AP649A - Heterocyclic and phenyl compounds. - Google Patents

Heterocyclic and phenyl compounds. Download PDF

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Publication number
AP649A
AP649A APAP/P/1996/000862A AP9600862A AP649A AP 649 A AP649 A AP 649A AP 9600862 A AP9600862 A AP 9600862A AP 649 A AP649 A AP 649A
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AP
ARIPO
Prior art keywords
optionally substituted
sch2ch2ch
alkyl
substituted
halogen
Prior art date
Application number
APAP/P/1996/000862A
Other versions
AP9600862A0 (en
Inventor
Michael Drysdale Turnbull
Harjinder Singh Bansal
Alison Mary Smith
Roger Salmon
Stephen Fitzjohn
Christopher Richard Ayles Godfrey
Matthiew Brian Hotson
Nan Catherine Sillars
Alan John Dowling
Original Assignee
Zeneca Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GB9404718A external-priority patent/GB9404718D0/en
Priority claimed from GB9404720A external-priority patent/GB9404720D0/en
Priority claimed from GB9404721A external-priority patent/GB9404721D0/en
Priority claimed from GB9404719A external-priority patent/GB9404719D0/en
Priority claimed from GB9404716A external-priority patent/GB9404716D0/en
Priority claimed from GB9404717A external-priority patent/GB9404717D0/en
Priority claimed from GBGB9500521.1A external-priority patent/GB9500521D0/en
Application filed by Zeneca Ltd filed Critical Zeneca Ltd
Publication of AP9600862A0 publication Critical patent/AP9600862A0/en
Application granted granted Critical
Publication of AP649A publication Critical patent/AP649A/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
    • C07D213/70—Sulfur atoms
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    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/16—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds containing nitrogen-to-oxygen bonds
    • A01N33/18—Nitro compounds
    • A01N33/20—Nitro compounds containing oxygen or sulfur attached to the carbon skeleton containing the nitro group
    • A01N33/22—Nitro compounds containing oxygen or sulfur attached to the carbon skeleton containing the nitro group having at least one oxygen or sulfur atom and at least one nitro group directly attached to the same aromatic ring system
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—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
    • A01N43/08—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 oxygen as the ring hetero atom
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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
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    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • 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
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • 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
    • A01N43/66—1,3,5-Triazines, not hydrogenated and not substituted at the ring nitrogen atoms
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • 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
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/713—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with four or more nitrogen atoms as the only ring hetero atoms
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
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    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
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    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/07—Preparation of halogenated hydrocarbons by addition of hydrogen halides
    • C07C17/087—Preparation of halogenated hydrocarbons by addition of hydrogen halides to unsaturated halogenated hydrocarbons
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    • C07C17/23—Preparation of halogenated hydrocarbons by dehalogenation
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/01—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton
    • C07C323/09—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • 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
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
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    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • 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
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

A compound of formula (i)r-s(o)nch2ch2ch=cf2, or a salt thereof, wherein n is 0, 1 or 2; and r is a group of formulae (ii)to (xxi), wherein: the s ch2ch2ch=cf2 group is at least one of r1 (when attached to a carbon atom). R2, r3, r4, r5 or r6; r1 (when attached to a ca atom)r2, r3 r4, r5 and r6 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, alkoxy, alkenyloxy, alkynyloxy, hydroxyalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, optionally substituted heteroaryloxyalky, haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, haloalkenyloxy, haloalkynyloxy, halogen, hydroxy, cyano, notro, -nr7r8, -nr7cor8, -nr7csr8, -nr7so2r8, -n(so2r7)(so2r8), -cor7, -conr7r8, -alkylconr7r8, cr7nr8, -coor7, -ocor7, -sr7, -sor7, so2r7, -alkylsr7, -alkylsor7, -alkylso2r7, -oso2r7, -so2nr7r8, -csnr7r8, sir7r8r9, -och2co2r7, -och2ch2co2r7, conr7so2r8, alkylconr7so2r8, -nhconr7r8, -nhcsnr7r8, or an adjacent pair of r1, r2, r3, r4, r5 and r6 when taken together form a fused 5- or 6-membered carbocyclic or heterocyclic ring; r1 (when attached to a nitrogen atom)is hydrogen, optionally substituted alkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryl, optionally substituted heteroarylakyl, optionally substituted heteroaryloxyalkyl, haloalkyl, hydroxy, cyano nitro, -nr7r8, -nr7cor8, nr7csr8, -nr7coor8, -nr7so2r8, -n(so2r7)(so2r8), -cor7, -conr7r8, alkylconr7r8, -cr7nr8, -coor7, -ocor7, -sor7, -so2r7, alkylsr7, -alkylsor7, alkylso2r7, -oso2r7, -so2nr7nr8, -sr7, -sor7, -so2r7, -csnr7r8, -sir7r8r7, -och2co2r7, och2ch2co2r7, conr7so2r8, alkylconr7so2r8, -nhcor7r8, or -nhcsr7r8; and r7, r8 and r9 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, optionally substituted aryl or optionally substituted arylalkyl, haloalkyl, haloalkeny, haloalkynyl, halogen, or hydroxy.

Description

(4,4-Dlfluorobut-3-enylth1o)-subst1tuted heterocyclic or carbocyclic ring compounds having pesticidal activity
The present invention relaxes to novel heterocyclic and phenyl derivatives hating nemaiicidal. insecticidal and acaricidal activity, to processes for their preparation. to compositions containing them, and to methods for killing or controlling nematode, insect or acarid pests using them.
According to the present invention there is provided a compound of formula (I). or a salt thereof, wherein n is 0. 1 or 2: and R is a group of formula (U) to (XXI). wherein:
the S(O)nCH2CH2CH=CF2 group is at least one of Rl (when attached to a carbon atom.), R2. R3, R4, R5 or R6;
Rl (when attached to a carbon atom), R2. R3, R4, R5 and R6 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, cycloalkyl, alkylcycloaikvl. alkoxy, alkenvloxy, alkynvloxy. hydroxyalkyl, alkoxvalkyl, optionally substituted aryl, optionally substituted arylalkvl, optionally substituted heteroaryl, optionally substituted heteroaiylalkyl, optionally substituted arvloxy, optionally substituted arylalkoxy, optionally substituted aryloxyalkvl, optionally substituted heteroaryloxy, optionally substituted heteroaryl alkoxy, optionally substituted heteroaryloxvalkyl. haloalkyl, haioalkenvl, haloalkynyl, haloalkoxy, haloalkenvloxy, haloalkynyloxv, halogen, hydroxy, cyano, nitro, -NR7R8. -NR7COR8. -NR7CSR8. -NR7SO2R8, -N(SO2R7)(SO2R8), -COR7, -CONR7R8, -alkylCONR7R8. -CR7NR8. -COOR7,-OCOR7. -SR7, -SOR7, -SO2R7, -alkylSR7, -alkylSOR7, -alkylSO2R7. -OSO2R7, -SO2NR7R8, -CSNR7R8, -SiR7R8R9, -OCH2CO2R7, -OCH2CH2CO2R7, -CONR7SO2R8. -alkvlCONR7SO2R8, -NHCONR7R8, -NHCSNR7R8. or an adjacent pair of Rl. R2. R3. R4, R5 and R6 when taken together form a fused 5- or '
6-membered carbocyclic or heterocyclic ring;
Rl (when attached to a nitrogen atom) is hydrogen, optionally substituted alkyl, cycloalkyl, alkylcycloaikvl. hydroxyalkyl, alkoxvalkyl, optionally substituted aryl, optionally substituted arylalkvl, optionally substituted aryloxyalkvl, optionally substituted heteroaryl, optional]}' substituted heieroaryiaikvl, optionally substituted heteroaryloxvalkyl, haloalkyl, hydroxy, cyano. nitro. -NR7R8. -NR7COR8. NR7CSR8. -NR7COOR8, -NR7SO2R8. -N(SO2R7)(SO2R8), -COR7. -CONR7R8. -alkylCONR7R8. -CR7NR8, -COOR7, -OCOR7, -SOR7. -SO2R7. -alkvlSR7. -alkylSOR7, -alkvlSO2R7, -OSO2R7. -SO2NR7NR8, -SR7. -SOR7. -SO2R7. -CSNR7R8. -SiR7R8R7. -OCH2CO2R7, -OCH2CH2CO2R7, -CONR7SO2R8. -alkviCONR7SO2R8. - NHCOR7R8. or -NHCSR7R8: and
AP/P/ 9 6 / 0 0 8 6 2
- 2 R7, R8 and R9 are each independently hydrogen, optionally substituted alky l, optionally substituted alkenyl, alkynyl. optionally substituted aryl, optionally substituted arylalkyl. haloalkyl, haloalkenvl, haloalkvnyl, halogen, or hydroxy.
We would explain that, for ease of reference only, the substituents on the R group have been named in accordance with their position on this R group. For example, when R has the formula (Π), substituents R2, R3, R4 and R5 are in positions 2, 3, 4, and 5, respectively, on the ring. For the avoidance of doubt, the -S(O)nCH2CH2CH=CF2 group can be at any of the substituent positions indicated by R1 (when attached to a carbon atom) to R6.
When any one of R1 to R9 is an alk\'l group, or contains an alkyd moiety; it may be straight or branched chain and is preferably Cl-6 alkyl, even more preferably Cl-4 alkyl, for example methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or t-butyl. When the alkyd group is acting as a linking” group, ie R-alkyl-, for example in R-alkvlSR7, Cl-4 alkyd or Cl-2 alkyd are particularly preferred.
When any one of R1 to R8 is a substituted alkyl group, or contains a substituted alkyl moiety, it may comprise one or more subsitutents chosen from halogen, nitro, cyano, COOR7 or a salt thereof hydroxy, alkoxy, alkoxyimino, alkoxvcarbonyl, carbamoyl, monoor di-alkydcarbamoyl, amino, mono- or di-alkylamino, acylamido (preferably Cl-6 acydamido), alkanesulfonyd, and arylsulfonyl, which may itself be substituted with halogen, alkoxy or nitro.
When any' one of R1 to R8 is an alkenyl or alkynyl group, or contains an alkenyl or alkynyl moiety, it may be straight or branched chain and is preferably C2-6 alkenyl or C2-6 alkynyl, even more preferably C2-4 alkenyl or C2-4 alkynyl, for example vinyl, allyl, but-3-enyl, 3-methyl-but-3-enyl, ethynyl or propargyl.
When any one of R1 to R8 is a substituted alkenyl group, or contains a substituted alkenyl moiety; it may comprise one or more subsitutents chosen from halogen, COOR7 or a salt thereof, hydroxy; nitro and cyano.
When any one of R1 to R6 is a cvcloalkyl or alkylcycloalkyl group, or contains a cvcloalkyl or alkylcycloalkyl moiety, it is preferably C3-6 cycloalkyl or C4-7 alkylcycloalkyl, for example, cyclopropyl, cyclopentyl, cyclohexvl or methylcyclopropyl.
When any one of R1 to R6 is an alkoxy, alkenvloxy, alkynyloxy or alkoxyalkyl group, or contains such a moiety; it is preferably Cl-6 alkoxy; for example, methoxy, ethoxy, n-propoxy; iso-propoxy, n-butoxy, iso-butoxy; sec-butoxv and t-butoxy; C2-6
AP.00649 —·
- J alkenyloxy, for example, vinyloxv, allvloxv. but-3-enyloxy and 3-methvlbut-3-enyloxy; C2-6 alkynyloxy, for example, propargyloxv; C2-6 monoalkoxyalkyl. for example, methoxymeihyl. methoxyethyl and ethoxymethyl; or C3-6 dialkoxvalkyl. for example, dimethoxymethyl and diethoxymethyl.
When any one of R1 to R9 is aiyl, or contains an aryl moiety, it is preferably C6-10 aryl, more preferably it is phenyl. When any one of R1 to R9 is arylalkyl, it is preferably C610 aryl-methyl or C6-10 aryl-ethyl, even more preferably benzyl or phenethyl.
When any one of R1 to R6 is heteroaryl, or contains a heteroaryl moiety', it is preferably a 5 or 6 membered ring containing at least one Ο, N or S atom as the heteroatom, for example, pyridine, pyrrole, pyrazine, furan or thiophene. When any one of R1 to R6 is heteroarylalkyl, it is preferably heteroaryl-Cl-2 alkyl.
When any one of R1 to R9 is a substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl group, it may comprise one or more substituents chosen from alkyl, alkoxy, haloalkyl halogen, hydroxy, COOR7 (or a salt thereof), aminosulfonyl, cyano or nitro. Examples of these groups are 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl,
3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-aminosulfonylphenvI, 4-chlorobenzyl,
4- fluorobenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-nitrobenzyl and
4-methylbenzyl.
When any one of R1 to R6 is a aryloxy or arvlalkoxy group, it is preferably phenoxy, benzyloxy or phenethoxy.
When any one of R1 to R6 is a substituted aryloxy, arvlalkoxy, heteroaryloxy or heteroarylalkoxy group, it may comprise one or more substituents chosen from alkyl, alkoxy, haloalkyl, hydroxy, cyano or nitro. Examples of these groups are 4-methylphenoxy,
4-chlorophenoxy, 4-fluorophenoxy, 4-nitrophenoxy, 3-trifluoromethylphenoxy, 4-trifluoromethylphenoxy 4-chlorobenzyloxy, 4-fluorobenzyloxy, 3-trifluoromethylbenzyloxy, 4-trifluoromethvlbenzyloxy, 4-nitrobenzyloxy and 4-methylbenzyloxy.
When any one of R1 to R9 is halogen, or contains a halogen moiety, it is preferably fluorine, chlorine, bromine or iodine. Even more preferably, it is fluorine, chlorine or bromine.
When any one of R1 to R9 is a haloalkyl, haloalkenyl or haloalkynyl group, it may contain one or more halogen atoms, preferably chlorine, fluorine or bromine. Examples of these groups are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 22-difluoroethenyl,
AP/P/ 96/00862
- 4 3.3- dichloroprop-2-enyl, 2-chloroprop-2-envl. 3,4.4-trifluorobut-3-enyl, 4-fluorobut-3-envl.
4.4- difluorobut-3-enyl and 3-methyM,4-difluorobut-3-enyl.
When any one of R1 to R6 is a haloalkoxy group, a haloalkenvloxy group or a haloalkynvloxy group, it may contain one or more halogen atoms, preferably chlorine, fluorine or bromine. Examples of the preferred Cl-6 alkoxy, C2-6 alkenvloxy and C2-6 alkynyloxy groups are trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy. 2-fluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 1,1,2,2-tetrafluoroethoxv.
2.2- difluoroethenyloxy, 3,4,4-trifluorobut-3-enyloxy, 4-fluorobut-3-enyloxy,
4.4- difiuorobut-3-enyloxv, 3-methyl-4,4-difluorobut-3-enyloxv, 2-chloroprop-2-enyloxy and
3.3- dichloroprop-2-enyloxy.
When any one of R1 to R6 is the group -NR7R8, it is preferably -NH2; a monoalkylamino group, for example, methylamino and ethylamino; or a di-alkvlamino group, for example, dimethylamino and diethylamino.
When any one of R1 to R6 is the group -NR7COR8, it is preferably -NHCHO; a C2-6 acylamino group, for example -NHC0CH3, -NHCOC2H5; or benzamido, which may be substituted with one or more substituents chosen from halogen, for example, chlorine, fluorine and bromine; alkyl, for example, methyl and ethyl; alkoxy, for example, methoxy and ethoxy; haloalkyl, for example, chloromethyl, fluoromethyl, trifluoromethyl and
2,2.2-trifluoroethyl; haloalkoxy, for example, trifluoromethoxy and 2,2,2-trifluoroethoxy; hydroxy; cyano and nitro.
When any one of R1 to R6 is -NR7CSR8, R7 and R8 are preferably alkyd, for example methyl and ethyl.
When any one of R1 to R6 is the group -NR7SO2R8, it is preferably an alkanesulfonamido group, for example, -NHSO2CH3 and -NHSO2C2H5.
When any one of R1 to R6 is the group -N(SO2R7/SO2R8), it is preferably a di-(alkanesulfonyl)amino group, for example, -N(SO2CH3)2 and -N(SO2C2H5)2.
When any one of R1 to R6 is the group -COR7, it is preferably a Cl-6 acyl group; or an optionally substituted benzoyl group. The benzoyl may be substituted with one or more substituents chosen from halogen, for example, chlorine, fluorine and bromine; alkyl, for example, methyl and ethyl; alkoxy', for example, methoxy and ethoxy; haloalkyl, for example, chloromethyl, fluoromethyl, trifluoromethyl and 2^,2-trifluoroethyl; haloalkoxy, for example, trifluoromethoxy and 2,2,2-trifluoroethoxy; hydroxy; cyano and nitro. Examples of preferred -COR7 groups are acetyl, propionyl, n-butanoyl, 4-chlorobenzoyl, 4-fluorobenzoyl,
AP.00649
- 5 4-bromobenzoyl, 4-methylbenzoyl and 4-rrifluoromethyIbenzoyl.
When any one of Rl to R6 is the group -CONR7R8. it is preferably -CONH2; an N-alkyl-carboxamido group, for example -CONHCH3, -CONHC2H5 and -CONHCH2CH2CH3; or an Ν,Ν-dialkyl-carboxamido group, for example -CON(CH3)2. -CON(CH3XC2H5) and -CON(C2H5)2.
When any one of Rl to R6 is the group -alkylCONR7R8, it is preferably -CM alkylCONR7R8.
When any one of more of Rl to R6 is the group -CR7NR8, it is preferably -CH=NOH.
When any one of Rl to R6 is the group -COOR7, it is preferably -COOH; an alkoxycarbonyl group, for example methoxycarbonyl and ethoxycarbonyl; or a haloalkenvloxycarbonyl group, for example 3,4,4-trifluorobut-3-enyloxycarbonyl, 4-fluorobut-3-enyloxy carbonyl, 4,4-difIuorobut-3-enyloxycarbonyl and 3-methyM,4-difluorobut-3-enyloxycarbonyl.
When any one of Rl to R6 is the group -OCOR7, it is preferably a C2-6 acyloxy group, for example -OCOCH3 and -OCOC2H5; or an optionally substituted benzoyloxy group. The benzoyloxy group may comprise one or more substituents chosen from halogen, for example, chlorine, fluorine and bromine; alkyl, for example, methyl and ethyl; alkoxy, for example, methoxy and ethoxy; haloalkyl, for example, chloromethyl, fluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl; haloalkoxy, for example, trifluoromethoxy and
2,2,2-trifluoroethoxy; hydroxy; cyano; and nitro.
When any one of Rl to R6 is the group -SR7, R7 is preferably hydrogen, optionally subsituted alkyl, optionally substituted alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substiuted aryl, or optionally substituted arylalkyl. Examples of the preferred Cl-6 alkvlthio (CM alkyl being especially preferred), C2-6 alkenylthio or C2-6 alkynylthio groups are methylthio, etbylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, t-butylthio, allylthio, but-3-enylthio, 3-methylbut-3-enylthio and propargylthio. Examples of the preferred Cl-6 haloalkylthio (Cl-4 alkyl being especially preferred), C2-6 haloalkenylthio or C2-6 haloalkvnylthio groups are fluoromethylthio, difluoromethylthio, trifluoromethylthio, trichloromethylthio, 2-fluoroethylthio, 2^2,2-trifluoroethylthio, 3-fluoro-n-propylthio, pentafluoroethylthio, 2-chloroprop-2-enylthio,
3.3- dichloroprop-2-enylthio, 3,4,4-trifluorobut-3-enylthio, 4-fluorobut-3-enylthio,
4.4- difluorobut-3-enylthio and 3-methyl-4,4-difluorobut-3-enylthio. An example of the
AP/P/ 9 6 / 0 0 8 6 2
- 6 preferred C6-10 arylthio and C6-10 ary 1-C1-2alk>ithio groups is 3-trifluoromethylbenzylthio.
When any one of Rl to R6 is the group -SOR7, it is preferably an alkanesulfinvl. alkenvlsulfinyl or alkynvlsulfinyl group, for example methanesulfinvl or ethanesulfinyl; or a haloalkanesulfinyl, haloalkenylsulfinyl or haloalkynylsulfinyl group, for example trifluoromethanesulfinvl. In another preferred embodiment -SOR7 is preferably -SOF. -SOBr or -SOC1.
When any one of Rl to R6 is the group -SO2R7, it is preferably an alkanesulfonyl, alkenvlsulfonyl, alkynylsulfonyl, a haloalkanesulfonyl, haloalkenylsulfonyl, haloalkynvlsulfonyl group; or an optionally substituted benzenesulfonyl group. The benzenesulfonyl group may comprise one or more substituents chosen from halogen, for example, chlorine, fluorine and bromine; alkyl, for example, methyl and ethyl; alkoxy, for example, methoxy and ethoxy; haloalkyl, for example, chloromethyl, fluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl; haloalkoxy such as trifluoromethoxy and
2.2.2- trifluoroethoxy; hydroxy; cyano and nitro. Examples of such groups are methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, and 4-methylbenzenesulfonyl. In another preferred embodiment -SO2R7 is preferably -SO2F, -SO2Br or -SO2C1.
It will thus be appreciated that the R group of formula (H) to (XXI) can comprise more than one -S(O)nCH2CH2CH=CF2 group. Preferably the R group contains one or two such substituents.
When any one of Rl to R6 is the group -OSO2R7, it is preferably an alkanesulfonyloxy group or an optionally substituted benzenesulfonyloxy group. The benzenesulfonyl may be substituted with one or more substituents chosen from halogen, for example, chlorine, fluorine and bromine; alkyl, for example, methyl and ethyl; alkoxy, for example, methoxy and ethoxy; haloalkyl, for example, chloromethyl, fluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl; haloalkoxy, for example, trifluoromethoxy and
2.2.2- trifluoroethoxy; hydroxy; cyano; and nitro.
When any one of Rl to R6 is the group -SO2NR7R8, it is preferably -SO2NH2; an alkylaminosulfonyl group, for example, -SO2NHCH3 and -SO2NHC2H5; or a dialkylaminosulfonyl group, for example, -SO2N(CH3)2 and -SO2N(C2H5)2.
When any one of Rl to R6 is the group -CSNR7RE it is preferably -CSNH2, -CSNHCH3 or -CSN(CH3)2.
When any one of Rl to R6 is the grot?) -SiR7R8R9, it is preferably a trialkylsily 1 group, for example, trimethylsilyl and triethylsilyl.
AP.00649
-7When any one of RI to R6 is the group -OCH2CO2R7, it is preferably an alkoxycarbonylmethoxy group, for example, methoxycarbonvlmethoxy and ethoxy carbonylmethoxy.
When any one of RI to R6 is the group -OCH2CH2CO2R7, it is preferably a alkoxvcarbonylethoxy group, for example, methoxycarbonvlethoxy and ethoxvcarbonylethoxy.
When any one of RI to R6 is the group -CONR7SO2R8, it is preferably an N-alkanesulfonylcarboxamido group or an N- alkyl-N-alkanesulfonylcarboxamido group, for example, N<methanesulfonyl)-carboxamido and N-methyl-N-(methanesulfonyl)carboxamido.
When any one or more of RI to R6 is the group -alkylCONR7SO2R8, R7 and R8 are preferably alkyl groups, for example, ethyl and methyl.
When any one of RI to R6 is -NHCONR7R8, R7 and R8 are preferably alkyl groups, for example, ethyl and methyl.
When any one of RI to R6 is -NHCSNR7R8, R7 and R8 are preferably alkyl groups, for example, ethyl and methyl.
When an adjacent pair of RI, R2, R3, R4, R5 and R6 taken together form a fused 5or 6-membered carbocyclic or heterocyclic ring, preferably containing two oxygen atoms, the pair of substituents taken together is preferably -{CH2)3-, -{CH2)4-, -CH=CH-CH=CH-, -O-CH2-O-, optionally substituted with one or two halogen atoms or methyl groups, for example -OCHF-O- or -OCF2-O, -0-CH(CH3)-0, -O-C(CH3)2-O- or -0-(CH2)2-O.
According to an especially preferred embodiment of the present invention RI (when attached to a carbon atom) to R6 are each independently hydrogen; nitro; halogen; cyano; -CH=NOH; Cl-4 alkyl; CM haloalkyl; Cl-4 alkenyl; Cl-4 haloalkenyl; cyclopropyl; hydroxy; Cl-4 alkoxy; C2-4 alkoxyalkyl; -COOH; C2-4 alkoxycaibonyl; C2-4 haloalkenyloxycarbonyl; -CONH2; mono or di-Cl-2 alkylaminocarbonyl; C2-4 alkanecaibonyl; -CONHSO2 Cl-4 alkyl, preferably -CONHSO2CH3; phenyl optionally mono- or di- substituted with groups independently chosen from halogen, nitro, Cl-4 alkyl,
Cl-4 alkoxy or aminosulfonyl; benzyl optionally mono- or di- substituted with groups independently chosen from halogen, nitro, Cl-4 alkyl or Cl-4 alkoxy; phenoxy optionally mono- or di- substituted with groups independently chosen from halogen, cyano, CM alkyl or Cl-4 alkoxy; amino optionally mono- or di- substituted with Cl-4 alkyl groups; -SH; Cl-4 aikylthio; benzylthio optionally mono- or di- substituted with groups independently chosen from halogen or Cl-4 haloalkyl; Cl-4 alkenylthio; C2-4 haloalkenylthio; a second S(O)nCH2CH2CH=CF2 group; Cl-4 alkanesulfonyl; Cl-4 haloalkanesulfonyl; fluorosulfonyl;
AP/P/ 9 6 / 0 0 8 6 2
- 8 mono- or di- Cl-4 alkylsulfamoyl; a 5 or 6 membered heteroaryl group, for example, furyl, pyrazinyl, pyridinvl or thienyl, optionally substituted with halogen; or any adjacent pair forms a fused 5- or 6- carbocvclic or heterocyclic ring; and
Rl (when attached to a nitrogen atom) is hydrogen; nitro; cyano; -CH=NOH; C1 -4 alkyl; Cl-4 haloalkyl; cyclopropvl; hydroxy; -COOH; C2-4 alkoxvcarbonyl; C2-4 haloalkenyloxycarbonyl; -C0NH2; mono or di-Cl-2 alkylaminocarbonyl; C2-4 alkanecarbonyl; -CONHSO2 Cl-4 alkyl, preferably -CONHSO2CH3; phenyl optionally mono or di- substituted with groups independently chosen from halogen, nitro, Cl-4 alkyl, Cl-4 alkoxy or aminosulfonyl; benzyl optionally mono or di- substituted with groups independently chosen from halogen, nitro, Cl-4 alkyl or Cl-4 alkoxy; phenoxy optionally mono or di- substituted with groups independently chosen from halogen, cyano, Cl-4 alkyl or Cl-4 alkoxy; amino optionally mono or di- substituted with Cl-4 alkyl groups; -SH; CM alkylthio; benzylthio optionally mono or di- substituted with groups independently chosen from halogen or Cl-4 haloalkyl; Cl-4 alkenylthio; C2-4 haloalkenylthio; a second S(O)nCH2CH2CH=CF2 group; Cl-4 alkanesulfonyl; Cl-4 haloalkanesulfonyl; fluorosulfonyl; mono or di- Cl-4 alkylsulfamoyl; a 5 or 6 membered heteroaryl group, for example, furyl, pyrazinyl, pyridinyl or thienyl, optionally substituted with halogen.
The following Tables give examples of compounds according to the invention.
Examples of compounds of Formula (Π) according to the invention are set R4 R, out in Table Π. // u
TABLEΠ
No. R2 R3 R4
Π.1 2-SCH2CH2CH=CF2 3-H 4-H
Π.2 2-SOCH2CH2CH=CF2 3-H 4-H
Π.3 2-SO2CH2CH2CH=CF2 3-H 4-H
Π.4 2-SCH2CH2CH=CF2 3-H 4-H
Π.5 2-SOCH2CH2CH=CF2 3-H 4-H
Π.6 2-SO2CH2CH2CH=CF2 3-H 4-H
Π.7 2-CH3 3-SCH2CH2CH=CF2 4-H
Π.8 2-CH3 3-SOCH2CH2CH=CF2 4-H
Π.9 2-CH3 3-SO2CH2CH2CH=CF2 4-H
R5
5-H
5-H
5-H
5-CH3
5-CH3
5-CH3
5-H
5-H
5-H
AP.00649
Examples of compounds of Formula (HI) according to the invention are set out in Table EQ.
TABLED!
No. R2 R3 R4 R5
ED.1 2-SCH2CH2CH=CF2 3-H 4-H 5-H
m.2 2-SOCH2CH2CH=CF2 3-H 4-H 5-H
ED.3 2-SO2CH2CH2CH=CF2 3-H 4-H -5-H
m.4 2-SCH2CH2CH=CF2 3-H 4-H 5-CHO
m.5 2-SCH2CH2CH=CF2 3-H 4-H 5-CH2OH
EQ.6 2-SCH2CH2CH=CF2 3-H 4-H (E) 5-CH=NOH
m.7 2-SCH2CH2CH=CF2 3-H 4-H (Z) 5-CH=NOH
EQ.8 2-SCH2CH2CH=CF2 3-H 4-H 5-CN
m.9 2-SCH2CH2CH=CF2 3-H 4-H 5-COCH3
m.io 2-SCH2CH2CH=CF2 3-H -CH=CH-CH=CH-
m.ii 2-SOCH2CH2CH=CF2 3-H -CH=CH-CH=CH-
ΙΠ.12 2-SO2CH2CH2CH=CF2 3-H -CH=CH-CH=CH-
Examples of compounds of Formula (TV) according to the invention are set out in Table IV.
R3 Λ
AP/P/ 96/00862 Rs
TABLE IV
No. R3 R4 R5
IV. 1 3-C6H5 4-H 5-SCH2CH2CH=CF2
IV.2 3-C6H5 4-H 5-SOCH2CH2CH=CF2
IV.3 3-C6H5 4-H 5-SO2CH2CH2CH=CF2
IV.4 3-CN 4-H 5-SCH2CH2CH=CF2
IV.5 3-C1 4-H 5-SCH2CH2CH=CF2
IV.6 3-CF3 4-H 5-SCH2CH2CH=CF2
IV.7 3-CH3 4-CONH2 5-SCH2CH2CH=CF2
IV.8 3-CH3 4-COOCH2CH3 5-SCH2CH2CH=CF2
- ιυ -
rv.9 3-CH3 4-COOH 5-SCH2CH2CH=CF2
rv.io 3-CH3 4-H 5-SCH2CH2CH=CF2
rv.n 3-H 4-CI 5-SCH2CH2CH=CF2
IV’. 12 3-H 4-CN 5-SCH2CH2CH=CF2
IV. 13 3-H 4-CN 5-SOCH2CH2CH=CF2
IV. 14 3-H 4-CN 5-SO2CH2CH2CH=CF2
IV.15 3-H 4-CF3 5-SCH2CH2CH=CF2
IV.16 3-H 4-H 5-SCH2CH2CH=CF2
IV.17 3-H 4-NO2 5-SCH2CH2CH=CF2
rv.i8 3-H 4-SCH2CH2CH=CF2 5-CN
IV.19 3-H 4-SCH2CH2CH=CF2 5-CF3
IV.20 3-SCH2CH2CH=CF2 4-H 5-C1
IV.21 3-SCH2CH2CH=CF2 4-CI 5-H
IV.22 3-SO2CH2CH2CH=CF2 4-CN 5-SO2CH2CH2CH=CF2
IV.23 3-(5-Cl-Fur-2-yl) 4-H 5-SCH2CH2CH=CF2
rv.24 3-(5-Cl-Fur-2-yl) 4-H 5-SO2CH2CH2CH=CF2
IV.25 3-{Thien-2-yl) 4-H 5-SCH2CH2CH=CF2
IV.26 3-(Thien-2-yl) 4-H 5-SO2CH2CH2CH=CF2
Examples of compounds of Formula (V) according to the invention are set out in Table V.
