can be made by methods described in the chemical literature.
Scheme III
Scheme IV
Scheme V
Scheme VI
In Scheme VII compounds of formula (XXVIII) can be oxidised, for example using pyridinium dichromate in a suitable solvent (such as methylene chloride) or oxalyl chloride in dimethyl sulphoxide in the presence of a base (the Swern oxidation), to give aldehydes (where R2 is H) or ketones (where R2 is alkyl) of formula (XXIII).The aldehydes or ketones of formula (XXIII) can react with oxyamines of formula ZONH2 or ZCHR1ONH2, or with hydrazines of formula ZNR1NH2, wherein Z and R1 are as defined above, to give compounds of the invention of formula (I) where X is the group ON=CR2, CHR1ON=CR2, or NR1N=CR2 respectively. Also, compounds of formula (XXIII) can react with Grignard reagents of formula ZMgHal or ZCRlR2MgHal, where Hal is chlorine, bromine or iodine and Z, R1 and R2 are as defined above, to give compounds of the invention of formula (I) where X is CR2 (OH) or CR1R2CR2(OH) respectively.Also, compounds of formula (XXIII) can react with amines of formula ZNHR1 or ZCR1R2NHR11 wherein Z, R1 and R2 are as defined above, in the presence of a reducing agent (such as sodium cyanoborohydride or hydrogen gas in the presence of a suitable metal catalyst) to give compounds of the invention of formula (I) where X is NR1CHR2 or CR1R2NRlCHR2. ;hen the reducing agent is left out and when R1 is H, then the immediately preceding procedure will give compounds of the invention of formula (I) where X is N=CR2 or CR1R2N=CR2.
Compounds of formula (XXVIII) where R2 is H, can also be oxidised to carboxylic acids of formula (XXIX), using for example Jones' reagent (chromium trioxide in sulphuric acid). The carboxylic acids (XXIX) can be converted directly into compounds of the invention of formula (I) where, for example, X is 02C, CHRlOCO, SCO, CHR1SCO, NR4Co or CHR1NR4CO, using one of the standard coupling reagents well known in the literature, such as dicyclohexylcarbodiimide or carbonyldiimidazole, in a suitable solvent.
Alternatively, the carboxylic acids of formula (XXIX) can be converted into the acid chlorides of formula (XXX) by treatment with, for example, thionyl chloride or oxalyl chloride. The acid chlorides of formula (XXX) can then react, for example, with compounds of formula ZOH, ZCHR1OH, ZSH, ZCHR1SH, ZNR4H or ZCHR1NR4H in a suitable solvent, in the presence of a base, to give compounds of the invention of formula (I) where X is 02C, CHR1OCO, SCO, CHR1SCO, NR4CO, or CHR1NR4CO respectively.
Compounds of formula (XXVIII) can also react directly with compounds of formula ZL, optionally in the presence of a base, where Z is a reactive aromatic group (for example nitrophenyl) or heteroaromatic group (for example 2-pyridyl or 2-pyrimidinyl) to give compounds of the invention of formula (XXI). It may be necessary first to generate the oxygen anion of compounds of formula (XXVIII) with a strong base such as sodium hydride.
Additionally, compounds of formula (XXVIII) can be converted into compounds of formula (XX) by treatment, for example, with a halogenation agent such as thionyl chloride or phosphorus tribromide, where L is chlorine or bromine, or by treatment with a sulphonyl halide (such as p-toluenesulphonyl chloride) in the presence of an acid acceptor, where L is a sulphonyloxy group. Compounds of formula (XX) can then be used as shown in Scheme V.
Additionally, where L is halogen, they can be converted by reaction with a phosphine of formula Z(R5)2P, wherein R5 is as defined above, into compounds of the invention of formula (I), where X is the group (R5)2P+CHR2Q-. These compounds can then react successively with a base and a carbonyl compound of formula ZCOR1, wherein Z and R1 are as defined above, to give olefins of formula (XXIV).
Scheme VIII illustrates examples of intermediates of formula (VIII), shown in Scheme II, where W is any group that can be converted to ZX-, and Y is any group that can be converted to the methyl beta-methoxypropenoate group.
Compounds of formula (XXXI) can react with compounds of formula (XXXII) to give compounds of formula (XXXIII), using the general Ullmann coupling conditions described in detail for the reaction of compounds of formula (XI) and (XII) in Scheme II. The acids of formula (XXXIII) can be converted into methyl esters of formula (XXXIV) by reaction with methanol in the presence of acid (for example hydrochloric acid). Compounds of formula (XXXIV) can then be converted into methyl beta-methoxypropenoates of formula (XXVIII) by the methods described in detail in Scheme I.
Alternatively, the intermediates of formula (XXXIV) can be converted into intermediates of formulae (XXXVIII), (XXXV), (XXXVI), (XXXVII) and (III) using the methods described in Scheme VII for the conversion of the propenoates of formula (XXVIII) into compounds of formula (XXIII), (XX), (XXIX), (XXX) and (I). Compounds of formula (III) can be converted into compounds of formula (I) as shown in Scheme I.
Scheme VII
Scheme VIII
In a further aspect the invention provides processes as hereindescribed for preparing the compounds of formula (I). It also provides intermediate chemicals of formulae (II)-(VII), (XIII)-(XXX), and (XXXIII)-(XXXVIII).
The compounds are active fungicides and may be used to control one or more of the following pathogens Pyricularia oryzac on rice.
Puccinia recondita, Puccinia striiformis and other rusts on wheat, Puccinia hordei, Puccinia striiformis and other rusts on barley, and rusts on other hosts, e.g. coffee, pears, apples, peanuts, vegetables and ornamental plants.
Erysiphe graminis (powdery mildew) on barley and wheat and other powdery mildews on various hosts such as Sphaerotheca macularis on hops, Sphaerotheca fuliginea on cucurbits (e.g. cucumber), Podosphaera leucotricha on apple and Uncinula necator on vines.
Helminthosporium spp., Rhynchosporium spp., Septoria spp., Pseudocercosporella herepotrichoides and Gaeumannomyces graminis on cereals. Cercospora arachidicola and Cercosporidium personata on peanuts and other Cercospora species on other hosts, for example, sugar beet, bananas, soya beans and rice.
Botrytis cinerea (grey mould) on tomatoes, strawberries, vegetables, vines and other hosts.
Alternaria species on vegetables (e.g. cucumber), oil-seed rape, apples, tomatoes and other hosts.
Venturia inaequalis (scab) on apples.
Plasmopara viticola on vines.
Other downy mildews such as Bremia lactucae on lettuce, Peronospora spp. on soya beans, tobacco, onions and other hosts and Pseudoperonospora humuli on hops and Pseudoperonospora cubensis on cucurbits.
Phytophthora infestans on potatoes and tomatoes and other Phytophthora spp. on vegetables, strawberries, avocado, pepper, ornamentals, tobacco, cocoa and other hosts.
Thanatephorus cucumeris on rice and other Rhizoctonia species on various host such as wheat and barley, vegetables, cotton and turf.
Some of the compounds show a broad range of activities against fungi in vitro. They may also have activity against various post-harvest diseases of fruit (e.g. Penicillium digitatum and italicum and Trichoderma viride on oranges, Gloeosporium musarum on bananas and Botrytis cinerea on grapes).
Further, some of the compounds may be active as seed dressings against Fusarium spp., Septoria spp., Tilletia spp., (bunt, a seed borne disease of wheat), Ustilago spp., Helminthosporium spp. on cereals, Rhizoctonia solani on cotton and Pyricularia oryzae on rice.
The compounds may have systemic movement in plants.
Moreover, the compounds may be volatile enough to be active in the vapour phase against fungi on the plant.
Many of the compounds of formula (I), including those in which X is 0, are safer on certain crops (e.g. vines) than known structurally related compounds.
The invention therefore provides a method of combating fungi, which comprises applying to a plant, to seed of a plant, or to the locus of the plant or seed, an effective amount of a compound as hereinbefore defined, or a composition containing the same.
The compounds may also be useful as industrial (as opposed to agricultural) fungicides, e.g. in the prevention of fungal attack on wood, hides, leather and especially paint films.
The compounds may be used directly for fungicidal purposes but are more conveniently formulated into compositions using a carrier or diluent. The invention thus provides a fungicidal composition comprising a compound of general formula (I) as hereinbefore defined, and a fungicidally acceptable carrier or diluent.
Used as fungicides, the compounds can be applied in a number of ways. For example they can be applied, formulated or unformulated, directly to the foliage of a plant, to seeds or to other medium in which plants are growing or are to be planted, or they can be sprayed on, dusted on or applied as a cream or paste formulation, or they can be applied as a vapour or as slow release granules. Application can be to any part of the plant including the foliage, stems, branches or roots, or to soil surrounding the roots, or to the seed before it is planted; or to the soil generally, to paddy water or to hydroponic culture systems. The invention compounds may also be injected into plants or sprayed onto vegetation using electrodynamic spraying techniques or other low volume methods.
The term "plant" as used herein includes seedlings, bushes and trees. Furthermore, the fungicidal method of the invention includes preventative, protectant, prophylactic and eradicant treatment.
The compounds are preferably used for agricultural and horticultural purposes in the form of a composition.
the type of composition used in any instance will depend upon the particular purpose envisaged.
The compositions may be in the form of dustable powders or granules comprising the active ingredient (invention compound) and a solid diluent or carrier, for example fillers such as kaolin, bentonite, kiesselguhr, dolomite, calcium carbonate, talc, powdered magnesia, Fuller's earth, gypsum, diatomaceous earth and China clay.
Such granules can be performed granules suitable for application to the soil without further treatment. These granules can be made either by impregnating pellets of filler with the active ingredient or by pelleting a mixture of the active ingredent and powdered filler.
Compositions for dressing seed may include an agent (for example a mineral oil) for assisting the adhesion of the composition to the seed; alternatively the active ingredient can be formulated for seed dressing purposes using an organic solvent (for example N-methylpyrrolidone, propylene glycol or dimethylformamide). The compositions may also be in the form of wettable powders of water dispersible granules comprising wetting or dispersing agents to facilitate the dispersion in liquids. The powders and granules may also contain fillers and suspending agents.
Emulsifiable concentrates or emulsions may be prepared by dissolving the active ingredient in an organic solvent optionally controlling a wetting or emulsifying agent and then adding the mixture to water which may also contain a wetting or emulsifying agent. Suitable organic solvents are aromatic solvents such as alkylbenzenes and alkylnaphthalenes, ketones such as isophorone, cyclohexanone, and methylcyclohexanone, chlorinated hydrocarbons such as chlorobenzene and trichlorethane, and alcohols such as benzyl alcohol, furfuryl alcohol, butanol and glycol ethers.
Suspension concentrates of largely insoluble solids may be prepared by ball or bead milling with a dispersing agent and including a suspending agent to stop the solid settling.
Compositions to be used as sprays may be in the form of aerosols wherein the formulation is held in a container under pressure in the presence of a propellant, e.g.
fluorotrichloromethane or dichlorodifluoromethane.
The invention compounds can be mixed in the dry state with a pyrotechnic mixture to form a composition suitable for generating in enclosed spaces a smoke containing the compounds.
Alternatively, the compounds may be used in microencapsulated form. They may also be formulated in biodegradable polymeric formulations to obtain a slow, controlled release of the active substance.
By including suitable additives, for example additives for improving the distribution, adhesive power and resistance to rain on treated surfaces, the different compositions can be better adapted for various utilities.
The invention compounds can be used as mixtures with fertilisers (e.g. nitrogen-, potassium-, or phosphoruscontaining fertilisers). Compositions comprising only granules of fertiliser incorporating, for example coated with, the compound are preferred. Such granules suitably contain up to 25% by weight of the compound. The invention therefore also provides a fertiliser composition comprising a fertiliser and the compound of general formula (I) or a salt or metal complex thereof.
Wettable powders, emulsifiable concentrates and suspension concentrates will normally contain surfactants e.g. wetting agent, dispersing agent, emulsifying agent or suspending agent. These agents can be cationic, anionic or non-ionic agents.
Suitable cationic agents are quaternary ammonium compounds, for example, cetyltrimethylammonium bromide.
Suitable anionic agents are soaps, salts of aliphatic monoesters of sulphuric acid (for example sodium lauryl sulphate), and salts of sulphonated aromatic compounds (for example sodium dodecylbenzenesulphonate, sodium, calcium or ammonium lignosulphonate, butylnaphthalene sulphonate, and a mixture of sodium diisopropyl- and triisopropyl-naphthalene sulphonates).
Suitable non-ionic agents are the condensation products of ethylene oxide with fatty alcohols such as oleyl or cetyl alcohol, or with alkyl phenols such as octyl- or nonyl-phenol and octylcresol. Other non-ionic agents are the partial esters derived from long chain fatty acids and hexitol anhydrides, the condensation products of the said partial esters with ethylene oxide, and the lecithins. Suitable suspending agents are hydrophilic colloids (for example polyvinylpyrrolidone and sodium carboxymethylcellulose), and swelling clays such as bentonite or attapulgite.
Compositions for use as aqueous dispersions or emulsions are generally supplied in the form of a concentrate containing a high proportion of the active ingredient, the concentrate being diluted with water before use. These concentrates should preferably be able to withstand storage for prolonged periods and after such storage be capable of dilution with water in order to form aqueous preperations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment. The concentrates may conveniently contain up to 95% suitably 10-85%, for example 25-60%, by weight of the active ingredient.After dilution to form aqueous preparations, suitable preparations may contain varying amounts of the active ingredient depending upon the intended purpose, but an aqueous preparation containing 0.00055 or 0.01% to 10% by weight of active ingredient may be used.
The compositions of this invention may contain other compounds having biological activity, e.g. compounds having similar or complementary fungicidal activity or which plant possess plant growth regulating, herbicidal or insecticidal activity.