r8
TABLE V
No. R3 R4 R5
V.l 3-CF3 4-H 5-SCH2CH2CH=CF2
V.2 3-C1 4-CN 5-SCH2CH2CH=CF2
V.3 3-C1 4-H 5-SCH2CH2CH=CF2
V.4 3-C1 4-H 5-SO2CH2CH2CH=CF2
V.5 3-H 4-CN 5-SCH2CH2CH=CF2
V.6 3-H 4-CN 5-SO2CH2CH2CH=CF2
V.7 3-H 4-SCH2CH2CH=CF2 5-CF3
V.8 3-H 4-SOCH2CH2CH=CF2 5-CF3
AP . 0 0 6 4 9
- ii -
V.9 3-H 4-SCH2CH2CH=CF2 5-CN
V.10 3-NO2 4-H 5-SCH2CH2CH=CF2
V.ll 3-SCH2CH2CH=CF2 4-C1 5-H
V.12 3-SCH2CH2CH=CF2 4-CN 5-SCH2CH2CH=CF2
V.13 3-SO2CH2CH2CH=CF2 4-CN 5-SOCH2CH2CH=CF2
V.14 3-SOCH2CH2CH=CF2 4-CN 5-SO2CH2CH2CH=CF2
V.15 3-SO2CH2CH2CH=CF2 4-CN 5-SO2CH2CH2CH=CF2
V.16 3-SCH2CH2CH=CF2 4-H 5-C1
Examples of compounds of Formula (VI) according to the invention are set out in Table VI,
TABLE VI
No. R2 R4 R5
VI.l 2-SCH2CH2CH=CF2 4-H 5-H
VI.2 2-SOCH2CH2CH=CF2 4-H 5-H
VI.3 2-SO2CH2CH2CH=CF2 4-H 5-H
VI.4 2-SCH2CH2CH=CF2 4-CF3 5-H
VI.5 2-SO2CH2CH2CH=CF2 4-CF3 5-H
VI.6 2-SCH2CH2CH=CF2 4-CH3 5-H
VI.7 2-SCH2CH2CH=CF2 4-CN 5-H
VI.8 2-SCH2CH2CH=CF2 4-CONH2 5-H
VI.9 2-SCH2CH2CH=CF2 4-COOCH2CH3 5-H
VI.10 2-SO2CH2CH2CH=CF2 4-COOCH2CH3 5-H
VI.11 2-SCH2CH2CH=CF2 4-COOH 5-H
VI. 12 2-SO2CH2CH2CH=CF2 4-H 5-Br
V1.13 2-SCH2CH2CH=CF2 4-H 5-C1
VI. 14 2-SO2CH2CH2CH=CF2 4-H 5-C1
VI. 15 2-SCH2CH2CH=CF2 4-CH3 5-C1
VL16 2-SO2CH2CH2CH=CF2 4-CH3 5-C1
VI.17 2-SCH2CH2CH=CF2 4-H 5-F
VI.18 2-SCH2CH2CH=CF2 4-H 5-C6H5
\\
9 8 0 0 / 9 6 /d/dV
Μ19 2-SOCH2CH2CH=CF2 4-H 5-C6H5
VI.20 2-SO2CH2CH2CH=CF2 4-H 5-C6H5
VI.21 2-SCH2CH2CH=CF2 4-H 5-CF3
VI.22 2-SCH2CH2CH=€F2 4-H 5-CN
VI.23 2-SOCH2CH2CH=CF2 4-H 5-CN
VI.24 2-SO2CH2CH2CH=CF2 4-H 5-CN
VI.25 2-SCH2CH2CH=CF2 4-CH3 5-CN
VL26 2-SOCH2CH2CH=CF2 4-CH3 5-CN
VI .27 2-SO2CH2CH2CH=€F2 4-CH3 5-CN
VI.28 2-SCH2CH2CH=CF2 4-H 5-COOCH2CH3
VI.29 2-SOCH2CH2CH=CF2 4-H 5-COOCH2CH3
VI.30 2-SO2CH2CH2CH=CF2 4-H 5-COOCH2CH3
VI.31 2-SCH2CH2CH=CF2 4-CF3 5-COOCH2CH3
VI .32 2-SCH2CH2CH=CF2 4-CH3 5-COOCH3
VI.33 2-SOCH2CH2CH=CF2 4-CH3 5-COOCH3
VI.34 2-SO2CH2CH2CH=CF2 4-CH3 5-COOCH3
VI.35 2-SCH2CH2CH=CF2 4-H 5-COOH
VI.36 2-SCH2CH2CH=CF2 4-CF3 5-COOH
VI.37 2-SCH2CH2CH=CF2 4-CH3 5-COOH
VI.38 2-SCH2CH2CH=CF2 4-CH3 5-CONHSO2CH3
VI.39 2-SCH2CH2CH=CF2 4-H 5-CONH2
VI.40 2-SCH2CH2CH=CF2 4-CH3 5-CONH2
VI.41 2-SOCH2CH2CH=CF2 4-CH3 5-CONH2
VI.42 2-SCH2CH2CH=CF2 4-H 5-NO2
VI.43 2-SOCH2CH2CH=CF2 4-H 5-NO2
VI.44 2-SO2CH2CH2CH=CF2 4-H 5-NO2
VL45 2-SCH2CH2CH=CF2 4-H 5-SO2F
VI.46 2-SOCH2CH2CH=CF2 4-H 5-SO2F
VL47 2-SCH2CH2CH=CF2 4-H 5-SO2NH2
VI.48 2-SO2CH2CH2CH=CF2 4-H 5-SO2NH2
VI.49 2-H 4-SCH2CH2CH=CF2 5-Br
VI. 50 2-H 4-SCH2CH2CH=CF2 5-C6H5
VI.51 2-H 4-SOCH2CH2CH=CF2 5-C6H5
AP.00649
VI.52 2-H 4-SCH2CH2CH=CF2 5-CF3
V1.53 2-H 4-SOCH2CH2CH=CF2 5-CF3
VI.54 2-H 4-SCH2CH2CH=CF2 5-C1
V1.55 2-H 4-SOCH2CH2CH=CF2 5-C1
VL56 2-H 4-SO2CH2CH2CH=CF2 5-C1
V1.57 2-H 4-SCH2CH2CH=CF2 5-CN
VI.58 2-CH3 4-SCH2CH2CH=CF2 5-CN
VL59 2-CH3 4-SOCH2CH2CH=CF2 5-CN
VI.60 2-CH3 4-SO2CH2CH2CH=CF2 5-CN
VL61 2-H 4-SCH2CH2CH=CF2 5-CONH2
VI.62 2-CH3 4-SCH2CH2CH=CF2 5-CONH2
V1.63 2-H 4-SCH2CH2CH=CF2 5-COOCH2CH3
VI.64 2-CH3 4-SCH2CH2CH=CF2 5-COOCH3
VI.65 2-CH3 4-SO2CH2CH2CH=CF2 5-COOCH3
VI.66 2-H 4-SCH2CH2CH=CF2 5-COOH
VI.67 2-H 4-SCH2CH2CH=CF2 5-F
VI.68 2-H 4-SCH2CH2CH=CF2 5-H
VI.69 2-H 4-SOCH2CH2CH=CF2 5-H
VI.70 2-H 4-SO2CH2CH2CH=CF2 5-H
VI.71 2-H 4-SCH2CH2CH=CF2 5-NO2
VI.72 2-H 4-SCH2CH2CH=CF2 5-SO2F
VI.73 2-H 4-SCH2CH2CH=CF2 5-SO2NH2
VI.74 2-H 4-Br 5-SCH2CH2CH=CF2
VI.75 2-H 4-C6H5 5-SCH2CH2CH=CF2
VI.76 2-H 4-CF3 5-SCH2CH2CH=CF2
VI.77 2-H 4-CF3 5-SO2CH2CH2CH=CF2
V1.78 2-H 4-CI 5-SCH2CH2CH=CF2
VI.79 2-H 4-CN 5-SCH2CH2CH=CF2
VI.80 2-H 4-CN 5-SOCH2CH2CH=CF2
VI.81 2-H 4-CN 5-SO2CH2CH2CH=CF2
VI.82 2-CH3 4-CN 5-SCH2CH2CH=CF2
VI.83 2-H 4-CONH2 5-SCH2CH2CH=CF2
VI.84 2-H 4-CONH2 5-SOCH2CH2CH=CF2
AP/P/ 9 6 / 0 0 8 6 2
V1.85 2-H 4-CONH2 5-SO2CH2CH2CH=CF2
VI.86 2-CH3 4-CONH2 5-SCH2CH2CH=CF2
VI.87 2-H 4-COOCH2CH3 5-SCH2CH2CH=CF2
V1.88 2-H 4-COOCH2CH3 5-SOCH2CH2CH=CF2
VI.89 2-H 4-COOCH2CH3 5-SO2CH2CH2CH=CF2
VI.90 2-CH3 4-COOCH3 5-SCH2CH2CH=CF2
VI.91 2-H 4-COOH 5-SCH2CH2CH=CF2
V1.92 2-H 4-F 5-SCH2CH2CH=CF2
V1.93 2-H 4-H 5-SCH2CH2CH=€F2
VI.94 2-H 4-H 5-SOCH2CH2CH=CF2
V1.95 2-H 4-H 5-SO2CH2CH2CH=CF2
VI.96 2-H 4-NO2 5-SCH2CH2CH=CF2
V1.97 2-H 4-NO2 5-SOCH2CH2CH=CF2
VI.98 2-H 4-SO2F 5-SCH2CH2CH=CF2
VI.99 2-H 4-SO2NH2 5-SCH2CH2CH=CF2
VI.100 2-Br 4-H 5-SCH2CH2CH=CF2
VI.1O1 2-C6H5 4-H 5-SCH2CH2CH=CF2
VI. 102 2-C6H5 4-H 5-SOCH2CH2CH=CF2
VI. 103 2-C6H5 4-H 5-SO2CH2CH2CH=CF2
VI.104 2-CF3 4-H 5-SCH2CH2CH=CF2
VL105 2-CF3 4-H 5-SO2CH2CH2CH=CF2
VI.106 2-C1 4-H 5-SCH2CH2CH=CF2
VI.107 2-CN 4-H 5-SCH2CH2CH=CF2
VI.108 2-CN 4-CH3 5-SCH2CH2CH=CF2
VI.109 2-CONH2 4-H 5-SCH2CH2CH=CF2
vi.no 2-CONH2 4-H 5-SOCH2CH2CH=CF2
VI.lll 2-CONH2 4-H 5-SO2CH2CH2CH=CF2
VI.112 2-CONH2 4-CH3 5-SO2CH2CH2CH=CF2
VI.113 2-COOCH2CH3 4-H 5-SCH2CH2CH=CF2
VI.114 2-COOCH3 4-CH3 5-SCH2CH2CH=CF2
VI.115 2-COOH 4-H 5-SCH2CH2CH=CF2
VI.116 2-F 4-H 5-SCH2CH2CH=CF2
VI.l 17 2-F 4-H 5-SOCH2CH2CH=CF2
AP.00649 • 15 -
VI.118 2-NO2 4-H 5-SCH2CH2CH=CF2
VI.119 2-SO2F 4-H 5-SCH2CH2CH=CF2
VI.120 2-SO2NH2 4-H 5-SCH2CH2CH=CF2
Examples of compounds of Formula (VII) according to the invention are set out in Table VII.
\\
TABLE VH
No. R2 R4 R5
VH.l 2-SCH2CH2CH=CF2 4-H 5-H
Vn.2 2-SOCH2CH2CH=CF2 4-H 5-H
VH.3 2-SO2CH2CH2CH=CF2 4-H 5-H
VH.4 2-SCH2CH2CH=CF2 4-CF3 5-H
Vn.5 2-SO2CH2CH2CH=CF2 4-CF3 5-H
VH.6 2-SCH2CH2CH=CF2 4-CN 5-H
VH.7 2-SCH2CH2CH=CF2 4-CONH2 5-H
Vn.8 2-SCH2CH2CH=CF2 4-COOCH2CH3 5-H
VH.9 2-SO2CH2CH2CH=CF2 4-COOCH2CH3 5-H
vn.io 2-SCH2CH2CH=CF2 4-COOH 5-H
VH.ll 2-SCH2CH2CH=CF2 4-COOCH2CH3 5-Br
VH.12 2-SO2CH2CH2CH=CF2 4-COOCH2CH3 5-Br
VD.13 2-SCH2CH2CH=CF2 4-COOH 5-Br
VII.14 2-SCH2CH2CH=CF2 4-H 5-Br
XT. 15 2-SOCH2CH2CH=CF2 4-H 5-Br
VH.16 2-SO2CH2CH2CH=CF2 4-H 5-Br
Vn.17 2-SCH2CH2CH=CF2 4-H 5-C6H5
VH.18 2-SOCH2CH2CH=CF2 4-H 5-C6H5
Vn.19 2-SO2CH2CH2CH=CF2 4-H 5-C6H5
VH.20 2-SCH2CH2CH=CF2 4-H 5-CF3
VI1.21 2-SCH2CH2CH=CF2 4-H 5-CH3
VH.22 2-SOCH2CH2CH=CF2 4-H 5-CH3
VH.23 2-SO2CH2CH2CH=CF2 4-H 5-CH3
AP/P/ 9 6 / 0 0 8 6 2
Vn.24 2-SCH2CH2CH=CF2 4-H 5-C1
νΠ.25 2-SOCH2CH2CH=CF2 4-H 5-C1
VH.26 2-SO2CH2CH2CH=CF2 4-H 5-C1
νΠ.27 2-SCH2CH2CH=CF2 4-CH3 5-C1
νΠ.28 2-SO2CH2CH2CH=CF2 4-CH3 5-C1
VH.29 2-SCH2CH2CH=CF2 4-H 5-CN
VH.30 2-SOCH2CH2CH=CF2 4-H 5-CN
VI1.31 2-SO2CH2CH2CH=CF2 4-H 5-CN
VII.32 2-SCH2CH2CH=CF2 4-CH3 5-CN
νΠ.33 2-SOCH2CH2CH=CF2 4-CH3 5-CN
VII.34 2-SO2CH2CH2CH=CF2 4-CH3 5-CN
νΠ.35 2-SCH2CH2CH=CF2 4-H 5-CONH2
VH.36 2-SCH2CH2CH=CF2 4-CH3 5-CONH2
VD.37 2-SOCH2CH2CH=CF2 4-CH3 5-CONH2
VH.38 2-SCH2CH2CH=CF2 4-H 5-COOCH2CH3
VH.39 2-SOCH2CH2CH=CF2 4-H 5-COOCH2CH3
VI1.40 2-SO2CH2CH2CH=CF2 4-H 5-COOCH2CH3
VH.41 2-SCH2CH2CH=CF2 4-CH3 5-COOCH3
VH.42 2-SOCH2CH2CH=CF2 4-CH3 5-COOCH3
VH.43 2-SO2CH2CH2CH=CF2 4-CH3 5-COOCH3
VH.44 2-SCH2CH2CH=CF2 4-H 5-COOH
VH.45 2-SCH2CH2CH=CF2 4-CH3 5-COOH
VH.46 2-SCH2CH2CH=CF2 4-H 5-F
VI1.47 2-SCH2CH2CH=CF2 4-H 5-NO2
νΠ.48 2-SOCH2CH2CH=CF2 4-H 5-NO2
νΠ.49 2-SO2CH2CH2CH=CF2 4-H 5-NO2
VH.50 2-SCH2CH2CH=CF2 4-H 5-SO2F
VH.51 2-SOCH2CH2CH=CF2 4-H 5-SO2F
VH.52 2-SCH2CH2CH=CF2 4-CH3 5-SO2F
νπ.53 2-SO2CH2CH2CH=CF2 4-CH3 5-SO2F
VH.54 2-SCH2CH2CH=CF2 4-H 5-SO2NH2
VH.55 2-SO2CH2CH2CH=CF2 4-H 5-SO2NH2
νΠ.56 2-SCH2CH2CH=CF2 4-CH3 5-SO2N(CH2CH3)2
AP.00649
Vn.57 2-H 4-SCH2CH2CH=CF2 5-H
Vn.58 2-H 4-SOCH2CH2CH=CF2 5-H
VH.59 2-H 4-SO2CH2CH2CH=CF2 5-H
VH.60 2-H 4-SCH2CH2CH=€F2 5-Br
VD.61 2-H 4-SCH2CH2CH=CF2 5-C6H5
VH.62 2-H 4-SOCH2CH2CH=CF2 5-C6H5
VH.63 2-H 4-SCH2CH2CH=CF2 5-CF3
Vn.64 2-H 4-SOCH2CH2CH=CF2 5-CF3
VH.65 2-H 4-SCH2CH2CH=CF2 5-C1
VD.66 2-H 4-SOCH2CH2CH=CF2 5-C1
VD.67 2-H 4-SO2CH2CH2CH=CF2 5-C1
VD.68 2-H 4-SCH2CH2CH=CF2 5-CN
VD.69 2-CH3 4-SCH2CH2CH=CF2 5-CN
VD.70 2-CH3 4-SOCH2CH2CH=CF2 5-CN
VD.71 2-CH3 4-SO2CH2CH2CH=CF2 5-CN
VD.72 2-H 4-SCH2CH2CH=CF2 5-CONH2
VH.73 2-CH3 4-SCH2CH2CH=CF2 5-CONH2
VH.74 2-H 4-SCH2CH2CH=CF2 5-COOCH2CH3
vn.75 2-CH3 4-SCH2CH2CH=CF2 5-COOCH3
VD.76 2-CH3 4-SO2CH2CH2CH=CF2 5-COOCH3
VD.77 2-H 4-SCH2CH2CH=CF2 5-COOH
VD.78 2-H 4-SCH2CH2CH=CF2 5-F
VD.79 2-H 4-SCH2CH2CH=CF2 5-NO2
VD.8O 2-H 4-SCH2CH2CH=€F2 5-SO2F
VD.81 2-H 4-SCH2CH2CH=CF2 5-SO2NH2
VD.82 2-H 4-H 5-SCH2CH2CH=CF2
VD.83 2-H 4-H 5-SOCH2CH2CH=CF2
VD.84 2-H 4-H 5-SO2CH2CH2CH=CF2
VD.85 2-H 4-Br 5-SCH2CH2CH=CF2
VD.86 2-H 4-C6H5 5-SCH2CH2CH=CF2
VD.87 2-H 4-CF3 5-SCH2CH2CH=CF2
VD.88 2-H 4-CF3 5-SO2CH2CH2CH=CF2
VU.89 2-H 4-C1 5-SCH2CH2CH=CF2
AP/P/ 9 6 / 0 0 8 6 2
VH.90 2-Η 4-CN 5-SCH2CH2CH=CF2
Vn.91 2-Η 4-CN 5-SOCH2CH2CH=€F2
VH.92 2-Η 4-CN 5-SO2CH2CH2CH=€F2
Vn.93 2-CH3 4-CN 5-SCH2CH2CH=CF2
Vn.94 2-Η 4-CONH2 5-SCH2CH2CH=CF2
Vn.95 2-Η 4-CONH2 5-SOCH2CH2CH=CF2
VH.96 2-Η 4-CONH2 5-SO2CH2CH2CH=CF2
VH.97 2-CH3 4-CONH2 5-SCH2CH2CH=CF2
VII.98 2-Η 4-COOCH2CH3 5-SCH2CH2CH=CF2
νπ.99 2-Η 4-COOCH2CH3 5-SOCH2CH2CH=CF2
VH.100 2-Η 4-COOCH2CH3 5-SO2CH2CH2CH=CF2
νπ.ιοι 2-CH3 4-COOCH3 5-SCH2CH2CH=CF2
νπ.102 2-Η 4-C00H 5-SCH2CH2CH=CF2
VH.103 2-Η 4-F 5-SCH2CH2CH=CF2
VU.104 2-Η 4-ΝΟ2 5-SCH2CH2CH=CF2
VH.105 2-Η 4-ΝΟ2 5-SOCH2CH2CH=CF2
νπ.106 2-Η 4-SO2F 5-SCH2CH2CH=CF2
VII.107 2-Η 4-SO2NH2 5-SCH2CH2CH=CF2
νπ.108 2-Βγ 4-Η 5-SCH2CH2CH=CF2
VH.109 2-C6H5 4-Η 5-SCH2CH2CH=CF2
VD.llO 2-C6H5 4-Η 5-SOCH2CH2CH=CF2
νπ.ιιι 2-C6H5 4-Η 5-SO2CH2CH2CH=CF2
νπ.112 2-CF3 4-Η 5-SCH2CH2CH=CF2
VH.113 2-CF3 4-Η 5-SO2CH2CH2CH=CF2
νΠ.114 2-C1 4-Η 5-SCH2CH2CH=CF2
VH.115 2-C1 4-Η 5-SOCH2CH2CH=CF2
VH.116 2-C1 4-Η 5-SO2CH2CH2CH=CF2
VD.117 2-CN 4-Η 5-SCH2CH2CH=CF2
VH.118 2-CN 4-CH3 5-SCH2CH2CH=CF2
VH.119 2-CONH2 4-Η 5-SCH2CH2CH=CF2
VI1.120 2-CONH2 4-Η 5-SOCH2CH2CH=CF2
VH.121 2-CONH2 4-Η 5-SO2CH2CH2CH=CF2
ΥΠ.122 2-CONH2 4-CH3 5-SO2CH2CH2CH=CF2
AP.00649
VH.123 2-COOCH2CH3 4-H 5-SCH2CH2CH=CF2
VD.124 2-COOCH3 4-CH3 5-SCH2CH2CH=CF2
VD.125 2-COOH 4-H 5-SCH2CH2CH=CF2
VD.126 2-F 4-H 5-SCH2CH2CH=CF2
VD.127 2-F 4-H 5-SOCH2CH2CH=CF2
VD.128 2-NH2 4-H 5-SCH2CH2CH=CF2
VD.129 2-NO2 4-H 5-SCH2CH2CH=CF2
VD.13O 2-O(4-CN-C6H4) 4-H 5-SCH2CH2CH=CF2
VH.131 2-SO2F 4-H 5-SCH2CH2CH=CF2
VD.132 2-SO2NH2 4-H 5-SCH2CH2CH=CF2
VD.133 2-S-(2X5-Cl Thiazole) 4-H 5-SCH2CH2CH=CF2
VD.134 2-SCH2CH2CH=CF2 4-dihydro 5-dihvdro
AP/P/ 9 6 / 0 0 8 6 2
-20Ή
V V, V V, V V V V Vs Vi V Vl V. V, ΙΠ ΙΑ ΙΛ
Examples of compounds of Formula (VI11) according to die invention tire set out in fable VIII.
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AP.00649
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AP.00649
-37Examples of compounds of Formula (X) according to the invention are set out in Table X
TABLE X
No. R3 R5
XI 3-C-C3H5 5-SCH2CH2CH=CF2
X2 3-OCH 5-SCH2CH2CH=CF2
X3 3-C6H5 5-SCH2CH2CH=CF2
X4 3-C6H5 5-SOCH2CH2CH=CF2
X5 3-C6H5 5-SO2CH2CH2CH=CF2
X6 3-CF2H 5-SCH2CH2CH=CF2
X7 3-CF3 5-SCH2CH2CH=CF2
X8 3-CH(CH3)2 5-SCH2CH2CH=CF2
X9 3-CH=CH2 5-SCH2CH2CH=CF2
X10 3-CH2Br 5-SCH2CH2CH=CF2
Xll 3-CH2C6H5 5-SCH2CH2CH=CF2
X12 3-CH2C6H5 5-SOCH2CH2CH=CF2
X13 3-CH2CF3 5-SCH2CH2CH=CF2
X14 3-CH2CF3 5-SOCH2CH2CH=CF2
X15 3-CH2CF3 5-SO2CH2CH2CH=CF2
X16 3-CH2CH=€H2 5-SCH2CH2CH=CF2
X17 3-CH2CH2F 5-SCH2CH2CH=CF2
X18 3-CH2CH3 5-SCH2CH2CH=CF2
X19 3-CH2CN 5-SCH2CH2CH=CF2
X20 3-CH2CN 5-SOCH2CH2CH=CF2
X21 3-CH2CONH2 5-SCH2CH2CH=CF2
X22 3-CH2COOCH2CH3 5-SCH2CH2CH=CF2
X23 3-CH2N(CH3)2 5-SCH2CH2CH=CF2
X24 3-CH2NHCOCH3 5-SCH2CH2CH=CF2
X25 3-CH2NHCOOCH3 5-SCH2CH2CH=CF2
X26 3-CH2OCH3 5-SCH2CH2CH=CF2
X27 3-CH2OCH3 5-SO2CH2CH2CH=CF2
AP/P/ 9 6 / 0 0 8 6 2
X2S 3-CH2OH 5-SCH2CH2CH=CF2
X29 3-CH2OH 5-SOCH2CH2CH=CF2
X30 3-CH2SO2C6H5 5-SCH2CH2CH=CF2
X31 3-CH2SO2C6H5 5-SO2CH2CH2CH=CF2
X32 3-CH3 5-SCH2CH2CH=CF2
Xjj 3-CH3 5-SOCH2CH2CH=CF2
X34 3-CH3 5-SO2CH2CH2CH=CF2
X35 3-COC6H5 5-SCH2CH2CH=CF2
X36 3-COCH3 5-SCH2CH2CH=CF2
X37 3-CON(CH3)2 5-SCH2CH2CH=CF2
X38 3-CONH2 5-SCH2CH2CH=CF2
X39 3-CONHCH2C6H5 5-SCH2CH2CH=CF2
X40 3-CONHCH2C6H5 5-SOCH2CH2CH=CF2
X41 3-CONHCH2CH2CH=CF2 5-SCH2CH2CH=CF2
X42 3-CONHCH3 5-SCH2CH2CH=CF2
X43 3-CONHSO2CH3 5-SCH2CH2CH=CF2
X44 3-COOC6H5 5-SCH2CH2CH=CF2
X45 3-COOC6H5 5-SOCH2CH2CH=CF2
X46 3-COOC6H5 5-SO2CH2CH2CH=CF2
X47 3-COOCH2CH2CH=CF2 5-SCH2CH2CH=CF2
X48 3-COOCH2CH2CH=CF2 5-SOCH2CH2CH=CF2
X49 3-COOCH2CH2CH=€F2 5-SO2CH2CH2CH=CF2
X50 3-COOCH2CH2F 5-SCH2CH2CH=CF2
X51 3-COOCH3 5-SCH2CH2CH=CF2
X52 3-COOH 5-SCH2CH2CH=CF2
X53 3-COSCH2CH2CH=CF2 5-SCH2CH2CH=CF2
X54 3-CSNH2 5-SCH2CH2CH=CF2
X55 3-H 5-SCH2CH2CH=CF2
X56 3-H 5-SOCH2CH2CH=CF2
X57 3-H 5-SO2CH2CH2CH=CF2
X58 3-N(SO2CH3)2 5-SCH2CH2CH=CF2
X59 3-NHCH2CH3 5-SCH2CH2CH=CF2
X60 3-NHCHO 5-SCH2CH2CH=CF2
AP.00649
X.61 3-NHCOOCH3 5-SCH2CH2CH=CF2
X.62 3-NHCOCF3 5-SCH2CH2CH=CF2
X63 3-NHCOCF3 5-SOCH2CH2CH=CF2
XS4 3-NHCOCH3 5-SCH2CH2CH=CF2
X65 3-NHCOCH3 5-SO2CH2CH2CH=CF2
X66 3-NHCSCH2CH3 5-SCH2CH2CH=CF2
X67 3-NHCSNHCH2CH3 5-SCH2CH2CH=CF2
X68 3-NHSO2CH3 5-SCH2CH2CH=CF2
X69 3-OCF2CF2H 5-SCH2CH2CH=CF2
X.70 3-OCF3 5-SCH2CH2CH=CF2
X71 3-OCF3 5-SOCH2CH2CH=CF2
X72 3-OCH2C6H5 5-SCH2CH2CH=CF2
X73 3-OCH2C6H5 5-SO2CH2CH2CHCF2
X74 3-OCH2CF3 5-SCH2CH2CH=CF2
X75 3-OCH2CF3 5-SOCH2CH2CH=CF2
X76 3-OCH2CF3 5-SO2CH2CH2CH=CF2
X77 3-OCH2CH=CC12 5-SCH2CH2CH=CF2
X78 3-OCH2CH2CH=CF2 5-SCH2CH2CH=CF2
X79 3-OCH2CH2CH=CF2 5-SOCH2CH2CH=CF2
X80 3-OCH2CH2CH=CF2 5-SO2CH2CH2CH=CF2
X81 3-OCH2CH2F 5-SCH2CH2CH=CF2
X82 3-OCH2COOH 5-SCH2CH2CH=CF2
X83 3-OCH3 5-SCH2CH2CH=CF2
X84 3-OCOC6H5 5-SCH2CH2CH=CF2
X85 3-OCOCH3 5-SCH2CH2CH=CF2
X86 3-OC6H5 5-SCH2CH2CH=CF2
X87 3-OC6H5 5-SOCH2CH2CH=CF2
X88 3-OC6H5 5-SO2CH2CH2CH=CF2
X89 3-OSO2CH3 5-SCH2CH2CH=CF2
X90 3-OSO2CH3 5-SOCH2CH2CH=CF2
X91 3-SCF3 5-SCH2CH2CH=CF2
X92 3-SCH2CH2CH=CF2 5-C6H5
X93 3-SOCH2CH2CH=CF2 5-C6H5
AP/P/ 9 6 / 0 0 8 6 2
X94 3-SO2CH2CH2CH=CF2 5-C6H5
X95 3-SCH2CH2CH=€F2 5-CF2H
X96 3-SCH2CH2CH=CF2 5-CF3
X97 3-SCH2CH2CH=CF2 5-CH2C6H5
X98 3-SOCH2CH2CH=CF2 5-CH2C6H5
X99 3-SCH2CH2CH=CF2 5-CH2CF3
X100 3-SCH2CH2CH=CF2 5-CH2CH2F
X101 3-SCH2CH2CH=CF2 5-CH2C1
X102 3-SCH2CH2CH=CF2 5-CH2CN
X103 3-SCH2CH2CH=CF2 5-CH2OCH3
X104 3-SCH2CH2CH=CF2 5-CH2OH
X105 3-SCH2CH2CH=CF2 5-CH3
X106 3-SO2CH2CH2CH=CF2 5-CH3
X107 3-SCH2CH2CH=CF2 5-C1
X108 3-SCH2CH2CH=CF2 5-CN
X109 3-SCH2CH2CH=CF2 5-CON(CH3)2
X110 3-SCH2CH2CH=CF2 5-COOCH2CH2CH=€F2
XI11 3-SCH2CH2CH=CF2 5-COOCH2CH2F
X112 3-SCH2CH2CH=CF2 5-COOCH3
X113 3-SCH2CH2CH=CF2 5-F
X114 3-SCH2CH2CH=CF2 5-H
X115 3-SCH2CH2CH=CF2 5-N(SO2CH3)2
X116 3-SCH2CH2CH=CF2 5-NHCHO
X117 3-SCH2CH2CH=CF2 5-NHCOCF3
X118 3-SCH2CH2CH=CF2 5-NHCOOCH3
X119 3-SCH2CH2CH=CF2 5-NHSO2CH3
X120 3-SCH2CH2CH=CF2 5-NO2
X121 3-SCH2CH2CH=CF2 5-OC6H5
X122 3-SCH2CH2CH=CF2 5-OCF2H
X123 3-SCH2CH2CH=CF2 5-OCF3
X124 3-SCH2CH2CH=CF2 5-OCH2CF3
X125 3-SOCH2CH2CH=CF2 5-OCH2CF3
X126 3-SO2CH2CH2CH=CF2 5-OCH2CF3
AP . 0 0 6 4 9
-41 ·
X127 3-SCH2CH2CH=€F2 5-OCOCH3
X128 3-SCH2CH2CH=€F2 5-OSO2CH3
X.129 3-SCH2CH2CH=CF2 5-SCH2CH2CH=CF2
X13O 3-SOCH2CH2CH=CF2 5-SCH2CH2CH=CF2
XI31 3-SO2CH2CH2CH=CF2 5-SCH2CH2CH=CF2
X132 3-SCH2CH2CH=CF2 5-SCH3
X133 3-SCH2CH2CH=CF2 5-SO2CF3
X134 3-SOCH2CH2CH=CF2 5-SO2CH2CH2CH=CF2
X135 3-SO2CH2CH2CH=CF2 5-SO2CH2CH2CH=CF2
X136 3-SCH2CH2CH=CF2 5-SO2CH3
X137 3-SO2CH2CH2CH=CF2 5-SO2CH3
X138 3-SCH2CH2CH=CF2 5-SO2N(CH3)2
X139 3-SCH2CH2CH=CF2 5-SOCF3
X14O 3-SOCH2CH2CH=CF2 5-SOCH2CH2CH=CF2
X141 3-SCH3 5-SCH2CH2CH=€F2
X142 3-SO2CF3 5-SCH2CH2CH=CF2
X143 3-SO2CF3 5-SO2CH2CH2CH=CF2
X144 3-SO2CH3 5-SCH2CH2CH=CF2
X145 3-SO2N(CH3)2 5-SCH2CH2CH=CF2
X146 3-SO2NH2 5-SCH2CH2CH=CF2
X147 3-SO2NHCH3 5-SCH2CH2CH=CF2
X148 3-SO2NHCH3 5-SO2CH2CH2CH=CF2
X149 3-SOCF3 5-SCH2CH2CH=CF2
X150 3-SOCF3 5-SOCH2CH2CH=CF2
X151 3-SOCH3 5-SCH2CH2CH=CF2
X152 3-SOCH3 5-SO2CH2CH2CH=CF2
X153 3-(4-CF3-C6H4) 5-SCH2CH2CH=CF2
X154 3-(4-CF3-C6H4) 5-SO2CH2CH2CH=CF2
X155 3-(4-CH3-C6H4) 5-SCH2CH2CH=CF2
X156 3/4-CN-C6H4) 5-SCH2CH2CH=CF2
X157 3-(4-CONH2-C6H4) 5-SCH2CH2CH=CF2
X158 3-(4-CONH2-C6H4) 5-SO2CH2CH2CH=CF2
X159 3-(4-NO2-C6H4) 5-SCH2CH2CH=CF2
9 8 0 0 / 9 6 /d/dV
- 42 XI60 3-(4-OCH5-C6H4)
5-SCH2CH2CH=CF2
Examples of compounds of Formula (XI) according to the invention are set out in Table XI.
R«
TABLE XI
No. R3 R5
XI.l 3-Br 5-SCH2CH2CH=CF2
XI.2 3-C-C5H9 5-SCH2CH2CH=CF2
XI.3 3-C-C5H9 5-SOCH2CH2CH=€F2
X1.4 3-CaCH 5-SCH2CH2CH=CF2
XI.5 3-C6H5 5-SCH2CH2CH=CF2
XI.6 3-C6H5 5-SOCH2CH2CH=CF2
XI.7 3-C6H5 5-SO2CH2CH2CH=CF2
XI.8 3-CF2H 5-SCH2CH2CH=CF2
XI.9 3-CF3 5-SCH2CH2CH=CF2
XI.10 3-CH=CH2 5-SCH2CH2CH=CF2
XI.ll 3-CH=CHCH3 5-SCH2CH2CH=CF2
XI.12 3-CH=CHCN 5-SCH2CH2CH=CF2
XI.13 3-CH=CHNO2 5-SCH2CH2CH=CF2
XI.14 3-CH=NOCH3 5-SCH2CH2CH=CF2
XI.I5 3-CH2(3-CF3-C6H4) 5-SCH2CH2CH=CF2
XI.16 3-CH2(3-CF3-C6H4) 5-SCH2CH2CH-CF2
XI.17 3-CH2C6H5 5-SCH2CH2CH=CF2
XL18 3-CH2C6H5 5-SOCH2CH2CH=CF2
XI.19 3-CH2C6H5 5-SO2CH2CH2CH=CF2
XI.20 3-CH2CF3 5-SCH2CH2CH=CF2
XI.21 3-CH2CF3 5-SOCH2CH2CH=CF2
XI.22 3-CH2CH=CH2 5-SCH2CH2CH=CF2
XI.23 3-CH2CH3 5-SCH2CH2CH=CF2
XI.24 3-CH2CH3 5-SO2CH2CH2CH=CF2
X.25 3-CH2C1 5-SCH2CH2CH=CF2
AP.00649
XI.26 3-CH2CN 5-SCH2CH2CH=CF2
XL27 3-CH2CONH2 5-SCH2CH2CH=CF2
XI.28 3-CH2N(CH3)2 5-SCH2CH2CH=CF2
XI .29 3-CH2NHCOCH3 5-SCH2CH2CH=CF2
XL30 3-CH2OCH2CH2CH2CH3 5-SCH2CH2CH=CF2
XI.31 3-CH2OCH2CH2CH3 5-SCH2CH2CH=CF2
XL32 3-CH2OCH2CH3 5-SCH2CH2CH=CF2
XI.33 3-CH2OCH2CH3 5-SOCH2CH2CH=CF2
XI.34 3-CH2OCH3 5-SCH2CH2CH=CF2
XI.35 3-CH2OCH3 5-SOCH2CH2CH=CF2
XI.36 3-CH2OCH3 5-SO2CH2CH2CH=CF2
XI.37 3-CH2OH 5-SCH2CH2CH=CF2
XI.38 3-CH2SCH2CH2CH=CF2 5-SCH2CH2CH=CF2
XI.39 3-CH2SO2C6H5 5-SCH2CH2CH=CF2
XI.4O 3-CH3 5-SCH2CH2CH=CF2
XI.41 3-CH3 5-SOCH2CH2CH=CF2
XI.42 3-CH3 5-SO2CH2CH2CH=CF2
XI.43 3-C1 5-SCH2CH2CH=CF2
XI.44 3-C1 5-SO2CH2CH2CH==CF2
XI.45 3-CN 5-SCH2CH2CH=CF2
XI.46 3-COC6H5 5-SCH2CH2CH=CF2
XI.47 3-COCH3 5-SCH2CH2CH=CF2
XI.48 3-CON(CH3)2 5-SCH2CH2CH=CF2
XI.49 3-CON(CH3)C2H5 5-SCH2CH2CH-CF2
XI.50 3-CONH2 5-SCH2CH2CH=CF2
XI.51 3-CONHCH2C6H5 5-SCH2CH2CH=CF2
XL52 3-CONHCH2CH2CH=CF2 5-SCH2CH2CH=CF2
XI.53 3-CONHCH2CH2CH3 5-SCH2CH2CH=CF2
XL54 3-CONHCH3 5-SCH2CH2CH==CF2
XI.55 3-CONHCH3 5-SOCH2CH2CH=CF2
XI.56 3-CONHCH3 5-SO2CH2CH2CH=CF2
XL57 3-CONHSO2CH3 5-SCH2CH2CH=CF2
XI.58 3-COOC6H5 5-SCH2CH2CH=CF2
AP/P/ 9 6 / 0 0 8 6 2
XI.59 3-COOCH2CH2CH=CF2 5-SCH2CH2CH=CF2
XI.60 3-COOCH2CH2F 5-SCH2CH2CH=€F2
XI.61 3-COOCH2CH3 5-SCH2CH2CH=CF2
XI.62 3-COOCH3 5-SCH2CH2CH=CF2
XI.63 3-COOH 5-SCH2CH2CH=CF2
XI.64 3-COSCH2CH2CH=CF2 5-SCH2CH2CH=CF2
XI.65 3-CSNH2 5-SCH2CH2CH=€F2
XI.66 3-F 5-SCH2CH2CH=CF2
XI.67 3-H 5-SCH2CH2CH=CF2
XI.68 3-H 5-SOCH2CH2CH=CF2
XI.69 3-H 5-SO2CH2CH2CH=CF2
XI.70 3-N(SO2CH3)2 5-SCH2CH2CH=CF2
XI.71 3-NHCHO 5-SCH2CH2CH=CF2
XI.72 3-NHCOC2H5 5-SCH2CH2CH=CF2
XI.73 3-NHCOCF3 5-SCH2CH2CH=CF2
XI.74 3-NHCOCH3 5-SCH2CH2CH=CF2
XI.75 3-NHCSCH2CH3 5-SCH2CH2CH=CF2
XI.76 3-NHCSNHCH2CH3 5-SCH2CH2CH=CF2
XI.77 3-NHSO2CH3 5-SCH2CH2CH=€F2
XI.78 3-NO2 5-SCH2CH2CH=CF2
XI.79 3-OC6H5 5-SCH2CH2CH=CF2
XI.80 3-OCF2CF2H 5-SCH2CH2CH=CF2
XI.81 3-OCF2H 5-SCH2CH2CH=CF2
XI. 82 3-OCF3 5-SCH2CH2CH=CF2
XI.83 3-OCH2CF3 5-SCH2CH2CH=CF2
XI.84 3-OCH2CF3 5-SOCH2CH2CH=CF2
XI.85 3-OCH2CF3 5-SO2CH2CH2CH=CF2
XI.86 3-OCH2CH=€C12 5-SCH2CH2CH=CF2
XI.87 3-OCH3 5-SCH2CH2CH=CF2
XI.88 3-OCOC2H5 5-SCH2CH2CH=CF2
XI.89 3-OCOC6H5 5-SCH2CH2CH=CF2
XI .90 3-OCOCH3 5-SCH2CH2CH=CF2
XI.91 3-OSO2CH3 5-SCH2CH2CH=CF2
AP.00649
XI.92 3-SCF3 5-SCH2CH2CH=€F2
X1.93 3-SCH2CH2CH=CF2 5-CF3
XI.94 3-SCH2CH2CH=CF2 5-CH2C6H5
XL95 3-SCH2CH2CH=CF2 5-CH2CF3
XI.96 3-SCH2CH2CH=CF2 5-CH2CH=CH2
XI.97 3-SCH2CH2CH=CF2 5-CH2CN
XI.98 3-SCH2CH2CH=CF2 5-CH2CONH2
XI.99 3-SCH2CH2CH=CF2 5-CH2NHCOCH3
XI.1OO 3-SCH2CH2CH=CF2 5-CH2OCH3
Xi.lOl 3-SCH2CH2CH=CF2 5-CH3
XI. 102 3-SCH2CH2CH=CF2 5-C1
XI.103 3-SCH2CH2CH=CF2 5-CN
XI.1O4 3-SCH2CH2CH=CF2 5-COOCH3
XI.105 3-SCH2CH2CH-CF2 5-NHCHO
XI.106 3-SCH2CH2CH=CF2 5-OC6H5
XI. 107 3-SCH2CH2CH=CF2 5-OCH2CF3
XI.1O8 3-SCH2CH2CH=CF2 5-OCH3
XI.109 3-SCH2CH2CH=CF2 5-SCH2CH2CH=CF2
XI.110 3-SCH3 5-SCH2CH2CH=€F2
XI.lll 3-SO2C2H5 5-SCH2CH2CH=CF2
XI.112 3-SO2CF3 5-SCH2CH2CH=CF2
XI.113 3-SO2CH2CH2CH=€F2 5-OCH2CF3
XI.114 3-SO2CH2CH2CH=CF2 5-SCH2CH2CH=CF2
XI.115 3-SO2CH2CH2CH=CF2 5-SOCH2CH2CH=CF2
XI.116 3-SO2F 5-SCH2CH2CH=CF2
XI.117 3-SO2N(CH3)2 5-SCH2CH2CH=CF2
XI.118 3-SO2NH2 5-SCH2CH2CH=CF2
XI.119 3-SO2NHCH3 5-SCH2CH2CH=CF2
XI. 120 3-SOCF3 5-SCH2CH2CH=CF2
XI.121 3-SOCH2CH2CH=€F2 5-CH2CN
X1.122 3-SOCH2CH2CH=CF2 5-OCH2CF3
XI. 123 3-SOCH2CH2CH=CF2 5-SCH2CH2CH=CF2
XI.124 3-SOCH3 5-SCH2CH2CH=CF2
AP/P/ 9 6 / 0 0 8 6 2
XI.125 3-(2-P>Tazinyl) 5-SCH2CH2CH=CF2
XI.126 3-(3-F-C6H4) 5-SCH2CH2CH=CF2
XI. 127 3-(3-NO2-C6H4) 5-SCH2CH2CH=CF2
XI.128 3-(3-NO2-C6H4) 5-SOCH2CH2CH=CF2
XI.129 3-(3-NO2-C6H4) 5-SO2CH2CH2CH=CF2
XI.130 3-(4-F-C6H4) 5-SCH2CH2CH=CF2
XI.131 3-(4-F-C6H4) 5-SOCH2CH2CH=CF2
XI.132 3-(4-F-C6H4) 5-SO2CH2CH2CH=CF2
Examples of compounds of Formula (XU) according to the invention are set n-n
TABLE ΧΠ
No. R2 R5
ΧΠ.1 2-SCH2CH2CH=CF2 5-C-C3H5
ΧΠ.2 2-SCH2CH2CH=CF2 5-OCH
ΧΠ.3 2-SCH2CH2CH=CF2 5-C6H5
ΧΠ.4 2-SOCH2CH2CH=CF2 5-C6H5
ΧΠ.5 2-SO2CH2CH2CH=CF2 5-C6H5
ΧΠ.6 2-SCH2CH2CH=CF2 5-CF2H
ΧΠ.7 2-SCH2CH2CH=CF2 5-CF3
ΧΠ.8 2-SCH2CH2CH=CF2 5-CH(CH3)2
ΧΠ.9 2-SO2CH2CH2CH=CF2 5-CH(CH3)2
ΧΠ.10 2-SCH2CH2CH=CF2 5-CH=CH2
ΧΠ.11 2-SCH2CH2CH=CF2 5-CH2(2,6-di F -C6H3)
ΧΠ.12 2-SCH2CH2CH=CF2 5-CH2(4-NO2-C6H4)
ΧΠ.13 2-SO2CH2CH2CH=CF2 5-CH2(4-NO2-C6H4)
ΧΠ.14 2-SOCH2CH2CH=CF2 5-CH2(4-OCH3-C6H4)
ΧΠ.15 2-SO2CH2CH2CH=CF2 5-CH2(4-OCH3-C6H4)
ΧΠ.16 2-SCH2CH2CH=CF2 5-CH2Br
ΧΠ.17 2-SCH2CH2CH=CF2 5-CH2C6H5
ΧΠ.18 2-SOCH2CH2CH=CF2 5-CH2C6H5
AP.00649
ΧΠ.19 2-SO2CH2CH2CH=CF2 5-CH2C6H5
ΧΠ.20 2-SCH2CH2CH=CF2 5-CH2CF3
ΧΠ.21 2-SOCH2CH2CH=CF2 5-CH2CF3
XH.22 2-SO2CH2CH2CH=CF2 5-CH2CF3
ΧΠ.23 2-SCH2CH2CH=CF2 5-CH2CH(CH3)2
XH.24 2-SCH2CH2CH=CF2 5-CH2CH=CH2
ΧΠ.25 2-SCH2CH2CH=CF2 5-CH2CH2CH2CH2CH3
XH.26 2-SOCH2CH2CH=€F2 5-CH2CH2CH2CH2CH3
ΧΠ.27 2-SO2CH2CH2CH=€F2 5-CH2CH2CH2CH2CH3
ΧΠ.28 2-SCH2CH2CH=€F2 5-CH2CH2CH2CH3
ΧΠ.29 2-SOCH2CH2CH=CF2 5-CH2CH2CH2CH3
ΧΠ.30 2-SO2CH2CH2CH=CF2 5-CH2CH2CH2CH3
ΧΠ.31 2-SCH2CH2CH=€F2 5-CH2CH2CH3
ΧΠ.32 2-SOCH2CH2CH=CF2 5-CH2CH2CH3
ΧΠ.33 2-SO2CH2CH2CH=CF2 5-CH2CH2CH3
ΧΠ.34 2-SCH2CH2CH=CF2 5-CH2CH2F
ΧΠ.35 2-SCH2CH2CH=CF2 5-CH2CH3
ΧΠ.36 2-SCH2CH2CH=CF2 5-CH2CN
ΧΠ.37 2-SOCH2CH2CH=CF2 5-CH2CN
ΧΠ.38 2-SCH2CH2CH=CF2 5-CH2CONH2
ΧΠ.39 2-SCH2CH2CH=CF2 5-CH2COOCH2CH3
ΧΠ.4Ο 2-SCH2CH2CH=CF2 5-CH2N(CH3)2
ΧΠ.41 2-SCH2CH2CH=CF2 5-CH2NHCOCH3
ΧΠ.42 2-SCH2CH2CH=€F2 5-CH2NHCOOCH3
ΧΠ.43 2-SCH2CH2CH=CF2 5-CH2OCH3
ΧΠ.44 2-SO2CH2CH2CH=CF2 5-CH2OCH3
ΧΠ.45 2-SCH2CH2CH=CF2 5-CH2OH
ΧΠ.46 2-SOCH2CH2CH=CF2 5-CH2OH
ΧΠ.47 2-SCH2CH2CH=CF2 5-CH2SO2C6H5
ΧΠ.48 2-SO2CH2CH2CH=€F2 5-CH2SO2C6H5
ΧΠ.49 2-SCH2CH2CH=CF2 5-CH3
ΧΠ.50 2-SOCH2CH2CH=CF2 5-CH3
ΧΠ.51 2-SO2CH2CH2CH=CF2 5-CH3
AP/P/ 9 6 / 0 0 8 6 2
XU.52 2-SCH2CH2CH=CF2 5-COC6H5
ΧΠ.53 2-SCH2CH2CH=CF2 5-COCH3
ΧΠ.54 2-SCH2CH2CH=CF2 5-CON(CH3)2
ΧΠ.55 2-SCH2CH2CH=CF2 5-CONH2
ΧΠ.56 2-SCH2CH2CH=CF2 5-CONHCH2C6H5
ΧΠ.57 2-SOCH2CH2CH=CF2 5-CONHCH2C6H5
ΧΠ.58 2-SCH2CH2CH=CF2 5-CONHCH2CH2CH=CF2
ΧΠ.59 2-SCH2CH2CH=CF2 5-CONHCH3
ΧΠ.60 2-SCH2CH2CH=CF2 5-CONHSO2CH3
ΧΠ.61 2-SCH2CH2CH=CF2 5-COOC6H5
ΧΠ.62 2-SOCH2CH2CH=CF2 5-COOC6H5
ΧΠ.63 2-SO2CH2CH2CH=CF2 5-COOC6H5
ΧΠ.64 2-SCH2CH2CH=CF2 5-COOCH2CH2CH=CF2
ΧΠ.65 2-SOCH2CH2CH=CF2 5-COOCH2CH2CH=CF2
ΧΠ.66 2-SO2CH2CH2CH=CF2 5-COOCH2CH2CH=CF2
XU.67 2-SCH2CH2CH=CF2 5-COOCH2CH2F
ΧΠ.68 2-SCH2CH2CH=CF2 5-COOCH2CH3
ΧΠ.69 2-SCH2CH2CH=CF2 5-COOCH3
ΧΠ.70 2-SCH2CH2CH=CF2 5-COOH
ΧΠ.71 2-SCH2CH2CH=CF2 5-COSCH2CH2CH=CF2
ΧΠ.72 2-SCH2CH2CH=€F2 5-CSNH2
ΧΠ.73 2-SCH2CH2CH=CF2 5-H
XU.74 2-SOCH2CH2CH=CF2 5-H
XU.75 2-SO2CH2CH2CH=CF2 5-H
ΧΠ.76 2-SCH2CH2CH=CF2 5-N(SO2CH3)2
ΧΠ.77 2-SCH2CH2CH=CF2 5-NHCH2CH3
XU.78 2-SCH2CH2CH=CF2 5-NHCHO
ΧΠ.79 2-SCH2CH2CH=CF2 5-NHCOOCH3
ΧΠ.80 2-SCH2CH2CH=CF2 5-NHCOCF3
ΧΠ.81 2-SOCH2CH2CHCF2 5-NHCOCF3
ΧΠ.82 2-SCH2CH2CH=CF2 5-NHCOCH3
ΧΠ.83 2-SO2CH2CH2CH=CF2 5-NHCOCH3
ΧΠ.84 2-SCH2CH2CH=CF2 5-NHCSCH2CH3
ΧΠ.85 2-SCH2CH2CH=CF2 5-NHCSNHCH2CH3
ΧΠ.86 2-SCH2CH2CH=CF2 5-NHSO2CH3
ΧΠ.87 2>SCH2CH2CH=CF2 5-OCF2CF2H
ΧΠ.88 2-SCH2CH2CH=CF2 5-OCF3
ΧΠ.89 2-SOCH2CH2CH=CF2 5-OCF3
ΧΠ.90 2-SCH2CH2CH=CF2 5-OCH2C6H5
ΧΠ.91 2-SO2CH2CH2CH=CF2 5-OCH2C6H5
ΧΠ.92 2-SCH2CH2CH=CF2 5-OCH2CF3
ΧΠ.93 2-SOCH2CH2CH=CF2 5-OCH2CF3
ΧΠ.94 2-SO2CH2CH2CH=CF2 5-OCH2CF3
ΧΠ.95 2-SCH2CH2CH=CF2 5-OCH2CH=€C12
ΧΠ.96 2-SCH2CH2CH=CF2 5-OCH2CH2CH=CF2
ΧΠ.97 2-SOCH2CH2CH=CF2 5-OCH2CH2CH=CF2
ΧΠ.98 2-SO2CH2CH2CH=CF2 5-OCH2CH2CH=CF2
ΧΠ.99 2-SCH2CH2CH=CF2 5-OCH2CH2F
ΧΠ.10Ο 2-SCH2CH2CH=CF2 5-OCH2COOH
ΧΠ.101 2-SCH2CH2CH=CF2 5-OCH3
ΧΠ.102 2-SCH2CH2CH=CF2 5-OCOC6H5
ΧΠ.103 2-SCH2CH2CH=CF2 5-OCOCH3
ΧΠ.104 2-SCH2CH2CH=CF2 5-OC6H5
ΧΠ.105 2-SOCH2CH2CH=CF2 5-OC6H5
ΧΠ.1Ο6 2-SO2CH2CH2CH=CF2 5-OC6H5
ΧΠ.107 2-SCH2CH2CH=CF2 5-OS02CH3
ΧΠ.108 2-SOCH2CH2CH=CF2 5-OSO2CH3
ΧΠ.109 2-SCH2CH2CH=CF2 5-SCF3
ΧΠ.110 2-SCH2CH2CH-CF2 5-SCH2CH2CH=CF2
ΧΠ.1Ι1 2-SCH2CH2CH=CF2 5-SCH3
ΧΠ.112 2-SCH2CH2CH=CF2 5-SO2CF3
ΧΠ.113 2-SO2CH2CH2CH=€F2 5-SO2CF3
ΧΠ.114 2-SCH2CH2CH=CF2 5-SO2CH2CH2CH=CF2
ΧΠ.115 2-SO2CH2CH2CH=CF2 5-SO2CH2CH2CH=CF2
ΧΠ.116 2-SCH2CH2CH=CF2 5-SO2CH3
ΧΠ.117 2-SCH2CH2CH=CF2 5-SO2N(CH3)2
AP/P/ 9 6 / 0 0 8 6 2
ΧΠ.118 2-SCH2CH2CH=CF2 5-SO2NH2
ΧΠ.119 2-SCH2CH2CH=CF2 5-SO2NHCH3
ΧΠ.120 2-SO2CH2CH2CH=CF2 5-SO2NHCH3
ΧΠ.121 2-SCH2CH2CH=CF2 5-SOCF3
ΧΠ.122 2-SOCH2CH2CH-CF2 5-SOCF3
XU.123 2-SCH2CH2CH=CF2 5-SOCH2CH2CH=CF2
ΧΠ.124 2-SOCH2CH2CH=CF2 5-SOCH2CH2CH=CF2
ΧΠ.125 2-SO2CH2CH2CH=CF2 5-SOCH2CH2CH=CF2
XU.126 2-SCH2CH2CH=CF2 5-SOCH3
ΧΠ.127 2-SO2CH2CH2CH=CF2 5-SOCH3
ΧΠ.128 2-SCH2CH2CH=CF2 5-(2-CH3-C6H4)
ΧΠ.129 2-SOCH2CH2CH=CF2 5-(2-CH3-C6H4)
ΧΠ.130 2-SO2CH2CH2CH=CF2 5<2-CH3-C6H4)
ΧΠ.131 2-SCH2CH2CH=CF2 5-(2-Furyl)
ΧΠ.132 2-SCH2CH2CH=CF2 5-(2-OCH3-C6H4)
ΧΠ.133 2-SCH2CH2CH=CF2 5-(2-Thiophenyl)
ΧΠ.134 2-SCH2CH2CH=CF2 5<3-Furyl)
ΧΠ.135 2-SCH2CH2CH=CF2 5<4-CF3-C6H4)
ΧΠ.136 2-SO2CH2CH2CH=CF2 5-(4-CF3-C6H4)
XU.137 2-SCH2CH2CH=CF2 5-(4-CH3-C6H4)
ΧΠ.138 2-SCH2CH2CH=CF2 5<4-CN-C6H4)
ΧΠ.139 2-SCH2CH2CH=CF2 5-(4-CONH2-C6H4)
ΧΠ.140 2-SO2CH2CH2CH=CF2 5-(4-CONH2-C6H4)
ΧΠ.141 2-SCH2CH2CH=CF2 5-(4-NO2-C6H4)
ΧΠ.142 2-SOCH2CH2CH=CF2 5-(4-NO2-C6H4)
ΧΠ.143 2-SO2CH2CH2CH=CF2 5-<4-NO2-C6H4)
ΧΠ.144 2-SCH2CH2CH=CF2 5-(4-OCH3-C6H4)
ΧΠ.145 2-SOCH2CH2CH=CF2 5-(4-OCH3-C6H4)
ΧΠ.146 2-SO2CH2CH2CH=CF2 5<4-OCH3-C6H4)
XU.147 2-SCH2CH2CH=CF2 5-(4-OH-C6H4)
ΧΠ.148 2-SCH2CH2CH=CF2 5-(4-PyridinyI)
AP.00649
- 51 Examples of compounds of Formula (XHI) according to the invention are set out in Table ΧΠ1.
n-n
TABLE ΧΙΠ
No. R2 R5
xm.i 2-SCH2CH2CH=CF2 5-Br
xm.2 2-SO2CH2CH2CH=CF2 5-Br
xm.3 2-SCH2CH2CH=CF2 5-C(CH3)3
xm.4 2-SO2CH2CH2CH=CF2 5-C(CH3)3
xm.5 2-SCH2CH2CH=CF2 5-C(O)C6H5
xm.6 2-SCH2CH2CH=CF2 5-C-C3H5
Xffl.7 2-SO2CH2CH2CH=CF2 5-C-C3H5
Xffl.8 2-SCH2CH2CH=CF2 5-G=CH
xm.9 2-SCH2CH2CH=CF2 5-C6H5
xm.io 2-SOCH2CH2CH=CF2 5-C6H5
xm.n 2-SO2CH2CH2CH=CF2 5-C6H5
xm.n 2-SCH2CH2CH=CF2 5-CF2H
xm.13 2-SOCH2CH2CH=CF2 5-CF2H
xm.u 2-SCH2CH2CH=CF2 5-CF3
Xffl.15 2-SO2CH2CH2CH=CF2 5-CF3
xm.16 2-SCH2CH2CH=CF2 5-CH(CH3)2
xm.17 2-SO2CH2CH2CH=CF2 5-CH(CH3)2
xm.i8 2-SCH2CH2CH=CF2 5-CH=CH2
xm.i9 2-SCH2CH2CH=CF2 5-CH2Br
xm.2o 2-SCH2CH2CH=CF2 5-CH2C6H5
xm.21 2-SOCH2CH2CH=CF2 5-CH2C6H5
xm.22 2-SO2CH2CH2CH=CF2 5-CH2C6H5
Xffl.23 2-SCH2CH2CH=CF2 5-CH2CF3
ΧΠ1.24 2-SCH2CH2CH=CF2 5-CH2CH2F
ΧΓΠ.25 2-SOCH2CH2CH=CF2 5-CH2CH2F
ΧΕΠ.26 2-SO2CH2CH2CH=CF2 5-CH2CH2F
XH1.27 2-SCH2CH2CH=CF2 5-CH2CH3
AP/P/ 9 6 / 0 0 8 6 2
xm.28 2-SOCH2CH2CH=CF2 5-CH2CH3
xm.29 2-SO2CH2CH2CH=CF2 5-CH2CH3
xm.30 2-SCH2CH2CH=CF2 5-CH2CHCH2
xm.3i 2-SCH2CH2CH=CF2 5-CH2CN
xm.32 2-SCH2CH2CH=CF2 5-CH2CONH2
XHI.33 2-SCH2CH2CH=CF2 5-CH2COCX2H2CH3
ΧΕΠ.34 2-SCH2CH2CH=CF2 5-CH2N(CH3)2
xm.35 2-SCH2CH2CH=CF2 5-CH2OCH3
XHI.36 2-SOCH2CH2CH=CF2 5-CH2OCH3
ΧΙΠ.37 2-SO2CH2CH2CH=CF2 5-CH2OCH3
ΧΠΙ.38 2-SCH2CH2CH=CF2 5-CH2OH
ΧΙΠ.39 2-SCH2CH2CH=CF2 5-CH2SO2C6H5
xm.4o 2-SCH2CH2CH=CF2 5-CH3
xm.4i 2-SOCH2CH2CH=CF2 5-CH3
Xffl.42 2-SO2CH2CH2CH=CF2 5-CH3
xm.43 2-SCH2CH2CH=€F2 5-COCH3
xm.44 2-SCH2CH2CH=CF2 5-CON(CH3)2
XHI.45 2-SCH2CH2CH=€F2 5-CONH2
xm.46 2-SCH2CH2CH=CF2 5-CONHCH2C6H5
xm.47 2-SCH2CH2CH=CF2 5-CONHCH2CH2CH=CF2
xm.48 2-SOCH2CH2CH=CF2 5-CONHCH2CH2CH=CF2
xm.49 2-SO2CH2CH2CH=CF2 5-CONHCH2CH2CH=CF2
xm.50 2-SCH2CH2CH=CF2 5-CONHCH3
xm.51 2-SCH2CH2CH=CF2 5-CONHSO2CH3
ΧΙΠ.52 2-SO2CH2CH2CH=CF2 5-CONHSO2CH3
xm.53 2-SCH2CH2CH=CF2 5-COOC6H5
ΧΠ1.54 2-SOCH2CH2CH==CF2 5-COOC6H5
Xffl.55 2-SCH2CH2CH=CF2 5-COOCH2CH2CH=CF2
xm.56 2-SOCH2CH2CH=CF2 5-COOCH2CH2CH=CF2
xm.57 2-SO2CH2CH2CH=CF2 5-COOCH2CH2CH=CF2
Xffl.58 2-SCH2CH2CH=CF2 5-COOCH2CH2F
xm.59 2-SCH2CH2CH=CF2 5-COOCH3
xm.6o 2-SCH2CH2CH=CF2 5-COOH
AP.00649
Xffl.61 2-SCH2CH2CH=CF2 5-COSCH2CH2CH=€F2
xm.62 2-SCH2CH2CH=CF2 5-CSNH2
Xffl.63 2-SCH2CH2CH=CF2 5-H
ΧΠ1.64 2-SOCH2CH2CHCF2 5-H
Xffl.65 2-SO2CH2CH2CH=CF2 5-H
Xffl.66 2-SCH2CH2CH=CF2 5-N(CH3)2
Xffl.67 2-SCH2CH2CH=€F2 5-N(SO2CH3)2
xm.68 2-SO2CH2CH2CH=CF2 5-N(SO2CH3)2
xm.69 2-SCH2CH2CH=CF2 5-NH2 ·
xm.70 2-SCH2CH2CH=CF2 5-NHCH3
XHL71 2-SOCH2CH2CH=CF2 5-NHCH3
Xffl.72 2-SO2CH2CH2CH=CF2 5-NHCH3
xm.73 2-SCH2CH2CH=CF2 5-NHCHO
Xffl.74 2-SOCH2CH2CH=CF2 5-NHCHO
xm.75 2-SCH2CH2CH=CF2 5-NHCOCF3
xm.76 2-SO2CH2CH2CH=CF2 5-NHCOCF3
xm.77 2-SCH2CH2CH=CF2 5-NHCOCH3
xm.78 2-SCH2CH2CH=CF2 5-NHCOOCH3
xm.79 2-SOCffiCH2CH=CF2 5-NHCOOCH3
xm.80 2-SCH2CH2CH=CF2 5-NHCSCH2CH3
xm.8i 2-SCH2CH2CH=CF2 5-NHCSNHCH2CH3
ΧΠΙ.82 2-SCH2CH2CH=CF2 5-NHSO2CH3
ΧΠΙ.83 2-SO2CH2CH2CH=CF2 5-NHSO2CH3
ΧΠΙ.84 2-SCH2CH2CH=CF2 5-OC6H5
ΧΠΙ.85 2-SOCH2CH2CH=CF2 5-OC6H5
XHL86 2-SO2CH2CH2CH=€F2 5-OC6H5
ΧΙΠ.87 2-SCH2CH2CH=CF2 5-OCF2CF2H
xm.88 2-SCH2CH2CH=CF2 5-OCF3
xm.89 2-SOCH2CH2CH=CF2 5-OCF3
xm.9o 2-SO2CH2CH2CH=CF2 5-OCF3
xm.91 2-SCH2CH2CH=CF2 5-OCH2C6H5
xm.92 2-SCH2CH2CH=CF2 5-OCH2CF3
xm.93 2-SOCH2CH2CH=CF2 5-OCH2CF3
AP/P/ 9 6 / 0 0 8 6 2
xm.94 2-SO2CH2CH2CH=CF2 5-OCH2CF3
xm.95 2-SCH2CH2CH=CF2 5-OCH2CH=CC12
ΧΠ.96 2-SCH2CH2CH=CF2 5-OCH2CH2CH=€F2
XL ” 2-SOCH2CH2CH=CF2 5-OCH2CH2CH=CF2
xm. 2-SO2CH2CH2CH=CF2 5-OCH2CH2CH=CF2
xm.& 2-SCH2CH2CH=CF2 5-OCH2CH2F
xm.ioo >SCH2CH2CH=CF2 5-OCH2COOCH3
xm.ioi 2-SCH2CH2CH=CF2 5-OCH3
xm.102 2-SOCH2CH2CH=CF2 5-OCH3
xm.103 2-SO2CH2CH2CH=CF2 5-OCH3
xm.icw 2-SCH2CH2CH=CF2 5-OCOC6H5
xm.i05 2-SCH2CH2CH=CF2 5-OCOCH3
xm.m 2-SCH2CH2CH=CF2 5-OSO2CH3
xm.107 2-SOCH2CH2CH=CF2 5-OSO2CH3
xm.io8 2-SO2CH2CH2CH=CF2 5-OSO2CH3
xm.109 2-SCH2CH2CH=€F2 5-SCF3
xm.no 2-SCH2CH2CH=CF2 5-SCH2(3-CF3C6H4)
xm.m 2-SOCH2CH2CH=CF2 5-SCH2(3-CF3C6H4)
xm.112 2-SO2CH2CH2CH=CF2 5-SCH2(3-CF3C6H4)
xm.m 2-SCH2CH2CH=CF2 5-SCH2(4-CF3-C6H4)
xm.m 2-SCH2CH2CH=€F2 5-SCH2(c-C3H5)
xm.m 2-SCH2CH2CH=CF2 5-SCH2GCH
xm.m 2-SCH2CH2CH=CF2 5-SCH2CH=CH2
xm.m 2-SCH2CH2CH=CF2 5-SCH2CH2CH=CF2
xm.ii8 2-SOCH2CH2CH=CF2 5-SCH2CH2CH=CF2
xm.m 2-SCH2CH2CH=CF2 5-SCH3
xm.120 2-SOCH2CH2CH=CF2 5-SCH3
xm.121 2-SO2CH2CH2CH=CF2 5-SCH3
xm.m 2-SCH2CH2CH=CF2 5-SH
xm.m 2-SCH2CH2CH=CF2 5-SO2CH2CH2CH=CF2
xm.m 2-SO2CH2CH2CH=CF2 5-SO2CH2CH2CH=€F2
xm.m 2-SCH2CH2CH=CF2 5-SO2CH3
xm.m 2-SO2CH2CH2CH=CF2 5-SO2CH3
AP.00649
xm.127 2-SCH2CH2CH=CF2 5-SO2N(CH3)2
XUI. 128 2-SCH2CH2CH=CF2 5-SO2NH2
ΧΠΙ.129 2-SCH2CH2CH=CF2 5-SO2NHCH3
ΧΠ1.130 2-SCH2CH2CH=CF2 5-SOCF3
xm.131 2-SOCH2CH2CH=CF2 5-SOCF3
ΧΓΠ.132 2-SCH2CH2CH=CF2 5-SOCH2CH2CH=CF2
xm.133 2-SOCH2CH2CH=CF2 5-SOCH2CH2CH=CF2
xm.134 2-SO2CH2CH2CH=CF2 5-SOCH2CH2CH=CF2
xm.135 2-SCH2CH2CH=CF2 5-SOCH3
xm.136 2-SCH2CH2CH=CF2 5-(4-CF3-C6H4)
xm.137 2-SO2CH2CH2CH=CF2 5-(4-CF3-C6H4)
xm.138 2-SCH2CH2CH=CF2 5-(4-CH3-C6H4)
xm.139 2-SO2CH2CH2CH=CF2 5-(4-CH3-C6H4)
xm.i40 2-SCH2CH2CH=CF2 5<4-CN-C6H4)
xm.141 2-SOCH2CH2CH=CF2 5<4-CN-C6H4)
xm.142 2-SCH2CH2CH=CF2 5-(4-CONH2-C6H4)
xm.143 2-SCH2CH2CH=CF2 5-(4-H2NSO2-C6H4)
xm.144 2-SCH2CH2CH=CF2 5-(4-NO2-C6H4)
xm.145 2-SCH2CH2CH=CF2 5-(4-OCH3-C6H4)
xm.146 2-SOCH2CH2CH=CF2 5-(4-OCH3-C6H4)
xm.147 2-SO2CH2CH2CH=CF2 5-(4-OCH3-C6H4)
AP/P/ 9 6 / 0 0 8 6 2
Examples of compounds of Formula (XTV) according to the invention are N — N set out in Table XTV. N _
TABLE XTV 7
No. R1 R5
XTV.l 1-CH3 5-SCH2CH2CH=CF2
- 56 Examples of compounds of Formula (XV) according to the invention are set out in Table XV.
TABLE XV
No. RI R2 R3
XV’.l 1-SCH2CH2CH=€F2 2-H 3-H
R4
4-NO2
AP . 0 0 6 4 9
Ix;unples ο I 'compounds olT'ormula (XVI) according lo the invent ion wc set out in Ί able XVI.
Γ3 CH U. — z z
vi — Ci. u_ — _ _ _ ZZ = zz u u u u u o
— vr, A uh uh uh uh uh uh uh vn uh A A A UH UH
CM CM r« CM $ CM CM CM r . u II
i< 5f II U ί U CM
u u cm ^M u mm
HJ cm D u CM CM u CM
u U u
CM CM — u a u
— - u CM CM
> u u o ΖΉ u o
X co ee ee ee ee ee
r-> 0M> ’’T T v V ΤΓ •v ’T 4 4 4 4
*** CM
u. V
ΰ
22
ΰ
22 22
re ii. z δ §
3 1 1 L__ r » 1 t I U 1 □ u 1 U 1 1 t 1 1 1 —
CH m ΓΗ CH CH CH CH CH ΓΗ CH CH CH CH ee CH CH
CM CM CM
U. Ci.
CM cm CM CM CM L) CM U CM u
U. Ci. Ci. Ci. Ci. ¥ Ci. ¥ Ci. ¥
V V V V V □ V □ V U
— __ . __ __ 22 — CM Μβ CM
u u u u u u MM u
cm CM ΓΝ 22 22 U 22 CM u 22 22 u
ΰ ΰ ϋ U ΰ ϋ O
22 cm 22 22 22 U CM o 22 U CM o 22 u CM o
U ϋ ΰ ϋ ϋ U ϋ
a u r » f · ee ee ee ee ee ee ee ee ee ee
CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM CM
© CM CH -T UH SO
—η CM CH ’T UH C- oo O' ,
-· > > > > > > > > > > δ δ >
z X X X X X X X X X X X X X X
CM
CO
CO
O
O
CO
O>
CL
CL <
I t > ί I I I ’ rs ϋ
- ϋ
Z C rs “ <5 ΓΤ 'm*' s> . - . ·*< o uurz^z^zz:
t I I I I I I I
rs O _ Z
rc r*i A rA rA rA m m
fS
fS CS rs u rs rs rs rs
_ Ii M_ MM •M
u φ u u u u
|| j_ u l· 2L
MM MM ^MM CM M MM MM MM
u u u u u u u
C-4 CM CS r ι rs rs rs Csl
u u u — u u u u
fS rs CM 1 ) rs (S rs rs
MM· MM· Ml M^M
MM • MM rs «ΜΜ MM MM MM·
Ό u u o u u u u
CO co co co co co co co
rA rA rs rs rA rA rs rs
r- oc © MM rs Γ-Ί rr
MM rs CM rs rs rs
> > > > > > > >
X X X X X X X X
AP. Ο Ο 6 4 9
- 59Examples of compounds of Formula (XVH) according to the invention are set our in Table XVII.