A fungicidal compound which may be present in the composition of the invention may be one which is capable of combating ear disease of cereals (e.g. wheat) such as Septoria, Gibberella and Helminthosporium spp., seed and soil-borne diseases and downy and powdery mildews on grapes and powdery mildew and scab on apple, etc. By including another fungicide, the composition can have a broader spectrum of activity than the compound of general formula (I) alone. Further the other fungicide can have a synergistic effect on the fungicidal activity of the compound of general formula (I).Examples of fungicidal compounds which may be included in the composition of the invention are carbendazim, benomyl, thiophanate-methyl, thiabendazole, fuberidazole, etridazole, dichlofluanid, cymoxanil, oxadixyl, ofurace, metalaxyl, furalaxyl, benalaxyl, fosetyl-aluminium, fenarimol, iprodione, prothiocarb, procymidone, vinclozolin, penconazole, myclobutanil, propamocarb, diniconazole, pyrazophos, ethirimol, ditalimfos, tridemorph, triforine, nuarimol, triazbutyl, guazatine, triacetate salt of 1,1'iminodi(octamethylene)diguanidine, buthiobate, propiconazole, prochloraz, flutriafol, hexaconazole, (2RS, 5RS)-5-(2,4-dichlorophenyl)tetrahydro-5-(lH-1,2,4- triazol-l-ylmethyl)-2-furyl-2, 2,2-trifluoroethyl ether, cyproconazole, terbuconazole, pyrrolnitrin, l-L(2B5, 4RS; 2RS, 4RS)-4-bromo-2-(2,4-dichlorophenyl)tetrahydrofur furyl)-lH-l, 2,4-triazole, 5-ethyl-5,8-dihydro-8-oxo(1,3)dioxolo (4,5-g)quinoline-7-carboxylic acid, (RS)-1aminopropylphosphonic acid, 3(2, 4-dichlorophenyl ) -2- (lH- 1,2, 4-triazol-l-yl)quinazolin-4(3H)-one, fluzilazole, triadimefon, triadimenol, diclobutrazol, fenpropimorph, pyrifenox, fenpropidin, chlorozolinate, imazalil, fenfuram, carboxin, oxycarboxin, methfuroxam, dodemorph, BAS 454, blasticidin S, kasugamycin, edifenphos, Kitazin P, cycloheximide, phthalide, probenazole, isoprothiolane, tricyclazole, 4-chloro-N-(cyano(ethoxy)methyl)benzamide, pyroquilon, chlorbenzthiazone, neoasozin, polyoxin D, validamycin A, mepronil, flutolanil, pencycuron, diclomezine, phenazin oxide, nickel dimethyldithiocarbamate, techlofthalam, bitertanol, bupirimate, etaconazole, hydroxyisoxazole, streptomycin, cyprofuram, biloxazol, quinomethionate, dimethirimol, 1-(2-cyano-2methoxyiminoacetyl)-3-ethyl urea, fenapanil, tolclofosmethyl, pyroxyfur, polyram, maneb, mancozeb, captafol, chlorothalonil, anilazine, thiram, captan, folpet, zineb, propineb, sulphur, dinocap, dichlone, chloroneb, binapacryl, nitrothal-isopropyl, dodine, dithianon, fentin hydroxide, fentin acetate, tecnazene, quintozene, dicloran, copper containing compounds such as copper oxychloride, copper sulphate and Bordeaux mixture, and organomercury compounds.
The compounds of general formula (I) can be mixed with soil, peat or other rooting media for the protection of plants against seed-borne, soil-borne or foliar fungal diseases.
Suitable insecticides which may be incorporated in the composition of the invention include pirimicarb, dimethoate, demeton-s-methyl, formothion, carbaryl, isoprocarb, XMC, BPMC, carbofuran, carbosulfan, diazinon, fenthion, fenitrothion, phenthoate, chlorpyrifos, isoxathion, propaphos, monocrotophas, buprofezin, ethroproxyfen and cycloprothrin.
Plant growth regulating compounds are compounds which control weeds or seedhead formation, or selectively control the growth of less desirable plants (eg.
grasses).
Examples of suitable plant growth regulating compounds for use with the invention compounds are the gibberellins (eg. GA3, GA4 or GA7), the auxins (eg.
indoleacetic acid, indolebutyric acid, naphthoxyacetic acid or naphthylacetic acid), the cytokinins (eg. kinetin, diphenylurea, benzimidazole, benzyladenine or benzylaminopurine), phenoxyacetic acids (eg. 2,4-D or MCPA), substituted benzoic acid(eg. triiodobenzoic acid), morphactins (eg. chlorfluoroecol), maleic hydrazide, glyphosate, glyphosine, long chain fatty alcohols and acids, dikegulac, paclobutrazol, fluoridamid, mefluidide, substituted quaternary ammonium and phosphonium compounds (eg. chloromequat chlorphonium or mepiquatchloride), ethephon, carbetamide, methyl-3,6- dichloroanisate, daminozide, asulam, abscisic acid, isopyrimol, 1-(4- chlorophenyl)-4, 6-dimethyl-2-oxo-l, 2-dihydropyridine-3- carboxylic acid, hydroxybenzonitriles (eg. bromoxynil), difenzoquat, benzoylprop-ethyl 3,6-dichloropicolinic acid, fenpentezol, inabenfide, triapenthenol and tecnazene.
The following Examples illustrate the invention.
Throughout the Examples, the term 'ether' refers to diethyl ether, magnesium sulphate was used to dry solutions, and solutions were concentrated under reduced pressure. Reactions involving water-sensitive intermediates were performed under an atmosphere of nitrogen and solvents were dried before use, where appropriate. Unless otherwise stated, chromatography was performed on a column of silica gel as the stationary phase. Where shown, infrared and n.m.r. data are selective; no attempt is made to list every absorption in all cases. 1H n.m.r. spectra were recorded using CDC13solutions unless otherwise stated.The following abbreviations are used throughout DME = dimethoxyethane THF = tetrahydrofuran s = singlet DMF = N,N-dimethylformamide d = doublet n.m.r.= nuclear magnetic resonance t = triplet IR = infrared m = multiplet m.p. = melting point br = broad GC = gas chromatography ppm = parts per TLC = thin layer chromatography million HPLC = high performance liquid chromatography EXAMPLE 1 This Example illustrates the preparation of (E)methyl 2-[2-(3-benzyloxyphenoxy)phenyl]-3methoxypropenoate (Compound No. 23 of Table I).
A mixture of 2-bromobenzaldehyde (100g; 0.54 mol), ethylene glycol (67.03g; 1.08 mol), p-toluenesulphonic acid (0.5g) and toluene was heated to and maintained at reflux temperature for 6 hours. During this period, water/ethylene glycol (23 ml) was removed by azeotropic distillation. The mixture was cooled and ether (1 1) was added. The ether solution was washed with saturated sodium bicarbonate solution (200 ml) water (3 x 150 ml) and saturated brine (1 x 150 ml). After drying and filtration, evaporation of the ether solution gave 2-(2bromophenyl)-1,3-dioxolane (121.96g, 98.6% yield) as an oil.
1H n.m.r. : (60 MHz) delta : 3.4 (4H, m), 6.0 (1H, s), 6.9-7.6 (4H, m), ppm.
This material was used without further purification for the following step.
Potassium hydroxide pellets (35.2g; 0.63 mol) were dissolved in water (50 ml) and 3-methoxyphenol (78g; 0.63 mol) was added together with toluene (250 ml). The mixture was heated to and maintained at reflux temperature until water ceased to distil over (a total of 65 ml of water was collected). The mixture was cooled to 80 C and 2-(2-bromophenyl)-1,3,-dioxolane (120 g; 0.524 mol), DMF (200 ml) and cuprous chloride (0.2g) were added. The mixture was slowly heated to 150-155"C and toluene was distilled off. The mixture was maintained at 150-155 C for 6 hours then cooled to 25"C and water (500 ml) was added. The mixture was filtered and the residue was washed with ether (200 ml).The filtrate was extracted with ether (3 x 150 ml). The combined ether extracts were washed with 2N sodium hydroxide solution (2 x 150 ml), water (4 x 150 ml) and saturated brine (1 x 200 ml).
After drying and filtration the ether solution on evaporation gave 2-[2-(3-methoxyphenoxy)phenyl]-1,3- dioxolane (124.lg, 87.1% yield) as an oil.
1H n.m.r. (60 MHz) delta : 3.65' (3H, s), 3.95 (4H, d), 6.12 (1H, s), 6.6-7.6 (8H, m) ppm.
This material was used without further purification for the following step.
2-E2-(3-Methoxyphenoxy)phenyl)-l, 3-dioxolane (32.7g; 0.12 mol) was stirred in a mixture of water (95 ml) and concentrated hydrochloric acid (5 ml) at ambient temperature for 19 hours. The mixture was extracted with ether (2 x 60 ml) and the combined ether extracts were washed with saturated aqueous sodium bicarbonate solution (30 ml), water (3 x 30 ml) and saturated brine (30 ml).
The resulting solution was dried, filtered and concentrated to give almost pure 2-(3-methoxyphenoxy)benzaldehyde (A) (26.17g, 95.4% yield) as an oil. This material was used without purification for the following step. However, an analytical sample was prepared by chromatography using a mixture of ether and hexane as eluant to give an amber oil.
1H n.m.r. (90 MHz) delta : 3.79 (3H, s), 6.58-7.97 (8H, m), 10.49 (1H, d) ppm.
IR maxima (film) : 1691, 1599 cm 1.
A mixture of 2-(3-methoxyphenoxy)benzaldehyde (25.0g, 0.109 mol), methyl methylthiomethylsulphoxide (13.64g, 0.11 mol) benzyltrimethylammonium hydroxide (8.0 ml of a 30% solution in methanol) and THF (150 ml), was stirred at reflux temperature for 45 minutes. The resulting solution was evaporated to dryness, and was then chromatographed using a mixture of ether and hexane as eluant to give the sulphoxide (B) (27.67g, 75.3% yield) as an amber gum.
1H n.m.r. (60 MHz) delta : 2.2 (3H, s), 2.55 (3H, s), 3.65 (3H, s),6.35-8.15 (9H, m) ppm.
Acetyl chloride (20 ml) was added to absolute methanol (200 ml) dropwise over 15 minutes with water bath cooling to maintain the temperature at 20-25"C. A solution of the sulphoxide (B) (27.67g; 0.083 mol) in methanol (40 ml) was added in one portion and the resulting solution was stirred at ambient temperature for 18 hours. The methanol solution was evaporated to dryness under reduced pressure to leave a brown gum (22.78g) which was dissolved in ether (200 ml). The ether solution was washed with saturated aqueous sodium bicarbonate solution and, after filtering off a small quantity of insoluble material, the ether solution was evaporated to dryness and the residue was chromatographed using a mixture of ether and hexane as eluant to give methyl 2-(3-methoxyphenoxy)phenylacetate (C) (15.62g, 69.3% yield) as a viscous oil.
1H n.m.r. (60 MHz) delta : 3.5 (3H, s), 3.59 (2H, s), 3.63 (3H, s), 6.35-7.32 (8H, m) ppm.
Boron tribromide (12.89g, 0.051 mol) was dissolved in dichloromethane (50 ml) and cooled to 0-50C. A solution of methyl 2- ( 3-methoxyphenoxy )phenylacetate (7.0g: 0.026 mol) in dichloromethane (80 ml) was added dropwise, with stirring over 1 hour. After stirring at 0-5"C for 20 minutes the mixture was added dropwise, with stirring to absolute methanol (100 ml) maintaining the temperature at 0-50C. The resulting solution was poured into water (250 ml) containing sodium bicarbonate (12g), and the resulting mixture was extracted with ether (500 mls). The organic phase was washed with water (3 x 200 ml) and saturated brine (150 ml).After drying and filtration, evaporation of the ether solution gave methyl 2-(3-hydroxyphenoxy)phenylacetate (D) (6.12g, 92.3% yield) as a brown gum. This material was suitable for use in subsequent steps without further purification. However, chromatography using mixtures of ether and hexane as eluant gave material of higher purity as a viscous golden oil which rapidly darkened on exposure to air.
In addition, methyl 2-(3-hydroxyphenoxy)phenylacetate (D) was prepared as follows: A mixture of 2-chlorophenylacetic acid (30g, 0.18 mol), potassium carbonate (48.6g, 0.34 mol), and 3-methoxyphenol (43.5g, 0.35 mol) was heated with stirring at 140"C in the presence of a catalytic amount of copper(I) chloride.
After 3 hours, GC and TLC analysis indicated the absence of the starting acid. The reaction mixture was allowed to cool (with the addition of dry DMF (5 ml) at 70"C to prevent the mixture from becoming too viscous), poured into water and acidified with concentrated hydrochloric acid. The resulting mixture was extracted with ether and the combined ether extracts were washed with water until neutral. The ether extracts were dried and evaporated to afford a mixture of 3-methoxyphenol (49%) and 2-(3methoxyphenoxy)phenylacetic acid (41%) as a brown mobile oil which was used in the next stage without further purification.
The brown oil was refluxed in methanol (70ml) -containing concentrated sulphuric acid (2 ml) for 2i hours.
The reaction mixture was allowed to cool to room temperature and was then poured into water. The resulting mixture was extracted (x 2) with ether and the combined ether extracts were washed with dilute aqueous sodium hydroxide solution, and then with water until neutral and then dried. Evaporation gave crude methyl 2-(3methoxyphenoxy)phenylacetate (34.9g) as an orange-brown oil (86% pure by GC). The crude product was combined with another batch (8.2g) which had been prepared by the same method. Repeated short-path distillation (50-120"C at 4x10'2 mbar) then afforded methyl 2-(3-methoxyphenoxy) phenylacetate as an oil (37.lg, 95% pure, ca. 60% yield from 2-chlorophenylacetic acid). Further amounts of product were obtained in subsequent preparations.
Methyl 2-(3-methoxyphenoxy)phenylacetate (97g, 0.36 mol) was heated with concentrated hydrobromic acid (194 ml) in acetic acid (150 ml) at 110 C for 8 hours. After standing at room temperature overnight, more concentrated hydrobromic acid (100 ml) was added and the reaction mixture was reheated to 110 C. After a further 7 hours, all of the starting material had been consumed. The reaction mixture was allowed to cool to room temperature, poured into brine and then extracted with dichloromethane (x 2).The dichloromethane was evaporated to give an oil which was heated at 70 C with methanol (400 ml) and concentrated sulphuric acid (2 ml) for 2 hours.The reaction mixture was allowed to cool to room temperature, poured into brine and extracted with dichloromethane (x 2).