TABLE XVII
No. R3 R4 R5 R6
xvn.i 3-SCH2CH2CH=CF2 4-H 5-H 6-CH3
XVH.2 3-SCH2CH2CH=CF2 4-H 5-H 6-C1
XVH.3 3-SCH2CH2CH=CF2 4-H 5-H 6-OCH3
XVH.4 3-SCH2CH2CH=CF2 4-H 5-H 6-C6H5
XVU.5 3-SOCH2CH2CH=CF2 4-H 5-H 6-C6H5
XVn.6 3-SO2CH2CH2CH=CF2 4-H 5-H 6-C6H5
XVH.7 3-SCH2CH2CH=CF2 -CH=CH-CH=CH- 6-H
Examples of compounds of Formula (XVIII) according to the invention are set out in Table XVUI.
TABLE XVHI
*3
AP/P/ 96/00862
No. R2 R3 R5 R6
xvm.i 2-SCH2CH2CH=CF2 3-H -CH=CH-CH=CH-
xvm.2 2-SOCH2CH2CH=CF2 3-H -CH=CH-CH=CH-
xvm.3 2-SO2CH2CH2CH=CE2 3-H -CH=CH-CH=CH-
xvm.4 2-SCH2CH2CH=CF2 3-H -CH=C(CI)CH=CH-
xvm.5 2-SOCH2CH2CH<T2 3-H -CH=C(C1)CH=CH-
xvm.6 2-SO2CH2CH2CH=CF2 3-H -CH=€(C1)CH=CH-
xvm.7 2-SCH2CH2CH=CF2 3-H 5-H 6-H
xvm.8 2-SOCH2CH2CH=CF2 3-H 5-H 6-H
xvm.9 2-SO2CH2CH2CH=CF2 3-H 5-H 6-H
xvm.io 2-SCH2CH2CH=CF2 3-C1 5-H 6-H
xvm.n 2-SOCH2CH2CH=CF2 3-C1 5-H 6-H
xvm.i2 2-SO2CH2CH2CH=CF2 3-C1 5-H 6-H
xvm.i 3 2-SCH2CH2CH=CF2 3-SCH2CH2CH=CF2 5-H 6-H
xvm.14 2-SCH2CH2CH=CF2 3-H 5-H 6-C1
xvnt.is 2-SOCH2CH2CH<F2 3-H 5-H 6-C1
xvm.i6 2-SO2CH2CH2CH=CF2 3-H 5-H 6-C1
Examples of compounds of Formula (XIX) according to the invention are set out in Table XIX
TABLE XX
No. R4 R5 R6
XXI 4-SCH2CH2CH=CF2 -CH=CH-CH=CHExamples of compounds of Formula (XX) according to the invention are set out in Table XX
TABLE XX
No. R3 R5 R6
XXI 3-SCH2CH2CH=CF2 5-Br 6-H
XX2 3-SCH2CH2CH=CF2 5-C-C3H5 6-H
XX3 3-SOCH2CH2CH=CF2 5-C-C3H5 6-H
XX4 3-SCH2CH2CH=CF2 5-C6H5 6-CH3
XX5 3-SOCH2CH2CH=CF2 5-C6H5 6-CH3
XX6 3-SO2CH2CH2CH=CF2 5-C6H5 6-CH3
XX7 3-SOCH2CH2CH=CF2 5-C6H5 6-CN
XX8 3-SCH2CH2CH=CF2 5-C6H5 6-H
XX9 3-SO2CH2CH2CH=CF2 5-C6H5 6-H
XX10 3-SCH2CH2CH=CF2 5-(4-F-C6H4) 6-H
XXII 3-SOCH2CH2CH=CF2 5-(4-F-C6H4) 6-H
XX12 3-SCH2CH2CH=CF2 5-CF2H 6-CH3
XX13 3-SCH2CH2CH=CF2 5-CF3 6-H
XX14 3-SOCH2CH2CH=CF2 5-CF3 6-OC6H5
>2X15 3-SCH2CH2CH=CF2 5-CH(CH3)2 6-H
AP,00649
XX16 3-SCH2CH2CH=CF2 - 61 - 5-CH=CH2 6-H
XX17 3-SCH2CH2CH=CF2 5-CH=CHCN 6-H
XX18 3-SCH2CH2CH=CF2 5-CH=CHNO2 6-H
XX 19 3-SCH2CH2CH=CF2 5-CH=NOCH3 6-CH3
XX20 3-SCH2CH2CH=CF2 5-CH2CCH 6-H
XX21 3-SCH2CH2CH=CF2 5-CH2C6H5 6-H
XX22 3-SOCH2CH2CH=CF2 5-CH2C6H5 6-H
XX23 3-SCH2CH2CH=CF2 5-CH2CF3 6-H
XX24 3-SCH2CH2CH=CF2 5-CH2CH=CH2 6-H
XX25 3-SCH2CH2CH=CF2 5-CH2CH2CH2CH3 6-H
XX26 3-SO2CH2CH2CH=CF2 5-CH2CH2CH2CH3 6-H
XX27 3-SCH2CH2CH=CF2 5-CH2CH2CH3 6-H
XX28 3-SO2CH2CH2CH=CF2 5-CH2CH2CH3 6-H
XX29 3-SCH2CH2CH=CF2 5-CH2CH2F 6-H
XX3O 3-SCH2CH2CH=CF2 5-CH2CH3 6-H
XX31 3-SCH2CH2CH=CF2 5-CH2CN 6-CH3
XX32 - 3-SCH2CH2CH=CF2 5-CH2CONH2 6-H
XX33 3-SCH2CH2CH=CF2 5-CH2N(CH3)2 6-CH3
XX34 3-SCH2CH2CH=CF2 5-CH2NHCOCH3 6-H
XX35 3-SCH2CH2CH=CF2 5-CH2OCH2CH3 6-H
XX36 3-SOCH2CH2CH=CF2 5-CH2OCH2CH3 6-H
XX37 3-SCH2CH2CH=€F2 5-CH2OCH3 6-CH3
XX38 3-SCH2CH2CH=CF2 5-CH2OH 6-H
XX39 3-SCH2CH2CH=CF2 5-CH2SO2C6H5 6-H
XX4O 3-SCH2CH2CH=CF2 5-CH3 6-CF2H
XX41 3-SCH2CH2CH=CF2 5-CH3 6-CH=CH2
XX42 3-SCH2CH2CH=CF2 5-CH3 6-CH2CH2F
XX43 3-SCH2CH2CH=CF2 5-CH3 6-CH2CN
XX 44 3-SCH2CH2CH=CF2 5-CH3 6-CH2N(CH3)2
XX45 3-SCH2CH2CH=CF2 5-CH3 6-CH2OH
XX46 3-SCH2CH2CH=CF2 5-CH3 6-CH3
XX47 3-SCH2CH2CH=CF2 5-CH3 6-CONH2
XX48 3-SCH2CH2CHCF2 5-CH3 6-CONHCH3
AP/P/ 9 6 / 0 0 8 6 2
ΧΧ49 3-SCH2CH2CH=CF2 5-CH3 6-CONHSO2CH3
ΧΧ.50 3-SCH2CH2CH=CF2 5-CH3 6-COOCH2CH3
ΧΧ51 3-SCH2CH2CH=CF2 5-CH3 6-COOCH3
ΧΧ52 3-SCH2CH2CH=CF2 5-CH3 6-H
ΧΧ53 3-SOCH2CH2CH=CF2 5-CH3 6-H
ΧΧ54 3-SO2CH2CH2CH=CF2 5-CH3 6-H
ΧΧ55 3-SCH2CH2CH=CF2 5-CH3 6-NHCHO
ΧΧ.56 3-SCH2CH2CH=CF2 5-CH3 6-NHCOCH3
ΧΧ57 3-SCH2CH2CH=CF2 5-CH3 6-NHCONH2
ΧΧ58 3-SCH2CH2CH=CF2 5-CH3 6-OCF2H
ΧΧ59 3-SCH2CH2CH=CF2 5-CH3 6-OCH2CF3
ΧΧ60 3-SCH2CH2CH=CF2 5-CH3 6-OCH2CH2F
ΧΧ.61 3-SCH2CH2CH=CF2 5-CH3 6-OCOCH3
ΧΧ62 3-SCH2CH2CH=CF2 5-CH3 6-OSO2CH3
ΧΧ63 3-SCH2CH2CH=CF2 5-CH3 6-SO2NH2
XX 64 3-SCH2CH2CH=CF2 5-CH3 6-SOCH3
ΧΧ65 3-SCH2CH2CH=CF2 5-CHC12 6-H
XX 66 3-SCH2CH2CH=CF2 5-CHO 6-CH3
ΧΧ67 3-SCH2CH2CH=CF2 5-C1 6-H
ΧΧ68 3-SO2CH2CH2CH=CF2 5-C1 6-H
ΧΧ69 3-SCH2CH2CH=CF2 5-CN 6-H
XX 70 3-SOCH2CH2CH=CF2 5-CN 6-H
ΧΧ71 3-SCH2CH2CH=€F2 5-COCH3 6-H
ΧΧ72 3-SCH2CH2CH=CF2 5-CON(CH3)2 6-H
XX 73 3-SCH2CH2CH=€F2 5-CONH2 6-H
ΧΧ74 3-SCH2CH2CH=CF2 5-CONHCH2C6H5 6-H
XX 75 3-SOCH2CH2CH=CF2 5-CONHCH2CH2CH=CF2 ! 6-H
ΧΧ76 3-SCH2CH2CH=CF2 5-CONHCH3 6-H
XX 77 3-SCH2CH2CH=CF2 5-CONHSO2CH3 6-CH3
ΧΧ78 3-SO2CH2CH2CH=CF2 5-COOCH2CH2CH<T2 6-H
ΧΧ79 3-SCH2CH2CH=CF2 5-COOCH2CH2F 6-H
XXSO 3-SCH2CH2CH=CF2 5-COOCH2CH3 6-H
ΧΧ81 3-SCH2CH2CH=CF2 5-COOCH3 6-CH3
AP.00649
XX82 3-SOCH2CH2CH=CF2 5-COOCH3 6-H
XX. 83 3-SCH2CH2CH=CF2 5-COOH 6-H
XX 84 3-SOCH2CH2CH=CF2 5-COOH 6-H
XX85 3-SCH2CH2CH=CF2 5-F 6-H
XX86 3-SCH2CH2CH=CF2 5-H 6-(l-CH3-cC3H4)
XX87 3-SCH2CH2CH=CF2 5-H 6-<4-F-C6H4)
XX88 3-SO2CH2CH2CH=CF2 5-H 6-(4-F-C6H4)
XX89 3-SCH2CH2CH=CF2 5-H 6-Br
XX90 3-SCH2CH2CH=CF2 5-H 6-C(CH3)3
XX91 3-SCH2CH2CHCF2 5-H 6-C-C3H5
XX92 3-SCH2CH2CH=CF2 5-H 6-C-C5H9
XX93 3-SCH2CH2CH=CF2 5-H 6-OCH
XX94 3-SCH2CH2CH=CF2 5-H 6-C6H5
XX95 3-SOCH2CH2CH=CF2 5-H 6-C6H5
XX96 3-SCH2CH2CH=CF2 5-H 6-CF3
XX97 3-SO2CH2CH2CH=CF2 5-H 6-CF3
XX98 - 3-SCH2CH2CH=CF2 5-H 6-CH(CH3)2
XX99 3-SCH2CH2CH=CF2 5-H 6-CH=CHCN
XX1OO 3-SCH2CH2CH=CF2 5-H 6-CH=CHNO2
XX101 3-SCH2CH2CH=CF2 5-H 6-CH=NOCH3
XX102 3-SOCH2CH2CH=CF2 5-H 6-CH2(4-CF3-C6H4)
XX103 3-SCH2CH2CH=CF2 5-H 6-CH2OCH
XX104 3-SCH2CH2CH=CF2 5-H 6-CH2C6H5
XX105 3-SOCH2CH2CH=CF2 5-H 6-CH2C6H5
XX106 3-SCH2CH2CH=CF2 5-H 6-CH2CF3
XX107 3-SCH2CH2CH=CF2 5-H 6-CH2CH=CH2
XX108 3-SCH2CH2CH=€F2 5-H 6-CH2CH2CH2CH3
XX109 3-SCH2CH2CH=CF2 5-H 6-CH2CH2CH3
XX110 3-SCH2CH2CH=CF2 5-H 6-CH2CH3
XX111 3-SCH2CH2CH=CF2 5-H 6-CH2CONH2
XX112 3-SCH2CH2CH=CF2 5-H 6-CH2NHCOCH3
XX113 3-SCH2CH2CH=CF2 5-H 6-CH2OCH2CH3
XXI34 3-SCH2CH2CH=CF2 5-H 6-CH2OCH3
AP/P/ 96/00862
XX115 3-SCH2CH2CH=€F2 5-H 6-CH2SO2C6H5
XX.116 3-SCH2CH2CH=€F2 5-H 6-CH3
XX.117 3-SOCH2CH2CH=CF2 5-H 6-CH3
XX118 3-SO2CH2CH2CH=CF2 5-H 6-CH3
XX119 3-SCH2CH2CH=€F2 5-H 6-CHO
XX. 120 3-SCH2CH2CH=CF2 5-H 6-C1
XX121 3-SOCH2CH2CH=CF2 5-H 6-C1
XX122 3-SCH2CH2CH=CF2 5-H 6-CN
XX123 3-SCH2CH2CH=CF2 5-H 6-COCH3
XX124 3-SCH2CH2CH=CF2 5-H 6-CON(CH3)2
XX125 3-SO2CH2CH2CH=CF2 5-H 6-CON(CH3)C2H5
XX126 3-SCH2CH2CH=CF2 5-H 6-CONHCH2C6H5
XX127 3-SCH2CH2CH=CF2 5-H 6-CONHCH2CH2CH=CF2
XX128 3-SCH2CH2CH=CF2 5-H 6-CONHCH2CH2CH3
XX129 3-SCH2CH2CH=CF2 5-H 6-COOC6H5
XX130 3-SCH2CH2CH=CF2 5-H 6-COOCH2CH2CH=CF2
XX131 3-SCH2CH2CH=€F2 5-H 6-COOCH2CH2F
XX132 3-SCH2CH2CH=CF2 5-H 6-COOCH3
XX133 3-SOCH2CH2CH=CF2 5-H 6-COOCH3
XX134 3-SCH2CH2CH=CF2 5-H 6-COOH
XX135 3-SO2CH2CH2CH=CF2 5-H 6-COOH
XX136 3-SCH2CH2CH=CF2 5-H 6-F
XX137 3-SCH2CH2CH=CF2 5-H 6-H
XX138 3-SCH2CH2CH=CF2 5-H 6-NHCH2CH3
XX139 3-SOCH2CH2CH=CF2 5-H 6-NHCH2CH3
XX140 3-SCH2CH2CH=CF2 5-H 6-NHCOC2H5
XX141 3-SCH2CH2CH=CF2 5-H 6-NHCOC6H5
XX142 3-SCH2CH2CH=CF2 5-H 6-NHCOCF3
XX143 3-SCH2CH2CH=CF2 5-H 6-NHCOCH3
XX144 3-SCH2CH2CH=CF2 5-H 6-NHCOOCH3
XX145 3-SCH2CH2CH=CF2 5-H 6-NHCSCH2CH3
XX146 3-SCH2CH2CH=CF2 5-H 6-NHCSNHCH2CH3
XX147 3-SCH2CH2CH=CF2 5-H 6-NHSO2CH3
AP.00649
XX.148 3-SCH2CH2CH=CF2 5-H 6-NO2
XX149 3-SCH2CH2CH=CF2 5-H 6-OC4H9
XX.150 3-SOCH2CH2CH=CF2 5-H 6-OC5H11
XX151 3-SCH2CH2CH=CF2 5-H 6-OC6H5
XX152 3-SOCH2CH2CH=CF2 5-H 6-OC6H5
XX.153 3-SCH2CH2CH=CF2 5-H 6-OCF2CF2H
XX.154 3-SCH2CH2CH=CF2 5-H 6-OCF3
XX.155 3-SOCH2CH2CH=CF2 5-H 6-OCF3
XX156 3-SO2CH2CH2CH=CF2 5-H 6-OCH(CH3)C2H5
XX157 3-SCH2CH2CH=CF2 5-H 6-OCH2(4-Cl-C6H4)
XX158 3-SO2CH2CH2CH=CF2 5-H 6-OCH2(4-Cl-C6H4)
XX159 3-SCH2CH2CH=CF2 5-H 6-OCH2C6H5
XX160 3-SCH2CH2CH=CF2 5-H 6-OCH2CCl=CH2
XX161 3-SCH2CH2CH=CF2 5-H 6-OCH2CH=CC12
XX162 3-SCH2CH2CH=CF2 5-H 6-OCH2CH=CH2
XX163 3-SO2CH2CH2CH=CF2 5-H 6-OCH2CH=CH2
XX164“ 3-SCH2CH2CH=CF2 5-H 6-OCH2CH2CH3
XX165 3-SCH2CH2CH=CF2 5-H 6-OCH2CH2COOCH3
XX166 3-SOCH2CH2CH=CF2 5-H 6-OCH2CH2CCXXZH3
XX167 3-SCH2CH2CH=CF2 5-H 6-OCH2CH2CH=CF2
XX168 3-SCH2CH2CH=CF2 5-H 6-OCH2CH3
XX169 3-SCH2CH2CH=CF2 5-H 6-OCH2COOH
XX170 3-SCH2CH2CH=CF2 5-H 6-OCH3
XX171 3-SOCH2CH2CH=CF2 5-H 6-OCH3
XX172 3-SCH2CH2CH=CF2 5-H 6-OCOC2H5
XX173 3-SCH2CH2CH=CF2 5-H 6-OCOC6H5
XX174 3-SCH2CH2CH=CF2 5-H 6-OH
XX175 3-SOCH2CH2CH=CF2 5-H 6-OH
XX176 3-SCH2CH2CH=CF2 5-H 6-SCF3
XX177 3-SOCH2CH2CH=CF2 5-H 6-SCF3
XX178 3-SCH2CH2CH=CF2 5-H 6-SCH2CH2CH3
XX179 3-SCH2CH2CH=CF2 5-H 6-SCH2CH2CH=CF2
XX180 3-SCH2CH2CH=CF2 5-H 6-SCH3
AP/P/ 9 6 / 0 0 8 6 2
XX181 3-SOCH2CH2CH=CF2 5-H 6-SCH3
XX182 3-SCH2CH2CH=CF2 5-H 6-SO2NHCH3
XX.183 3-SCH2CH2CH=CF2 5-H 6-SOCF3
XX184 3-SCH2CH2CH=€F2 5-H 6-SOCH2CH2CH=CF2
XX185 3-SCH2CH2CH=CF2 5-NH2 6-CH3
XX186 3-SO2CH2CH2CH=CF2 5-NHCH2CH3 6-C6H5
XX187 3-SCH2CH2CH=CF2 5-NHCH2CH3 6-H
XX188 3-SCH2CH2CH=CF2 5-NHCHO 6-H
XX189 3-SCH2CH2CH=CF2 5-NHCOCF3 6-CH3
XX190 3-SOCH2CH2CH=CF2 5-NHCOCH3 6-C6H5
XX191 3-SCH2CH2CH=CF2 5-NHCOCH3 6-H
XX192 3-SCH2CH2CH=CF2 5-NHCONH2 6-CH3
XX193 3-SCH2CH2CH=CF2 5-NHCOOCH3 6-H
XX194 3-SCH2CH2CH=€F2 5-NHSO2CH3 6-CH3
XX195 3-SCH2CH2CH=CF2 5-NMe2 6-H
XX196 3-SOCH2CH2CH=CF2 5-NO2 6-C6H5
XX197 3-SCH2CH2CH=CF2 5-NO2 6-H
XX198 3-SCH2CH2CH=CF2 5-OC6H5 6-H
XX199 3-SOCH2CH2CH=CF2 5-OC6H5 6-H
XX200 3-SOCH2CH2CH=€F2 5-OC6H5 6-NHCOCH3
XX201 3-SCH2CH2CH=CF2 5-OCF2CF2H 6-CH3
XX202 3-SCH2CH2CH=CF2 5-OCF2H 6-H
XX203 3-SCH2CH2CH=CF2 5-OCF3 6-H
XX204 3-SOCH2CH2CH=€F2 5-OCF3 6-H
XX205 3-SCH2CH2CH=CF2 5-OCH(CH3)2 6-H
XX206 3-SOCH2CH2CH=CF2 5-OCH(CH3)C2H5 6-H
XX207 3-SCH2CH2CH=CF2 5-OCH2(4-Cl-C6H4) 6-H
XX208 3-SO2CH2CH2CH=CF2 5-OCH2(4-Cl-C6H4) 6-H
XX209 3-SCH2CH2CH=CF2 5-OCH2C6H5 6-H
XX210 3-SCH2CH2CH=CF2 5-OCH2CCl=CH2 6-H
XX211 3-SCH2CH2CH=CF2 5-OCH2CF3 6-H
XX212 3-SCH2CH2CH=CF2 5-OCH2CH=CH2 6-H
XX213 3-SO2CH2CH2CH=CF2 5-OCH2CH2COOCH3 6-CH3
AP.00649
XX.214 3-SCH2CH2CH=CF2 5-OCH2CH2COOCH3 6-H
XX215 3-SO2CH2CH2CH=CF2 5-OCH2CH2COOCH3 6-H
XX216 3-SCH2CH2CH=CF2 5-OCH2CH2CH=CF2 6-H
XX217 3-SCH2CH2CH=CF2 5-OCH2CH2F 6-CH3
XX218 3-SCH2CH2CH=CF2 5-OCH2CH3 6-H
XX219 3-SCH2CH2CH=CF2 5-OCH2COOCH3 6-H
XX 220 3-SCH2CH2CH=CF2 5-OCH2COOH 6-H
XX221 3-SCH2CH2CH=CF2 5-OCH3 . 6-H
XX.222 3-SCH2CH2CH=CF2 5-OCOC2H5 6-H
XX223 3-SOCH2CH2CH=CF2 5-OCOC6H5 6-H
XX 224 3-SCH2CH2CH=CF2 5-OCOCH3 6-CH3
XX225 3-SOCH2CH2CH=€F2 5-OH 6-C6H5
XX226 3-SCH2CH2CH=CF2 5-OH 6-CH3
XX227 3-SCH2CH2CH=CF2 5-OH 6-H
XX228 3-SCH2CH2CH=CF2 5-OSO2CH3 6-H
XX.229 3-SCH2CH2CH=CF2 5-SCF3 6-H
XX230- 3-SOCH2CH2CH=CF2 5-SCF3 6-H
XX.231 3-SCH2CH2CH=CF2 5-SCH2CH2CH=CF2 6-H
XX232 3-SCH2CH2CH=CF2 5-SCH2CH2CH3 6-H
XX233 3-SCH2CH2CH=CF2 5-SCH2CH2CH=CF2 6-H
XX.234 3-SCH2CH2CH=CF2 5-SCH3 6-H
XX.235 3-SOCH2CH2CH=CF2 5-SCH3 6-H
XX236 3-SCH2CH2CH=€F2 5-SO2NH2 6-CH3
XX237 3-SCH2CH2CH=CF2 5-SO2NHCH3 6-H
XX238 3-SCH2CH2CH=CF2 5-SOCF3 6-H
XX.239 3-SCH2CH2CH=CF2 5-SOCH3 6-CH3
XX240 3-CH3 5-CH3 6-SCH2CH2CH=CF2
XX241 3-CH3 5-H 6-SCH2CH2CH=CF2
XX.242 3-CH3 5-OC4H9 6-SO2CH2CH2CH=CF2
XX.243 3-CH3 5-SCH2CH2CH=CF2 6-CH3
XX.244 3-CH3 5-SCH2CH2CH=CF2 6-H
XX.245 3-H 5-CH3 6-SCH2CH2CH=CF2
XX246 3-H 5-H 6-SCH2CH2CH=CF2
AP/P/ 9 6 / 0 0 8 6 2
XX.247 3-H 5-SCH2CH2CH=CF2 6-CH3
XX248 3-H 5-SCH2CH2CH=CF2 <>H
XX.249 3-H 5-SOCH2CH2CH=CF2 6-CPC
XX.250 3-H 5-SO2CH2CH2CH=CF2 6-CH3
XX.251 3-SCH2CH2CH=CF2 -(CH2CH2CH2CH2)-
XX.252 3-SOCH2CH2CH=CF2 -(CH2CH2CH2CH2F
XX.253 3-SO2CH2CH2CH=CF2 -(CH2CH2CH2CH2)-
Examples of compounds of Formula (XXI) according to the invention are set out in Table XXI.
TABLE XXI
No. R2 R4 R6
XXI. 1 2-SCH2CH2CH=CF2 4-H 6-H
The compounds of formula (I) wherein n is 0 may be prepared by a variety of methods.
They may be prepared, for example, by the reaction of a corresponding thiol compound of formula (ΧΧΠΙ) and an appropriate difluorobut-l-ene alkylating agent of formula (XXTV), where L is a good leaving group. This reaction is preferably conducted in the presence of a mild base such as an alkali metal carbonate, for example sodium or potassium carbonate, in an inert solvent, at a temperature of from 0°C to 200°C.
Conveniently the reaction may be conducted at the reflux temperature of a suitable inert solvent, for example acetone, which has a boiling point within this range.
In formula (XXIV) the leaving group L is preferably a halogen or an ester of sulfonic acid having the formula OSO2Rb, as illustrated by formula (XXV), where Rb is a Cl-4 alkyl group or a phenyl group optionally substituted with a Cl-4 alkyl group. More preferably, L is bromine as shown in formula (XXVI).
The sulfonic ester of formula (XXV) may be prepared by reaction of 1,4-dibromo1.1.2-trifluorobuiane with the silver salt of the chosen sulfonic acid and debromofluorination of the resulting intermediate. 4-toluenesulfonate ester.
In copending International Patent Application No. PCT/GB94/01570, we disclose a method for preparing the compound of formula (XXVI), namely 4-bromo-l, 1-difluorobut-lAP.00649
-69ene. in which hydrogen bromide is reacted with commercially available 4-bromo-1.1.2trifluorobut-l-ene in an inert solvent to give 1.4-dibromo-1.1.2-trifluorobutane. This intermediate can then be treated with a debromofluorinating agent in a suitable solvent, for example acetone or water, to give the compound of formula (XXVI).
It will be appreciated by those skilled in the art that compounds of Formula (ΧΧΠΙ) may exist in tautomeric equilibrium between the equivalent mercapto and thione forms. For the sake of convenience, these compounds are referred to herein in their mercapto form unless otherwise stated.
Compounds of Formula (XXHI) are commercially available or may be prepared from commercially available precursors by standard procedures well known in the art
Alternatively, the compounds of formula (I) may be prepared by reacting a corresponding compound of formula (XXVH), where L is again a good leaving group, with a mercapto compound of formula (XXVIII), under conditions well known in the art for such displacement reactions. Preferably, L is halogen or a nitro group. Conveniently the reaction may be carried out using a two phase solvent system, such as water/dichloromethane, in the presence of a phase transfer catalyst, for example tetra-n-butvl ammonium bromide, at ambient-temperature under a nitrogen atmosphere.
The mercapto compound of formula (XXVEH) is conveniently reacted in the form of its S-acetyl or its isothiouronium hydrogen bromide salt, which compounds are readily hydrolysed to the mercapto compound of formula (XXVHI).
The compounds of formula (I) may also be prepared from the corresponding amino compound of formula (XXIX), which can be diazotised, for example with an alkylnitrite, such as ter., butyl nitrite, in the presence of the disulfide of formula (XXX), in asuitable solvent, such as dichloromethane or acetonitrile.
The compounds of formula (I) where n is 1 or 2, may be prepared by oxidising the correspondingly substituted compound of formula (I) when n is 0, using conventional methods, for example by treatment with a suitable oxidising agent in an inert organic solvent. In general, oxidation of a compound of Formula (I) with one equivalent of a suitable oxidising agent provides the corresponding compound wherein n is 1, and oxidation using two equivalents of the oxidising agent provides the corresponding compound wherein n is 2. Suitable oxididising agents include organic and inorganic peroxides such as peroxy carboxylic acids, or their salts, for example, meta-chloroperbenzoic acid, perbenzoic acid, magnesium monoperoxv-phthalic acid or potassium peroxymono-sulfate.
AP/P/ 96/00862
- 70Thus. according to a further aspect of the present invention there is provided a process for the preparation of compounds of formula (I) where n is 1 or 2. which comprises oxidation of the correspondingly substituted compound of formula (I) when n is 0.
As well as the compounds of formula (I) being prepared from the corresponding substituted compounds of formula (ΧΧΠΙ), (XXVII) or (XXIX), it will be appreciated thai subsequent functional group transformations may be carried out using known chemistry to obtain the required ring substitution. Examples of such functional group transformations include the reduction of nitro groups to amine groups, halogenation, e.g. chlorination, hydrolysis of an ester to the acid, oxidation of an alcohol to the acid, salt formation.
Various further preferred features and embodiments of the present invention will now be described in futher detail with reference to the following illustrative examples in which percentages are by weight and the following abbreviations are used: mp = melting point; bp = boiling point; g = grammes; gc = gas chromatography; NMR = nuclear magnetic resonance; s = singlet; d = doublet; dd = double doublet; t = triplet; q = quartet; m = multiplet; br = broad; M=mole; mNHnillimoles; CDC13 = deuteriochloroform. Chemical shifts (δ) are measured in parts per million from tetramethylsilane. CDC13 was used as solvent for NMR spectra unless otherwise stated. M* = molecular ion as determined by mass spectrometry; FAB = fast atom bombardment; tic = thin layer chromatography.
The synthesis of a number of intermediate compounds of use in the preparation of compounds according to the invention is given below. Some of these compounds are known in the art.
EREEARAWN.1
This illustrates a 3-step preparation of 4-bromo-4,4-difluorobutyl methanesulfonate.
Step 1: 4-bromo-4.4-difluorobutanoic acid.
To a stirred solution of acrylic acid (1.44g) and acetonitrile (80cm3) was added sodium dithionite (4.18g), sodium bicarbonate (2.01g), water (20cm3) and finally dibromodifluoromethane (5cm3). The biphasic mixture was stirred at the ambient temperature with the inorganic salts gradually dissolving. GC analysis after 4 hours indicated complete consumption of acrylic acid. The aqueous phase was saturated with solid sodium chloride. The organic phase was separated, dried over magnesium sulfate, filtered and evaporaied under reduced pressure to give a pale yellow oil with a small amount of a white solid. This mixture was taken up in ethyl acetate, filtered and solvent evaporated under reduced pressure to give a pale yellow oil (2.54g). ’H NMR (DMSO-dJ: δ 2.45(2H,t); 2.65(2H.m).
AP. Ο Ο 6 4 9
-71 Step 2: 4-bromo-4.4-difluorobuianol.
Under an atmosphere of nitrogen, a solution of lithium aluminium hydride in dietbylether (5cm3. 5mM) was cooled to 0°C. Maintaining this temperature. 4-bromo-4.4-difluorobutanoic acid (lg) dissolved in dry dietbylether (5cm3) was added dropwise with stirring. After an hour at 0°C the reaction mixture was cautiously quenched by the addition of 2M hydrochloric acid. The organic phase was separated, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a colourless oil (0.57g). *H NMR; δ 1.82-1.96(2H.m); 2.40-2.60 (2H,m); 3.74(2H,t).
Step 3: 4-bromo-4.4-difluorobutyl methanesulfonate.
A stirred solution of 4-bromo-4,4-difluorobutanol (0.57g) in dry diethvlether (5cm3) was cooled to 0°C. Maintaining this temperature, triethylamine (1.7cm3) was added. After ten minutes methanesulfonyl chloride (0.3cm3) was added and the mixture stirred for a further hour at 0°C. The reaction mixture was poured into 2M hydrochloric acid (2cm3) and diethvlether (20cm3). The organic phase was separated, washed with saturated brine, then passed through a plug of silica gel eluting with further diethvlether. The diethvlether fractions-w'ere evaporaied under reduced pressure to give a light yellow oil (0.705g). Ή NMR; δ 2.04-2.18(2H.m); 2.46-2.64(2H,m); 3.04(3H,s); 4.32(2H,t).
ΕΕΕΕΔΚΔΙΚΜ2
This illustrates a 3-step preparation of the 4,4-difluorobut-3-enyl ester of 4-methvlbenzenesulfonic acid from commercially available 4-bromo-l,l,2-trifluorobut-l-ene.
Step 1; Preparation of 1.4-dibromo-1.1.2-trifluorobutane.
4-Bromo-l,12-trifluorobut-l-ene (Fluorochem Ltd.) (240g) was washed with water (300cm3) and then with brine (300cm3) and dried (MgSOJ before use. Benzoyl peroxide (ca. 0.7g) was added in one portion and hydrogen bromide gas was bubbled through the mixture at such a rate that the reaction temperature was maintained at 30 to 40°C. After 2 hours, gc of a sample of the reaction mixture showed that little starting material remained. The reaction mixture was washed with water (300cm3), then with saturated sodium bicarbonate solution and then again with water (300cm3), dried (MgSO4), and filtered to give a pale yellow oil (296.7g) identified as l,4-dibromo-l,12-trifluorobutane. The material was shown by gc analysis to be greaier than 98% pure. Ή NMR; δ 2.38(2H.m); 3.57(2H.m);
4.90( lH.m).
AP/P/ 9 6 / 0 0 8 6 2
Step 2: Preparation of 4-bromo3.4AtrifluorobuT)-] 4-methyI-benzenesulfonate
The product from Step 1 (lg) was added dropwise to a stirred suspension of silver tosvlaie (1.03 g) in acetonitrile (10cm3) ai ambient temperature, protected from the light. Tne reaction was then heated under reflux for 24 hours after which gc analysis indicated complete consumption of starting material. The reaction mixture was cooled to the ambient temperature and the precipitate was filtered off and washed with ethyl acetate. The filtrate and ethyl acetate washings were combined and washed with water and the aqueous layer extracted with ethyl acetate. The combined ethyl acetale layers were washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a brown oil (1.21g). GC analysis showed this material to be > 99% pure. Ή NMR; δ 2.20(2H.m); 2.46(3H.s); 4.19(2H.m); 4.74(lH.m); 7.38(2H,d); 7.80(2H,d).
Step 3: Preparation of 4.4-difluorobut-3-enyl 4-methvl-benzenesulfonaie
To a stirred suspension of powdered zinc (1.41g) and iodine (one grain, catalytic) in methanol (3cm3) was added a solution of 4-bromo-3,4,4-difluorobutvl p-tolylsulfonate (0.71 g) in methanol (2cm3). The reaction mixture was heated under reflux for 2½ hours after which gc analysis indicated complete consumption of starting material. The organic phase was pipetted from the zinc suspension and the zinc was washed with 3 portions of ethyl acetate. The combined ethyl acetate portions were washed with 2M hydrochloric acid, dried over magnesium sulfate and evaporated under reduced pressure to give a brown liquid (0.47g).
GC analysis showed this material to be > 99% pure. Ή NMR: 5 2.35(2H.m); 2.46(3H,s); 4.01(2H,m); 4.15(lH,m); 7.38(2H,d); 7.79(2H,d).
PREPARATON 3
This illustrates a preparation of 4-bromo-l, l-difluorobut-l-ene from 1,4-dibromo1,1,2-trifluorobuiane.