The combined extracts were washed with water (until neutral) and then dried, filtered and evaporated to give a brown oil (92.8g). Short-path distillation (1500C, 1x10-3 mbar) of a portion (72.8g) afforded methyl 2-(3hydroxyphenoxy)phenylacetate (D) (41.4g, 578 yield from methyl 2-(3-methoxyphenoxy)phenylacetate) as a golden syrup.
1H n.m.r. (60 MHz) delta : 3.57 (3H, s), 3.63 (2H, s), 5.82 5.82 (1H, s), 6.4-7.35 (8H, m) ppm.
IR maxima (film) : 3408, 1713 cm'l.
To a suspension of sodium hydride (0.558g, 0.023 moles in DMF (20ml) was added dropwise a solution of methyl 2-(3-hydroxyphenoxy)phenylacetate (D) (2.0g; 0.0077 mol) in DMF (10ml) and methylformate (log; 0.167 mol) After stirring for 45 minutes, water (100 mls) was added and the mixture was extracted with ether (50 mls). The aqueous layer was acidified with hydrochloric acid to pH 3-4 and the mixture was extracted with ether (2 x 40 mls).
The combined ether extracts were washed with water (3 x 30 mls) and saturated brine (1 x 30 ml), and then dried.
The ether was evaporated off and the residue was dissolved in DMF (20 ml), and anhydrous potassium carbonate (0.64g; 0.0046 moles) and dimethyl sulphate (0.55g; 0.0044 moles) was added. The mixture was stirred at ambient temperature for 1 hour, then water (100 ml) was added, and the mixture was extracted with ether (2 x 40 ml).The combined ether extracts were washed with water (3 x 20 ml) and saturated brine (20 ml), dried, filtered, evaporate to dryness, then chromatographed using a mixture of ether and hexane as eluant to give (E)-methyl 2-t2-(3- hydroxyphenoxy)phenyl]-3-methoxypropenoate (E) as an amber gum which, on trituration with a mixture of hexane and dichloromethane, gave a white solid, 0.7g, 30% yield from methyl 2-(3-hydroxyphenoxy)phenylacetate (D)] m.p. 115 116CC.
In addition, (E)-methyl 2-E2-(3-hydroxyphenoxy)- phenyl)-3-methoxypropenoate (E) was prepared as follows A solution of methyl 2-(3-hydroxyphenoxy)phenylacetate (D) (12g, 0.0465 mol) and methyl formate (55.8g, 0.93 mol) in dry DMF (35 ml) was added dropwise over 45 minutes to a stirredsuspensionof sodium hydride (6.696g of a 50% dispersionin oil, 0.1395 mol, pre-washed with 40-60 petroleum ether) in dry DMF (65 ml). The reaction mixture was stirred at room temperature for 2 hours, poured into water (200 ml), acidified to pH3 with concentrated hydrochloric acid and then extracted with ether (2 x 200ml). The combined organic extracts were washed with brine (2 x 200 ml), dried, filtered and evaporated to give a yellow oil (12.5g, 0.0433 mol).
The oil (12.5g, 0.0433mol) was dissolved in dry DMF (100 ml) and potassium carbonate (5.98g, 0.0433 mol) was added.
After stirring for 10 minutes, a solution of dimethyl sulphate (5.19g, 0.042 mol) in DMF (10 ml) was added in one portion. The resulting mixture was stirred overnight at room temperature, poured into water (200 ml) and extracted with ether (2 x 200 ml). The combined ether extracts were washed with brine (3 x 200 ml), dried, filtered and evaporated to give a sticky gum.
Crystallisation from dichloromethane-hexane gave (E)methyl 2-E2-( 3-hydroxyphenoxy)phenyl)-3-methoxypropenoate (E) (9.54g, 73%), m.p. 117-118 C.
1H n.m.r. (90 MHz) delta : 3.58 (3H, s), 3.75 (3H, s), 538 (1H, s), 6.39-7.33 (8H, m), 7.4 (1H, s) ppm.
IR maxima (nujol) : 3295, 1672, 1630 cm'l.
A mixture of (E)-methyl 2-t2-(3-hydroxyphenoxy)- phenyl3-3-methoxypropenoate (l.Og; 0.0033 mol), benzyl bromide (0.57g; 0.0033 mol) potassium carbonate (0.8g; 0.0053 mol) and dry DMF (15 ml) was stirred at ambient temperature for 3 hours. Water (50 ml) was added and the mixture was extracted with ether (2 x 30 ml). The combined organic extracts were washed with water (2 x 20 ml) and after drying and filtration the ether solution was evaporated to dryness then chromatographed using a mixture of ether and hexane as eluant to give the title compound (F) as a colourless gum (l.llg, 85% yield).
1H n.m.r. (90 MHz) delta : 3.55 (3H, s), 3.7 (3H, s), 4.97 (2H, s), 6.5-7.32 (13H, m), 7.44 (1H, s) ppm.
IR maxima (film) : 1710, 1638 cm 1.
EXAMPLE 2 This Example illustrates the preparation of (E)methyl 3-methoxy-2-E2- (3-phenylsulphonyloxyphenoxy)- phenyl]propenoate (Compound No. 51 of Table I).
A mixture of (E)-methyl 2-t2-(3-hydroxyphenoxy)- phenyl]-3-methoxypropenoate (0.5; 0.00166 moles, prepared as described in Example 1), benzenesulphonylchloride (0.36g; 0.002 mol) and pyridine (10 ml), was stirred at 60-70"C for 3 hours. The mixture was cooled to 25 CC, water (60 ml) was added and the mixture was extracted with ether (2 x 30 ml). The combined ether extracts were washed with water (20 ml), dilute hydrochloric acid (20 mls), water (93 x 200 ml) and saturated brine (20 ml).
The ether solution was dried, filtered, concentrated and chromatographed using a mixutre of chloroform and hexane as eluant to give the title compound (0.21g, 28.78 yield) as a colourless gum.
1H n.m.r. (90 MHz) delta : 3.56 (3H, sO, 3.75 (3H, s), 6.52-7.96 (13H, m), 7.40 (1H, s) ppm.
EXAMPLE 3 This Example illustrates the preparation of (E)methyl 3-methoxy-2-(2-E3-(4-nitrophenoxy)phenoxy)phenyl)- propenoate (Compound No. 133 of Table I).
A mixture of E-methyl 2-E2-(3-hydroxyphenoxy)phenyl)- 3-methoxypropenoate (1.2g; 0.004 mol, prepared as described in Example 1), 4-nitrofluorobenzene (0.68g; 0.008 mol), potassium carbonate (l.lg; 0.008 mol) and DMF (15 ml) was stirred at ambient temperature for 16 hours then poured into water (80 mls) and extracted with ether (2 x 30 ml). The combined organic extracts were washed with water (3 x 25 ml) and then saturated brine (25 ml).
They were then dried, filtered, concentrated and chromatographed using a mixture of chloroform and hexane as eluant to give the title compound as an amber-coloured gum (O.93g, 55.2% yield).
1H NMR (90 MHz) delta : 3.55 (3H, s), 3.72 (3H, s), 6.67 8.41 (12H, m), 7.44 (1H, s) ppm.
EXAMPLE 4 This Example illustrates the preparation of (E)methyl 2-(2-L3-(4-fluorophenoxy)phenoxy)phenyl)-3- methoxypropenoate (Compound No. 124 of Table I).
A mixture of (E)-methyl 2-E2-(3-(hydroxyphenoxy)- phenyl)-3-methoxypropenoate (l.Og, 0.0033 mols, prepared as described in Example 1), bis (4-fluorophenyl)iodonium bromide (2.63g; 0.0069 mol), triethylamine (0.5 ml), copper powder (0.5g) and absolute methanol (15 ml) was heated at reflux for 6 hours. Further bis (4-fluorophenyl)iodonium bromide (lg; 0.0069 mol) was added and the mixture was stirred at reflux temperature for a further 3 hours. After cooling and filtration, water (80 ml) was added to the filtrate and the mixture was extracted with ether (2 x 30 ml). The combined ether extracts were washed with water (3 x 15 ml) and saturated brine (15 ml).
After drying and filtration the ether solution was concentrated to give the title compound as an amber gum (0.16g, 12.3% yield).
1H n.m.r. (60 MHz) delta : 3.42 (3H, s), 3.51 (3H, s), 6.35 7.30 (12H, m), 7.35 (1H, s) ppm.
IR maxima (film) : 1710, 1641 cm'l, EXAMPLE 5 This Example illustrates the preparation of (E) methyl 2-[2-(3-benzoyloxyphenoxy)phenyl]-3-methoxyprop- enoate (Compound No. 49 of Table I).
A mixture of (E)-methyl 2-L2-(3-hydroxyphenoxy)- phenyl]-3-methoxypropenoate (0.5g, 0.00166 -mol, prepared as described in Example 1, benzoyl chloride (0.26g; 0.00185 mol), potassium carbonate (0.23g; 0.00166 mol) and DMF (10 ml) was stirred at ambient temperature for 1 hours. Further benzoyl chloride (0.26, 0.00166 mol) and potassium carbonate (0.23gel 0.00166 mol) were added and the mixture was stirred at ambient temperature for 16 hours. Water (80 ml) was added and the mixture was extracted with ether (2 x 40 ml).The combined ether extracts were washed with water (3 x 20 ml) and saturated brine (20 ml), then dried, filtered, concentrated and chromatographed using a mixture of ether and hexane as eluant to give a white solid. Recrystallisation from aqueous methanol gave the pure title compound (0.32g, 47.7% yield) as a white solid, m.p. 94-95"C.
1H n.m.r. (90 MHz) delta : 3.62 (3H, s); 3.74 (3H, s), 6.76 8.38 (13H, m), 7.46 (1H, s) ppm.
IR maxima (nujol) : 1741, 1698, 1627 cm 1.
EXAMPLE 6 This Example illustrates the preparation of (E,E)methyl 2-E2-(3-(4-chlorophenylazo]-4-hydroxyphenoxy)- phenyl]-3-methoxypropenoate (Compound No. 282 of Table I).
1M Hydrochloric acid (2.5 ml) was added to 3chloroaniline hydrochloride (6.64 ml of 0.25M aqueous solution) and the mixture was cooled to below 10C.
Sodium nitrite (3.32 ml of 0.SM aqueous solution) was added dropwise and the resulting mixture was stirred at below 10 C for 10 minutes. The resulting solution of 3chlorobenzenediazonium chloride was added dropwise with stirring to a mixture of (E)-methyl 2-E2-(4-hydroxy phenoxy)phenyl]-3-methoxypropenoate (0.5g, 0.00166 mol, prepared by a route analogous to that described in Example 1 for the preparation of the corresponding 3-hydroxycompound) in sodium hydroxide (16.6 ml of 0.1M aqueous solution), and acetone (30 ml). Further aqueous sodium hydroxide solution was added simultaneously to maintain the pH between 8-10 and the temperature was maintained below 10 C. After stirring for 20 minutes the mixture was extracted with ether (2 x 40 ml).The combined ether extracts were washed with water (3 x 15 ml) and saturated brine (15 ml), then dried, filtered, concentrated, and chromatographed using a mixture of ether and hexane as eluant to give an orange solid. Recrystallisation from a mixture of hexane and dichloromethane gave the pure title compound (99.3mg, 13.6% yield), m.p. 143-144 C.
EXAMPLE 7 This Example illustrates the preparation of (E)methyl 2-E2-(3-E3-methoxyphenoxy]phenoxy)phenyl]-3- methoxypropenoate (Compound No. 129 of Table I).
To a stirred solution of sodium (0.61g) in methanol (10 ml) was added resorcinol (4.34g) in one portion.
After stirring the resulting mixture for h hour at room temperature, the excess methanol was removed under reduced pressure. To the resulting orange oil was added pyridine (6.6 mls), 3-bromoanisole (14.74g) and cuprous chloride (192mg). The mixture was stirred at 1250C for 66 hours.
The reaction mixture was allowed to cool and was then poured into dilute hydrochloric acid and extracted with ether. The ether extracts were re-extracted with dilute aqueous sodium hydroxide and these aqueous extracts were acidified with dilute hydrochloric acid and extracted with ether. These ether extracts were washed successively with water and brine, then dried and concentrated to give 3.72g of a red oil. Bulb-to-bulb distillation of this oil (170 C oven temp./0.05 mmHg) gave 3-(3-methoxyphenoxy)phenol (1.71g) as a thick pale yellow oil.
1H n.m. r. delta : 3.78 (3H, s), 4.93 (1H, s) ppm.
To a stirred solution of sodium (0.18g) in methanol (4 ml) was added 3-(3-methoxyphenoxy)phenol (1.70g) in one portion. After stirring the resulting mixture for 2 hour at room temperature the excess methanol was removed under reduced pressure. To the resulting orange oil was added o-bromophenylacetic acid (0.85g) and cuprous chloride (40mg), and the reaction mixture was stirred at 1300C for 1 hour. Further o-bromophenylacetic acid (0.4g) and sodium ethoxide (0.13g) were added and the mixture was stirred at 130 CC for a further 3 hours, allowed to cool, then acidified with dilute hydrochloric acid and extracted with ether.The ether extracts were washed successively with water and brine, then dried and concentrated to give 3.12g of a red oil containing 2-E3-(3-methoxyphenoxy)- phenoxy]phenylacetic acid. To this crude acid (3.12g) was added methanol (40 ml) and 3 drops of concentrated sulphuric acid. This reaction mixture was stirred at 900C for 1 hour, then allowed to cool, poured into water and extracted with ether. The ether extracts were washed successively with dilute aqueous sodium hydroxide, water and brine, then dried and concentrated to give 1.33g of a yellow oil.Bulb-to-bulb distillation of this oil (160 C oven temp./0.07 mmHg) gave methyl 2-E3-(3- methoxyphenoxy)phenoxy]phenylacetate tl.03g, 36% yield from 3- (3-methoxyphenoxy)phenol).
lH N.m.r. delta : 3.62 (3H, s), 3.68 (2H, s), 3.78 (3H, s) ppm.
A mixture of methyl 2-3-(3-methoxyphenoxy)phenoxy]- phenylacetate (1.00g) and methyl formate (3.34 ml) in DMF (1 ml) was added dropwise over 10 minutes to a stirred suspension of sodium hydride (0.13g) in DMF (10 mls) cooled in ice to below 10 C (effervescence). Following the addition, the reaction mixture was stirred at room temperature for 2 hours, poured into water, acidified with dilute hydrochloric acid, and then extracted with ether.
The extracts were washed with water, dried and concentrated to give a yellow oil (1.09g). Potassium carbonate (0.76g) and dimethyl sulphate (0.33g) were added successively to a stirred solution of this yellow oil in DMF (20 ml) and the resulting mixture was stirred at room temperature for 2 hours, poured into water and then extracted with ether. The extracts were washed with water, dried, concentrated and chromatographed using a 1:1 mixture of ether and petrol as eluant to give the title compound 0.61g, 55% yield from methyl 2-:3-(3- methoxyphenoxy)-phenoxy]phenylacetate] as a colourless viscous oil.
1H n.m.r. delta : 3.60 (3H, s), 3.75 (3H, s), 3.78 (3H,s) 6.55-6.72 (5H, m), 6.97 (1H, d), 7.10 7.30 (6H, m), 7.48 (1H, s) ppm.
IR maxima (nujol) 1713, 1638cm'l.
EXAMPLE 8 This Example illustrates the preparation of (E)methyl 3-methoxy-2-E2-(3-Ephenoxymethyl]phenoxy)phenyl)- propenoate (Compound No. 21 of Table I).
(E)-methyl 3-methoxy-2-t2-(3-methylphenoxy)phenyl]- propenoate (0.50g, prepared from 3-methylphenol and 2bromobenzaldehyde by the method described in Example 1) and N-bromosuccinimide (0.30g) were refluxed in carbon tetrachloride (25 mls) with a trace of azobisisobutyronitrile (AIBN), for 4.5 hours, with further traces of AIBN being added at intervals of 1.5 hours. The reaction was monitored by GC. After standing at room temperature overnight a further trace of AIBN was added to the reaction mixture and refluxing was continued until GC analysis showed almost complete disappearance of the starting material (1 hour). The reaction mixture was filtered through celite, washed with water and evaporated to give a pale yellow gum (0.69g).GC and NMR analysis showed that this gum consisted of (E)-methyl 2-E2-(3- bromomethylphenoxy)phenyl]-3-methoxypropenoate (80%), the corresponding dibromomethyl compound (11%) and unreacted propenoate starting material (8%).
1H n.m.r. data for the major component : delta 3.61 (3H, s), 3.77 (3H, s), 4.42 (2H, s), 6.90-7.40 (8H, m), 7.48 (1H, s), ppm.
This material was carried through without further purification.
Part of the crude material (0.42g, 80% pure), was stirred with phenol (0.105g) and potassium carbonate (0.077g) in DMF (20 ml), and heated to 60"C for 1 hour.
After standing overnight at room temperature the mixture was heated to 600C for a further 1 hour, cooled, poured into water, and extracted with ethyl acetate. The organic fraction was washed with water, dried and evaporated to yield a pale yellow oil (0.42g). Attempted purification by high performance liquid chromatography, eluting with a 3:1 mixture of petrol and ethyl acetate, gave the title compound (0.13g) as a colourless gum containing as an impurity 20% of (E)-methyl 2-E2- (3-dibromomethylphenoxy )- phenyl ] -3-methoxypropenoate.
1H n.m.r. data for the title compound : delta 3.58 (3H, 3.70 (3H, s), 4.98 (2H, s), 6.88 7.36s), (13H, m), 7.46 (1H, s) ppm.
EXAMPLE 9 This Example illustrates the preparation of (E)methyl 2-E2-(2-acetyl-5-phenoxyphenoxy)phenyl]-3-methOxy- propenoate and (E)-methyl 2-E2-C4-acetyl-3-phenoxy- phenoxy)phenyl]-3-methoxypropenoate (Compound Nos. 366 and 365 respectively of Table I).
Methyl 2-(3-phenoxyphenoxy)phenylacetate was prepared from 3-phenoxyphenol and 2-bromobenzaldehyde by the steps described in Example 1 for the preparation of methyl 2-(3methoxyphenoxy)phenylacetate. This was the converted into (E)-methyl 3-methoxy-2-E2-(3-phenoxyphenoxy)phenyl)- propenoate E1H n.m.r (250 MHz) 3.61 (3H, s), 3.78 (3H, s), 6.68-7.35 (13H, m), 7.48 (1H, s) ppm] using sodium hydride and methyl formate, and then potassium carbonate and dimethyl sulphate, using the procedure described in Example 1 for the preparation of (E)-methyl 2-t2-(3- hydroxyphenoxy)phenyl]-3-methoxypropenoate, except that just 2 equivalents of sodium hydride were used in this case.
Powdered aluminium chloride (0.512g, 3.84 mmol) was added to a stirred solution of (E)-methyl 3-methoxy-2-E2- (3-phenoxyphenoxy)phenyl)propenoate (0.722g, 1.92 mmol) in dry dichloromethane (20 ml) at 0-5eC. A solution of acetyl chloride (0.151g, 1.92 mmol) in dry dichloromethane (3 ml) was then added dropwise over 10 minutes and the resulting mixture was stirred overnight, being allowed to warm to ambient temperature. The reaction mixture was diluted with ether (125 ml) and washed with 2N hydrochloric acid (x 2), 10% aqueous sodium carbonate solution and finally with water.The residue obtained after removal of the solent was purified by flash chromatography using a mixture of ether and petrol as eluant to give an approximately 3:1 mixture of the two title compounds (individual identities not assigned) as a colourless gum (0.424g). Part of this gum(0.400g) was separated by high performance liquid chromatography on silica gel using a 70:25:5 mixture of hexane:dichloromethane:methyl t-butyl ether as eluant to give (i) Regioisomer A (0.179g), eluted first, major component of the mixture, as a white crystalline solid, m.p. 90-92"C.
1H n.m.r. (250 MHz) : delta 2.52 (3H, s), 3.56 (3H, s), 3.72 (3H, s), 6.48 (1H, d), .64 (lH, q), 6.9-7.4 (9H, m), 7.43 (1H, s), 7.84 (1H, d) ppm.
and (ii) Regioisomer B (0.061g, containing ca. 5% of regioisomer A), eluted second, minor component of the mixture, as a white crystalline solid, m.p. 82-85"C.
1H n.m.r (250 MHz) : delta 2.51 (3H, s), 3.60 (3H, s), 3.75 (3H, s), 6.45 (1H, d), 6.59 (1H, q), 6.9-7.4 (9H, m), 7.48 (1H, s), 7.82 (Ia, d) ppm.
EXAMPLE 10 This Example illustrates the preparation of (E)methyl 3-methoxy-2-t2-(3-pyrimidin-2-yloxyphenoxy)phenyl]- propenoate (Compound No. 22 of Table II).
A mixture of (E)-Methyl 2-E2-(3-hydroxyphenoxy)- phenyl]-3-methoxypropenoate (0.5g, prepared as described in Example 1), potassium carbonate (0.46g), 2-chloropyrimidine (0.23g) and cuprous chloride (0.Olg) in DMF (15 ml) was heated under reflux for 4 hours. After cooling, the mixture was poured into water and filtered. The filtrate was extracted with ether. The combined ether extracts were washed successively with water and brine, dried, concentrated and chromatographed using a mixture of ether and hexane as eluant to ovive the title compound as a gum (0.26g, 41% yield).
IR (film) : 1707, 1633 cm 1, 1H n.m.r. (90 MHz) : delta 3.54 (3H, s), 3.68 (3H, s), 6.74-7.34 (9H, m), 7.38 (1H, s), 8.28 (2H, d) ppm.
EXAMPLE 11 This Example describes the preparation of (E)-methyl 3-methoxy-2-E2- (3-phenoxyphenylthio)phenyl]propenoate (Compound No. 446 of Table III)
2-Mercaptophenylacetic acid was prepared by a method described in the chemical literature (see D. Papa et al, J.Org.Chem., 1949, 24, 723, R.H. Glauert and F.G. Mann, J.Chem.Soc., 1952, 2127 and references therein). 2-Mercaptophenylacetic acid (1.68g) was added to a stirred solution of sodium hydroxide (0.8g) in methanol (10 ml), (compare D.C. Atkinson et al, J.Med.Chem., 1983, 26, 1361). The resulting orange solution was stirred at room temperature for 90 minutes then concentrated under reduced pressure, removing the final residues of methanol by azeotroping with toluene, to leave a yellow solid.
Cuprous chloride (0.2g) and a solution of 3-phenoxybromobenzene (2.49g, prepared from 3-phenoxyphenol and triphenylphosphine dibromide by the method described by J.P.
Schaefer et al, Org.Synth., Coll. Vol.5, 142) in DMF (10 ml) were added successively to a stirred solution of this yellow solid in DMF (20 ml). The resulting mixture was heated at 950C for 1 hours, at 125 CC for 2 hours, and then at reflux for a further 2 hours. After cooling, the reaction mixture was poured into aqueous sodium hydroxide then washed with ether (x 3). The aqueous solution was acidified with concentrated hydrochloric acid and extracted with ether (x 3). These extracts were washed with water, dried and concentrated to give a purple oil (2.2g) consisting mainly of 2-(3-phenoxyphenylthio)phenylacetic acid.A solution of this oil in methanol (20 ml) was added to acidic methanol Prepared by carefully treating methanol (30 ml) with acetyl chloride (3.5 ml)] and the resulting mixture was stirred for 90 minutes at room temperature. The reaction mixture was concentrated and the residue was partitioned between ether and aqueous sodium bicarbonate. The organic layer was separated and washed successively with aqueous sodium hydroxide (x 2) and water (x 3) then dried and concentrated to give crude methyl 2-(3-phenoxyphenylthio)phenylacetate (2.06g) as a purple oil.
IR maximum (film) : 1740 cm'l, 94% pure by GC.
The crude methyl 2-(3-phenoxyphenylthio)phenylacetate was converted into the title compound in a yield of 53% by the 2 steps described in Example 7 for the conversion of methyl 2-E3- (3methoxyphenoxy)phenoxy]phenylacetate into (E)-methyl 2-C2-(3-C3-methoxyphenoxyfphenoxy)phenyl methoxypropenoate, that is by formulation with methyl formate and sodium hydride, followed by O-methylation with dimethyl sulphate and potassium carbonate. The product was an orange gum, 98% pure by GC, which crystallised on standing.
m.p. 48-51.5 C.
IR maxima (film) : 1710 and 1632 cm 1.
1H n.m.r. (270 MHz) : delta 3.62 (3H, s), 3.73 (3H, s), 6.78 (1H, dd), 6.88-7.00 (4H, m), 7.05-7.36 (7H, m), 7.42 (1H, d), 7.48 (1H, s) ppm.
EXAMPLE 12 This example illustrates the preparation of (E)-methyl 2-E2-(3-pyrimidin-2-yloxyphenylthio)phenyl]-3- methoxypropenoate (compound No 22 of Table IV).
A mixture of the sodium salt of 3-methoxythiophenol Prepared by treatment of 3-methoxythiophenol (2.8g) with sodium hydroxide (0.8g) in methanol (20 ml) followed by evaporation to dryness], 2-bromophenylacetic acid (4.3g) and copper(I) chloride (0.4g) in dry DMF (25 ml) was heated overnight at reflux. The reaction mixture was cooled, poured into water and acidified with dilute hydrochloric acid. The aqueous mixture was extracted with ether (x 3) and the combined ether extracts were extracted in turn with dilute sodium hydroxide solution (x 2). The combined aqueous hydroxide extracts were acidified with dilute hydrochloric acid and re-extracted with ether (x 3). These combined ether extracts were washed with water (x 3), dried and evaporated to give an orange oil (3.5g, 96.8% by GC). The oil was treated with acidic methanol overnight at room temperature.Normal work-up afforded methyl 2-(3-methoxyphenylthio)phenylacetate (2.9g, 91% by GC) as a yellow liquid which was used in the next stage without further purification.
1H n.m.r. delta : 3.64 (3H, s), 3.74 (3H, s), 3.86 (2H, s) ppm.
IR maxima (film): 1739 cm 1 Methyl 2-(3-methoxyphenylthio)phenylacetate (0.86g) and pyridinium hydrochloride (2.08g, excess) were heated together at 200 C under an atmosphere of nitrogen. After 3 hours, the reaction mixture was cooled and then partitioned between dilute hydrochloric acid and ethyl acetate. The acidic aqueous layer was extracted further (x 2) with ethyl acetate and the combined organic layers were extracted with dilute sodium hydroxide (x 3). The combined basic layers were acidified with concentrated hydrochloric acid and then extracted (x 3) with ethyl acetate.These organic extracts were combined and washed with water (x 3), dried and evaporated to give an of fwhite solid (0.64g). The off-white solid was treated with methanolic hydrogen chloride to afford after standard work-up conditions methyl 2-(3-hydroxyphenylthio)phenylacetate (0.44g) as a red oil (90.5% pure by GC) which was used in the next stage without further purification.
IR max. : 3384, 1738 cm'l.
A solution of crude methyl 2-(3-hydroxyphenylthio) phenylacetate (0.44g) and methyl formate (1.92 ml) in dry DMF (2 ml) was added dropwise to a stirred suspension of sodium hydride (0.21g, 55% dispersion in oil, pre-washed with petroleum ether) in dry DMF (3 ml) at 0-5 C. After a total of 15 minutes, the temperature was allowed to rise to room temperature. After 2 hours, the reaction mixture was poured into water, acidified with concentrated hydrochloric acid, and then extracted with ether (x 3).
The combined ether extracts were washed with water (x 3), dried and evaporated to give a red gum (0.49g). The red gum was dissolved in DMF (5 ml) and cooled to OOC.