Zinc powder (0.88p) was added to a stirred solution of 1,4-dibromo-1,1,2trifluorobutane (1.38g) in acetone (6cm3) containing water (1 drop), under an atmosphere of nitrogen. After 45 minutes, gc analysis showed that a large proportion of the starting materia] had been consumed. The mixture was then added to more zinc powder (3g) in acetone containing a trace of water, which had been preheated to 55°C. After a further 20 minuies at this temperature, gc analysis indicated that all of the starting material had been consumed, showing thai the de-bromofluorination reaction had initiated. More starting materia] (12.34g) was then added to the reaction over a period of 75 minutes while the reanion mixture was kept at 55°C. Healing was then continued for a further 95 minutes.
AP . 0 0 6 4 9
- 73 GC analysis of a sample indicaied thai about 3% of the starting dibromo compound remained unchanged. Further zinc powder (0.16ε) was added and healing continued until gc analysis showed all the starting material had been consumed. The acetone solution was decanted from the zinc residues to give a solution of 4-bromo-l.l-difluorobut-l-ene suitable for use in further chemical reactions.
PREPARATION 4
This illustrates a preparation of 4,4-difluorobut-3-enyl thioacetaie.
Potassium thioacetate. (1.98g), 4-bromo-l,l-difluorobut-l-ene (3.0g) and tetra-nburvlammonium bromide (0.3 g, catalyst) were stirred at the ambient temperature under nitrogen for 5 hours and stored for 18 hours. The mixture was distilled using a Kugelrohr appararus to give 4.4-difluorobut-3-envl thioacetaie as a colourless liquid (1.12s): Ή NMR: δ 2.25(2H.m): 2.30(3Rs); 2.90(2H,t); 4.20(lH.m); (bp 115°C at 120mmHg).
PREPARAOQN 5
This illustrates a preparation of 4,4-difluorobut-3-envlisothiouronium 4-methylbenzenesulfonate salt.
Thiourea (0.29g) and 4.4-difluorobut-3-enyl 4-methyl-benzenesulfonate (lg) were heated together under reflux in ethanol (20cm3) for 24 hours. The reaction mixture was cooled and the solvent evaporated under reduced pressure to give an oil which slowly crystallised. Trituration with hexane gave (4,4-difluorobut-3-enyl)-thiourea as its 4-methylbenzenesulfonate salt (1.14g). MH*(FAB>=167; Ή NMR (DMSO-d^: 5 2.48(3H,s); 2.462.58(2H.m); 3.42(2H,t); 4.66ri.84(lH,m); 7.32(2H,d); 7.68(2H,d); 9.10-9.40(3H,br)
PREPARATION 6
This illustrates a preparation of 4,4-difluorobut-3-enylisothiouronium hydrobromide.
Thiourea (18.5g) was added to a solution of 4-bromo-l,l-difluorobut-l-ene (41.5g) in ethanol (150cm3) and heated to reflux with stirring for 18h. The reaction mixture was cooled to ambient temperature and evaporated under reduced pressure. The waxy solid obtained was washed with diethyl ether, filtered, washed with further diethyl ether and sucked to dryness to give the required product as a colourless solid, (57g). MH* =167; *H NMRfDMSO-d^): 6 2.20(2H.m); 3.20(2H,t); 4.50(lH,m); 8.95(4H,broad signal).
The N-methvl derivative of the foregoing intermediate was prepared by the above procedure but using N-methvl thiourea in place of thiourea. It had ΜΤΓ =181; *H
NMRTDMSOdJ: δ 2.45-2.55(2H.m); 3.0-3.05(3H,d); 3.4-3.5(2H,t); 4.30-4.45(lH,m); (imp.
74-77.2=0).
AP/P/ 9 6 / 0 0 8 6 2
- 74PREPARATION 7
This illustrates a preparation of bis-(4.4-difluorobut-3-enyl)disulfide.
A solution of sodium disulfide (previously prepared from sodium sulfide nonahydraie (53 g) and sulfur (7.0g) in ethanol (250cm3)) was added to l-bromo4.4-difluorobut-3-ene (50g) in ethanol (100cm3). The mixture was gradually healed and stirred under reflux for 2 hours, then cooled and evaporaied under reduced pressure. The residue was extracted with diethyl ether, the organic phase filtered to remove sodium bromide and the ether evaporated under reduced pressure to give a liquid which was distilled at 16mm Hg. bp 120°C to give the bis-(4.4-difluorobut-3-envl)disulfide (24g) as a colourless liquid.
EXAMPLE Π.1
This Example illustrates a preparation of 2-(4,4-difluorobut-3-envlthio)furan (Compound Π.1).
Butyllithium (6.5cm3,2.5M in ether) was added dropwise with stirring to a solution of furan (lg) in diethyl ether (40cm3). After 90 minutes, the reaction mixture was heated to reflux for 30 minutes and then cooled to the ambient temperaiure. Powdered sulfur (0.48g) was added portionwise with stirring. After 2 hours, 4-bromo-l,l-difluorobut- 1-ene (3.0g) was added and stirring continued at the ambient temperature for 18 hours. The reaction was quenched with water and the product extracted into diethyl ether. The combined organic extracts were dried, filtered and evaporaied to give a dark brown liquid. Chromatography on silica (eluant hexane-diethvl ether mixtures) afforded Compound Π.1 (0.965g). Ή NMR: δ
2.2-2.3(2H,m); 2.7-2.8(2H,t); 4.15-4.35(lH,m); 6.4<lH,dd); 6.53(lH,d); 7.5(lH,d); (oil).
EXAMPLE Π.2
This Example illustrates a preparation of 2-(4,4-difluorobut-3-enylthio)-5-methylfuran (Compound Π.4).
Butyllithium (5.4cm3, 2.5M in ether) was added dropwise with stirring to a soluiion of furan (lg) in diethyl ether (40cm3). After 90 minutes, the reaction mixture was healed under reflux for 30 minutes and then cooled to the ambient temperature. Powdered sulfur (0.38g) was added portionwise with stirring. After 2 hours, 4-bromo-l,l-difiuorobut-1-ene (2.05g) was added and stirring continued for 18 hours. The reaction was quenched with water and the product extracted into diethyl ether. The combined organic extracts were dried, filtered and evaporated. Chromatography on silica (eluant hexane-ether mixtures) afforded Compound Π.4 (1.25g). Ή NMR· δ 2.2-2.3(2H.m); 2.3(3H,s); 2.7-2.77(2H,t); 4.16-.SLlRm:: 5.97(lH.m): 6.43(lH.d); (oil).
AP.00649
- 75 EXAMPLE HJ
This Example illustrates a preparation of 3-(4.4-difluorobut-3-en\'lthioV2-methylfuran (Compound Π.7).
A solution containing 2-methvl-3-furanthiol (2.0g), 4-bromo-l. 1-difluorobui-l-ene (3.24g) and potassium carbonate (2.48g) in acetone (50cm3) was heated under reflux for 2 hours and then left to stand for 18 hours. The reaction was quenched with water and the product extracted into diethyl ether. Ihe combined organic extracts were dried, filtered and evaporated. Chromatography on silica (eluant 10% ether in hexane) afforded Compound Π.7 (2.338g); M=2O4; Ή NMR δ 2.1-2.25(2H.m); 2.35(3H,s); 2.65(2H.t); 4.1-4.3(lH.m); 6.3 (lH.d); 7.3(1H, d); (oil).
EXAMPLE Π.4
This Example illustrates a preparation of 2-(4,4-difluorobut-3-enylsulfinvl)furan (Compound Π.2).
3-Chloroperbenzoic acid (0.54g of a 50% by weight solid. 1.58mM) was added portionwise to a solution of Compound Π.1 (0.30g) in dichloromethane (5cm3) with ice-bath cooling. After stirring for 4 hours, the reaction was partitioned between ethyl acetate and 2M NaOH solution. The organic layer was separated, washed with more 2M NaOH solution, dried over magnesium sulfate, filtered and evaporated to give Compound H.2 (0.210g). Ή NMR: δ 2.3-2.5(2H.m); 3.1-3.4(2H.m); 4.15-4.35(lH,m); 6.5(lH.dd); 7.0(lRd); 7.7(lH.d); (oil).
The following compounds according to the invention were prepared by the above procedure:
(i) 2-(4.4-<iifluorobut-3-enylsulfonyl)furan (Compound K.3); *H NMR: δ 2.4-2.55(2H,m);_
3.25-3.3(2H,t); 4.M.3 (lH.m); 6.6(lH,dd); 7.23(lH,d); 7.67(lH,d) (oil) from
Compound Π.1 using 2.1 equivalents of oxidant.
(ii) 2-(4.4-difluorobut-3-enylsulfinyl)-5-methylfuran (Compound H.5); *H NMR δ 2.32.45(5H,m); 3.0-3.15 and 3.3-3.4(total 2H.m); 4.2-4.3(lHjn); 6.1(lH,d); 6.85(lH,d);
(oil) from Compound Π.4 using 1 equivalent of oxidant (iii) 2-{4.4-difluorobut-3-enylsulfonvl)-5-methylfuran (Compound EL6); Ή NMR δ 2.4' 2.55(5H.m); 3.2-3.28 (2H,t); 4.15-4.3(lH,m); 6.2(lH,d); 7.1(lH,d); (oil) from
Compound fl.4 using 2.1 equivalents of oxidant.
(iv) 3-(4,4-difluorobut-3-enylsulfinvl)-2-methylfuran (Compound Π.8); *H NMR δ 2.32.45(5H.m): 2.8-2.9 and 3.l-3.2(total 2H. m): 4.2-4.35(lH.m); 6.66(lH.d); 7.4<lH.d)
AP/P/ 96/00862
- 76 from Compound Π.4 using 1 equivalent of oxidant.
(y) 3-(4,4-difluorobut-3-enylsulfonyl)-2-methylfuran (Compound Π.9); Ή NMR: δ 2.422.52(2Rm); 2.6(3Rs): 3.2-3.28(2Rt): 4.1-4.23( IRm); 6.6(lRd): 7.36(lRd) from
Compound Π.4 using 2.1 equivalents of oxidant.
EXAMPLE ΠΙ. 1
This Example illustrates a preparation of 2-(4,4-difluorobut-3-envlthio)thiophene (Compound ΠΙ.1).
A solution containing 2-mercaptothiophene (lOg), 4-bromo-l,l-difluorobut-l-ene (15.47g) and potassium carbonate (11.87g) in acetone (250cm3) was heated under reflux for 2 hours and then left to stand for 18 hours. The reaction was quenched with waier and extracted several times with diethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to give an amber oil. Chromatography on silica (eluant 5% ether in hexane) afforded Compound HI. 1 (9.5g); M*=206; Ή NMR δ 222.4(2Rm); 2.8(2Rt); 4.1-4.3(lRm); 6.95-7.0( lH,dd); 7.15(lH,d); 7.35(lH,d); (oil).
The following compound according to the invention was prepared by the above procedure.
(i) 2-(4,4-difluorobut-3-enylthio)benzo[b]thiophene (Compound IH. 10); ‘H NMR 52.22.3(2Rm); 2.7-2.8(2H,t); 4.15-4.35( IRm); 6.4(lRdd); 6.53(lH,d); 7.5(lRd). from benzthiophene.
EXAMPLE HL2
This Example illustraies a preparation of 2-(4,4-difluorobut-3-enylthio)-5formylthiophene (Compound ΓΠ.4).
Compound IH.l (l.Og) was added slowly to a solution containing dimethyl formamide (0.48cm3) and phosphoryl chloride (0.56cm3). The reaction mixture was healed at 100°C for 2 hours, cooled in an ice-bath and then neutralised with 2M NaOH solution. The aqueous solution was extracted twice with diethyl ether and the combined organic layers were washed with water and NaHCO3 solution. The organic extracts were dried over magnesium sulfaie, filtered and evaporated to give a dark liquid. Filtraiion through silica (eluant 20% diethyl ether in hexane) afforded Compound IH.4 (0.91 g). M*=234; Ή NMR δ 2.4(2H,m); 3.0(2Rt); 4.2-4.4(lRm); 7.1(lRd); 7.7(lH,d); 9.8(lRs); (oil).
EXAMPLE HU
This Example illustrates a preparation of 2-(4,4-difluorobut-3-enylthio)-5hydroxATOethylthiophene (Compound ΙΠ.5).
AP.00649
- 77Sodium borohydride (0.065g) was added to a solution of Compound ΠΙ.4 (0.75g) in ethanol (21cm5) and water (9cm5). The reaction mixture was stirred at the ambient temperature for 2 hours, quenched with 2M hydrochloric acid and then partitioned between water and diethyl ether. The organic phase was dried over magnesium sulfaie. filtered and evaporated to give a greenish liquid. Chromatography on silica (eluant 20% ethyl acetate in hexane) afforded Compound ΠΙ.5 (0.44g). M*=236; Ή NMR: δ 1.8-2.0(lH.br s); 2.3(2H.m): 2.8(2Rt); 4.1-4.3(lH.m); 4.8(2Rs); 6.8( Hid); 7.0(lRd); (oil).
EXAMPLE ΠΙ.4
This Example illustrates a preparation of (£)- and (Z)-2-(4,4-difluorobut-3-enylthio)-5hydroximinothiophene (Compounds ΓΠ.6 and ΕΠ.7).
Hydroxylamine hydrochloride (0.9g) and sodium hydrogen carbonate (1.09g) were stirred together in ethanol (15cm3) and water (15cm5) for 5 minutes. Compound ΠΙ.4 (3g) was added and the reaction mixture was stirred at the ambient temperature for 2 hours and then left to stand for 18 hours. The reaction mixture was partitioned between water and diethyl ether. The organic phase was dried over magnesium sulfate, filtered and evaporated to give an amber liquid (3.4g). Chromatography on silica (eluant 20% ethyl acetate in hexane^-afforded Compounds HI.6 (1.5g) and ΙΠ.7 (1.3g). M=249; Ή NMR δ 2252.35(2Rm); 2.85(2H,t); 4.14^.35(lH,m); 7.05(2Rm); 7.52(lRbr s); 8.18(lRs); (oil) and M =249; δ 2.25-2.38(2H.m); 2.85-2.95(2H,t); 4.1M.35(lRm); 7.08(lH,d); 7.25(lH,d);
7.64( IRs); (oil).
EXAMPLE ΠΙ.5
This Example illustrates a preparation of 5-cyano-2-(4)4-difluorobui-3-enylthio)thiophene (Compound HI.8).
Ι,Γ-carbonyl-diimidazole (0.326g) was added to a solution of Compound ΠΙ.6 (0.5g) and the reaction mixture was stirred al the ambient temperature for 10 minutes, then heated under reflux for 2 hours and left to stand for 18 hours. A further equivalent of Ι,Γ-carbonyldiimidazole was added and the reaction mixture heated under reflux for 1 hour. The reaction mixture was filtered through celite and then evaporated to give Compound ΙΠ.8 (0.28g). Ή NMR· δ 2.27-2.38(2Rm); 2.94(2Rt); 4.15-4.33(lRm); 7.05(lRd); 7.5(lH,d); (oil).
EXAMPLE m.6
This Example illustrates a preparation of 5-acetvl-2-(4,4-difluorobut-3-enylthio)thiophene (Compound ΙΠ.9).
A solution of methylmagnesium bromide (1.3cm5, 3M solution in diethyl ether, 3
AP/P/ 9 6 / 0 0 8 6 2
- 78 equiv.) was added slowly to a solution of Compound Hl.8 (0.3g) in tetxahydrofuran (10cm3). The reaction mixture was stirred at the ambient temperarure for 3 hours and then the solvent was evaporated. The residue was partitioned between ammonium hydroxide solution and chloroform. The organic layer was washed with water, dried over Na,SO4 and evaporated The residue was chromatographed on silica (eluant 10% ethyl acetate in hexane) to give Compound ΠΙ.9 (0.16g). lH NMR: δ 2.30-2.40(2Rm); 2.50(3Rs); 2.97(2H,t); 4.154.33(lRm); 7.04(lRd); 7.55(lRd); (oil).
ΕΧΔΜΕίΕΠΠ
This Example illustrates a preparation of 2-(4,4-difluorobui-3-enylsulfinyl)thiophene (Compound Hf.2).
Compound HI. 1 (0.50g) was stirred at ambient temperarure in dichloromethane (5cm3) and 3-chloro perbenzoic acid (0.834g of a 50% by weight solid, 1 equiv.) was added. After tic indicated consumption of starting material the reaction was quenched by the addition of a saturated aqueous solution of sodium bicarbonate and the product was extracted into dichloromethane. The organic phase was separated, washed with saturated brine and dried over magnesium sulfate. After filtration and concentration by evaporation under reduced pressure, there was obtained a liquid (0.584g) which was purified by chromatography on silica gel using 20% ethyl acetate in hexane as eluant, and then diethyl ether to elute Compound H1.2 (0.29g). Ή NMR: δ 2.3-2.55 (2R m); 2.9-32 (2H, m); 4.24.5 (1H, m); 7.15 (IR m); 7.5 (1H, m): 7.7 (IR m); (oil).
The following compounds according to the invention were prepared by the above procedure:
(i) 2-(4,4-difluorobut-3-en}'lsulfonyl)thiophene (Compound ΙΠ.3). Ή NMR: δ 2.42.6(2H,m); 3.2-3.4<2Rt); 4.1-4.3 (IR m); 7.15(lRdd); 7.7-7.8(lRm); (oil) from
Compound HI. 1 using two equivalents of oxidant (ii) 2-(4,4-difiuorobut-3-envlsulfinyl)benzo[b]thiophene (Compound HI. 11). Ή NMR: δ
2.3-2.4(2Rm); 3.0-3.2(2Rm); 4.2-4.4(lH,m); 7.45(2Rm); 7.9(2Rm); 7.75(lRs) from
Compound HI. 10 using one equivalent of oxidant (iii) 2-(4,4-difluorobut-3-enylsulfonyl)benzo[b]thiophene (Compound HI. 12). Ή NMR: δ
2.5(2Rm); 3.3(2Rt); 4.24.35( lH,m); 7.5(2Rm); 7.9(3Rm) from Compound HI. 10 using two equivalents of oxidant.
EXAMELETYJ.
This Example illustrates a preparation of ethyl 5-(4.4-difiuorobut-3-enylthio)-3AP.00649
-79methylisoxazole-4-carboxylaie (Compound IV.8).
A solution of 4.4-difluorobut-3-enyl thioacetaxe (2g) in 50% sodium hydroxide solution (6.7cm3) was stiiTed vigorously for 30 minuies. A solution of ethyl 5-chloro-4methylisoxazole (2.2g) in dichloromethane (12cm3) was added followed by tetra-nbutylammonium bromide (catalyst) and the reaction stirred at the ambient temperature under nitrogen. After 3 hours the layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and evaporaied under reduced pressure. The residue was stirred with 880 ammonia resulting in crystallisation.. The crystals were isolated by filtration to give Compound IV.8 (2.87g). Ή NMR δ 1.35(3H,t); 2.45(3H.s); 2.50(2H.m); 3.20(2H.t); 4.25(lH,m); 4.30(2H,q); (πφ 41-42°C).
EXAMPLE IV.2
This Example illustrates a preparation of 5-(4,4-difluorobut-3-enylthio)-3methylisoxazole-4-carboxylic acid (Compound IV.9).
A solution of Compound IV.8 (0.5g) in isopropanol (5cm3) and 2MNaOH (1cm3) was stirred for 3 hours. The mixture was then poured into water and washed with ethyl acetate. The aqueous layer was then acidified with 2M HCI and the product extracted into ethyl acetate.-This extract was dried (MgSO4), filtered and evaporated under reduced pressure to give Compound IV.9 (0.16g). M*=2- Ή NMR δ 2.45(3Ks); 2.50(2Hjn); 3.20(2H,t); 4.204.40(lH,m); (mp 132-133°C).
EXAMPLE IV.3
This Example illustrates a preparation of 5-(4,4-difluorobut-3-enylthio)-3methylisoxazole-4-carboxamide (Compound IV.7).
Triethylamine (0.33cm3) and ethyl chloroformaxe (0.24cm3) were added to Compound IV.9 (0.56g) in dichloromethane (15cm3) at 0°C. The reaction was allowed to warm to the ambient temperature and stirred for 2 hours. Ammonia was bubbled through the solution until it was saturated and the reaction was then stirred for a further 1 hour. Aqueous ammonia was added and the product extracted into dichloromethane. The organic phase was washed with water, dried (MgSO4), filtered and evaporated under reduced pressure.
Purification by distillation in a kugelrohr apparatus gave Compound IV.7 (0.069g). lH NMR δ 2.45(2H.m); 2.50(3H,s); 3.25(2H,t); 4.25(lH,m); (πφ 87°C).
EXAMPLE TV,4
This Example illustrates a preparation of 3-(5-chlorofur-2-yl)-5-(4,4-difluorobui-3enylthio)isoxazole (Compound IV.23).
AP/P/ 9 6 / 0 0 8 6 2
- 80Hvdrogen sulfide was bubbled through a stirred solution of potassium methoxide (1.9s) in ethanol (10cm3) cooled in an acetonedce bath. 5-Chloro-3-(5-chlorofur-2vl)isoxazole (2.2g) was added and the reaction was then heated under reflux for 1 hour during which time the solvent evaporated. Acetone (10cm3) and 4-bromo-l.l-difluorobut-lene (2g) were added and the mixture heated under reflux for a further 2 hours. The resulting solution was cooled, poured into diethyl ether and brine and the layers separated. The aqueous layer was extracted with ether. The combined organic phases were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to give a black solid. Purification by column chromatography on silica gel using 10% ether in hexane as eluant gave Compound IV.23 (2g). M*=291; Ή NMR δ 2.35-2.50(2H.m); 3.10(2H.t); 4.30(lH.m); 6.30(lH.d); 6.43(lH,s); 6.90(lH.d); (mp 80-82°C).
The following compound according to the invention was prepared by the above procedure:
(i) 5-(4.4-difluorobut-3-envlthio)-3-phenylisoxazole (Compound IV. 1). Μτ=267; Ή
NMR· δ 2.43(2H,m); 3.1O(2H.t); 4.28(lH,m); 6.50(lH,s); 7.45(3H,m); 7.78(2H,m);
(oil) from 5-chloro-3-phenvlisoxazole.
EXAMPLE IV.5
This Example illustrates a preparation of 2-(4,4-difluorobut-3-enylthio)-3methvlisoxazole (Compound TV. 10).
To a stirred solution of acetone oxime (0.365g) in dry tetrahydroftiran (20cm3) at 0°C under nitrogen was added n-buryl lithium (4.6cm3 of a 2.5M solution in hexanes) resulting in formation of a pale yellow precipitate. After stirring at 0°C for 30 minutes, carbon disulfide (0.3cm3) was added producing a bright orange solution. After a further 10 minutes, 3M HCI (20cm3) was added and the reaction was heated under reflux for 3 hours and then cooled.
The layers were separated and the aqueous layer was extracted with chloroform. The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure to give a brown oil. The oil was then taken up in acetone (11cm3) and l-bromo-4,4difiuorobut-3-ene (0.77g) and potassium carbonate (0.87g) were added and the reaction heated under reflux for 3.5 hours and then cooled. The mixture was then poured into ethyl acetate and 2M HCI and the layers separated. The aqueous layer was extracted with ethyl acetate and the combined organic phases were dried (MgSO4), filtered and evaporated under reduced pressure to give a brown oil. Purification by column chromatography on silica gel using 1:9 ethyl acetate : hexane as eluant gave 2-{4.4-difluorobut-3-enylthio)-3AP.00649 ,81 methylisnxa7nle (0.105g). M~=2O5; Ή NMR: δ 2.3O(3H_s): 2.40(2H.m); 3.05(2H.t): 4.25(lH.m); 6.00(lH.s); (oil).
EXAMPLE TV.6
This Example illustrates a preparation of 3-(5-chlorofur-2-vl)-5-(4.4-difluorobut-3enylsulfonvl)isoxazole (Compound TV.24).
To a stirred solution of Compound IV.23 (2g) in methanol (40cm3), cooled in an ice'acetone bath was added magnesium monoperoxyphthalate (9.4g). After stirnng for 30 minutes the cooling bath was removed and the reaction allowed to warm to the ambient temperature and stirred for 1 hour. The mixture was poured into diethyl ether and brine and the layers separated. The combined organic phases were washed with 2M NaOH, water and brine, dried (MgSO4), filtered and evaporaied under reduced pressure to give Compound IV.24 (1.9g). M*=323; ‘H NMR δ 2.50-2.60(2H,m); 3.40(2H,t); 4.25(lH,m); 6.38(lH,d); 7.05(lH,d); 7.20(lH,s); (mp 86.5-88.5°C).
The following compounds according to the invention were prepared by the above oxidation procedure:
(i) 5-(4.4-difluorobut-3-enylsulfinyl)-3-phenylisoxazole (Compound TV2). M*=283; *H
NMR: δ 2.53(2HLm); 3.25(2H,t); 4.29(lH.m); 7.18(lH,s); 7.50(3Hjn); 7.80(2H,m);
(oil) from Compound IV. 1 and one equivalent of oxidant (ii) 5-(4,4-difluorobut-3-enylsulfonyl)-3-phenylisoxazole (Compound IV.3). M*=299; ’H
NMR: 62.57(2H,m); 3.43(2H,t);_4.27(lH,m); 7.2(lH,s); 7.51(3Hm); 7.80(2Iim); (mp
57-58.5°C) from Compound IV. 1 and two equivalents of oxidant.
(iii) 3-(thien-2-yl)-5-(4,4-difluorobut-3-enylsulfonyl)isox2zole (Compound IV.26).
M*=3O5; Ή NMR δ 2.50-2.63(2H,m); 3.41(2H,t); 4.27(lHqn); 720(lH,s); 7.147.23(lH.m); 7.52(2H,m); (mp 55-57°C) from 3-(thien-2-yl)-5-(4,4-difluorobut-3envlthio)isoxazole, Compound IV.25, itself prepared from 5-chloro-3-(thien-2yl)isoxazole by the procedue of Example IV.4.
EXAMPLE V.l
The Example illustrates a preparation of 3-chloro4-cyano-5-(4,4-difluorobui-3enylthio)isothiazole (Compound V.2).
A solution of 4-cvano3,5-dichloroisothiazole (lg) in methanol (10cm3) was added over 15 min to a solution of sodium sulfide nonahydrate (1.3g) in water (2.6cm3) and methanol (25cm3) heated at 50°C. The reaction was stirred for 1 hour and then the solvent was evaporaied under reduced pressure to give a yellow solid. This residue was dissolved in
AP/P/ 9 6 / 0 0 8 6 2
- 82 acetone (20cm3). 4-bromo- 1.1-difluorobut-l -ene (0.68s) was added and the reaction was stirred for 12 hours. The resulting mixure was poured into water and the layers separated. The aqueous layer was extracted with ethyl acetaie. The combined organic phases were dried (MgSO4), filtered and evaporated under reduced pressure. Purification by column chromatography on silica gel using 1:1 ethyl acetaie : hexane as eluant gave Compound V.2. (0.88g). M*=266; Ή NMR δ 2.50(2H.m); 3.20(2H,t); 4.204.40(1 Hun); (oil).
The following compound according to the invention was prepared by the above procedure but using 2 equivalents of sodium sulfide nonahvdrate and 4-bromo-1.1difiuorobut-l-ene:
(i) 3,5-bis-(4,4-difiuorobut-3-enylthio)-4-cyanoisothiazole (Compound V.12). Ή NMR δ
2.40-2.60(4H.m); 3.20(2H,t); 3.30(2H,t); 4.20-4.40(2H,m); (oil).
EXAMPLE V.2
The Example illustrates a preparation of 5-(4,4-difluorobut-3-enylsulfony 1)-4cyanoisothiazole (Compound V.6) and 3.5-bis-(4,4-<iifluorobut-3-enylsulfonyl}4cyanoisothiazole (Compound V.15).
To a solution of Compound V.12 (O.lg) in dichloromethane (5cm3) was added 3chloroperbenzoic acid (0.42g) and the reaction mixture was stirred until starting material had disappeared. The reaction mixture was poured into ethyl acetaie and water and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined ethyl acetaie phases were washed with sodium hydrogen carbonate, dried (MgSO4), filtered and evaporated under reduced pressure. The residue was taken up in diethyl ether and triethylamine was added causing the solution to become cloudy. The ether solution was then washed with water, dried (MgSO4), filtered and evaporated. Purification of the residue by column chromaiography on silica gel using 1:1 ethyl acetate : hexane as eluant gave Compound V.15 (0.01 g); M*=41 S; Ή NMR δ 2.60-2.70(4H,m); 3.60(4H,t); 4.30(2H,m); (oil) and Compound V.6 (0.08g); M*=264; *H NMR δ 2.60(2H,m); 3.60(2H,t); 4.30(lH,m);
9.40( lH,s); (oil).
EXAMPLE VI,1
Oxazoles substituted with a 4,4-difluorobut-3-enylthio group in the 2, 4 or 5-position may be prepared starting from a correspondingly substituted mercapto-oxazole and an appropriate difluorobut-l-ene alkylating agent. This is illustrated by the following preparation of 2-(4.4-difluorobut-3-enylthio)-5-phenyloxazole (Compound VI. 18).
To a solution of 2-mercapto-5-phenvloxazole (0.44g) in acetone (15cm3) was added
AP.00649
-.83 4.4-difluoro-3-butenyl 4-methyl-benzenesulfonaie (0.7g) and potassium carbonate (0.369g) and the reaction was healed at reflux for a total of 8 hours after which time some of the starting tosvlaie remained. Further 2-mercapto-5-phenyloxazole (0.05g) was added and the healing continued for 5 hours. The reaction mixture was cooled, poured into diethyl ether and water and the layers separated. The aqueous layer was extracted with ether and the combined organic phases were dried (MgSO4) and evaporaied under reduced pressure to give a yellow' liquid. Chromatography on silica gel using 5% tert-butvl dimethyl ether in hexane gave Compound VI. 18; M*=267; Ή NMR (CDC13) δ 2.51(2H.m); 3.23(2H.t); 4.30(lH.m); 7.23-7.47(4H,m); 7.58(2H,d); (oil).
The following compounds according to the invention were prepared by the above procedure:
(i) 2-(4.4-difluorobut-3-envlthio)-oxazole (Compound VI. 1). *H NMR (CDC13) δ 2.45(2H,m); 3.20(2H,t); 4.25(lH,m); 7.10(lH,s); 7.66(lH,s); (oil) from oxazole-2thione.
(ii) 2-(4,4-difluorobut-3-envlthio)-4-methyloxazole (Compound VI.6). M* 205; Ή NMR δ : 2.04(3H,s); 2.45(2H,m); 3.18(2H,t); 4.25(lH.m); 7.38(lH,q); (oil) from 2mercapto-4-methyloxazole.
EXAMPLE VI.2
This Example illustrates a 3-step preparation of methyl 2-(4,4-difluorobut-3-enylthio>4-methyloxazole-5-carboxylate (Compound VL32).
Slgp.H Methyl 2-amino4-methyloxazole-5-carboxylate.
Methyl 3-chloroacetoacetate (75g) and urea (90g) in methanol (200cm3) were stirred and healed to reflux for 24 hours. The reaction mixture was cooled to ambient temperature and the precipitate filtered from solution, washed with cold methanol and sucked to dryness. This solid was treated with aqueous 2M sodium hydroxide and the product extracted into ethyl acetate (several portions). Evaporation of solvent under reduced pressure gave a colourless solid (14.5g) which was recrystallised from acetonitrile, mp 225°C (dec.) *H NMR (DMSO-d*): 62.15(3H,s); 3.75(3H,s); 7.4(2H,br).
Slgp 2; Methyl 2-chloro4-methyloxazole-5-carboxylate,
The product from Step 1 (1.56g) was partially dissolved in dry acetonitrile (40cm3) and added in portions at 8°C to a stirred mixture of copper (Π) chloride (1.61 g) and tertiary' butyl nitrite in acetonitrile (dry. 20cm3) under an atmosphere of nitrogen. The resulting brown solution was stirred at 20°C for 2 hours and evaporated under reduced pressure. The
AP/P/ 9 6 / 0 0 8 6 2
- 84 residue was treated with aqueous 2M hydrochloric acid, and the product extracted into diethy l ether. The organic phase was dried (MsSO4) and then washed through a short column of silica gel with more ether. The filtrate was evaporated under reduced pressure to give the required intermediate (0.9g) as a yellow solid. M*=175.
Step 3: Methyl 244.4-difluorobut-3-enylthioY4-methyloxazole-5-carbo\ylate
The product from Step 2 (0.176g) and thiourea (0.084g) were stirred in ethanol (5cm·') and heated to reflux under an atmosphere of nitrogen for 5 hours. The reaction was cooled and solvent removed by evaporation under reduced pressure to give a yellow gum which was dissolved in acetone containing 4-bromo-l.l-difiuorobut-l-ene (0.17g) and potassium carbonate (0.2g). This mixture was stirred for 1 hour under an amnosphere of nitrogen at ambient temperarure and stored for 18 hours. The solvent was evaporated under reduced pressure and the residue treated with water and diethyl ether. The organic phase was separated, dried (MgSO4) and evaporated to give Compound VI.32 (0.095g); M*=175. Ή NMR; 52.45(5H.m); 3.22 (2Rt); 3.90(3Rs); 4.25(lH.m); (oil).
EXAMPL E VI.3
This Example illustrates a preparation of 2-(4,4-difluorobut-3-envlthio)-4methyloxazole-5-caihoxylic acid (Compound VI.37).
Compound VI.32 (0.4g) was dissolved in propan-2-ol (10cm3) containing aqueous sodium hydroxide (2cm3 of 2M solution) and stirred for 5 hours at ambient temperarure. The mixture was evaporated under reduced pressure and the residue diluted with water, extracted with ethyl acetate, acidified with dilute hydrochloric acid and re-extracted with ethyl acetate (3x100cm3). The latter extracts were combined, washed with saturated brine, dried (MgSO4) and evaporated under reduced pressure to give the required product as a colourless solid (0.3g). M*=249; >H NMR; δ 2.5(5H,m); 3.27(2H,t); 4.27(lHqn); 6.5(lH,br s); (mp 66-68°C). The sodium salt of this compound was prepared by treating a sample (0.7g) with a solution of sodium methoxide in dry methanol (0.06lg of sodium metal dissolved in methanol (10cm3)) at ambient temperarure. Evaporation of solvent under reduced pressure gave the sodium salt of Compound VI.37 as a colourless solid; M*(FAB)=271; (mp 211-212°C).
The following compound according to the invention was prepared by the above procedure:
(i) 2-(4,4-difluorobut-3-enylthio)-4-trifluoromethyloxazole-5-carboxylic acid (Compound
VI.36). M*=303; Ή NMR; δ 2.54(2H.m); 3.32(2H,t); 4.28(lH,m) 7.65(lH,br s) from
Compound VI.31.
AP.00649
- 85 EXAMPLE VI,4
This example illusttaies a preparation of 2-(4.4-difluorobut-3-envlthio)-4trifluoromeihvloxazole (Compound VI.4).
2-Amino-4-trifluoromethvloxazole (0.84e) in dichloromethane (25cm3) containing bis(4,4-difluorobut-3-envl)disulfide (2.71 g) at 0°C was stirred and treated dropwise with tert, butyl nitrite (0.62ε) under niirogen. The reaction solution was evaporated under reduced pressure and the residue fractionated by chromatography (silica, eluant hexane) to give Compound VI.4 (0.35g). M-=259; *H NMR: δ 2.50(2H.m); 3.26(3H.t); 4.28(lH.m); 7.95(lH,q); (oil).