Potassium carbonate (0.132g) was added followed by the dropwise addition of a solution of dimethyl sulphate (O.lllg) in DMF. After stirring for 4Lz hours, the reaction mixture was poured into water, and extracted with ether (x 3). The combined ether extracts were washed with water (x 3 ), dried and evaporated to give methyl 2- 2-(3- hydroxyphenylthio)phenyl]-3-methoxypropenoate (0.45g) as a red gum; IR maxima 3240, 1709, 1665 cm'l; M+316 1H n.m.r. delta : 3.65 (3H, s); 3.76 (3H, s), 7.47 (1H, s) ppm.
Crude (E)-methyl 2-[2-(3-hydroxyphenylthio)phenyl]-3methoxypropenoate (0.4g) was treated with 2-chloropyrimidine (0.45g) and potassium carbonate (0.17g) in dry DMF (10 ml) at 80-900C under nitrogen. After 4 hours, GC analysis indicated complete formation of a single product.
The reaction mixture was cooled, poured into water and then extracted with ether (x 4). The combined yellow ether extracts were washed with water (x 2), dried and evaporated to give an orange gum (0.39g). Chromatography (eluant ether) afforded the title compound as an orange viscous gum (0.34g); IR maxima 1706, 1632cm~l; 1H n.m.r. delta : 3.64 (3H, s),3.75 (3H, s); 6.97-7.06 (3H, m), 7.08-7.12 (1H, d), 7.25-7.35 (4H, m), 7.46-7.48 7.48 (1H, d), 7.49 (1H, s); 8.53-8.56 (2H, d) ppm.
EXAMPLE 13 This Example illustrates the preparation of (E)methyl 2-[2-(3-phenylthiophenoxy)phenyl]-3-methoxypropenoate (Compound No 1 of Table I).
3-Hydroxydiphenylsulphide (2.02g; O.Olmol), (E)- methyl 2-(2-bromophenyl)-3-methoxypropenoate (1.35g; 0.005 mol, prepared from methyl o-bromophenyl acetate, methyl formate and sodium hydride then potassium carbonate and dimethyl sulphate in the 2 steps described in Example 7 for a similar transformation), anhydrous potassium carbonate (0.69g; 0.005 mol), and a catalytic quantity of cuprous chloride, were mixed and heated to 175 CC with stirring. After 10 hours, the mixture was cooled to ambient temperature and dissolved in DMF (50 ml). The solution thus obtained was poured into water (100 ml) and the resultant emulsion was extracted with ether (2 x 100 ml). The combined ether extracts were washed sequentially with water (2 x 100 ml), 2M sodium hydroxide solution (2 x 100 ml), and water (2 x 100 ml). The resulting ether solution was dried, filtered, and evaporated to dryness under reduced pressure. Chromatography using hexane and chloroform as eluants gave the title compound (0.83g) as a viscous oil.
1H n.m.r. (60 MHz) delta : 3.52 (3H, s), 3.64 (3H, s), 6.5 7.3 (13H, m), 7.42 (1H, s) ppm.
EXAMPLE 14 This Example illustrates the preparation of (E) Methyl 2-52-(3-phenylthiophenoxy)phenyl]-3- methoxypropenoate-S,S-dioxide (compound No 3 of Table I).
3-Hydroxydiphenylsulphone (3.66g; 0.0156 mol), (E)methyl 2-(2-bromophenyl)-3-methoxypropenoate (1.5g: 0.0055 mol, prepared as described in Example 13), and anhydrous potassium carbonate (l.lg; 0.0079 mol)-, were mixed with catalytic quantities of cuprous chloride and copper bronze. The mixture was heated to 1700C under nitrogen for ten hours. After the melt had cooled to ambient temperature, the residue was dissolved in DMF (50 ml).
The resultant solution was diluted with ether (100 ml), and the solution was filtered to remove inorganic salts.
The solution was washed sequentially with water (100 ml), 2M sodium hydroxide solution (2 x 100 ml), water (100 ml), and saturated brine (100 ml). The ether solution was dried, filtered, and evaporated to dryness under reduced pressure. Chromatography of the residue using hexane and chloroform as eluants gave the title compound (0.66g).
1H n.m.r. (60 MHz) delta : 3.46 (3H, s), 3.57 (3H, s), 6.6-8.0 (14H, m) ppm.
EXAMPLE 15 This Example illustrates the preparation of (E) methyl-2-52-(3-anilinophenoxy)phenyl]-3-methoxypropenOate (Compound No. 4 of Table I).
3-Hydroxydiphenylamine (1.365g; 0.0074 mol), (E)methyl 2-(2-bromophenyl)-3-methoxypropenoate (Ig; 0.0037 mol, prepared as described in Example 13), and anhydrous potassium carbonate (0.517gut 0.0037 mol), were combined with catalytic quantities of cuprous chloride and copper bronze. The mixture was heated to 1700C for nine hours, and then cooled and dissolved in DMF (20 ml). This solution was then partitioned between ether and water.
The ether layer was washed with water (2 x 100 ml), then with 1M sodium hydroxide solution (2 x 100 ml). The ether solution was then dried, filtered, and evaporated to dryness under reduced pressure. The residual gum was purified by chromatography using hexane and dichloromethane as eluants, to give the title compound (0.40g).
1H n.m.r. (60 MHz) delta : 3.57 (3H, s), 3.67 (3H, s), 5.75 (1H, brs), 6.3-7.4 (13H, m), 7.44 (1H, s) ppm.
EXAMPLE 16 This Example illustrates the preparation of (E)methyl 2-:2-(3-N-methylanilinophenoxy)phenyl]-3- methoxypropenoate (Compound No 5 of Table I).
Sodium hydride (300mg of an 80% dispersion in oil; 0.0-1 mol) was washed oil-free with hexane (2 x 50 ml).
The hydride was then suspended in dry DMF (10 ml). To this suspension was added a solution of (E)-methyl 2-t2- (3-anilinophenoxy)phenyl)-3-methoxypropenoate (290 mg, prepared as described in Example 15) in dry DMF (10 ml), at such a rate as to maintain a steady effervescence.
When effervescence had ceased, the mixture was stirred for a further 15 minutes and then iodomethane (2 ml; large excess) was added over a period of 5 minutes. Stirring was continued for a further 30 minutes before the suspension was cautiously diluted with water (50 ml). The aqueous emulsion was extracted with ether (2 x 50 ml).
These ether extracts were washed with water (2 x 50 ml), dried, filtered, and evaporated to dryness under reduced pressure to give the title compound as a viscous oil (211 mg).
1H NMR (60 MHz) delta : 3.20 (3H, s), 3.54 (3H, s), 3.65 (3H, s), 6.3-7.4 (13H, m), 7.44 (1H, s) ppm.
EXAMPLE 17 This Example illustrates the preparation of (E)methyl 3-methoxy-2-(2-53-(alpha-hydroxybenzyl)phenoxy]- phenyl)propenoate (Compound No. 380 of Table I).
3-Hydroxybenzyl alcohol (31.0g) was ground finely and stirred with potassium carbonate (34.6g), 2-bromophenylacetic acid (26.9g) and cuprous chloride (large spatula full) under nitrogen. The mixture was warmed to 1400C, and stirred vigorously for 3 hours. DMF (60 ml) was then added to the stirred melt and the solution was allowed to cool, poured into water and acidified with dilute hydrochloric acid. The aqueous layer was extracted with ether, and the ether extracts were washed with water, dried and evaporated to give 2-(3-hydroxymethylphenoxy)phenylacetic acid as a brown oil (42.03g) which was used without further purification.
The crude acid (41.0g) was refluxed in methanol (600 ml) containing concentrated sulphuric acid (2.5 ml), for 3.5 hours. After evaporation of the methanol, the residue was dissolved in ethyl acetate, washed with dilute aqueous sodium hydroxide and then water, dried and evaporated to yield a brown oil (26.31g). 1.31g was purified by HPLC (eluant 1:1, ethyl acetate:hexane) to give pure methyl 2 (3-hydroxymethylphenoxy)phenylacetate as a pale yellow oil.
lH n.m.r. (400 MHz) delta: 2.12(1H, s), 3.60 (3H, s), 3.69 (3H, s), 4.62 (2H, s), 6.95 (1H, s), 6.85-6.90 (2H, t), 7.04-7.14 (2H, m), 7.21-7.32 (3H, m) ppm.
IR maxima (film): 3450, 1742 cm'l.
A mixture of the crude methyl 2-(3-hydroxymethylphenoxy)phenylacetate (25.0g) and methyl formate (56 ml) in dry DMF (50 ml) was added dropwise to sodium hydride (7.35g of a 60% dispersion in oil, washed with hexane) in dry DMF (100 ml) over 30 minutes at 50C. After stirring at 5 C for another 30 minutes, the mixture was allowed to warm to room temperature over several hours and then stood overnight. The reaction mixture was then poured into water and extracted with ether. The aqueous layer was then acidified with dilute hydrochloric acid and extracted with ether. The ether extracts were dried and evaporated to give crude methyl 3-hydroxy-2-(2-E3-hydroxymethylphenoxy]- phenylpropenoate as an orange oil (32.19g).The crude methyl ester (32.10g) was stirred in DMF (80 ml) at 5 10 C with potassium carbonate (25.4g) and a solution of dimethyl sulphate (11.6g) in DMF (20 ml) was added dropwise over 10 minutes. The mixture was allowed to warm to room temperature over a few hours and then stood overnight. The reaction mixture was poured into water, acidified with dilute hydrochloric acid and extracted with ether. The ether extracts were washed with water, dried and evaporated to give an orange brown oil (14.38g).
Purification by HPLC yielded (E)-methyl 3-methoxy-2-(2-E3- hydroxymethylphenoxy]phenyl)propenoate as a slightly pinkish crystalline solid (7.8g).
1H n.m.r. (270 MHz) delta : 2.55 (1H, s), 3.58 (3H, s), 3.74 (3H, s), 4.55 (2H, s), 6.8-7.28 (8H, m), 7.44 (1H, s) ppm.
IR maxima (nujol): 3515, 1705, 1625 cm'l, Part of this alcohol (0.314g) was stirred in dry methylene chloride (5 ml) and pyridinium dichromate (0.564g) was added, and the mixture was stirred for 4 hours at room temperature. The mixture was then filtered and the precipitate washed with ether. The combined methylene chloride and ether washings were evaporated to give (E)-methyl 3-methoxy-2-(2-E3-formylphenoxy]phenyl)- propenoate as a brown oil (0.309g).
n.m.r. (270 MHz) delta : 3.59 (3h, s), 3.65 (3H, s), 6.98 (1H, d), 7.17-7.36 (4H, m), 7.40-7.47 (3H, m), 7.47 (1H, s), 7.55 (1H, d) ppm.
IR maxima (film): 1710, 1640 cm'l.
(E)-Methyl 3-methoxy-2-(2-[3-formylphenoxy]phenyl)propenoate (0.50g) was stirred in dry THF (20 ml) at -20 C under nitrogen. Phenylmagnesium bromide (0.53 ml of a 3M solution in ether) as a dilute solution in dry THF (5 ml) was added slowly dropwise. After completion of the addition the reaction was stirred at -20 C for 30 minutes and then slowly warmed to room temperature over 1 hour, and then stood overnight. The mixture was then cooled to 5 C, water was added, and the resulting mixture was extracted with ethyl acetate. After washing with brine and drying, the ethyl acetate solution was evaporated to give a yellow oil. This was purified by HPLC (eluant 2:1, hexane:ether) to give the title compound as a colourless oil (0.340g).
1H n.m.r. (400MHz) delta : 2.30 (1H, d), 3.57 (3H, s), 3.72(3H, s), 5.78 (1H, d), 6.82 (1H, d), 6.91 (1H, d), 7.02 7.08 (2H, m), 7.10-7.16 (1H, m), 7.20-7.38 (8H, m), 7.45 (1H, s) ppm.
IR maxima (film): 3460, 1715, 1635 cm'l.
EXAMPLE 18 This Example illustrates the preparation of (E)methyl 3-methoxy-2-(2-[3-(2-pyridyloxymethyl)phenoxy] phenyl)propenoate, (Compound No. 6 of Table II).
Silver carbonate (0.28g) was added to (E)-methyl 3 methOxy-2-(2-D3-bromomethylphenoxy]phenyl)propenOate (0.75g, 70% pure, prepared by the method described in Example 8) and 2-pyridone (0.19g) in hexane. The mixture was refluxed and excluded from light by wrapping with foil, for 3 hours, and then stood overnight. The hexane was evaporated and the residue was taken up in methylene chloride and filtered through celite. The filtrate was washed with aqueous sodium bicarbonate and then water, dried and evaporated to yield an orange gum (0.72g).
This was purified by HPLC (eluant 1:1, ether:hexane) to give the title compound as a colourless gum (0.188g).
1H n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.76 (3H, s), 5.32 (2H, s), 6.78 (1H, d), 6.84-6.96 (3H, m), 7.04-7.16 (3H, m), 7.21-7.31 (3H, m), 7.48 (lH,s), 7.52-7.60 (1H, m), 8.15 (1H, d) ppm.
IR maxima (film) : 1715, 1670, 1645, 1600 cm 1.
EXAMPLE 19 This Example illustrates the preparation of (E)methyl 3methoxy-2-(2-E3-pyrimidin-2-yloxymethy1phenoxy]- phenyl)propenoate (Compound No 85 from Table II).
(E )-Methyl 3-methoxy-2-(2-C3-hydroxymethylphenoxyl- phenyl)propenoate (0.5g, prepared as described in Example 17) in dry DMF (a few ml) was added to sodium hydride (0.072g of 60% dispersion in oil, washed with hexane) stirred in dry DMF (10 ml), at room temperature. After completion of the addition, the mixture was stirred for 5 minutes, and then 2-chloropyrimidine (0.92g) was added, and then stood overnight. It was then poured into water, acidified and extracted with ether. The ether extracts were dried and evaporated to give a yellow oil (0.95g).
This was purified by HPLC (eluant 1:1, ethyl acetate hexane) to give the pure title compound (0.104g), as an oil.
1H n.m.r. !270 MHz) delta : 3.60 (3H, s), 3.75 (3H, s), 5.39 (2H, s), 6.86-6.96 (3H, m), 7.03-7.31 (6H, m), 7.49 (1H, s), 8.50 (2H, d) ppm.
IR maxima (film): 1713, 1640 cm'l.
EXAMPLE 20 This Example illustrates the preparation of (E,E)and (E,Z)-methyl 3-methoxy-2-(2-:3-(4-nitrostyryl)- phenoxy]phenyl)propenoate (Compound mixture No. 403 of Table I).
Dimethyl phosphite (1.39g) in dry DMF (5 ml) was added dropwise to a stirred suspension of sodium hydride (0.61g of a 50% dispersion in oil, washed with hexane) in dry DMF (10 ml), at 20 C. After completion of the addition, and stirring for a further 20 minutes, (E)methyl 3-methoxy-2-(2-E3-bromomethylphenoxy]phenyl ) - propenoate (7.0g of 70% pure material, prepared as described in Example 8) was added dropwise. The reaction mixture stood for 60 hours, and was then heated to 550C for 10 hours, and then poured into water and extracted with ethyl acetate.The extract was dried and evaporated to give a viscous yellow gum, which was purified by flash chromatography (eluant 5% methanol in ethyl acetate) to give the phosphonate (E )-methyl 3-methoxy-2-E3-(dimethyl- phosphonomethyl)phenoxy]phenylpropenoate as a nearly colourless oil (1.50g).
lH n.m.r. (400 MHz) delta : 3.13 (2H, d), 3.62 (3H, s), 3.66 (3H, s), 3.68 (3H, s) 3.78 (3H, s), 6.85 (lH, d), 6.92 (2H, d), 7.00 (lH, d), 7.13 (lH, t), 7.20-7.31 (4H, m), 7.48 (lH,s) ppm.
IR maxima (film): 1715, 1645 cm'l, This phosphonate (0.61g) in dry DME (5 ml) was added dropwise to sodium hydride (0.072g of a 50% dispersion in oil, washed with hexane) stirred in dry DME (10 ml) at 5 C under nitrogen. After completion of the addition, the reaction mixture was warmed to room temperature and stirred for 15 minutes. 4-Nitrobenzaldehyde (0.227g) in dry DME (5 ml) was slowly added dropwise to the reaction mixture which was then stirred overnight at room temperature. Water was then added and the mixture was extracted with ether. The ether layer was dried and evaporated to give a viscous yellow oil, which was purified by HPLC (eluent 3:1, hexane: ethyl acetate) to give the title compound as a 5:1 mixture of (Z):(E)stilbene isomers (yellow gum, 0.20g).
1H n.m.r. (270 MHz) delta : Edata for (Z)-isomer] 3.57 (3H, s), 3.74 (3H, s), 6.58 (1H, d), 6.72 (1H, d), 6.72 6.98 (3H1 m), 7.05-7.36 (7H, m), 7.45(1H, s) 8.06 (2H, d) ppm.
This mixture could be isomerised to an 85:15 (E):(Z)stilbene isomer mixture by heating uner reflux with a trace of iodine in toluene.
1H n.m.r. (400 MHz) delta (data for (E)-isomer) : 3.62 (3H, s), 3.78 (3H, s), 6.92-7.35 (lOH, m), 7.49 (lH, s), 7.61 (2H, d), 8.22 (2H, d) ppm.
EXAMPLE 21 This Example illustrates the preparation of (E)methyl 3-methoxy-2-(2-E3-benzoyloxymethylphenoxy]phenyl)- propenoate (Compound No. 398 of Table I).
(E)-Methyl 3-methoxy-2-(2-[3-bromoethylphenoxy]phenyl)propenoate (0.5g of 75% pure material, prepared as described in Example 8), benzoic acid (0.13g) and potassium carbonate (0.076g) were stirred in dry DMF at room temperature overnight. Water was then added and the mixture was extracted with dilute aqueous bicarbonate, dried and evaporated to give a yellow viscous oil (0.49g), which was purified by HPLC (eluent 5:2, hexane:ethyl acetate) to give the title compound (0.120g).
1H n.m.r. (400 MHz) delta : 3.60 (3H, s), 3.75 (3H, s), 5.31 (2H, s), 6.93 (1H, d), 6.96 (1H, d), 7.06 (1H, s), 7.12(lH, d), 7.16 (1H, d), 7.44 (2H, t), 7.25-7.32 (2H, m), 7.47 (1H, s), 7.55 (1H, d), 8.05 (2H, d) ppm.
EXAMPLE 22 This Example illustrates the preparation of (E)methyl 3-methoxy-2-(2-[3-(triphenylphosphoniomethyl) phenoxyzphenyl)propenOate bromide salt (Compound No. 404 of Table I).
(E)-Methyl 3-methoxy-2-(2-[3-bromomethylphenoxy]phenyl)propenoate (4.58g of 708 pure material, prepared as described in Example 8) and triphenylphosphine (2.33g) were stirred in dry THF (40 ml) at room temperature, for 4 hours, and then stood overnight. The solvent was evaporated to give a sticky residue which was triturated with ether/ethyl acetate to give the title compound as a yellow-white solid (4.38g), m.p. 176-177 C.
1H n.m.r. (270 MHz) delta : 3.56 (3H, s), 3.74 (3H, s), 5.28 (2H, d), 6.48 (1H, s), 6.62 (1H, d), 6.77 (1H, d), 6.97 (1H, d), 7.04 (1H, t), 7.10-7.28 (3H, m), 7.40 (1H, s) 7.54-7.80 (15H, m) ppm.
EXAMPLE 23 This example illustrates the preparation of (E,E)methyl 3-methoxy-2-(2-[3-styrylphenoxy]phenyl)propenoate (Compound No. 18 of Table I).
(E)-Methyl 3-methoxy-2-(2-[3-(triphenylphosphonio methyl )phenoxy]phenyl ) propenoate bromide salt (lOg, prepared as described in Example 22) in dry DMF (5 ml) was added dropwise to sodium hydride EO.075g of a 50% dispersion in oil, washed with hexane] in dry DMF (5 ml) to give an orange solution. After completion of hydrogen evolution (2 hours), benzaldehyde (0.66g) in dry DMF (5 ml) was added and the reaction mixture was stirred at room temperature for 20 hours and then heated to 600C for 2 hours. Water was then added and the mixture was extracted with ethyl acetate. The organic extract was dried and evaporated to give a yellow oil (1.3g) which was purified by HPLC (eluent THF: hexane, 1:4) to give a 1:1 mixture of the title compound and the corresponding (Z)-styryl isomer (0.362g).
This (Z):(E) mixture was isomerised to the (E)-isomer only by refluxing in toluene with a crystal of iodine for a few hours to give the (E)-isomer as a colourless gum.
1H n.m.r. (270 MHz) delta : 3.64 (3H, s), 3.77 (3H, s), 6.88(1H, d), 6.96-7.40 (10H, m), 7.49(1H, s), 7.48 (2H, m) ppm.
IR maxima (film) : 1710, 1640 cm 1.
EXAMPLE 24 This Example illustrates the preparation of (E)-methyl 3-methoxy-2-(2-[3-phenoxycarbonylphenoxy]phenyl)propenoate (Compound No. 50 of Table I).
To (E)-methyl 3-methoxy-2-(2-E3-hydroxymethyl- phenoxy]phenyl)propenoate (2.43g, prepared as described in Example 17) stirred in acetone (100 ml) at 5-10 C, was added chromic acid Remade by dissolving chromium trioxide (6.5g) in 18.5 ml water containing 5.5 ml of concentrated sulphuric acid] until a reddish brown colour persisted, and GC indicated the disappearance of all the starting alcohol. The mixture was then poured into water and extracted with ether. The ether extracts were washed with water, dried and evaporated to give (E)-methyl 3-methoxy2-(2-[3-carboxyphenoxy]phenyl)propenoate as a pale yellow oil (2.495g).
1H n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.76 (3H, s), 6.95 (1H, d), 7.14-7.40 (5H, m), 7.50 (1H, s), 7.66 (1H, s), 7.78 (1H, d), 9.35 (1H, br s) ppm.
IR maxima (film): 3500-2500, 1725, 1640 cm 1.
The carboxylic acid from the previous stage (0.33g) stirred in dry THF (10 ml) was treated with oxalyl chloride (0.11 ml) and one drop of dry DMF. The reaction mixture was stirred for 45 minutes, stood overnight and then evaporated to give crude ()methyl 3-methoxy-2-(2 [3-chlorocarbonylphenoxy]phenyl)propenoate as an orangeyellow oil.
IR maxima (film): 1760, 1715, 1640 cm' 1 To the acid chloride from the previous stage in dry THF (15 ml) was added a mixture of phenol (0.090g) and triethylamine (0.096g) in dry THF (5 ml). The reaction mixture was stirred at room temperature for 1.5 hours and then poured into water and extracted with ether. The ether extracts were washed with dilute sodium hydroxide and then water, and were then dried and evaporated to give the title compound (136mg) as an orange oil.
1H n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.77 (3H, s), 6.94(lH, d), 7.14 (2H, t), 7.23-7.38(3H, m), 7.47 (1H, s), 7.61 (1H, t), 7.72 (1H, d) ppm.
IR maxima (film) : 1755, 1710, 1640 cm 1.
EXAMPLE 25 This Example illustrates the preparation of (E)methyl 2-[2-(3-[6-chloropyrimidin-4-yloxy-]phenoxy)phenyl]3-methoxypropenoate (Compound No. 89 of Table II).
Potassium carbonate (0.46g), cuprous chloride (0.027g) and 4,6-dichloropyrimidine (0.41g) were added successively to a stirred solution of (E)-methyl 2-E2-(3- hydroxyphenoxy)phenyl]-3-methoxypropenoate (1.0g, prepared as described in Example 1) in DMF (10 ml) and the resulting mixture was stirred for 10 hours at room temperature. The mixture was diluted with water and extracted with ether. The extracts were washed successively with aqueous sodium bicarbonate and water, dried, concentrated and chromatographed using ether:hexane (1:1) as eluant to give the title compound (0.39g, 28% yield) as a colourless oil.
1H n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.76 (3H, s), 6.74 (lH, t), 6.81 (1H, dd), 6.90 (2H, m), 7.03 (1H, m), 7.17 (1H, t), 7.26-7.36 (3H, m), 7.49 (1H, s), 8.59 (1H, s) ppm.
EXAMPLE 26 This Example illustrates the preparation of (E)methyl 3-methoxy-2-E2- (3-pyrimidin-4-yloxyphenoxy)phenyl] - propenoate (Compound No. 92 of Table II).
A solution of sodium hypophosphite (0.27g) in water (5 ml) was added dropwise with stirring to a mixture of (E)-methyl 2-E2-(3-E6-chloropyrimidin-4-yloxy]phenoxy) phenyl]-3-methoxypropenoate (0.4g, prepared as described in Example 25), potassium carbonate (0.2g) and 5% palladium on carbon (0.08g) in THF (4 ml). The resulting mixture was stirred at room temperature for 2 hours, then filtered through 'Hyflo', rinsing with ethyl acetate and water. The combined filtrate and washings were separated into aqueous and organic layers. The latter was dried, concentrated and chromatographed using a 1:1 mixture of ether and hexane as eluant to give the title compound (0.19g, 52% yield) as a colourless oil.
1H n.m.r. (270 MHz) delta : 3.61 (3H, s), 3.75 (3H, s), 6.75 (1H, t), 7.48 (1H, s), 8.56 (1H, d), 8.76 (1H, s) ppm.
EXAMPLE 27 This Example illustrates the preparation of (E)methyl 3-methoxy-2-[2-(3-[3-nitrophenoxy]phenoxy)phenyl]propenoate (Compound No. 132 of Table I).
A mixture of 3-(3-nitrophenoxy)phenol (1.7g), (E)- methyl 2-(2-bromophenyl)-3-methoxypropenoate (2.0g, prepared as described in Example 13), potassium carbonate (1.0g) and cuprous chloride (1.0g) was stirred at 170 180 CC for 5 hours then allowed to cool. The mixture was diluted with water and extracted with ether. The extracts were washed successively with aqueous sodium hydroxide and brine, then dried and concentrated to give a brown oil (3.12g). Chromatography using varying proportions of ether (up to 20%) in hexane as eluant gave the title compound (1.06g, 34% yield) as a yellow oil.
1H n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.76 (3H, s), 6.66-6.83 (3H, m), 7.02 (1H, d), 7.18 (1H, d), 7.22-7.38 (3H, m), 7.45-7.52 (1H, m), 7.49 (1H, s), 7.78 (1H, m), 7.92-7.97 (1H, m) ppm.
EXAMPLE 28 This Example illustrates the preparation of (E)methyl 3-methoxy-2-(2-[3-(3-methoxyphenoxymethyl)phenoxy]phenyl)propenoate (Compound No. 372 of Table I).
(E)-Methyl 3-methoxy-2-(2-[3-methylphenoxy]phenyl)propenoate (0.50g, prepared as described in Example 8), 1,3-dibromo-5,5-dimethylhydantoin (0. 32g) and azoisobutyronitrile (0.033g) were heated under reflux in carbon tetrachloride (40 ml), while being irradiated with a 400 watt tungsten lamp. After 1 hour the mixture was cooled and poured into water. The organic layer was separated, washed with water, dried and evaporated to give a yellow viscous oil (0.825g), containing about 65% of (E)-methyl 3-methoxy-2-(2-E3-bromomethylphenoxy]phenyl) propenoate, which was used without further purification (see Example 8 for 1H n.m.r. data).
A solution of the crude bromide (0.41g) in dry DMF (4 ml) was added to a solution of sodium 3-methoxyphenoxide (generated from 3-methoxyphenol and sodium hydride) in dry DMF (6 ml), and the mixture was stirred for 4 hours and then allowed to stand overnight. The reaction mixture was poured into dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic fractions were dried and evaporated to give a brown oil. This was purified by HPLC (eluant 7:3, 40/60 petroleum ether:ethyl acetate) to give the title compound (0.20g) as a colourless gum.