The following compound according to the invention was prepared by the above procedure from the corresponding aminooxazole:
(i) Ethyl 2-(4,4-difluorobut-3-enylthio)-4-trifluoromethyloxazole-5-carboxylaie (Compound VI.31). MH'=322; lH NMR 8 1.40(3H,t); 2.52(2H,m); 3.30(2H,m);
4.28( lH,m); 4.43(2H,q); (oil) from ethyl 2-amino-4-trifIuoromethyloxazole-5carboxvlaie (prepared from ethyl 1,1,1-trifluoromethylacetoacetate and urea in a procedure analogous to Example VI.2).
EXAMPLE VI,5
This Example illustrates a preparation of 2-(4,4-difluorobut-3-enylthio)-5chlorooxazole (Compound VI. 13).
Compound VI. 1 (2.0g) was dissolved in acetonitrile (50cm3) containing Nchlorosuccinimide (1.50g) and stirred at ambient temperature for 24 hours. The mixture was evaporated under reduced pressure, extracted with hexane (50cm3), filtered and the filtrate evaporated under reduced pressure. The residue was fractionated by chromatography (silica; “ eluant 20% diethyl ether in hexane) to give Compound VI. 13 (0.75g). M*=225; Ή NMR· δ 2.46(2H.m); 3.16(2H,t); 4.28(lHun); 6.86(lH,s); (oil).
The following compound according to the invention was prepared from Compound VI.6 by the above procedure:
(i) 2-(4,4-difIuorobut-3-enylthio)-4-methyl-5-chlorooxazole (Compound VI. 15). M=239;
Ή NMR δ 2.05(3H,s); 2.45(2H,m); 3.15(2H,t); 4.25(lH.m); (oil).
EXAMPLE VI.6
This Example illustrates a preparation of 2-(4,4-difluorobut-3-enylthio)-4methyloxazole-5-carboxamidc (Compound VI.40).
Compound VI.32 (1.5 s) was dissolved in methanol (10cm3) and treated with aqueous
AP/P/ 9 6 / 0 0 8 6 2
- 86ammonia (35cm3. density 0.88) at ambient temperature. The mixture was stirred for 5 hours dili I with brine and the product extracted into ethyl acetate (2x100cm3). The combined organ 'res were washed with brine (4x50cm3). dried (MgSOJ and evaporaied under reduced j. x the residue was washed with hexane to give Compound V1.40 (lg). M*=248; ‘H x (OMSO-d^): δ 2.50(5H,m); 3.26(2H.t); 3.85(3H,s); 4.28(lH,m); 5.6. 6.0 (2H.br s); (mp 72-73°C). EXAMPLE VI.7
This Example illustrates a preparation of 5-cvano-2-(4,4-difluoiObut-3-enylthio)-4methvloxazole (Compound VI.25).
Compound V1.40 (0.64g) was dissolved in dichloromethane (10cm3) containing diy pyridine (1cm3) at ambient temperature and treated with methane sulfonyl chloride (0.5cm3). The solution was stirred for 5 hours, stored for 72 hours, further methane sulfonyl chloride (0.25cm3) and pyridine (0.5cm3) added, stirred for 8 hours, and stored for 48 hours. The mixture was treated with dilute hydrochloric acid, and the product extracted into ethyl acetate. The combined organic phase was washed with brine and dried (MgSO4). After filtration, the solvent was evaporated under reduced pressure and the residue fractionated by chromatography (silica; eluant 10% ethyl acetate in hexane) to give Compound VI.25 (0.46s). M-=230: Ή NMR; δ 2.32(3H.s); 2.50(2H,m); 2.58(3H,s); 3.25(2H,t); 3.85(3H.s); 4.28(lH.m); (oil).
EXAMPLE VI,8
This Example illustrates a preparation of N-methvlsulfonyl 2-(4,4-difluorobut-3envlthio)-4-methyl-oxazolecarboxamide (Compound VI.38).
The sodium salt of Compound VI.37 (0.52g) was stirred in hexane (6.5cm3) and treated with oxalyl chloride (0.275g) at ambient temperature. The mixture was stirred for 6 hours, stored for 18 hours and evaporaied under reduced pressure. The residue, containing the oxazole carbonyl chloride derivative, was treated with a solution of methane sulfonamide (0.20g) in dry butan-2-one (5cm3), heated under reflux with stirring for 8 hours, cooled to ambient temperature and stored for 18 hours. The mixture was evaporated under reduced pressure, the residue dissolved in water, acidified with 2M hydrochloric acid and the product extracted into diethyl ether (2x150cm3). The ether extracts were combined, washed with aqueous saturated sodium chloride, dried (MgSO4), evaporated under reduced pressure and the residue purified by chromatography, (silica; eluant acetonitrile), to give Compound VI.38 (0.20g). M-=326; Ή NMR; δ 2.50(5HLm); 3.27(2H,t); 3.40(3H,s); 4.28(lH.m); (mp 60622C).
AP.00649
- 87EXAMELE.VL2
This Example illustrates a preparation of 2-(4.4-difluorobut-3-enylsuifmyl)-5phenvloxazole (Compound VI. 19).
To a solution of Compound VI. 18 (lg) in dichloromethane (40cm3) was added 3chloroperbenzoic acid (1.3g of a 50% by weight solid, (1 eq)) and the reaction was stirred at ambient temperature for 5 hours. The reaction mixture was poured into a mixture of diethyl ether and aqueous sodium bicarbonate and the layers separated. The organic layer was dried (MgSO4) and evaporated under reduced pressure to give a white solid which was purified by chromatography on silica gel, eluting with 1:4 ethyl acetate ; hexane to give Compound VI. 19 (0.567g). M*=283; lH NMR: δ 2.50(2H,m); 3.41 (2H,t); 4.29(lH,m); 727(lH.s); 7.387.55(3H.m); 7.71(2H,d); (oil).
The following compounds were prepared from the corresponding thioethers by the general method described above but using 2 equivalents of 3-chloroperbenzoic acid:
(i) 2-(4,4-difluorobut-3-enylsulfonyl)-4-trifluoromethyloxazole (Compound VI.5). ‘H
NMR: δ 2.65(2H,m); 3.58(2H,t); 4.28(lH,m); 8.24(lH,q); (oil).
(ii) 5-chloro-2-(4!4-difluorobut-3-enylsulfonyl)oxazole (Compound VI.14). ΜΝΗ/=275;
Ή NMR: δ2.60(2Η,ιη); 3.47(2H,t); 4.26(lRm); 7.18(lH,s); (oil).
(iii) 5-chloro-2-(4,4-<iifluorobut-3-enylsulfonyl)-4-rnethyloxazole (Compound VI.16). *H
NMR: b2.25(3H,s); 2.60(2H,m); 3.45(2H,t); 4.26(lH,m); (oil).
(iv) 2-(4,4-difluorobut-3-enylsulfonyl)-5-phenyloxazole (Compound VI20). M”=299; Ή
NMR: 6 2.62(2H,m); 3.51(2H,t); 4.27(lH,m); 726(lH,s); 7.42-7.55(3H,m); 7.697.79(2H,d); (mp 55-59°C).
EXAMPLE Vn.l
This Example illustrates a general method for the preparation of thiazoles substituted with a 4,4-difluorobut-3-enylthio group in the 2, 4 or 5-position starting from a correspondingly substituted mercapto thiazole and an appropriate difluorobut-l-ene alkylating agent. This is demonstrated by the following preparation of 2-(4,4-difluorobut-3-enylthio)-5phenylthiazole (Compound VH. 17).
To a solution of 2-mercapto-5-phenylthiazole (0.483g) in acetone (15cm3) was added 4,4-difluoro-3-butenyl 4-methyl-benzenesulfonaie (0.7g) and potassium carbonate (0.369g) and the reaction was heated at reflux for a total of 8 hours after which time some of the starting tosylate remained. Further 2-mercapto-5-phenylthiazole (0.05 g) was added and the healing continued for 5 hours. The reaction mixture was cooled, poured into diethyl ether
AP/P/ 9 6 / 0 0 8 6 2
- 88 and water and the lavers separated. The aqueous layer was extracted with ether and the combined organic phases were dried (MgSO4) and evaporated under reduced pressure to give a yellow liquid. Chromatography on silica gel using 5% tert-butyl dimethyl ether in hexane gave Compound VH.17 (0.582g). M*=283; ‘H NMR: δ 2.51(2Rm); 3.3l(2Rt); 4.32(lRm): 7.26(lRs); 7.30-7.48(3Rm): 7.89(2Rd); (oil).
The following compounds according to the invention were prepared by the above procedure:
(i) 2-(4,4-difluorobut-3-enylthio)-thiazole (Compound VH. 1). M*=207; !H NMR: δ
2.47(2Rm); 3.26(2Rt); 4.27(lRm); 7.22(lRd); 7.68( IRd); (oil) from 2mercaptothi azole.
(ii) 2-(4,4-difluorobut-3-envlthio)-thiazoline (Compound VH. 134). M*=209; *H NMR· δ
2.40(2Rm); 3.15(2Rt); 3.4(2Rt); 4.18-4.31( IRm); 4.2(2Rt); (oil) from 2mercaptothi azoline.
EXAMPLE Vn.2
This Example illustrates a two-step preparation of 2-(4,4-difiuorobut-3-enylthio)-4trifluoromethylthiazole (Compound VII.4).
Step 1: Preparation of 2-mercaptM-trifluoromethylthiazole l-Bromo-3,3,3-trifluoropropan-2-one (5.0g) in tert, butanol (20cm3) was treated with ammonium dithiocarbamaie (2.9g), the mixture stirred at ambient temperature for 18 hours, poured into water, extracted with ethyl acetate and the organic phase dried (MgSO4). The solvent was evaporated under reduced pressure and the residue fractionated by chromatography (silica: eluant hexane:ethyl acetate 17:3 to 7:3 by volume) to give a hydrate (2.16g) of the required mercaptothiazole. A portion (l.Og) of this material was added to toluene (20cm3) containing para toluene sulfonic acid (0.005g, catalyst) and healed under reflux for 4 hours. The water formed during the reaction was removed using a Dean-Stark apparatus. The solution was cooled to ambient temperature, washed with water, dried (MgSO4) and evaporated under reduced pressure to give the required intermediate product (0.37g); Ή NMR δ 7.10(lRs); 7.80(lRs).
Step 2: Preparation of Compound VII.4
The product from Step 1 (0.37g) in acetone (15cm3) containing anhydrous potassium carbonate (0.3g) and 4-bromo-l,l-difluorobut-l-ene (0.34g) were stirred and healed under reflux for 4 hours. The mixture was cooled, poured into water, extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure to give Compound VH.4 (0.30g).
AP.00649
-89M-=275; Ή NMR: δ 2.50(2H.m); 3.32(2H.t);4.28(lH.m);7.60(lH.s); (oil).
The following compounds according to the invention were prepared from the corresponding mercaptothiazoles using Step 2 of the above procedure:
(i) Ethyl 2-(4,4-difiuorobut-3-enylthio)thiazole-4-carboxylaie (Compound VII.8). *H NMR; δ 1.40(3H,t); 2.48(2H,m); 3.32(2H.t); 4.28(lH.m); 4.40(2H.q); 8.03( 1H.S); (oil) from ethyl 2-mercaptothiazole-4-carboxvlate.
(ii) Methyl 2-(4.4-difluorobut-3-enylthio)-4-methylthiazole-5-carboxylate (Compound VH.41). Ή NMR; δ 2.48(2H.m); 2.68(3H,s); 3.26(2H,t); 3.85(3H.s); 4.28(lRm);
(oil) from methyl 2-mercapto-4-methylthiazole-5-carboxylate.
(iii) 2-(4,4-difluorobut-3-enylthio)-5-nitrothiazole (Compound VII.47). M*=252; Ή NMR; δ 2.52(2H.m); 3.35(2H.m); 4.27(lH.m); 8.35(lH,s); (oil) from 2-mercapto-5nitrothiazole (obtained from 2-bromo-5-nitrothiazole and thiourea).
EXAMPLE Vn.3
This Example illustrates a three-step preparation of 5-chloro-2-(4,4-difluorobut-3enylthio)thiazole (Compound VII.24).
Sl£p_li 2-(4-bromo-3.4.4-mfluoiObutylthio)thi azole
2-Mercaptothiazole (11.7g) in acetone (30cm3) containing 1,4-dibromo-1,12trifluoroburane (27.0g) was treated portionwise with anhydrous potassium carbonate (13.8g) under an atmosphere of nitrogen. The reaction was stirred for 1.5 hours, filtered and the insolubles washed with further acetone (4x25cm3). The filtrate was evaporated under reduced pressure and the residue fractionated by chromatography (silica, eluant 10% ethyl acetate in hexane) to give 2-(4-bromo-3,4,4-trifluorobutylthio)thiazDle (29.5g). *H NMR; δ 222.5(2H,m); 3.2-3.6(2H,m); 4.7-5.0(lH,m); 7.23(lH,d); 7.68(lH,d).
Slsp-l 2-(4-bromo-3.4.4-trifluorobutylthio)-5-ch]orothia2ole
The compound from Step 1 (30.6g) in dichloromethane (130cm3) was trcaied at ambient temperature with sulfuryl chloride (9.6cm3) in dichloromethane (30cm3) over 1 hour with stirring under an atmosphere of nitrogen. The reaction was stirred for a further 1 hour, poured slowly into water (250cm3) and stirred for 025 hours. The organic phase was separated, the aqueous phase extracted with dichloromethane (2x75cm3), the combined organic phases washed with aqueous sodium hydrogen carbonate, brine and dried (MgSO4). The solvent was evaporated under reduced pressure and the residue fractionated by chromatography (silica; eluant 5% diethyl ether in hexane) to give 2-(4-bromo-3,4,4trifiuorobutylthio)-5-chlorothiazole (28.0g); *H NMR; δ 220-2.45 (2H,m); 325-3.50(2H.m);
AP/P/ 9 6 / 0 0 8 6 2
-904.70-5.0( lH.m): 7.45(lH.s); (oil).
Sigg-2; Compound VILN
Zinc powder (33g) in water (600cm3) was stirred with iodine (0.17g. catalyst), heated to 80=C and concentrated hydrochloric acid (0.5cm3) added followed by the compound from Step 2 (125g) in portions over 1.5 hour under an atmosphere of nitrogen. Further zinc (16.6g). iodine (O.lg) and hydrochloric acid (0.6cm3) were added over 4 hours in portions to complete the reaction. The mixture was cooled to ambient temperature, filtered through keiselghur using dichloromethane as solvent and the filtrate extracted with dichloromethane (5x250cm3). The combined organic phases were dried (MgSOJ, evaporaied under reduced pressure and the residue fractionated by chromatography on silica, eluting with hexane to give Compound VH.24 (140g). ΝΓ=241; Ή NMR: δ 2.42(2H.m); 3.20(2KLt); 4.25(lFLm); 7.45(lH.s); (oil).
EXAMPLE YH.4
This Example illustrates a preparation of 5-bromo-2-(4,4-difluorobut-3enylthio)thiazole (Compound VII.14).
2-Amino-5-bromothiazole hydrobromide (llg) was treated with aqueous sodium hydrogen carbonate, extracted into dichloromethane (2x250cm3) and dried (MgSO4). The mixture was filtered and the filtrate added to bis-(4,4-difluorobut-3-enyl)disulfide (20g). Tert. butyl nitrite (9.6cm3) in dichloromethane (40cm3) was added dropwise to the stirred solution at ambient temperature under an atmosphere of nitrogen. The reaction was stirred for 18 hours, evaporaied onto silica, the residue added to a short column of silica which was eluted with (1) hexane and (2) hexane : diethyl ether, 20:1 by volume to give Compound VII.14 (6.4g). M=285; Ή NMR: δ 2.46(2H,m); 3.24(3H,t); 4.27(lH,m); 7.54(lH,s); (oil).
ΕΧΔΜΕίΕΔΠΙ
This Example illustraxes a preparation of 2-(4,4-difluorobut-3-enylthio)-4methylthiazole-5-suIfonyl fluoride (Compound VH.52) using an alternative diazotisation procedure to that given in Example VII.4.
2-Amino-4-methylthiazole sulfonylfluoride (1.5g) in acetonitrile (10cm3) was added dropwise to a stirred mixture of tert, butyl nitrite (1.65cm3) and bis-(4,4-<iifluorobut-3enyl)disulfide (2.25 g) in acetonitrile (50cm3) at 60°C under an atmosphere of nitrogen. The mixture was heated for 1 hour, evaporated under reduced pressure and the residue fractionated by chromatography (silica; eluant hexane : ethyl acetate 4:1 by volume) to give Compound VU.52 (1.84g). ΝΓ=303; Ή NMR· δ 2.50(2H.m); 2.68(3H,s); 3.32(2H,t);
AP.00649
- 91 4.28( lH.m); (oil).
The following compounds according to the invention were prepared from the corresponding aminothiazoles using the above procedure.
(i) 2-(4.4-difluorobui-3-enylthio)-5-methylthiazole (Compound VH.21). 1VT=221: Ή NMR: 5 2.45(5Hjn); 3.22(2H.t); 4.26(lH.m); 7.30(1^ (oil) from 2-amino-5methvlthiazole.
(ii) 5-chloro-2-(4.4-dif]uorobut-3-enylthio)thiazole (Compound VII24). M*=241; *H NMR: δ 2.45(2H,m); 3-22(2Kt); 4.26(lH,m); 7.45(lHs); (oil) from 2-amino-5chlorothiazole in an alternative method to that of Example VH.3 above.
(iii) 5-chloro-2-(4,4-difluorobut-3-enylthio)-4-methylthiazole (Compound VH.27).
M*=255; Ή NMR: δ 2.35(3H,s); 2.42(2Rm); 3.18(2H,t); 4.26(lH.m); (oil) from 2amino-5-chloro-4-methvlthi azole.
EXAMPLE VII.6
This Example illustrates a two-step preparation of ethyl 5-bromo-2-(4,4-difluorobut-3enylthio)thiazole-4-carboxylate (Compound VII. 11).
Step 1; Preparation of ethyl 2-ammo-5-bromothiazole-4-qgboxylale Ethyl 2-aminothiazole-4-carboxylate (5.0g) (prepared from ethyl bromopyruvate and thiourea by the procedure described in J, Med, Chem.. 1971, 14, 1075 for the corresponding oxazole) in concentrated hydrobromic acid (9cm3) was stirred at ambient temperature and treated dropwise with bromine (3.2g), then heated to 60°C for 2 hours, neutralised with sodium carbonate and the product extracted into ethyl acetate. The organic phase was dried (MgSO„) and evaporated under reduced pressure to give ethyl 2-amino-5-bromothiazole-4carboxylate (1.54g). MH*=251; Ή NMR: δ 1.40(3H,t); 4.4O(2H,t); 5.6(2H,br s).
Step 2; Preparation of Compound Vn.l 1
The product from Step 1 was treated in a diazotisation reaction, as described in
Example VH.5 above and gave Compound VII. 11; M=357; ‘HNMR: δ 1.4O(3H,t); 2.50(2H,m); 3.30(2H,t); 4.30(lH,m); 4.45(2H,q); (oil).
EXAMPLE ΥΠ.7
This Example illustrates a three-step preparation of Ν,Ν-diethyl 2-(4,4-difluorobut-3envlthio)-4-methylthiazole-5-sulfonamide (Compound VH.56).
Stgp I; N.N-Diethyl 2-acetamidt>4-methylthiazole-5-sulfonamide 2-Acetamido-4-methylthiazole-5-sulfonyl chloride (5.2g) in tetrahydrofuran (100cm3) was stirred ai ambient temperature and treated portionwise with diethvlamine (4.5cm3). The
AP/P/ 96/00862
- 92 mixture was stirred for 4 hours, evaporated under reduced pressure and the residue extracted into ethyl acetate (200cm3). washed with waier (2x100cm3). dried (MgSO4) and re-evaporaied under reduced pressure to give Ν,Ν-diethyl 2-acetamido-4-methvlthiazole-5-sulfonamide (4.9g). Ή NMR δ 1.20(6H,t); 2.28(3H,s); 2.57(3H.s); 3.32(4H,q); 9.7(lH.br s); (solid).
Step 2: N.N-Diethyl 2-amino4-methylthiazole-5-sulfonamide
The product from Step 1 (2.5g) was dissolved in methanol (25cm3) and cooled to 5°C with stirring under an atmosphere of nitrogen. Sodium methoxide in methanol (2cm3 of 25% wt./vol. solution) was added dropwise and the mixture allowed to warm to the ambient temperaiure for 18 hours. The reaction was healed under reflux for 1 hour, cooled, diluted with water (250cm3), extracted with diethyl ether (2x100cm3), dried (MgSO4) and evaporated under reduced pressure to give N.N-diethvl 2-amino4-methylthiazole-5-sulfonamide (0.48g). M-249; Ή NMR δ 1.20(6H,t); 2.48(3H,s); 3.28(4H,q); 5.25(2H,br s); (solid).
Stcp.3; Preparation of Compound VII.56
The product from Step 2 was treated in a diazotisation reaction, as described in Example VII.5 above and gave Compound VH.56; M*=356; Ή NMR δ 1.15(6H,t); 2.45(2H,m); 2.60(3H,s); 3.25(2H,t); 3.26(4H,q); 4.25(lH,m); (oil).
EXAMPLE VH.8
This Example illustrates a preparation of 2-amino-5-(4,4-difluorobut-3enylthio)thiazole (Compound VII. 128)
4,4-Difluorobut-3-enylisothiouronium hydrobromide (16.87g) was added to a solution of potassium hydroxide (18.0g) in ethanol (150cm3) at ambient temperature and stirred for 0.2 hours under an atmosphere of nitrogen. 2-Amino-5-bromothiazole hydrobromide (17.76g) in ethanol (150cm3) was added in portions, the mixture heated to 40°C for 2 hours, neutralised with hydrochloric acid and evaporated under reduced pressure. The residue was dissolved in 2M hydrochloric acid, extracted with diethyl ether, basified with 2M sodium hydroxide and re-extracted with diethyl ether. The latter ether extracts were combined, dried (MgSO4) and evaporated under reduced pressure to give Compound VH.128 (8.0g). M*=222; Ή NMR δ 2.28(2H.m); 2.67(2H,t); 4.24(lH,m); 5.3(2H,two br s); 7.08(lH,s); (mp 34.635.4°C).
EXAMPLE Vn.9
This Example illustrates a preparation of 5-(4,4-difluorobut-3-enylthio)thiazole (Compound VII.82).
Compound VII. 128 (0.30g) was dissolved in dry tetrahydroiuran (14cm3) and healed
AP.00649
- 93 · under reflux in an atmosphere of nitrogen. Ten. bund nitrite (0.52cmJ) in tetrahydrofuran (8cm3) was added dropwise over 0.25 hours, the mixture heated for 2 hours, further ten. butylnitnte (0.52cm3) added and heating continued for a further 2 hours. The solmion was cooled, evaporated under reduced pressure and the residue fractionated by chromaiographv (silica: eluant hexane : ethyl acetate 1:1 by volume) to give Compound VII. 128 (0.1 Og) *H NMR: δ 2.28(2H,m); 2.82(2H,t); 4.24(lRm); 7.86(lH.s); 8.86(lH.s); (oil).
EXAMPLE VH.1Q
This Example illustrates a preparation of 2-chloro-5-(4,4-difluorobut-3envlthio)thiazole (Compound VII. 114).
Compound VII. 128 (4.0g) in acetonitrile (50cm3) was added at 0°C to a stirred mixture of copper(II) chloride (5.38g) and ten. butyl nitrite (3.71 g) in acetonitrile (50cm3) and allowed to slow-lv warm to ambient temperature over 18 hours. The solvent was evaporated under reduced pressure, the product dissolved in diethyl ether, filtered and the filtrate re-evaporaied to give a yellow-brown liquid which was fractionated by chromaiographv (silica: eluant hexane : diethyl ether 4:1 by volume) to give Compound VII. 114 (2.43g). M=241; Ή NMR δ 2.28(2H,m); 2.68(2H,t); 4.22(lH,m); 7.52(lH,s) (oil).
EXAMPLEVn.il
This Example illustrates a preparation of 2-(4~cyanophenoxy)-5-(4,4-difluorobut-3envlthio) thiazole (Compound Vn.130).
Compound Vn.114 (0.483g), 4-cyanophenol (0.238g), anhydrous potassium carbonate (0.276g) and cesium fluoride (0.304g) in N-methylpyrrolidin-2-one (3cm3) were stirred together under an atmosphere of nitrogen and heated to 90°C for 36 hours. The reaction mixture was diluted with water, the product extracted into diethyl ether, dried (MgSOJ, evaporated under reduced pressure and the residue fractionated by thick layer chromatography (silica: eluted with hexane : diethyl ether 4:1 by volume) to give Compound ΥΠ.130 (0.125g). M=324; Ή NMR 6 2.28(2H,m); 2.80(2H,t); 420(lHjn); 7.40(2H,m);
7.75(2H,m); (oil).
EXAMPLE ΥΠ.12
This Example illustrates a preparation of ethyl 5-(4,4-difluorobut-3-enylthio)-thiazole4-carboxvlaie (Compound VH.98).
Ethyl isocyanoacetate (2.3g) in dry tetrahydrofuran (15cm3) was added to a stirred mixture of potassium tert butoxide (2.24g) at -40°C under an atmosphere of nitrogen. After 10 minutes the reaction was cooled to -78°C and carbon disulfide (1.52g) in tetrahydrofuran
AP/P/ 9 6 / 0 0 8 6 2
-94(20cm3) was added slowly. On complete addition the reaction temperature was allowed to rise ' °°C and 4.4-difluorobut-3-envl 4-methyl-benzenesulfonaie (5.24g) in tetrahydrofuran (10cm :ded. The mixture was allowed to warm to ambient temperature and was stirred for. .urs, heated to reflux for 3 hours and cooled to ambient temperature. The reaction mixture was poured into aqueous 2M hydrochloric acid and product was extracted into ethyl acetate. The organic phase was dried (MgSO4) and solvent removed by evaporation under reduced pressure. Column chromatography of the residue on silica gel. eluting with 1:1 hexane : ethyl acetate gave Compound VII.98 (3.15g). *H NMR δ 1.45(3H,t); 2.50(2H.m); 3.10(2H,t); 4.3^.4(lH.m); 4.50(2H,q); 8.65(lRs); (oil).
EXAMPLE VIL13
This Example illustrates a preparation of 5-(4,4-difluorobut-3-envlthio)-thiazole-4carboxamide (Compound VII.94).
Compound VH.98 (0.5g) in methanol (8cm3) was stirred with aqueous ammonia (35cm3; density 0.88) for 4 hours. Compound VH.94 was obtained as a solid which was filtered from solution and sucked to dryness (0.27g). Ή NMR δ 2.50(2H,m); 3.00(2H,t); 4.30-4.41(lH.m); 5.5 and 7.0(2H.broad); 8.55(lRs); (solid mp 140-141°C).
The following compounds according to the invention were prepared from the corresponding esters using the above procedure:
(i) 2-(4,4-difluorobur-3-enylthio)thiazole-4-carboxamide (Compound VII.7). NT=250; ‘H
NMR: δ 2.50(2H.m); 3.27(2H,t); 4.28(lH,m); 5.9 and 7.1(2H,br s); 8.03(lH,s); (mp
57-58°C) from Compound VII.8.
(ii) 2-(4,4-difluorobut-3-enylthio)-4-methylthiazole-5-carboxamide (Compound VII.36).
>H NMR: δ 2.48(2H,m); 2.66(3H,s) 3.26(2H,t); 3.85(3H,s); 4.28(lKm); 5.7(2H,br s);
(mp 99-100°C) from Compound VII.41.
EXAMPLE ΥΠ. 14
This Example illustrates a preparation of 4-cyano-5-(4,4-difluorobut-3-enylthio)thiazole (Compound VH.90).
Compound VII.94 (0.27g) in dry dichloromethane (13cm3) was treated with pyridine (lcm3) and methane sulfonyl chloride (0.26cm3) .The mixture was stirred for 5 days, further methane sulfonyl chloride (0.2cm3) added and again stirred for 2 hours. The reaction was then poured into aqueous 2M hydrochloric acid and the product was extracted into ethyl acetate. The organic phase was dried (MgSOJ and evaporated under reduced pressure. Chromatography of the residue on silica gel gave Compound VII.90 (0.142g). *H NMR δ
AP. Ο Ο 6 4 9
- 95 2.40(2Rm): 3.20(2Rt); 4.30(lRm): 8.80( IRs).
The following compounds according to the invention were prepared from the corresponding carboxamides using the above procedure:
(i) 4-cyano-2-(4,4-difluorobut-3-enylthio)thiazole (Compound VEI.6). Ή NMR: δ
2.50(2Rm); 3.32(2Rt); 4.26(lRm); 7.86(lRs); (oil) from Compound VH.7.
(ii) 5-cyano-2-(4,4-difluorobut-3-enylthio}-4-methylthiazole (Compound VH.32). *H
NMR: 62.48(2Rm); 2.58(3Rs) 3.3O(2H,t); 3.85(3Rs); 4.28(lRm); (oil) from
Compound VII.36.
EXAMPLE ATI. 15
This Example illustrates a preparation of 5-bromo-2-(4,4-difiuorobut-3envlthio)thiazole-4-carbo?cylic acid (Compound VII. 13).
Compound VH. 11 (0.30g) in methanol (5cm3) containing aqueous sodium hydroxide (1.2cm3 of a 2M solution) was stirred at ambient temperarure for 18 hours, poured into water and acidified with 2M hydrochloric acid. The product was extracted into ethyl acetate, dried (MgSOJ and evaporated under reduced pressure to give Compound VII. 13 (0.18g). M*=329; Ή NMR: δ 2.48(2Rm); 3.30(2Rt); 4.28( IRm); 7.0(lRbroad signal); (mp 86.5-87.5°C).
The following compounds according to the invention were prepared from the corresponding esters using the above procedure:
(i) 2-(4,4-difiuorobut-3-envlthio)thiazoIe-4-carboxyIic acid (Compound VH. 10). ^=251;
Ή NMR: δ2.50(2Ηπι): 3.35(2Rt); 4.28(lRm); 8.18(lH,s); (mp 114-115°C) from
Compound VH.8.
(ii) 2-(4,4-difluorobut-3-enylthio)4-methylthiazole-5-carboxylic acid (Compound VII.45).
M=265; *H NMR: δ 2.50(2Rm); 2.70(3Rs); 3.27(2H,t); 4.28(lRm); 9.8(lRbroad signal); (mp 52.0-53.5°C) from Compound VII.41.
(iii) 5-(4,4-difluorobut-3-enylthio)thiazole-4-carboxylic acid (Compound VII. 102).
M*=251; ‘HNMR: b2.50(2Rm); 3.10(2H,t); 4.28(lRm); 8.70(lH,s); (mp 128.5°C) from Compound VH.98.
EXAMPLE YIL16
This Example illustrates methods suitable for the preparation of compounds according to the invention in which the sulfur atom of the 4,4-difluorobut-3-enylthio substituent of the corresponding unoxidised compound is oxidised to sulfoxide (sulfinyl) or sulfone (sulfonyl).
Method A: Using potassium peroxymonosulfate as oxidant.
Preparation of 5-chloro-2-(4.4-difluorobut-3-enylsulfonyl)thiazole (Compound VII.26)
AP/P/ 9 6 / 0 0 8 6 2
- 96 A stirred solution of Compound VII.24 (4.83s) in methanol (50cm3) at 8°C was treated dropwise with potassium peroxymonosulfate (27.0g) in water (100cm3) with cooling over 0.25 hours, and further methanol (dOcnr1) added. The reaction was stirred for 18 hours at ambient temperarure. the insolubles filtered from solution, the filtrate extracted with dichloromethane (4x50cm3) and dried (MgSO4). The solvent was removed under reduced pressure and the residue fractionated by chromatography (silica; eluant hexane : ethyl acetate 4:1 by volume) to give Compound VII.26 (3.91 g). M(NH4)*=291; *H NMR 52.60(2H.m); 3.50(2H,t); 4.25(lH,m); 7.85(lH,s); (oil).
Method B: Using monomagnesium peroxyphthalic acid
Preparation of 5-bromo-2-(4.4-difluorobut-3-enylsulfinyl)thia2ole (Compound VH. 15).
Compound VH.14 (1.50g) was dissolved in dichloromethane (10cm3) and treated with monomagnesium peroxyphthalic acid hexahvdrate (1.6g, 80% peracid) and water (15cm3).
The mixture was stirred at ambient temperature for 1 hour, diluied with dichloromethane (90cm3) and the organic phase washed with aqueous sodium hydrogen carbonate and water. The organic phase was dried (MgSO4), evaporated under reduced pressure and the residue fractionated by chromatography (silica; eluant hexane : ethyl acetate 10:1 by volume) to give Compound VH.15 (l.Og). M(NH4)*=321; Ή NMR δ 2.38 (Him); 2.60(lH,m); 3.20(2H,m); 4.20(lH,m); 7.85(lH,s); (oil).
The following compounds according to the invention were prepared from the corresponding thioethers using the above procedure, Method B.
(i) 2-(4,4-difluorobut-3-enylsulfinyl)thiazole (Compound VII.2). ΜΗ*=224; *H NMR δ
2.36(lH,m); 2.50-2.70(lH,m); 3.20(2H,m); 422(lRm); 7.67(lH,d); 7.98(lH,d); (oil) from Compound VTI. 1 and one equivalent of oxidant.
(ii) 2-(4,4-difluorobut-3-enylsulfonyl)thiazole (Compound VH.3). MH*=240; Ή NMR δ
2.55(2H,m); 3.45(2H,t); 4.24(lH,m); 7.78(lH,d); 8.08(lH,d); (oil) from Compound
VH.l and two equivalents of oxidant (iii) 5-bromo-2-(4,4-<iifluorobut-3-enylsulfonyl)thiazole (Compound VH.16).
M(NH4)*=335; Ή NMR δ 2.58(2H,m); 3.46(2H,t); 425(lH,m); 7.96(lH,s); (oil) from Compound VII.14 and two equivalents of oxidant (iv) 2-(4,4-difluorobut-3-enylsulfinyl)-5-methylthiazole (Compound VII.22). *H NMR δ
2.38(lH,m); 2.50-2.65(4H,m); 3.15(lH,m); 4.23(lH,m); 7.60(lH,q); (oil) from
Compound VII.21 and one equivalent of oxidant.
(v) 2-(4,4-difluorobut-3-enylsulfonyl)-5-methylthiazole (Compound VII.23). ‘H NMR δ
AP . 0 0 6 4 9
-972.55(2H.m); 2.60(3H.s); 3.45(2H,t); 4.25( lH.m): 7.73(lH.q); (oil) from Compound VD.21 and two equivalents of oxidant (vi) 5-chloro-2-(4,4-<iifluorobut-3-enylsulfinyl)thiazole (Compound VH.25).
M(NH4)=275; 'HNMR 52.38(lKm); 2.60(lKm); 3.18(2Hun); 4.25(lH.m);
7.74( lH.s); (oil) from Compound VD.24 and one equivalent of oxidant.
(vii) 5-(4,4-difluorobut-3-enylsulfinyl)thiazole (Compound VD.83). Ή NMR: δ 2.50(2H.m); 3.05(lKm); 3.20(lH.m); 428(lH,m); 82O(lHLs); 9.12(lH,s); (oil) from Compound VD.82 and one equivalent of oxidant.