IR maxima (film) : 1715, 1640 cm'l, 1H n.m.r. (400 MHz) delta : 3.60 (3H, s), 3.73 (3H, s), 3.77 (3H, s), 4.99 (2H, s), 6.50-6.55 (3H, m), 6.88-6.95 (2H, m), 7.05 (1H, s), 7.09 7.20 (3H, m), 7.24-7.31 (3H, m), 7.47 (1H, s) ppm.
EXAMPLE 29 This Example illustrates the preparation of (E)methyl 3-methoxy-2- (2-E3-benzoylphenoxy)phenyl )propenoate, (Compound No. 12 of Table I).
Methyl 2-(3-hydroxymethylphenoxy)phenylacetate (10.0gel preparared as described in Example 17) and celite (log) were mixed in methylene chloride (100 ml), and pyridinium chlorochromate (15.85g) was added in one portion. After stirring at room temperature for 2.5 hours, the mixture was filtered and the filtrate was evaporated to give methyl 2-(3-formylphenoxy)phenylacetate as an orange oil (8.48g), which was pure enough to use without further purification.
IR maxima (film) : 1740, 1700 cm 1.
1H n.m.r. (270 MHz) delta : 3.59 (3H, s), 3.69 (2H, s), 6.92 (1H, d), 7.14-7.20 (1H, t), 7.23-7.37 (3H, m), 7.43 (1H, m), 7.50 (Ia, t), 7.60 (1H, dd), 9.95 (1H, s) ppm.
Phenylmagnesium bromide (2.84 ml of a 3M solution in ether) was added dropwise to a cooled and stirred solution of the aldehyde from the preceding stage (2.30g) in THF so that the temperature did not rise above -30 C. After completion of the addition (35 minutes), the reaction mixture was slowly warmed to room temperature, stirred ovenight and then cooled in an ice bath while water was carefully added. Dilute hydrochloric acid was then added, and the mixture was extracted with ethyl acetate. The extracts were dried and evaporated to give a yellow oil which was purified by flash chromatography (eluant 2:1, hexane:ethyl acetate) to give methyl 2-t(3-(alpha- hydroxy)benzyl)phenoxy)phenylacetate as a pale yellow oil (1.69g).
1H n.m.r. (270 MHz) delta : 3.57 (3H, s), 3.68 (2H, s), 5.79 (1H, s), 6.79-6.90 (2H, m), 7.05-7.13 (3H, m), 7.18 7.40 (9H, m) ppm.
The hydroxy-ester from the preceding preparation (0.91g) was stirred in methylene chloride (25 ml) at room temperature, with two spatula portions of celite.
Pyridinium chlorochromate (0.65g) was then added, and the reaction mixture was stirred for 3 hours. The mixture was filtered and the filtrate was evaporated and purified by HPLC (eluant 3:1, hexane:ethyl acetate) to give methyl 2 (3-benzoylphenoxy)phenylacetate as a pale yellow gum (0.56g).
1H n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.70 (2H, s), 6.93 (1H, d), 7.10-7.63 (lOH, m), 7.81 (2H, d) ppm.
IR maxima (film) : 1740, 1660 cm 1.
This material was converted into the title compound using sodium hydride and methyl formate and then potassium carbonate and dimethyl sulphate in the two steps described for a similar transformation in Example 7.
IR maxima (film) : 1710, 1660, 1635 cm 1.
1H n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.75 (3H, s), 6.98 (1H, d), 7.12-7.20 (2H, m), 7.26-7.52 (8H, m), 7.47 (1H, s), 7.55-7.63 (1H, m), 7.80 (2H, dd) ppm.
EXAMPLE 30 This Example illustrates the preparation of (E)methyl 3-methoxy-2-(2-[3-benzylphenoxyaphenyl)propenOate, (Compound No. 9 of Table I).
Trifluoroacetic acid (3.28g) was added dropwise with stirring to methyl 2-[(3-(alpha-hydroxy)benzyl)phenoxy]- phenylacetate (1.68g, prepared as described in Example 29) at 5CC. After completion of the addition, triethylsilane (2.24g) was slowly added dropwise. The resultant clear solution was then stirred overnight, diluted with water and extracted with ether. The ether fraction was washed with aqueous sodium bicarbonate, dried, concentrated and purified by HPLC (eluant 4:1, hexane:ether) to give methyl 2-(3-benzylphenoxy)phenylacetate (1.03g) as a colourless oil.
IR maximum (film) : 1742 cm 1.
This material was converted into the title compound using sodium hydride and methyl formate and then potassium carbonate and dimethyl sulphate in the two steps described for a similar transformation in Example 7.
IR maxima (film) : 1708, 1635 cm 1.
1H n.m.r. (270 MHz) delta : 3.56 (3H, s), 3.72 (3H, s), 3.93 (2H, s), 6.76-6.93 (4ski m), 7.08-7.31 (lOH, m), 7.47 (1H, s) ppm.
EXAMPLE 31 This Example illustrates the preparation of (E)methyl 3-methoxy-2-E2-(3-EN-phenylsulphonamido]phenoxy)- phenyl]propenoate (Compound No. 78 of Table I).
A mixture of 2-bromophenylacetic acid (21.5g), 3nitrophenol (29.2g), potassium carbonate (27.6g) and cuprous chloride (0.5g) was heated with stirring at 1300C for 6 hours. After cooling, the mixture was poured into water (500 ml), acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 200 ml). The extracts were dried, filtered and concentrated to give a dark oil. The oil was dissolved in methanol (400 ml) containing concentrated sulphuric acid (4 ml) and the resulting solution was heated at reflux for 3 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (300,my). This solution was washed successively with sodium hydroxide (2 x 100 ml of 1M aqueous solution) and brine, then dried, filtered and concentrated to give a dark oil.Bulb-to-bulb distillation of this oil (220"C oven temperature, 0.2 mmHg) gave methyl 2-(3-nitrophenoxy)phenylacetate (16.74g, 58% yield from 2-bromophenylacetic acid) as a clear pale oil.
H n.mr. (270 MHz) delta : 3.60 (3H, s), 3.70 (2H, s), 6.9-8.0 (8H, m) ppm.
IR maximum (film) : 1739 cm 1.
A mixture of methyl 2-(3-nitrophenoxy)phenylacetate (15g), methanol (100 ml), glacial acetic acid (100 ml), and iron powder (15.0g) was gently heated with stirring to reflux. After 30 minutes the mixture was cooled and the excess iron powder was filtered off. This filtrate was poured into water (700 ml) and extracted with ether (2 x 200 ml). The ether extracts were neutralized by stirring with aqueous sodium bicarbonate then dried, filtered and concentrated to give methyl 2-(3aminophenoxy)phenylacetate (13.0g, 97% yield) as a pale yellow oil.
1H n.m.r. (270 MHz) delta : 3.63 (3H, s), 3.68 (2H, s), 3.9 (1H, br s), 6.2-7.3 (8H, m) ppm.
IR maxima (film) : 3400, 3373, 1733 cm 1.
A mixture of methyl 2-(3-aminophenoxy)phenylacetate (11.54g) and methyl formate (27.7 ml) in DMF (25 ml) was added dropwise to a stirred suspension of sodium hydride (3.25g) in DMF (50 ml) cooled in ice to below 10 C (effervescence). Following the addition, the reaction mixture was stirred at room temperature for 3 hours, poured into water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. These extracts were washed with brine, dried and concentrated to give a viscous yellow oil. Potassium carbonate (12.4g) and dimethyl sulphate (4.25 ml) were added successively to a stirred solution of this yellow oil in DMF (50 mls) and the resulting mixture was stirred at room temperature for 3 hours, poured into water and extracted with ethyl acetate.The extracts were washed with water, dried and concentrated to give (E)-methyl 2-E2-(3-formamidophenoxy )- phenyl]-3-methoxypropenoate (13.67, 93% yield) as a clear green gum.
1H n.mr. (270 MHz) delta : 3.60 (3H, s), 3.78 (3H, s), 7.47 (1H, s) ppm.
IR maxima (film) : 3309, 1702, 1606 cm 1 Phosphoryl chloride (7.8 ml) was added dropwise to a stirred solution of (E)-methyl 2-E2-(3-formamidophenoxy)- phenyl]-3-methoxypropenoate (13.67g) in methanol (100 ml), the temperature during the addition being kept below 50 C with the aid of a cooling bath. After stirring for 20 minutes, the reaction mixture was poured into water (500 ml), neutralized with sodium bicarbonate and extracted with ether. The extracts were dried and concentrated to give a yellow oil which was chromatographed using ether as the eluant to give (E)-methyl 2-E2-(3-aminophenoxy)- phenyl]-3-methoxypropenoate (8.57g, 68% yield) as a yellow solid, m.p. 83-85"C.
n.m.r. (270 MHz) delta : 3.6 (2H, br s), 3.62 (3H, s), 3.77 (3H, s), 6.2-6.4 (3H, m), 6.9-7.3 (5H, m), 7.48 (1H, s) ppm.
IR maxima (film) : 3450, 3370, 1703, 1632 cm"l, A solution of (E)-methyl 2-E2-(3-aminophenoxy)- phenyl3-3-methoxypropenoate (0.4g) in glacial acetic acid (2 ml) was treated with 5.8M hydrochloric acid (1 ml), at -10 C. The stirred solution was then treated with sodium nitrite (0.lg in 2 ml of water) still at -100C. After 30 minutes, the resulting solution (containing the diazonium salt) was added to a stirred mixture of glacial acetic acid (0.5 ml) saturated with sulphur dioxide, containing O.lg of cuprous chloride (effervescence). After 30 minutes, the reaction mixture was poured into water and extracted with ether.The ether extracts were neutralized with a saturated aqueous solution of sodium bicarbonate, dried and concentrated to give (E)-methyl 2-E2-(3-chloro- sulphonylphenoxy)phenyl]-3-methoxypropenoate (0.14g) as a yellow oil.
IR maxima (film) : 1710, 1636 cm 1 A solution of methyl 2-E2- (3-chlorosulphonylphenoxy)- phenyl)-3-methoxypropenoate (0.14g) in pyridine (0.5ml) was treated dropwise with aniline (0.05 ml) at room temperature with stirring. After 3 hours the reaction mixture was poured into water. 2M Hydrochloric acid was added to the resulting mixture until it was slightly acidic and it was extracted with ether. The ether extracts were washed with brine, dried, concentrated and chromatographed using ether as the eluant to give the title compound (0.145g) as a clear oil.
IR maxima (film) : 3240, 1693, 1635, 1600 cm 1.
1H n.m.r. (270 MHz) delta ; 3.55 (3H, s), 3.69 (3H, s), 6.53 (1H, br s), 6.8 (1H, m), 7.0-7.4 (12H, m), 7.43 (1H, s) ppm.
EXAMPLE 32 This Example illustrates the preparation of (E)methyl 2-[2-(3-[3-bromobenzoylamino]phenoxy)phenyl]-3methoxypropenoate (Compound No. 421 of Table I).
3-Bromobenzoyl chloride (0.37g) was added to a stirred solution of (E)-methyl 2-E2-(3-aminophenoxy)- phenyl]-3-methoxypropenoate (0.5g, prepared as described in Example 31) in dichloromethane (20 ml) containing triethylamine (0.17g). After 3 hours, the reaction mixture was poured into water and extracted with dichloromethane (2 x 50 ml). The extracts were dried, concentrated and chromatographed using ether as the eluant to give the title compound (0.61g) as a pale yellow foam.
IR maxima (nujol) : 1710, 1680, 1640, 1605 cm 1.
1H n.m.r. (270 MHz) delta : 3.62 (3H, s), 3.78 (3H, s), 6.73-8.0 (13H, m), 7.47 (1H, s) ppm.
EXAMPLE 33 This Example illustrates the preparation of (E)methyl 2-[2-(3-pyridin-2-yloxyphenoxy)phenyl]-3methoxypropenoate (Compound No. 1 of Table II).
Potassium carbonate (0.92g), cuprous chloride (catalytic), copper bronze (catalytic) and 2-fluoropyridine (1.94g) were added successively to a stirred solution of (E)-methyl 2-E2-(3-hydroxyphenoxy)phenyl]-3- methoxypropenoate (2.0g, prepared as described in Example 1) in DMF (15 ml). The resulting mixture was stirred for 3 hours at 130 C. After cooling, the mixture was diluted with water and extracted with ether (x 2). The combined extracts were washed successively with aqueous sodium hydroxide, water and brine, then dried and concentrated.
Chromatography using ether-hexane mixtures as eluant gave the title compound (1.68g, 67% yield) as an orange-yellow gummy oil.
1H n.m.r. (270 MHz) delta : 3.60 (3H1 s), 3.73 (3H, s), 6.72-7.32 (lOH, m), 7.48 (1H, s), 7.67 (1H, m), 8.19 (1H, m) ppm.
EXAMPLE 34 This Example illustrates the preparation of (E)methyl 2-[2-(3-[6-chloropyridazin-3-yloxy]phenoxy)phenyl]3-methoxypropenoate (Compound No. 130 of Table II).
Potassium carbonate (0.93g), cuprous chloride (catalytic) and 3,6-dichloropyridazine (1.0g) were added successively to a stirred solution of (E)-methyl 2-E2-(3- hydroxyphenoxy )phenyl]-3-methoxypropenoate (2.01g, prepared as in Example 1) in DMF (30 ml). The resulting mixture was stirred for 12 hours at 95 C. After cooling, the mixture was diluted with water and extracted with ether (x 2). The combined extracts were washed successively with aqueous sodium hydroxide, water and brine, then dried and concentrated. Chromatography using ether-hexane mixtures gave the title compound (1.71g, 62% yield) as a yellow gum.
1H n.m.r. (270 MHz) delta : 3.60 (3H, s), 3.73 (3H, s), 6.73-7.36 (9H, m), 7.46 (1H, m), 7.50 (1H, s) ppm.
The following are examples of compositions suitable for agricultural and horticultural purposes which can be formulated from the compounds of the invention. Such compositions from another aspect of the invention.
Percentages are by weight.
EXAMPLE 35 An emulsifiable concentrate is made up by mixing and stirring the ingredients until all are dissolved.