(viii) 5-(4.4-difluorobut-3-enylsulfonyl)thiazole (Compound VD.84). Ή NMR· δ
2.50(2H.m); 3.30(2Hun); 4.25(lH,m); 8.20(lH,s); 9.12(lH,s); (oil) from Compound VD.82 and two equivalents of oxidant (ix) 2-cHoro-5-(4,4-difluorobut-3-enylsulfinyl)thiazole (Compound VD. 115). ‘HNMR; δ 2.50(2H,m); 3.05(lHjn); 3.20(lH.m); 4.28(lHim); 7.85(lH,s); (oil) fiom Compound VD.l 14 and one equivalent of oxidant (x) 2-chloro-5-(4.4-difluorobut-3-enylsulfonyl)thiazole (Compound VD.l 16). Ή NMR: δ 2.52(2H.m); 3.30(2FLm); 4.28(lHun); 8.08(lH,s); (oil) from Compound VD.l 14 and two equivalents of oxidant
Method C: Using 3-chloroperbenzoic acid
The following compounds according to the invention were prepared from the corresponding thioetheis using the above procedure, Method B, but with 3-chloroperbenzoic acid in place of monomagnesium peroxyphthalic acid hexahydrate.
(xi) ethyl 2-(4,4-difluorobut-3-enylsulfonyl)thiazole-4-caiboxylaie (Compound VD.9). M*=311; Ή NMR δ 1.43(3H,t); 2.60(2H,m); 3.56(2H,t); 4.28(lH,m); 4.48(2H,q); 8.50(lH,s); (mp 64-65°C) from Compound VD.8 and two equivalents of oxidant (xii) ethyl 5-bromo-2-(4,4-difluorobut-3-enylsulfonyl)thiazole-4-carboxylate (Compound VD.12). M*=389; Ή NMR δ 1.43(3H,t); 2.60(2H,m); 3.56(2H,t); 428(lH,m); 4.48(2H,q); (mp 72-73°C) from Compound VD.ll and two equivalents of oxidant.
(xiii) 5-chloro-2-(4,4-difluorobut-3-enylsulfonyl>4-methyIthiazole (Compound VD28). Ή NMR δ 2.55(2H,m); 2.45(3H.s); 3.40(2H,t); 4.25(lH,m); (oil) from Compound VD.27 and two equivalents of oxidant (xiv) methyl 2-(4,4-difluorobut-3-enylsulfonyl)-4-methylthiazole-5-carboxylaie (Compound
VD.43). Ή NMR δ 2.60(2H.m); 2.85(3H,s); 3.5O(2H,t); 3.95(3H,s); 4.25(lHLm);
(oil) from Compound VD.41 and two equivalents of oxidant
AP/P/ 9 6 / 0 0 8 6 2
- 98(xv) 2-(4.4-difluorobut-3-envlsulfonyl)-4-methylthiazole-5-sulfonyl fluoride (Compound
VH.53). Ή NMR δ 2.60(2Rm); 2.85(3H.s); 3.55(2H.t); 4.28( IRm); (mp 67°C) from Compound VII.52 and two equivalents of oxidant.
EXAMPLE YULI
This Example illustrates a preparation of 2-(4,4-difiuorobut-3-envlthio> 1methylimidazole (Compound VIH.5).
To a solution of 2-mercapto-l-methylimidazole (9.78g) in acetone (300cm3) was added potassium carbonate (14.2g) and 4-bromo-l,l-difluorobut-l-ene (16.12g) as a solution in acetone (100cm3). The mixture was heated ai reflux for 18 hours and allowed to cool. Inorganic solids were removed by filtering the reaction mixture through a plug of sorbsil-C30 silica, washing with ethyl acetate. The filtrate was evaporated under reduced pressure to give crude Compound VHI.5 (17.8g), which was suitable for further reaction (see Example Vm.7).
A portion (lg) was purified by chromatography on sorbsil C-30, eluting with ethyl acetate : hexane 3 : 7, and gave pure Compound VHL5 (0.776g). ‘H NMR· δ 2.3-2.4(2Rm); 3.053.15(2Rt); 3.60(3Rs); 4.15A.35(lRm); 6.95(lH,s); 7.05(lH,s); (oil).
The following compounds according to the invention were prepared by the above procedure, using the appropriate mercapto imidazole:
(i) 2-(4,4-difiuorobut-3-enylthio)-l-phenylimidazole (Compound VIH.3). M*=266; Ή
NMR δ 2.3-2.4(2H,m); 3.1-3.15(2H,t); 4.M.25(lH,m); 7.1-7.2(2H,m); 7.37.55(5H,m); (oil).
(ii) 2-(4,4-difluorobut-3-enylthio)-l-ethylimidazole (Compound VUI. 10). ΙνΓ=218; *H
NMR δ 1.4(3Rt); 2.3-2.4(2H,m); 3.15(2Rt); 4.0(2H,q); 4.2A.35(lH,m); 6.95(lRs);
7.1(lH,s); (oil).
(iii) 2-(4,4-difluorobut-3-enylthio)-4-ethyl-5-methylimidazole (Compound VHI.27).
M*=232; Ή NMR δ 1.15(3H,t); 2.15(3Rs); 2.35-2.45(2Rm); 2.5-2.6(2H,q);
2.95(2H,t); 4.14.3( IRm); (imp. 54-56°C).
(iv) 2-(4,4-difluorobut-3-enylthio)-4-methylimidazole (Compound VHI.58). M*=204; Ή
NMR δ 2.25-2.35(5Rm); 3.0(2H,t); 4.154.3(lRm); 6.75(lRs); (oil).
(v) 2-(4,4-difluorobut-3-envlthio)-4-ethoxycarbonylimidazole (Compound VEI.64).
M*=262: Ή NMR δ 1.3-1.35(3Rt); 2.25-2.35(2H,m); 3.05-3.15(2H,t); 4.14.25( IRm); 4.3-4.4<2Rq); 7.8(lRbr s); (mp 57.8-61 °C).
(vi) 3-(4.4-difluorobut-3-enylthio)imida2O-[l,5a]-pyridine (Compound VUI. 151). Ή NMR
AP.00649
-996 2.30 (2H.m): 3.00(2H.t)·. 4.20(lH.m); 6.65(lH.m): 6.80(lH.m); 7.45(lH.dt):
7.55(lH.s); 8.15(lH.dd); (oil) from 2.3-dihydroimidazo-[1.5a)-p>Tidine-3-thione. EXAMPLE VIII2
This Example illustrates a preparation of 2-(4,4-difluorobut-3-enylthio>-imidazole (Compound VUI.l) and l-(4.4-difluorobut-3-enyl)-2-(4,4-difluorobut-3-enylthio)imidazole (Compound VIII.8) as a mixture of products separable by chromatography.
To a solution of 2-mercapto-imidazoIe (10.01 g) in acetone (400cm3) was added potassium carbonate (20.73g) and 4-bromo-l,l-difluorobut-l-ene (18.79g). The mixture was heated at reflux for 18 hours and allowed to cool. Inorganic solids were removed by filtering the reaction mixture through a plug of sorbsil-C30 silica, washing with ethyl acetate. The filtrate was evaporated under reduced pressure to give a pale browm oil (19.2g) which was chromatographed on silica, eluting with 15% ethyl acetate in hexane, progressing to 50% ethyl acetate in hexane. Two main fractions were obtained, the first of 'which (7.4g) was shown by tic to contain two products. The second fraction (10.75g), obtained as a white solid, was shown to be pure Compound VUI.l. The first fraction was subjected to further chromatography as before to give Compound VIH.8 (1.61 g); NT=280; *H NMR: δ 2.32.45(4H.m); 3.l-3.15(2H,t); 3.9-4.0(2H,t); 4.05-4.3(2H,m); 6.95(lH,s); 7.05(lH,s); (oil) and Compound VEI.l (5.3 lg). This sample of Compound VIII.l was recrystallised from ethyl acetate and hexane to provide 4.2g which had M=190; Ή NMR: δ 2.3-2.4(2H,m); 3.03.1(2H.t); 4.15-4.3( lH.m); 7.0-7.1(2H,br s); 92(lH,br s); (m.p. 58.6-59.6°C).
EXAMPLE Vm.3
This Example illustrates a preparation of 2-(4,4-difluorobut-3-enylthio)-4phenvlimidazole (Compound VUI.l9).
Phenacyl bromide (1.61 lg) in chloroform (7cm3) was added to 4,4-difluorobut-3envlisothiouronium hydrobromide (2g) in 84% ethanol/water (20cm3) and sodium bicarbonate (2.72s) was slowly added with stirring. The resultant yellow suspension was heated under reflux for 3 hours. The mixture was cooled and solvent was removed by evaporation under reduced pressure. The residue was washed twice with warm water (2x20cm3) which was decanted off to remove inorganic material. The crude product so obtained was purified by chromatography on silica, eluting with 20% ethyl acetate in hexane, and product-containing fractions were recolumned using 5% ethyl acetate in toluene. This gave Compound VIII. 19 (0.78g); ΝΓ=266; Ή NMR: δ 2.3-2.4(2H,m); 3.05-3. l(2H,t); 4.1S4.3(lHjn); 7.2-7.4(4H.m); 7.6-7.75(2H.br s) free of a byproduct the corresponding N-phenacyl derivative.
AP/P/ 9 6 / 0 0 8 6 2
- 100 The following compounds according to the invention were prepared by the above procedure:
(i) 2-(4.4-difluorobut-3-envlthio)-l-methyl-4-phenylimidazole (Compound ΥΊΠ.22). M*=280; Ή NMR: δ 2.35-2.45(2H.m); 3.10-3.18(2H,t): 3.65(3H.s); 4.19-4.35( IRm): 7.2-7.25(2Rm); 7.33-7.3 8(2Rt); 7.72-7.78(2H,d) (oil) using N-methyl 4.4-difluorobut 3-enylisothiouronium hydrobromide.
(ii) 2-(4.4-difluorobut-3-envlthio)-5-ethyl-4-methoxycarbonyl-l-methyliniidazole (Compound VHI.68). M“=290; Ή NMR: δ 1.2-125(3Rt); 2.35-2.45(2Rm): 2.82.9(2Rq); 3.2-3.25(2Rt); 3.78(3Rs); 3.85(3Rs); 4.16-4.32(IRm); (oil) using Nmethyl 4,4-difluorobut-3-enylisothiouronium hydrobromide and methyl 2-bromo-3oxopentanoate.
EXAMPLE VHI.4
This Example illustrates a preparation of 2-(4,4-difluorobut-3-enylthio)-4,5dimethvlimidazole (Compound VHI.29).
Potassium carbonate (18.9g) and 4,4-difluorobut-3-enylisothiouronium hvdrobromide (16.9g) were added to a solution of 3-bromobutan-2-one (10.32g) in dimethyl formamide (100cm3) and the mixture was stirred at 60°C for 90 minutes, then at 80°C for 30 minutes. The resulting mixture was cooled, water (100cm3) added, and the product extracted into diethyl ether. The combined organic phases were washed with water and brine and dried (MgSOJ. Concentration by evaporation under reduced pressure gave a pale orange liquid (12.2g), which was purified by chromatography on sorbsil C30 silica, eluting with 30% ethyl acetate in hexane. Three components were obtained. The first eluted was identified as 3(4.4-difluorobut-3-enylthio)buian-2-one (0.68g); M*=194; Ή NMR: δ 1.4(3H,d); 2.152.3(5Rm); 2.45(2Rt); 3.3-3.4(lRq); 4.1-4.3 5( IRm). The second compound eluted was the desired Compound VHI.29 (4.lg); M*=218; lH NMR: δ 2.15(6Rs) 225-2.35(2H,m); 2.93.0(2Rt); 4.15-4.3(lRm); (mp 81.4-84.4°C). The third compound eluted was identified as the product of a further N-alkylation of Compound VHI.29 with additional 3-bromobuian-2one, namely N-(l-methylpropan-2-one) 2-(4,4-difluorobut-3-enylthio)-4,5-dimethylimidazole (1.1 lg); M*=217; Ή NMR: δ 1.55(3Rs); 2.0(3Rs); 2.05(3Rs); 2.15(3Rs); 2.3-2.4(2Rm); 3.0-3.05(2Rt); 4.15-4.35(IRm); 5.0-5.l(lRm); (oil).
EXAMPLE Vm.5
This Example illustrates a preparation of 2-(4,4-difluorobul-3-enylthio)-1propylimidazole (Compound VHI.12) from the corresponding N-H imidazole, Compound
AP.00649
- 101 VIH.l. by alkylation using propyl iodide.
Compound VUI.l (2g) was added in portions (effervescence) to a suspension of sodium hydride (0.736g of a 60% solid in oil) in dimethyl formamide (20cm3) under a nitrogen aimosphere. After stirring the mixture for 30 minutes, n-propyl iodide (2.68g) was added and the reaction mixture was stirred at the ambient temperarure for 18 hours. Water and diethyl ether were then added and the product extracted into ether. The combined organic phases were washed with water and saturated brine and dried (MgSOJ. After filtraiion, the solvent was removed by evaporation under reduced pressure to give crude product (2.7g) which was purified by chromatography on sorbsil C-30, eluting with ethyl acetate : hexane 3 : 7 and gave Compound VO. 12 (2.15g); Μ*=232; Ή NMR; δ 0.90.95(3H.t); 1.75-1.85(2H.m); 2.3-2.45(2H.m); 3.1-3.15(2H.t); 3.85-3.95(2H.t); 4.154.35(lH.m); 6.9(lH.s); 7.1(lH.s); (oil).
The following compounds according to the invention were prepared by the above procedure, using the appropriate alkylating agent and starting N-H imidazole:
(i) 2-(4,4-difluorobut-3-enylthio)-l-(l-methylethyl)-imidazole (Compound VIII. 14). M~=232; Ή NMR; δ 1.4(6H.d); 2.3-2.4(2H?m); 3.1-3.15(2H,t); 4.15-4.3(lH,m); 4.54.6(lH,m); 7.0(lH,s); 7.1(lH,s); (oil) from Compound Vin.l.
(ii) 2-(4,4-difiuorobut-3-envlthio)-l,4,5-trimethyliniidazole (Compound VHI.31). Ή NMR; 62.15(6Rtwo s); 2.25-2.35(2H,m); 2.95(2H,t); 3.5(3H,s); 4.15-4.3(lHLm); (oil) from Compound VHL29.
(iii) l-ethyl-2-(4,4-difluorobut-3-enylthio)-4,5-dimethylimidazole (Compound VHI.33). *H NMR; δ 1.25(3H,t); 2.15(6H.br s); 2.3-2.4(2H,m); 3.0(2H,t); 3.9-3.95(2H,q); 4.154.3( lH,m); (oil) from Compound VHL29.
(iv) A mixture of 2-(4,4-difluorobut-3-enylthio)-l,5-dimethylimidazole (Compound VIII.35) and 2-(4,4-difluorobut-3-enylthio)-l,4-dimethylimidazole (Compound Vm.60); Ή NMR; δ 2.15(3H,s); 2.3-2.4(2Rm); 3.0-3.05(2H,t); 3.5 and 3.55(3H.two s); 4.15-4.3( lH,m); 6.65 and 6.80(lH,two s) from Compound VHI.58.
(v) A mixture of 2-(4,4-difluorobut-3-enylthio)-5-methyl-l-(l-rnethylethyI}-imidazole (Compound VHI.37) and 2-(4,4-difluorobut-3-enylthio}-4-methyl-';-(l-methylethyl)imidazole (Compound VIII.62); shown to be mainly the latter isomer, Ή NMR; δ 1.35(6H.d); 2.2(3H.s); 2.3-2.4(2H.m); 3.05(2H,t); 4.15-4.3(lH,m); 4.5-4.6(lH,m); 6.70(lH.s) from Compound VHI.58.
(vi) 2-{4.4-difluorobu’-3-enylthio)-5-ethoxycarbonyl-l-methylimidazole (Compound
9 8 0 0 / 9 6 /d/dV
- 102 VHL52). M=276; Ή NMR δ 1.32-1,40(3H.t): 2.37-2.47(2H.m): 3.2-3.3(2H.t);
3.82(3H.s); 4.17-4.32(lH.m); 4.25-4.35(2H.q); 7.7( 1H.S); (oil) from Compound
Vm.64. This reaction produced a chromatoeraphically separable mixture of
Compound VHI.52 and VHI.65, the former eluting first.
(vii) 2-(4.4-difluorobut-3-envlthio)-4-ethoxycarbonyl-l-methylimidazole (Compound
Vm.65). M=276; *H NMR δ 1.35-1,40(3H.t); 2.35-2.42(2H.m); 3.20-3.27(2H.t);
3.63(3H,s); 4.15-4.30(lH,m); 4.3-4.4(2H,q); 7.60(lH,s); (oil) from Compound VEI.64.
EXAMPLE Vm.6
This Example illustrates a preparation of 2-(4,4-difluorobut-3-envlthio)-N-(methane sulfonyl)imidazole (Compound VUL18).
A solution of Compound VUI.l (0.49g) in dry tetrahvdrofuran (3cm3) was added dropwise to a suspension of sodium hydride (55% in oil, 0.12g, washed with hexane prior to use) in dry tetrahvdrofuran (5cm3) cooled in a cold water bath. The reaction mixture was allowed to stir at the ambient temperature for 2 hours and then methanesulfonvlchloride (0.3g) was added and the reaction stirred for a further 16 hours. The reaction mixture was poured into ethyl acetaie'water and the layers separated. The aqueous layer was extracted with ethyl acetate and the combined organic phases were dried (MgSO4), filtered and evaporated under reduced pressure to give a yellow oil. Purification by column chromatography on silica gel using 3:7 ethyl acetateihexane gave Compound VUI.l8 (0.3lg). Ή NMR δ 2.40-2.50(2H.m); 3.30 (2H,t); 3.30(3H,s); 4.25(lHun); 7.05(lH,d); 7.35(lH,d); (oil).
EXAMPLE Vm.7
This Example illustrates a method suitable for the preparation of compounds according to the invention in which the sulfur atom of the 4,4-difluorobut-3-enylthio substituent of the corresponding unoxidised compound is oxidised to sulfoxide (sulfinyl) or sulfone (sulfonyl).
Preparation of Compound VEI.7 from Compound VEI.5.
Compound VEI.5 .(18.lg) was cooled to 0°C in dichloromethane (400cm3) and 3chloroperbenzoic acid (61.2g of water-wet solid, 2 equiv.) was added. The mixture was stirred at the ambient temperature for 18 hours and then poured into saturated aqueous sodium bicarbonate. The product was extracted into dichloromethane, the organic phase washed with water and saruraied brine and dried (MgSO4). Evaporation of solvent under reduced pressure gave crude Compound VHI.7 which was chromaiographed on silica, eluting
AP.00649
- 103 with 15% ethv 1 acetate in hexane, progressing to 50% ethyl acetate in hexane, to give pure Compound Vm.7. Ή NMR δ 2.55-2.6(2H.m): 3.5-3.55(2H.t); 4.0(3H.s); 4.15^.3( lH.m); 7.0(lH.s); 7.15(lH.s); (oil).
The following compounds according to the invention were prepared by the above procedure of Example VUI.. using two equivalents of oxidant unless otherwise specified, with the appropriate starting thioether (i) 2-(4,4-difluorobut-3-enylsulfonyl)-imidazole (Compound VIIIJ2). ΜΗ=223; Ή NMR δ 2.4-2.6(2H.m); 3.4-3.45(2H.t); 4.M.3(lH.m); 7.3-7.4(3H.br s); (white solid, mp. 113-114°C).
(ii) 2-(4,4-difluorobut-3-enylsulfonyl)-l-phenylimidazole (Compound VHI.4). M*=298; *H NMR δ 2.45-2.55(2H,m); 3.45-3.55(2H,t); 4.1M.3(lRm); 72(lH,d); 7.25(lH,d); 7.45-7.55(5H.m); (oil).
(iii) l-(4,4-<iifluorobut-3-enyl)-2-(4,4-difluorobut-3-enylsulfonyl)-imidazole (Compound vm.9). M*=312; Ή NMR δ 2.5-2.65(4H,m); 3.5-3.6(2H,t); 4.1-4.35(2H,m); 4.44.45(2H,t); 7.05(lH,s); 7.15(lH,s); (oil).
(iv) 2-(4,4-difluorobut-3-enylsulfonyl)-l-ethylimida2X»le (Conpound VE.ll). M*=250; Ή NMR δ 1.5(3H,t); 2.5-2.65(2H.m); 3.5-3.6(2H,t); 4.15-4.35( IRm); 4.4-4.45(2H,q); 7.05(lH,s); 7.15(lH.s); (oil).
(v) 2-(4,4-difluorobut-3-enylsulfony 1)-1-propylimidazole (Compound VHI.13). MH*=265; Ή NMR 60.9-1.0(3Rt); 1.8-2.0(2Rm); 2.5-2.6(2Rm); 3.5-3.6(2H,t); 4.154.35(3H,m); 7.05(lRs); 7.15(lH,s); (oil).
(vi) 2-(4,4-difluorobut-3-enylsulfonyl)-l-(l-methylethyl}-imidazole (Compound VIH.15). MX264; Ή NMR δ 1.5(6H,d); 2.55-2.65(2H,m); 3.5-3.6(2Rm); 4.15-4.35(lHjn); 5.15-5.35(lH,m); 7.15(2Rbr); (oil).
(vii) 2-(4,4-difluorobut-3-enylsulfinyl>4-phenyIimidazole (Compound VE20). M=282;
Ή NMR δ 2.35-2.65(2H,m); 3.25-3.4(2H,t); 4.15-4.3(IRm); 725-7.5(4Rm); 7.67.8(2Rm); (oil) using 1.5 equivalents of oxidant (viii) 2-(4,4-difluorobut-3-enylsulfonyl)-4-phenyIimidazole (Compound VE21). M*=298;
Ή NMR δ 2.45-2.6(2Rm); 3.4-3.5(2Rt); 4.M.28(lRm); 7.3-7.55(4Rm); 7.7 7.75(2H,d); (mp. 109.6-110.4°C) using 1.5 equivalents of oxidant.
(ix) 2-(4,4-difluorobut-3-enylsulfinyl)-l-methyl-4-phenylimidazole (Compound VE_23). M*=296; Ή NMR δ 2.5-2.65(2Rm); 3.4-3.65(2Rm); 4.0(3Rs); 425-4.4( IRm); 7.25-7.45(4H.m); 7.7-7.75(2H.dd); (mp. 106-106.6°C) using 1.5 equivalents of
AP/P/ 9 6 / 0 0 8 6 2
- 104 oxidant.
(x) 2-(4.4-difluorobut-3-envlsulfonyl)-l-methy 14-phenylimidazole (Compound VO.24). M=312: Ή NMR; δ 2.6-2.7(2H.m); 3.58-3.65(2H.t); 4.02(3Rs); 4.24.35(lH.m); 7.25-7.42(4Rm); 7.7-7.75(2Rdd); (m.p. 78.6-79.6°C) using 1.5 equivalents of oxidant.
(xi) 2-(4.4-difiuorobut-3-enylsulfonyl)-4-ethyl-5-methylimidazole (Compound VTH.28). M*=264; Ή NMR; δ 1.15-1.3(3Rq); 2.25(3Rtwo s (tautomers)); 2.45-2.7(4Rm); 3.35-3.45(2Rt); 4.14.3(lRm); 11.3(lRbr s); (oil).
(xii) 2-(4.4-dif]uorobut-3-enylsulfonyl)-4,5-dimethylimidazole (Compound VIH.30).
Μ·=250; Ή NMR; δ 2.25(6H,two s); 2.45-2.55(2Rm); 3.35(2Rt); 4.14.25(lRm); 10.3-10.6(lRbr s); (mp 113.4-114.6°C).
(xiii) 2-(4,4-difluorobut-3-enylsulfonvl)-l,4,5-trimethylimidazole (Compound VIH.32). M*=264; Ή NMR: h2.2(6Rbr s); 2.5-2.6(2Rm); 3.4-3.5(2H,t); 3.85(3Rs); 4.154.3( IRm); (oil).
(xiv) l-ethvl-2-(4,4-difluorobut-3-enylsulfonyl)4,5-dimethyliinidazole (Compound VHI.34). M*=278; Ή NMR; δ 1.4(3Rt); 2.15(6Rbr s); 2.5-2.6(2H,m); 3.5(2Rt); 4.154.3( IRm); (oil).
(xv) A mixture of 2-(4,4-difluorobut-3-enylsulfonyl)-l,5-dimethylimidazole (Compound VIH.36) and 2-(4,4-difluorobut-3-enylsulfonyl)-l,4-diinethylimidazole (Compound Vm.61); Ή NMR; δ 2.20(3H,s)^2.25(3H,s); 2.5-2.6(4Rm); 3.45-3.55(4Rm); 3.85(3Rs); 3.95(3Rs); 4.154.3(2H,m); 6.75(lH,s); 6.95(lH,s); from the mixture of Compounds VEL35 and VHI.60 prepared in Example VKI.5(iv) above.
(xvi) An 18:82 mixture of 2-(4.4-difiuorobut-3-enylsulfonyl)-5-methyl-l-(l-methylethyl)imidazole (Compound VHI.38); Ή NMR; δ 1.55(6H,d); 2.4(3H,s); 2.55-2.65(2Rm); 3.6(2H,t); 4.154.35( IRm); 5.15-5.30(lH,m); 6.85(lH,s); and 2-(4,4-difluorobut-3enylsulfonyl)4-methyi-1-(1 -methylethyl)-imidazole (Compound Vm.63); Ή NMR; δ 1.45(6Rd); 2.25(3Rs); 2.55-2.65(2H,m); 3.55(2H,t); 4.154.35(lRm); 5.155.30(lRm); 6.90(lH,s); from the mixture of Compounds VHI.37 and VHI.62 prepared in Example VIII.5(v) above.
(xvii)· 2-(4.4-difluorobut-3-enylsulfonyl)-5-ethoxycarbonyl-l-methylimidazole (Compound Vm.53). M*=308; Ή NMR; δ 1.37-1,42(3Rt); 2.55-2.67(2Rm); 3.6-3.65(2Rt); 4.24.35( IRm); 4.25(3Rs); 4.324.4(2Rq); 7.7(lH,s); (oil).
(xvni) 2-<4.4-difluorobut-3-enylsulfonyl)4-methylimidazole (Compound VHI.59). M*=236;
AP.00649
- 105 Ή NMR δ 2.3-2.4(3Rbr); 2.45-2.55(2Rm): 3.4(2Rt): 4.24.4(IRm): 7.0(lRbr): (oil).
(xix) 2-(4.4-difluorobut-3-enylsulfinvl)4-ethoxycarbonyl-l-methylimidazole (Compound Vffl.66). M*=292: Ή NMR δ 1.35-1.4(3Rt); 2.49-2.7(2Rm); 3.35-3.6(2Rm): 4.02(3Rs); 4.2-4.38(1 Hun); 4.354.42(2Rq); 7.67(lRs); (oil) using 1.5 equivalents of oxidant.
(xx) 2-{4,4-difluorobut-3-enylsulfonvl)4-€thoxycarbonyl-l-methylimidazole (Compound Vffl.67). M*=308; Ή NMR δ 1.35-1.4(3Rt); 2.55-2.65(2Rm); 3.65-3.70(2H,t); 4.02(3H,s); 4.24.38(lRm); 4.354.42(2Rq); 7.65(lH,s); (oil) using 1.5 equivalents of oxidant.
(xxi) 3-(4,4-difluorobut-3-enylsulfonyl)imidazD-[1.5a]-p\Tidine (Compound VUI. 152). M*= 272; *H NMR δ 2.50(2Rm); 3.50(2Rt); 4.15(lRm); 6.90(lRm); 7.10(lRm); 7.20(lRs); 7.65(lRm); 8.95(lRdd); (oil).
EXAMELEJXl
This Example illustrates a preparation of 5(4.4-difluorobut-3-envlthio)-l,3-dimethyl4-nitropyrazole (Compound 1X82).
4,4-Difluorobut-3-envlisothiouronium hydrobromide (2.46g) was stirred at ambient temperature with aqueous sodium hydroxide (1.2g in 12cm3 water) for 0.3 hours.
5-Chloro-l,3-dimethyl4-nitropyrazole (1.76g) in dichloromethane (12cm3) containing tetra-n-buty 1 ammonium bromide (0.01 g; catalyst) was added at ambient temperature and the reaction mixture stirred for 18 hours under an atmosphere of nitrogen. The reaction was diluted with water (100cm3) and the product extracted into dichloromethane (100cm3). The organic phases were combined, washed with water, dried (MgSO4) and evaporated under reduced pressure to give a pale yellow liquid (2.6g). A sample (0.9g) was fractionated using chromatography (silica; hexane : ethyl acetate 10:1 by volume) to give Compound 1X82 (0.78g). M*=263; Ή NMR δ 2.25(2H,m); 2.55(3H,s); 3.08(2H,t); 3.94<3H^); 4.20(lRm); (oil).
EXAMPLE 1X2
This Example illustrates a preparation of 5(4.4-difluorobut-3-enylsulfonyl)-l,3-dimethyl4-nitropyrazole (Compound 1X84).
3-Chloroperbenzoic acid (1.74g of 50% by weight solid) was added to a solution of
Compound 1X82 (0.526g) in di chloromethane (10cm3) and the reaction was stirred at ambient temperature for 3 days. The reaction was diluted with dichloromethane (100cm3),
AP/P/ 9 6 / 0 0 8 6 2
- 106 washed wiih aqueous sodium hydrogen carbonaie and then waier. dried (MgSO4) and evaporated under reduced pressure to give an oily solid. The crude product was fractionated using chromotography to give Compound 1X84 (0.15g). *H NMR: δ 2.52(3H.m);
2.60(2H,m); 3.74(2H,t); 4.20(3H,s); 4.25(lH.m); (gum).
EXAMPLE 1X3
This Example illustrates a 3-step preparation of 5(4,4-difluorobut-3-enylthio)-1.3-diniethyI-4-iodopyrazoIe (Compound 1X61) . Step ,1: Preparation of 4-aminp-5(4.4-difluorobut-3-enylthioV 1.3-dimethylpyrazole
Compound 1X82 (1.0s) was dissolved in propan-2-ol (10cm3) containing water (2cm3) and concentrated hydrochloric acid (catalyst, 0.1cm3) and treated with reduced iron powder (1,0g). The mixture was stirred and healed under reflux for 3 hours, cooled, neutralised with solid sodium hydrogen carbonate and filtered through keiselgel. The insolubles were washed with propan-2-ol, and the filtrate evaporated under reduced pressure to give the amino pyiazole intermediate as a red-brown oil, (l.Og). M*=233.
Step 2:
The product from Step 1 (4.6g) was dissolved in dry di chloromethane (25cm3) and added to a stirred solution of boron trifluororide diethyl etherate (4.26g) in dry dichloromethane (25cm3) at -15°C. Tert, butyl nitrite in dichloromethane (10cm3) was added dropwise to the mixture. The reaction was allowed to warm to 5°C for 0.3 hours, diluted with hexane and the required diazonium tetrafluoroborate salt was filtered from solution as a brown solid (6.7g).
Step 3: Compound 1X61
The product from Step 1 (1,33g) was added in portions to a stirred solution of potassium iodide (1.7g) in water (5cm3) at 35°C. The reaction mixture evolved gas during the process and gave a red-brown oil. After 1 hour at 35°C the mixture was cooled, diluted with water, extracted with diethyl ether (100cm3), the organic phase washed successively with aqueous sodium metabisulfite then water and dried (MgSO4). The solvent was removed under reduced pressure and the residual oil fractionated by chromatography (silica: hexane : ethyl acetate 10:1 by volume) to give Compound 1X61 as a brown oil (0.2g). M*=344.
EXAMPLE 1X4
This Example illustrates a preparation of 5(4.4-difluorobut-3-enylthio)-1.3-<iiinethyl-pyrazole (Compound 1X55).
AP . 0 0 6 4 9
- 107The diazonium salt from Example 1X3. Step 2 (2.0s) was stirred in methanol (20cnr') at 0°C and sodium borohydride (powder. 0.25g) was added in portions. Gas was evolved and ihe solution changed from colourless to orange-brown. The mixture was allowed to warm to 15°C over 0.5 hours, stored at ambient temperature for 18 hours, diluted with water, extracted with diethyl ether, dried (MgSO4) and evaporated under reduced pressure to give a red-brown liquid. The liquid was fractionated using chromatography (silica; hexane : diethyl ether 1:1 by volume) to give Compound 1X55 (0.42g). M=218; Ή NMR; δ
2.20-2.30(5Rm); 2.74(2Rm); 3.75(3Rs); 4.23(2Rm); 6.12(lRs); (oil).
EXAMPLE 1X5
This Example illustrates a preparation of ethyl 5(4.4-difluorobut-3-envlthio)-l-methylpyrazol-4-yl carboxylaie (Compound 1X34).
Bis-(4.4-difluorobut-3-enyl)disulfide (2.90g) and tert, butyl nitrite (1.22g) in acetonitrile (40cm3) were heated to 60°C under an atmosphere of nitrogen. To the stirred solution was added dropwise ethyl 5-amino-l-methylpyrazol-4-vl carboxylaie (l.OOg) in acetonitrile (10cm3). On complete addition the reaction solution was heated for 2 hours at 60°C, evaporated under reduced pressure and fractionated by chromatography (silica; hexane : diethyl ether, 5:1 by volume) to give Compound 1X34 (yield 42%). M*=276; Ή NMR δ 1.38(3Rt); 2.20(2Rm); 3.05(2Rt); 3.97(3H,s); 4.25(lRm); 4.34(2Rq); 7.98(lH,s); (oil).
The following compounds according to the invention were prepared using the above procedure and the appropriate amino-pyrazole:
(i) 4-bromo-5-(4,4-difluorobut-3-enylthio)-l-methylpyrazole (Compound 1X31).
ΝΓ=282; Ή NMR δ 2.32(2Rm); 2.95(2H,t); 3.88(3Rs); 4.30(lHqn); 7.38(lRs);
(oil).
(ii) 4-cyano-5-(4,4-difluorobut-3-enylthio)-l,3-dimethylpyrazole (Compound 1X73). ‘H
NMR δ 1.38(3Rt); 2.20(2Rm); 2.38(3H,s); 3.02(2H,t); 3.97(3H,s); 425(lRm); (oil).
(iii) ethyl 5-(4,4-difluorobut-3-envlthio)-l-phenylpyrazol-4-yl carboxylaie (Compound
1X124). M*=338; Ή NMR δ 1.40(3Rt); 2.05(2Rm); 2.88(2H,t); 3.97(lRm);
4.37(2H,q); 7.50(5Rm); 8.16(lRs); (oil).
EXAMPLE 1X6
This Example illustrates a preparation of 4-cvano-5-(4,4-difluorobut-3-enylsulfonyl)1.3- dimethylpyrazole (Compound 1X75).