Compound No. 212 of Table I 10% Benzyl alcohol 30% Calcium dodecylbenzenesulphonate 5% Nonylphenolethoxylate (13 moles ethylene oxide) 10% Alkyl benzenes 45% EXAMPLE 36 The active ingredient is dissolved in methylene dichloride and the resultant liquid sprayed on to the granules of attapulgite clay. The solvent is then allowed to evaporate to produce a granular composition.
Compound No. 212 of Table I 5% Attapulgite granules 95% EXAMPLE 37 A composition suitable for use as a seed dressing is prepared by grinding and mixing the three ingredients.
Compound No. 212 of Table I 50% Mineral oil 2% China clay 48% EXAMPLE 38 A dustable powder is prepared by grinding and mixing the active ingredient with talc; Compound No. 212 of Table I 5% Talc 95% EXAMPLE 39 A suspension concentrate is prepared by ball milling the ingredients to form an aqueous suspension of the ground mixture with water.
Compound No. 212 of Table I 40% Sodium lignosulphonate 10% Bentonite clay 1% Water 49% This formulation can be used as a spray by diluting into water or applied directly to seed.
EXAMPLE 40 A wettable powder formulation is made by mixing together and grinding the ingredients until all are thoroughly mixed.
Compound No. 212 of Table I 25% Sodium lauryl sulphate 2% Sodium lignosulphonate 5% Silica 25% China clay 43% EXAMPLE 41 The compounds were tested against a variety of foliar fungal diseases of plants. The technique employed was as follows.
The plants were grown in John Innes Potting Compost (No. 1 or 2) in 4cm diameter minipots. The test compounds were formulated either by bead milling with aqueous Dispersol T or as a solution in acetone or acetone/ethanol which was diluted to the required concentration immediately before use. For the foliage diseases, the formulations (100 ppm active ingredient except where otherwise indicated) were sprayed onto the foliage and applied to the roots of the plants in the soil. The sprays were applied to maximum retention and the root drenches to a final concentration equivalent to approximately 40 ppm a.i./dry soil. Tween 20, to give a final concentration of 0.05%, was added when the sprays were applied to cereals.
For most of the tests the compound was applied to the soil (roots) and to the foliage (by spraying) one or two days before the plant was inoculated with the disease. An exception was the test on Erysiphe graminis in which the plants were inoculated 24 hours before treatment. Foliar pathogens were applied by spray as spore suspensions onto the leaves of test plants. After inoculation, the plants were put into an appropriate environment to allow infection to proceed and then incubated until the disease was ready for assessment. The period between inoculation and assessment varied from four to fourteen days according to the disease and environment.
The disease control was recorded by the following grading 4 = no disease 3 = trace -5% of disease on untreated plants 2 = 6-258 of disease on untreated plants 1 = 26-59% of disease on untreated plants 0 = 60-1008 of disease on untreated plants The results are shown in Table VI.
TABLE VI
COMPOUND TABLE PUCCINIA ERYSIPHE VENTURIA PYRICULARIA CERCOSPORA PLASMOPARA PHYTOPHTHORA NO NO. RECONDITA GRAMINIS INAEQUALIS ORYZAE ARACHIDICOLA VITICOLA INFESTANS (WHEAT) (BARLEY) (APPLE) (RICE) (PEANUT) (VINE) (TOMATO) 1 I 4 4 4 4 4 4 3 2 I 4 2 4 4 4 4 0 3 I 3 0 4 2 4 4 0 4 I 4 4 4 3 4 4 3 5 I 4 4 4 3 4 4 2 6 II 4 4 4 4 4 4 4 7 I 3 4 4 3 4 4 0 12 I 4 3 4 4 4 4 4 18 I 4 3 4 4 - 4 0 21 I 4 4 0 0 4 4 4 22 II 4 4 4 3 4 4 4 22 IV 4 0 4 4 4 4 3 23 I 4 3 4 4 4 4 4 24 I 4 4 4 3 4 4 2 25 I 4 3 4 3 4 4 3 27 I 4 0 4 4 3 4 3 29 I 4 3 4 0 4 4 3 38 I 4 3 3 4 4 4 4 38 II 4 4 4 4 2 4 3 47 II 0 4 4 3 4 4 3 49 I 4 2 4 3 4 4 3 50 I 3 0 3 2 0 4 2 51 I 4 4 3 4 4 4 4 52 II 4 4 4 4 4a - 0 53 II 4 3 4 4 4 4 4 62 I 4 3 4 4 4 3 4 67 I 3 4 4 3 3 4 3 81 II 4 4 0 3 1 4 3 TABLE VI (CONT/D)
COMPOUND TABLE PUCCINIA ERYSIPHE VENTURIA PYRICULARIA CERCOSPORA PLASMOPARA PHYTOPHTHORA NO NO. RECONDITA GRAMINIS INAEQUALIS ORYZAE ARACHIDICOLA VITICOLA INFESTANS (WHEAT) (BARLEY) (APPLE) (RICE) (PEANUT) (VINE) (TOMATO) 83 II 3 4 4 4 2 4 3 84 I 3 0 4 0 0 4 0 84 II 4 4 4 3 4 4 1 85 II 4 4 4 4 4 4 4 86 I 1 0 4 1 4 4 0 86 II 0 0 0 0 0 2 0 87 II 3 4 4 4 2 4 3 87 IV 3a 0a 4a 3a 4a 4a 0a 89 II 4 4 4 3 4 4 3 90 II 4 4 4 4 4 4 3 93 II 4 3 4 3 2 4 0 94 II 4 3 4 4 4 4 4 95 II 1 0 4 0 1 4 0 96 I 4 4 4 2 4 4 2 96 II 4 0 3 1 0 4 3 98 II 4 4 4 4 4 4 4 99 II 3 4 4 3 1 4 0 100 II 4 4 4 4 4 4 3 105 II 3 4 4 4 4 4 3 111 I 3 0 4 3 2 4 0 115 I 4 3 4 4 4 4 3 119 I 4 4 4 4 4 4 4 120 I 4 3 4 3 4 4 4 122 I 4 4 4 3 4 4 4 124 I 4 4 4 4 4 4a 4 125 I 4 4 4 3 4 4 4 126 I 4 3 4 3 4 4 3 127 I 4 3 4 4 4 4 2 TABLE VI (CONT/D)
COMPOUND TABLE PUCCINIA ERYSIPHE VENTURIA PYRICULARIA CERCOSPORA PLASMOPARA PHYTOPHTHORA NO NO. RECONDITA GRAMINIS INAEQUALIS ORYZAE ARACHIDICOLA VITICOLA INFESTANS (WHEAT) (BARLEY) (APPLE) (RICE) (PEANUT) (VINE) (TOMATO) 128 I 4 4 4 3 4 4 4 129 I 4 2 4 4 4 4 4 130 I 4 3 4 - 4 4 4 131 I 4a 4a 4a 4a - 4a 4a 131 III 0a 0a 4c 4a 4a 0c 0c 132 I 4 4 4 4 4 4 3 133 I 4 2 4 4 4 4 2 134 I 4 4 4 4 4 4 4 135 I 4 4 4 4 4 4 3 138 I 4 4 4 3 4 4 4 141 I 4 4 4 3 4 4 0 143 I 4 4 4 3 4 3 3 144 I 4 4 4 3 4 4 0 145 I 4 3 4 3 4 4 1 150 I 3 3 4 4 3a - 0 157 I 3 3 4 3 4 0 0 171 I 4 4 4 4 3a - 0 175 I 4 4 4 4 3 4 0 177 I 4 4 4 3 - 4 0 179 I 1 1 0 0 2 4 0 204 I 4 4 4 4 4a - 0 205 I 4 4 4 4 3a - 1 206 I 4 4 4 4 4 4 3 208 I 4 4 4 - 3 4 3 212 I 4 4 4 4 4 4 0 214 I 4 4 4 - 4 4 4 216 I 4 3 4 - 4 4 4 217 I 4 4 4 3 3a - 0 TABLE VI (CONT/D)
COMPOUND TABLE PUCCINIA ERYSIPHE VENTURIA PYRICULARIA CERCOSPORA PLASMOPARA PHYTOPHTHORA NO NO. RECONDITA GRAMINIS INAEQUALIS ORYZAE ARACHIDICOLA VITICOLA INFESTANS (WHEAT) (BARLEY) (APPLE) (RICE) (PEANUT) (VINE) (TOMATO) 218 I 4 3 3 - 4 4 4 220 I 4 3 4 2 4 4 0 230 I 4 2 4 4 4 4 0 247 I 4 4 4 0 3 4 3 248 I 4 3 4 - 4 4 2 282 I 4 2 4 0 4 4 2 283 I 4 3 4 4 3 4 0 284 I 4 4 4 4 3 4 0 285 I 4 4 4 4 3 4 2 288 I 4 3 4 4 4 4 0 290 I 4 1 4 3 4 4 0 291 I 4 0 0 3 - 4 1 294 I 3 4 4 4 4 4 1 295 I 4 0 4 1 4 4 0 296 I 4 0 4 4 - 4 0 332 I 0a 0a - 2a - 4a 2a 333 I 4 1 2 3 - 4 0 360 I 4 4 4 4 4 4 1 365 I 4 3 4 3 - 4 3 366 I 0a 4a 3a 0a - 4a 0a 367 I 3a 1a 0a 1a 4a 3a 3a 368 I 1 0 0 0 - 0 0 369 I 4 0 3 2 - 4 0 370 I 4 2 4 4 - 4 4 371 I 4 4 4 3 4 4 3 372 I 4 4 4 3 4 4 2 373 I 3 4 4 3 4 4 3 374 I 3 4 4 4 3 4 3 375 I 4 4 4 3 1 4 2 TABLE VI (CONT/D)
COMPOUND TABLE PUCCINIA ERYSIPHE VENTURIA PYRICULARIA CERCOSPORA PLASMOPARA PHYTOPHTHORA NO NO. RECONDITA GRAMINIS INAEQUALIS ORYZAE ARACHIDICOLA VITICOLA INFESTANS (WHEAT) (BARLEY) (APPLE) (RICE) (PEANUT) (VINE) (TOMATO) 376 I 4 3 0 4 1 4 3 377 I 4 4 0 4 3 4 3 378 I 3 4 0 4 4 4 4 380 I 3 4 0 4 4 4 3 381 I 3 4 0 4 4 4 4 382 I 4 4 4 3 4 4 2 383 I 4 3 4 4 4 4 0 384 I 4 4 4 4 4 0 0 385 I 4 1 4 4 4 4 0 386 I 4 4 4 3 4 4 2 387 I 4 1 0 4 4 4 3 388 I 3a 4a 4a 4a 4a 3a 0a 389 I 4 3 4 3 4 4 4 390 I 4 4 4 2 4 4 2 391 I 4 3 4 4 4 4 2 392 I 4 2 4 4 4 4 0 393 I 4 4 4 4 4 4 0 394 I 4 3 4 4 4 4 0 395 I 3a 1a 4b 4a 4a 4b 3b 396 I 4 3 4 3 4 4 3 397 I 4 4 4 4 4 4 0 398 I 3 0 3 2 2 4 2 399 I 4a 3a 4a 4a 4a 4a 2a 400 I 2 0 4 4 2 4 0 401 I 4a 3a 4a 4a 4a - 0a 402 I 4 2 2 3 4 4 3 403 I 4 4 4 3 3 3 0 404 I 4 3 3 0 4 3 0 TABLE VI (CONT/D)
COMPOUND TABLE PUCCINIA ERYSIPHE VENTURIA PYRICULARIA CERCOSPORA PLASMOPARA PHYTOPHTHORA NO NO. RECONDITA GRAMINIS INAEQUALIS ORYZAE ARACHIDICOLA VITICOLA INFESTANS (WHEAT) (BARLEY) (APPLE) (RICE) (PEANUT) (VINE) (TOMATO) 405 I 4 4 4 4 4a - 0 406 I 3 0 4 0 0 4 0 407 I 4 4 4 0 - 4 0 408 I 3 0 4 1 4 4 0 409 I 4 0 3 0 4 4 0 410 I 4 2 4 3 4 4 1 410 III 4 2 3 3 - 4 1 411 I 4 3 4 4 4 4 3 411 III 4 2 3 0 0 3 0 412 I 4 3 4 4 4 4 2 413 I 4 2 4 4 4 4 0 414 I 4 1 4 3 4 4 0 423 I 4 4 4 4 4 4 3 424 I 4 3 4 4 4 3 4 a = 25 ppm foliar spray b = 15 ppm foliar spray c = 10 ppm foliar spray - = test failed/missing

Claims (1)

  1. CLAIM 1. A compound of the formula (IV):
    is herein defined.
GB9105678A 1987-09-09 1991-03-18 Acetals of methyl propenoate compounds Expired - Fee Related GB2241236B (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB878721221A GB8721221D0 (en) 1987-09-09 1987-09-09 Chemical process
GB878721706A GB8721706D0 (en) 1987-09-15 1987-09-15 Fungicides
GB888801485A GB8801485D0 (en) 1988-01-22 1988-01-22 Fungicides
GB888806317A GB8806317D0 (en) 1988-03-17 1988-03-17 Fungicides
GB888814734A GB8814734D0 (en) 1988-06-21 1988-06-21 Fungicides
GB8819878A GB2210041B (en) 1987-09-09 1988-08-22 Fungicidal derivatives of propenoic acid

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GB2241236A true GB2241236A (en) 1991-08-28
GB2241236B GB2241236B (en) 1992-07-08

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GB9105680A Expired - Fee Related GB2241238B (en) 1987-09-09 1991-03-18 Methyl esters of aryl-keto acid
GB9105678A Expired - Fee Related GB2241236B (en) 1987-09-09 1991-03-18 Acetals of methyl propenoate compounds
GB9105679A Expired - Fee Related GB2241237B (en) 1987-09-09 1991-03-18 Methyl esters of substituted phenyl propenoic acids

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GB9105679D0 (en) 1991-05-01
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GB2241238B (en) 1992-07-08
GB9105678D0 (en) 1991-05-01

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