Compound 1X73 (1.32g) in dichloromethane (120cm3) was treated at ambient temperature with 3-chloroperbenzoic acid (3.94g containing 50% peracid). The mixture was
AP/P/ 9 6 / 0 0 8 6 2
- 108 stirred for 18 hours, diluted with further dichloromethane and washed successively with aqueous solutions of sodium carbonate, sodium metabisulfite. Further washing with water, sodium carbonaie. and water were performed before the organic phase was dried (MgSO..). The solvent was evaporated under reduced pressure and the residue fractionated by chromaxography (silica; hexane : diethyl ether 1:1 by volume) to give Compound 1X75 (0.47 ε). M*=275; Ή NMR; 52.42(3H.s); 2.30(2H.m); 2.58(3H.s); 3.38(2H.t): 4.14(3H.s); 4.36( Him); (mp 78-81 °C).
The following compounds according to the invention were prepared using the above procedure and the appropriate pyrazole:
(i) 4-bromo 5-(4,4-difluorobut-3-enylsulfonyl)-l-methylpyrazole (Compound 1X33). Ή
NMR; δ 2.54(2FLm); 3.35(2H,t); 4.00(3H.s); 4.27(lH.m); 7.55(lH.s); (mp
42.6-43.6°C) from Compound 1X31.
(ii) ethyl 5-(4,4-difluorobut-3-enylsulfonyl)-l-methylpyrazole-4-carboxylaie (Compound
1X36). Ή NMR; δ 1.38(3H,t); 2.50(2Hym); 3.78(2H,t); 4.154.30(1 Hun); 4.36(2H,q);
7.95(lH,s); (oil) from Compound 1X34.
(iii) ethyl 5-(4,4-difluorobut-3-envlsulfonyl)-l-phenylpyrazole4-cafboxylate (Compound
1X126). Ή NMR; δ 1.42(3H,t); 2.45(2H,m); 3.72(2H,t); 4.18(lHjn); 4.40(2H,q);
7.35-7.55(5H,m); 8.13(lH,s); (mp 62.5-63.0°C) from Compound 1X124.
EXAMPLE 1X7
This Example illustrates a preparation of 5(4,4-difluorobut-3-enylthio)-l-methylpyrazole-4-carboxylic acid (Compound 1X40) and propan-2-yl 5-(4,4-difluorobut-3-envlthio)-l-methylpyrazole-4-cartx)xylaie (Compound 1X37).
Compound 1X34 (1,5g) was dissolved in propan-2-ol (40cm3) and treated with 2M aqueous sodium hydroxide (8cm3) and stirred at ambient temperature for 18 hours. The mixture was diluted with waier (100cm3), acidified with 2M aqueous hydrochloric acid and extracted with ethyl acetate (3x50cm3). The combined organic phase was dried (MgSO4) and evaporated under reduced pressure to give a yellow oil which solidified on treatment with hexane'diethyl ether. The solid was filtered from solution, washed with hexane and sucked to dryness to give Compound 1X40 (0.76g). Ή NMR· δ 2.24(2FLm); 3.06(2H,t); 4.00(3H,s); 4.20( lELm); 8.08( lH.s); (mp 59.4-60.0°C).
The hexane'diethyl ether filtrate was evaporated under reduced pressure and the oil (containing (Compound 1X37 with about 10% of the ethyl ester starting material from step 1) was treated with propan-2-ol (20cm3) containing sodium methoxide (transesterification
AP.00649 ' Π· . I
- 109 catalyst lOmg) and the mixture heated under reflux for 5 hours. The reaction was cooled, diluted with water, and product extracted into diethyl ether. The organic phase was dried (MgSO4) and evaporated under reduced pressure to give Compound 1X37 (O.lg). MH=291: >H NMR δ 1.35(6H.d); 2.22(2H.m): 3.05(2H.t): 3.97(3H.s); 4.20(lH.m): 5.20OH. septuple!): 7.95( 1H.S); (oil).
EXAMPLE,1X8
This Example illustrates a preparation of 5(4,4-difluorobut-3-enylsulfonvl)-l-methylpyrazole-4-carboxylic acid (Compound 1X42).
Compound 1X36 (0.83g) was dissolved in ethanol (35cm3) and treated with lithium hydroxide monohvdraie (0.34g) in waier (7cm3) at ambient temperature. The reaction mixture was stirred for 18 hours, the ethanol evaporated under reduced pressure, the aqueous phase acidified with 2M hydrochloric acid, and product extracted into ethyl acetate. The organic phase was dried (MgSO4) and solvent was removed under reduced pressure to give a gum which was trituraied with diethyl ether/hexane, giving Compound 1X42 (0.43g). Μ(ΝΉ4)-=298; Ή NMR fi2.52(2H,m); 3.72(2H,t); 4.10-4.30(3H,m); 8.05(lH,s); (tip
118.4-122.0°C).
EXAMPLE XI
This Example illustrates two related syntheses of mercapto-l^,4-oxadiazoles required as intermediates for preparation of compounds of the invention. A general method for synthesis of 5-mercapto-12,4-oxadiazoles is by cyclisation of an amidoxime and an activated thiocarbonvl compound such as thiophosgene or 1,1-thiocarbonyldiimidazole. Use of the first of these reagents is illustrated by the preparation of 5-mercapto-3-phenyl-l,2,4-oxadiazole.
Benzonitrile (15g), hydroxylamine hydrochloride (lOg), potassium carbonate (lOg), ethanol (150cm3) and water (15cm3) were heated together at reflux for 6 hours and then allowed to cool overnight. The reaction mixture was filtered and the solid residue washed with ethanol. The filtrate and washings were combined and evaporated and the resultant brown residue partitioned between ethyl acetate and water. The organic phase was separated, washed with brine and dried (MgSO4). Evaporation gave a brown oil which crystallised on addition of ethyl acetate and hexane to give a grey solid (10.3g). The solid (4.4g) was stirred in ether (50cm3) and thiophosgene (0.55cm3) was added causing a thick white precipitate to form. The reaction was healed at reflux for 1 hour and then allowed to cool. A solution of sodium hydroxide in water (50cm3) was then added and the reaction heated for a further 4 hours, then allowed to cool to leave a yellow biphasic reaction mixture. The organic phase
AP/P/ 9 6 / 0 0 8 6 2
- 110was separated and the aqueous layer was extracted twice with ether. The aqueous layer was acidified to pH 1 causing formation of a yellow ppt. The aqueous layer was extracted with ethyl acetaie and the combined ethyl acetate layers were dried (MgSO4) and evaporated to give 5-mercapto-3-phenvl-1.2.4-oxadiazole as an orange-brown solid (0.554g), which was used withoui further purification. *H NMR: δ 7.45-7.63(3H,m); 7.70-7.90(2Rm).
Use of the alternative reagent. 1,1-thiocarbonyldiimidazole, is illustrated by the preparation of 5-mercapto-3-methoxymethvl-12,4-oxadiazole.
Methoxyacetonitrile (7.lg), hydroxylamine hydrochloride (7g), potassium carbonate (13.8g), ethanol (90cm3) and water (9cm3) were heated together at 50°C for 9 hours and then allowed to cool. The reaction mixture was filtered and the white solid residue washed with ethyl acetaie. The filtrate and washings were combined and evaporated and the resultant residue dissolved in dichloromethane. Insoluble material was removed by filtration and the filtrate evaporated to give a viscous oil (92g). The oil was added to toluene (60cm3) and dry dimethylformamide (4cm3) containing 1,1-thiocarbonyldiimidazole (5.655g) and the mixture was stirred at the ambient temperature for 2 hours. After standing for a further 60 hours the beige solid which had formed was recovered by filtration (5.2g obtained) and shown by NMR to be the uncvclised product of reaction between the hydroxy group of the amidoxime and the thiocarbonyl group. A portion of the solid (2g) was added to a suspension of sodium hydride (0.33g) in dry dimethylformamide (30cm3) (frothing) and the mixture was stirred at the ambient temperature for 5 hours and left to stand for 18 hours. The reaction product was poured into water and the product extracted into ethyl acetaie. The combined organic phases were separated, dried (MeSO4) and evaporated under reduced pressure, finally at high vacuum to remove traces of dimethylformamide. The crude 5-mercapto-3-methoxymethyl1.2,4-oxadiazole had *H NMR: δ 3.2(3H,s); 4.10(2H,s); 6.92-6.98(lH.br s) and was used without further purification.
EXAMPLE X2
This Example illustrates a general process for the preparation of 5-(4,4-difluorobut-3envlthio)-3-substituied-l,2,4-oxadiazoles using the corresponding 5-mercapto intermediate prepared for example as above. This is illustrated by the following preparation of 5-(4,4difluorobut-3-envlthio)-3-methoxymethyl-l,2,4-oxadiazole, Compound X26.
To a solution of 5-mercapto-3-methoxymethyl-12,4-oxadiazole (2.78g) in acetone (150 cm3) was added 4-bromo-1,1-difluorobut-l-ene (4.87g) and potassium carbonate (3.15g) and the mixture heated under reflux for 18 hours. Gc indicated that reaction was complete.
AP . 0 0 6 4 9
- Ill Inorganic solids were removed by filtering the reaction mixture through a plug of sorbsil-C30 silica, washing with acetone. The filtrate was evaporated under reduced pressure and the yellow oily residue was chromatographed on sorbsil-C30. eluting with 5% ethyl acetate in hexane, to give Compound X26 (1.6g) ‘H NMR; δ 2.47-2.58(2Rm); 3.28-3.35(2Rt); 3.49(3H.s); 4.18-4.36(IRm); 4.54(2Rs); (oil).
The following compounds according to the invention were prepared using the above procedure and the appropriate intermediates indicated:
(i) 5-(4.4-difluorobut-3-enylthio)-3-methoxymethyl-12,4-oxadiazole (Compound X.32).
Ή NMR: b2.37(3Rs); 2.45-2.55(2Rm); 322-3.30(2Rt); 4.1M.35(lRm); (oil) from
5-mercapto-3-methyl-12,4-oxadiazole.
(ii) 5-(4,4-difluorobut-3-envlthio)-3-phenyl-1.2.4-oxadiazole (Compound XI). M*=268;
Ή NMR: b2.58(2Rm); 3.35(2Rt); 4.31(lRm); 7.45-7.56(3Rm); 8.07(2Rd); (oil) from 5-mercapto-3-phenyl-l.2,4-oxadiazole.
EXAMPLE X3
This Example illustrates a preparation of 5-(4,4-difiuorobut-3-enylthio)-3methox\rnethyl-l 2,4-oxadiazole (Compound X27) from Compound X26.
Compound X26 (0.6g) was cooled to 0°C in dichloromethane (50cm3) and 3chloroperbenzoic acid (2.19g, 2.5 equiv.) was added over a period of five minutes. The mixture was stirred at the ambient temperature for 1 hour and stood for 40 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and the product was extracted into dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated brine and dried (MgSOJ. Evaporation of solvent under reduced pressure gave a light brown solid which was chromatographed on silica, eluting with 10% ethyl acetate in hexane, progressing to 20% ethyl acetate in hexane, to give Compound X27 having *H NMR δ 2.6-2.71 (2Rm); 3.51(3H,s); 3.58-3.65(2H,t); 4214.37(lRm); 4.69(2H,s); (oil). This material was found to be unstable and on standing for 60 hours at the ambient temperature had hydrolysed appreciably.
EXAMPLE XI, 1A
This Example illustrates a general procedures for the preparation of 5-chloro-3substituted-12,4-thiadiazoles as demonstrated by the following preparation of 5-chloro-3chloromethyl-12,4-thiadiazole from chloroacetamidine hydrochloride.
A suspension of chloroacetamidine hydrochloride (12.9g) in dichloromethane (100cm3) was cooled to -5°C and perchloromethyl mercaptan (20.44g) was added. Sodium hydroxide
AP/P/ 96/00862
- 112 in water (20g in 30cmJ) was added dropwise (exotherm), maintaining the temperature of the reaction mixture below 5°C. After the addition was complete, the reaction was allow'ed to warm to the ambient temperarure and stirred overnight. The mixture was diluted with water and dichloromethane and the whole filtered through a pad of celite to remove insoluble material. The organic phase was separated, washed with saruraied brine and dried over magnesium sulfate. The solution of product was then filtered and evaporated under reduced pressure to give a brown oil (9.72g) which was used without further purification. M*=168; *H NMR;. δ 4.75(s).
The following intermediate compounds were prepared according to the procedure of
Example XI. 1 A. The starting materials were known compounds.
(i) 5-chioro-3-trifluoromethyl-1.2,4-thiadiazole. M“=188 (bp 50°C at I2mmHg).
(ii) 5-chJoro-3-methylmercapto-l,2,4-thiadiazole. M=166.
(iii) 5-chloro-3-methoxy-I.2.4-thiadiazole. M'=150.
(iv) 5-chloro-3-(2-p\Tazinyl)-l,2,4-thiadiazole. M*=198.
A related procedure was used to prepare Compound XI. 102 of the invention, as follows. Preparation of 5-chloro-3-(4.4-difluorobut-3-enyithio)-L2.4-thiadiazole A suspension of 4,4-difluorobut-3-enylisothiouronium hydrobromide (8.68g) in water (200cm3) containing sodium lauryl sulfate (O.lg catalytic) and perchloromethyl mercaptan (7.17g) was cooled to 0°C and sodium hydroxide in water (5.6g in 200cm3) was added dropwise. maintaining the temperature of the reaction mixture below 5°C. After the addition was complete, the reaction was allowed to warm to the ambient temperature and stirred overnight. The mixture was extracted twice with ethyl actetate, the organic phase was separated, washed with saturated brine and dried (MgSOJ. The solution of product was then filtered and evaporated under reduced pressure to give a brown oil (82g) which was chromatographed on silica gel (Sorbsil C30) using 3% ethyl acetate in hexane as eluant to give Compound XI. 102 (2.82g). M~=242; Ή NMR; δ 2.4-2.6(2H,m); 3.2-3.3(3H,t); 4.24.4{lH.m); (oil).
EXAMPLE XI.IB
A general procedure for the preparation of 5-[(4-methyiphenyl)-suIfonyI]-3-substituted1.2.4-thiadiazoles is illustrated by the following two-step preparation of 3-methoxymethvl-5[(4-methylphenyl)-sulfonyl]-12,4-thiadiazole from methoxyacetamide.
Step 1: Preparation of 5-methoxymethyl-L3.4-oxathiazoI-2-one
Chlorocarbonylsulfenvl chloride (7.35g) was added to a suspension of
AP.00649
- 113 methoxyacetamide (5g) in toluene (30cm3). The reaction mixture was stirred and healed at 90-100°C for 5 hours, then cooled. The solvent was removed by evaporation under reduced pressure to give a brown gum (6.6g). M* =147: Ή NMR (DMSO-d^): δ 3.30(3H.s): 4.30(2H,s) which was used in the next step without further purification.
Step 2: Preparation of 3-methoxymethyl-5-[(4-methylphenylLsulfonvl]-1.2.4thiadiazole
4-Methvlbenzenesulfonyl cyanide (16.26g) was added to an emulsion of 5methoxymethvl-1.3,4-oxaihiazol-2-one (6.6g) in dodecane (60cm3). The reaction mixture was stirred and heated at 150°C for 18 hours, then cooled. Waier was added and the product extracted into ethyl acetate. The combined organic phases were dried (MgSO4) and ethyl acetate was removed by evaporation under reduced pressure. The residue separated into a brown liquid and a clear dodecane layer which was removed and discarded. Chromatography of the brown liquid on silica gel (Sorbsil C30) using 3:7 ethyl acetate : hexane as eluant give a pale orange oil which solidified on standing (6.94g). M=284; *H NMR δ 2.40(3H,s); 3.45(3H_s); 4.7(2H,s); 7.4(2H.d); 8.0(2H,d); (mp 43.445-4°C).
The following intermediate compounds were prepared according to the two-step procedure of Example XI.IB. The starting materials were known compounds.
(i) 3-ethyl-5-[(4-methylphenvl)-sulfonyl]-12,4-thiadiazole. M*=268; Ή NMR δ 1.31.4(3H,t); 2.45(3H.s); 2.95-3.05(2H,q); 7.4{2H,m); 8.0(2Hm) from propionamide.
(ii) 3-(E-prop-l-enyl)-5-[(4-methylphenyl)-sulfonyl]-12,4-thiadiazole. Mt=280;lHNMR δ 1.95(3H.dd); 2.45(3H,s); 6.5-6.6( lH.m); 7.0-7.l(lH,m); 7.4{2H,ro); 8.0(2Hjn) from crotonamide.
EXAMPLE XI,2
This Example illustrates a process for the preparation of 5-(4,4-difluorobut-3envlthio)-3-substituted-12,4-thiadiazoles using either the corresponding 5-chIoro- or 5-((4methylphenyl)-sulfonyl]-1.2,4-thiadiazole intermediate prepared as above The general procedure is illustrated by the following preparation of 5-(4,4-difluorobut-3-enylthio)-3methoxymethvl-12,4-thiadiazole (Compound XI.34).
Sodium hydroxide in water (0.848g in 10cm3) was added to 4,4-difluorobut-3envlisothiouronium hydrobromide (1.75g) and the mixiure stirred at ambient temperarure for minutes. A solution of 3-methoxymethyl-5-[(4-methylphenyl)-sulfonyl]-l,2,4-thiadiazole (2.01 g) in dichloromethane (10cm3) and tetrabutylammonium bromide (O.lg, catalyst) were added and the mixture was stirred for 20 minutes. Tic showed that the product had formed.
AP/P/ 96/00862
- 114 The mixture was diluted with more dichloromethane (10cmJ) and the organic phase was separated, washed with saturated brine, dried (MgSO4). filtered and evaporaied under reduced pressure to give an orange-vellow liquid. Chromatography of the crude product on silica gel (Sorbsil C30) using 1:4 ethyl acetaie : hexane as eluant give Compound XI.34 (1.67g). M =252; Ή NMR; δ 2.45-2.55(2Rm); 3.25-3.35(2Rt); 3.5(3Rs); 4.15-4.35(IRm); 4.65(2Rs): (oil).
The following compounds according to the invention were prepared using the above procedure but with the appropriate intermediates.
(i) 5-(4,4-difluorobut-3-enyIthio)-3-trifluoromethyl-1.2.4-thiadiazole (Compound XI.9). M”=276; Ή NMR; δ 2.5-2.6(2Rm); 3.3-3.4(2Rt); 4.24.4(lRm); (oil).
(ii) 5-(4.4-difluorobut-3-enylthio)-3-(E-prop-l-enyl)-l,2,4-thiadiazole (Compound XI.ll). M=248; ‘HNMR: δ 1.95(3Rdd); 2.5-2.6(2Rm); 3.3(2Rt); 4.24.4(lRm); 6.456.55(lRm); 6.9-7. l(lRm); (oil).
(iii) 3-ethvl-5-(4,4-difluorobut-3-enylthio)-12,4-thiadiazole (Compound XI.23). M*=236; ‘H NMR; δ 1.3-1.4(3Rt); 2.45-2.55(2Rm); 2.9-3.0(2Rq); 3.3(2H,t); 4.24.4{lRm); (oil).
(iv) 3-chloromethvl-5-(4,4-dif3uorobut-3-enylthio)-12,4-thiadiazole (Compound XI.25). M*=256; ‘HNMR; δ 2.45-2.55(2Rm); 3.35(2Rt); 4.24.35( IRm); 4.7(2H,s); (oil). Two further products were produced in this reaction, which were separated during the chromatography and characterised. These were 3-(4,4-difluorobut-3-enylthiomethyl}5-(4,4-difluorobut-3-enylthio)-1,2,4-thiadiazole (Compound XI.38). 1VT=344; ‘H NMR; δ 2.25-2.35(2Rm); 2.45-2.55(2Rm); 2.65(2Rt); 3.3(2Rt); 3.9(2Rs); 4.154.35(2Rm); (oil) and 5-chloro-3-(4,4-difluorobut-3-enylthiomethyl)-l^,4-thiadiazole. M=256; ‘HNMR; δ2.2-2.3(2H,m); 2.65(2Rt); 3.9(2Rs); 4.14.3(lRm); (oil) (v) 5-(4,4-difluorobut-3-envlthio)-3-methoxy-1,2,4-thiadiazole (Compound XI.87).
M*=238; Ή NMR; δ 2.45-2.55(2Rm); 3.3(2Rt); 4.1(3Rs); 4.24.35(lRm); (oil) (vi) 3.5-bis-(4,4-difluorobut-3-enylthio)-1,2,4-thiadiazole (Compound XI.109). M*=330;
‘H NMR; δ 2.45-2.6(4Rm); 3.2-3.35(4Rm); 4.24.4(2Rm); (oil) from Compound XI.102.
(vii) 5-(4,4-difluorobut-3-envlthio)-3-(2-pyrazinyl)-1.2,4-thiadiazole (Compound XI.125).
M*=286; Ή NMR; δ 2.55-2.65(2Rm); 3.35-3.45(2Rt); 4.254.40(lRm); 8.65(lRd);
8.75(lRdd); 9.55(lRd); (oil)
EXAMPLE XI.3
- 115 This Example illustrates the preparation of 3-butox>Tnethvl-5-(4,4-difluorobui-3enylthio)-l,2,4-thiadiazole (Compound XI.30).
Potassium carbonate (0.444g) and n-butanol (0.397g) were added to a solution of Compound XI.25 (0.275g) in dimethylformamide (2cm3) and the mixture was stirred at ambient temperature for 18 hours. Tic indicated that Compound XI.25 was still present in the mixture, so sodium hydride (O.lg) and n-butanol (0.4g) were added and stirring continued for a further 24 hours. Water was added and the product was extracted into diethyl ether.
The organic phase was dried (MgSO4), filtered and evaporated under reduced pressure to give an oil (0.442g) which was purified by chromatography on silica gel (Sorbsil C30) using 10% ethyl acetate in hexane as eluant to give Compound XI.30 (0.131g). NT=294; ‘H NMR; δ 0.95-1.0(3H,t); 1.4-1.55(2Rm); 1.75-1.9(2HLm); 2.25-2.45(2Hun); 2.6-2.7(2H,t); 3.75(2H,s);
4.15-4.3( IRm); 4.4-4.5(2H,t); (oil).
The following compound according to the invention was prepared using the above procedure, with n-propanol in place of n-butanol.
(i) 5-{4.4-difluorobut-3-enylthio}-3-propoxymethyl-lT2,4-thiadiazole (Compound XI.31).
M“=280; ‘HNMR; δ 1.0-1.l(3H,t); 1.8-1.95(2Rm); 225-2.35(2Rm); 2.6-2.7(2H,t);
3.75(2HLs); 4.15-4.4( lH,m); 4.44.45(2H,t); (oil).
EXAMPLE XI.4
This Example illustrates a two step process for the preparation of 5-(4,4-difiuorobut-3envlthio)-3-methyl-l,2,4-thiadiazole (Compound XI.40).
Step 1; Preparation of 3-methyl-1.2.4-thiadiazole-5(4HVthione
To a solution of acetamidine (5g) in methanol (100cm3) was added carbon disulfide (4g), sulfur (1.7g), and sodium methoxide (5.7g) and the mixture was heated under reflux for 6 hours. The mixture was cooled, filtered through hi-flo filter aid to remove excess sulfur and the filtrate was partitioned between water and ethyl acetate. The ethyl acetate was evaporated to give a brown solid and on acidification of the aqueous layer a red solid was formed and filtered off. Both the solids obtained from the filtrate appeared to be a mixture of 3-methyl-122,4-thiadiazole-5(4H)-thione and sulfur. These two solids were combined and used in the next step.
Step 2: Preparation of Compound XI.40
To a solution of 3-methyl-l,2,4-thiadiazole-5(4H)-thione (l-2g) in acetone (100 cm3) was added 4.4-difluorobut-3-enyl 4-methylbenzenesulfonate (2.4g) and potassium carbonate (1.2g) and the mixture was refluxed for 4 hours after which tic indicated complete
AP/P/ 96/00862
- 116consumption of starting maierial. The reaction was poured into ethyl acetate and water and the lavers separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (MgSO4). The solution of product was then filtered and evaporaied under reduced pressure to give a brown oil which was purified by flash chromatography (silica, 7% ethyl acetate in hexane) to give 5-(4,4-difluorobut-3-enylthio)-3-methy 1-1.2.4thiadiazole as a brown oil (0.645g). M*=222; Ή NMR: δ 2.56(2H. br q); 2.63 (3H.s); 3.30(2H.t); 4.30(lH,m).
The following compound according to the invention was prepared using the above procedure but with 3-phenyl-l,2,4-thiadiazole-5(4H)-thione as starting material.
(i) 5-(4,4-difluorobut-3-enylthio)-3-phenyl-l^,4-thiadiazole (Compound XI.5). lH NMR:
2.53(2H.q); 3.30(2H,t); 4.24(lH.m); 7.38(3H.m); 8.2(2H.m).
EXAMPLE XI.5
This Example illustrates the preparation of 3-(4,4-difluorobut-3-enylthio)-5-methoxy1.2.4-thiadiazole (Compound XI. 108).
Sodium hydroxide (0.182g) was added to a solution of Compound XI. 102 (lg) in methanol (5cm3) and the mixture stirred at the ambient temperature for 45 minutes, when tic indicated consumption of starting material. Water and diethyl ether were added to the mixture and the product was extracted into diethyl ether. The organic phase was dried (MgSO4), filtered and evaporated under reduced pressure to give a yellow oil (0.9g). Purification by flash chromatography (silica, 5% ethyl acetate in hexane) gave Compound XI.108 (0.78g). NT =238; Ή NMR: δ 2.4-2.5(2Rm); 3.2(2H,t); 4.15(3H,s); 4.24.35(lH.m); (oil).
EXAMPLE XI,6
This Example illustrates the preparation of 5-(4,4-difluorobut-3-enylthio)-3-methylthio1.2.4-thiadiazole (Compound XI. 110).
Sodium sulfide nonahvdraie (0.555g) was added to 5-chloro-3-methylthio-1,2,4thiadiazole (1.5g) in ethanol (10cm3) and the mixture stirred and heated under reflux for 18 hours. The reaction mixture was cooled and solvent removed by evaporation under reduced pressure to give a yellow solid (1.76g) which was dissolved in actetone (30cm3). Potassium carbonate (2.22g) and 4-bromo-l,l-difluorobut-l-ene (1.83g) were added and the mixture stirred and heated under reflux for 18 hours. The reaction mixture was cooled, filtered through hi-flo filter aid to remove inorganic material, washing with ethyl acetate, and solvent removed by evaporation under reduced pressure to give a brown gum which was purified by
AP.00649
- 117 chromaiographv on silica eel (Sorbsil C30) using 5% ethyl acetate in hexane as eluant to give Compound XI. 110 (0.392g). M* =254: Ή NMR: δ 2.45-2.55(2H.m); 2.65(3H.s): 3.253.35(2Ht); 4.2-4.4(lH.m); (oil).
EXAMPLE XL7
This Example illustrates the preparation of 5-(4,4-difluorobut-3-envlthio)-3-(3nitrophenvl)-l,2,4-thiadiazole (Compound XI. 127).
Hydrogen sulfide gas was bubbled for 40 minutes through a stirred mixture of potassium methoxide (2.2 e) and absolute ethanol (25cm3), cooled at ~ .-10oC. The flask was removed from the cooling bath, 5-chloro-3-(3-nitrophenyl)-12Z,4-thiadiazole (3g) was added, and the mixture was heated under reflux for 1 hour. The reaction was cooled and poured into ether and the resulting precipitate was filtered off. The filtrate, containing 5-mercapto3-(3-nitrophenvl)-12,4-thiadiazole. was then placed in a flask and 4,4-difluorobut-3-envl 4meihvlbenzenesulfonaie (1.5 s) and ~ lg of potassium carbonate were added and the mixture was heated under reflux for 3 hours after which gc indicated virtually complete consumption of tosylaie. The reaction was poured into ethyl acetate and water and the layers separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (MgSOJ. Evaporation under reduced pressure gave a brown liquid which was purified by flash chromatography (silica; eluant 5% ethyl acetate in hexane) to give Compound XI.127 (0.901g). M’=329; Ή NMR· δ 2.60(2H.broad q) 3.44(2H,t); 4.34(lH,m); 7.65(lH,t); 8.32(lHdd); 8.6(lH.d); 9.1(lH,d) (oil).
EXAMPLE XI.8
This Example illustrates a method suitable for the preparation of compounds according to the invention in which the sulfur atom of the 4,4-difluorobut-3-enylthio substituent of the corresponding unoxidised compound (prepared according to the procedures of the preceding Examples) is oxidised to sulfoxide (sulfinyl) or sulfone (sulfonyl).
Preparation of Compounds XI.35 and XI.36 from Compound XI.34.
Compound XI.34 (0.85g) was stirred at ambient temperature in dichloromethane (10cm3) and 3-chloro perbenzoic acid (0.814g, 1.4 equiv.) was added. After three and a half hours, tic indicated consumption of starting material, with the formation of two products.
The reaction was quenched by the addition of a saturated aqueous solution of sodium bicarbonate and the products were extracted into dichloromethane. The organic phase was separated, washed with saturated brine and dried over magnesium sulfate. After filtration and concentration by evaporation under reduced pressure, there was obtained a white solid (1.2g)
AP/P/ 9 6 / 0 0 8 6 2
- 1 IS which was purified by chromatography on silica gel using 3 : 7 ethyl acetate : hexane as eluant to give first 5-[(4,4-difiuorobut-3-enyl)sulfonyl]-3-methoxymethyl-1.2.4-thiadiazole (Compound XI.36) (0.298g). M=284: Ή NMR: δ 2.55-2.65(2H.m): 3.55(3H.s); 3.53.6(2H.t); 4.2-4.35(lH,m); 4.80(2H,s); (oil). Futher elution gave 5-[(4,4-difiuorobut-3enyl)sulfinyl]-3-methoxymethyl-1.2,4-thiadiazole (Compound XI.35) (0.402g). M'=268; Ή NMR: δ 2.3-2.75(2H.m): 3.15-3.4(2H.m); 3.55(3H.s); 4.1M.35(lRm); 4.75(2H.s); (oil).
The following compound according to the invention was prepared by the above procedure, using two equivalents of oxidant (i) 5-[(4,4-difluorobut-3-enyl)sulfonyl]-3-ethyl-l,2,4-thiadiazole (Compound XI.24)
NT-268; Ή NMR: δ 1.4-1.5(3H,t); 2.55-2.65(2H.m); 3.05-3.15(2Rq); 3.5-3.55(2H.t);
4.2-4.4( Him); (oil).
EXAMPLE ΧΠ.1
Methods for synthesis of the mercapto 1,3,4-oxadiazoles used as intermediates in preparing compounds according to the invention are well known in the art. Two representative methods are illustrated below.
Method A Preparation of 2-mercapto-5-methyl-1.3.4-oxadiazole,
To a solution of acetic hydrazide (5g) in ethanol (10cm3) was added carbon disulfide (7.7g) followed by a solution of potassium hydroxide in ethanol (5.7g in 20cm3) which caused a white precipitate to form. The reaction was then stirred at ambient temperature for 2 hours and left to stand overnight. The reaction was filtered to give a white solid (1 lg).
This salt (5g) was taken up in pyridine (10cm3) and the mixture heated under reflux for a total of 14 hours. After cooling, the reaction was acidified and extracted twice with diethyl ether. The ether layer was dried over magnesium sulfate, filtered and evaporaied under reduced pressure to give an orange solid. This was recrystallised from ethyl acetate to give 2-mercapto-5-methyl-l,3,4-oxadiazole (0.655g). M=116; Ή NMR: δ2.43(3Η,5); 10.9(lH.br s).
Method B Preparation of 5-i4-methoxyben2ylV1.3.4-oxadiazole-2f3HVthione,
Step 1: Preparation of (4-methoxyphenyl)acetic acid hydrazide.
Hydrazine hydrate (4.7cm3) was added dropwise to ethyl (4-methoxyphenyl)acetate (3.73g) and then methanol (20cm3) was added to form a homogeneous reaction mixture. This mixture was stirred for 18 hours ar ambient temperature during which time a white precipitate formed. The precipitate was isolated by filtration and washed with methanol and water, then air-dried to give (4-methoxyphenyl)acetic acid hydrazide (2g). M*=180; Ή
AP.00649
- 119 NMR δ 3.5O(2H.s): 3.8O(3H.s); 3.85(2H.br s): 6.70(lH.br s); 6.90(2H.d); 7.20(2H.d): (solid). The following intermediate compounds were made by the above methods:
(i) 2-methvlpropanoic acid hydrazide. M*=102; (solid).
(ii) cyclopropvlacetic acid hydrazide. M=100; (solid).
(iii) butanoic acid hydrazide. Ή NMR δ 0.95(3H.t): 1.60-1.75(2H.m); 2.15(2H.t): 3.90(2H.br s): 6.95(lH.br s); (solid).
(iv) propanoic acid hydrazide. M*=88; (solid).
(v) pentanoic acid hydrazide. ‘H NMR δ 0.90(3H.t); 1.30-1.40(2H.m); 1.60-1.70(2H.m); 2.20(2H,t); 3.90(2H.br s); 6.80(lH.br s); (solid).
(vi) hexanoic acid hydrazide. Ή NMR δ 0.90(3H.t); 1.20-1.35(4H.m); 1.60-1.70(2H.m); 2.15(2H.t); 3.90(2H.br s); 6.70(lH.br s); (solid).
(vii) (4-nitrophenyI)acetic acid hydrazide. Ή NMR δ (DMSO-dJ 3.50(2HLs); 7.50(2H.d): 8.10(2H.d); (solid).
(viii) (2,6-difluorophenvl)acetic acid hydrazide. M*=186; ‘HNMR δ 3.60(2H,s); 6.907.00(2H,m); 720-7.30(1 Hun); (solid).
(ix) 2-methvlbenzoic acid hydrazide. M^= 150; ‘H NMR δ 2.45(3H.s); 4.10(2H.br s); 7.00( lH.br s); 7.20-7.40(4H.m); (solid).
Step 2: Preparation of 5-(4-methoxybenzyl)-l,3,4-oxadiazole-2(3H)-thione.
A solution of potassium hydroxide (0.7g) in water (2cm3) was added to a stirred solution of (4-methoxyphenvl)acetic acid hydrazide (1.99g) in ethanol (30cm3). carton disulfide (0.7cm3) was added and the reaction was heated to reflux for 6 hours and then left to cool. The reaction mixture was evaporated to dryness under reduced pressure and the solid residue dissolved in water. The pH was adjusted to 1 with concentrated hydrochloric acid, resulting in formation of a white precipitate. The precipitate was isolated by filtration, washed with water and ether and air dried to give 5-(4-methoxybenzyl)-l,3,4-oxadiazole2(3H)-thione (1.96g). M*=222; Ή NMR δ 3.80(3H,s); 3.95(2H,s); 6.90(2H,d); 720(2H,d); (solid).
The following compounds were prepared by the above method, using the appropriate intermediate (either known compounds or as prepared in Step 1):
(i) l,3,4-thiadiazole-2(3H)-thione-5-carboxamide. M=145; (solid).
(ii) 5-thienyl-1.3.4-thiadiazoie-2(3H)-thione. M^l 84; (solid).
(iii) 5-isopropyl-1.3.4-thiadiazole-2(3H)-thione. Μ·=144; (gum).
(i\) 5-c\'clopropyl-1.3.4-thiadiazole-2(3H)-thione. M*=142; (gum).
AP/P/ 9 6 / 0 0 8 6 2
- 120 (v) 5-propyl-1.3,4-thiadiazole-2(3R)-thione. M=144; (oil).
(vi) 5-«hyl-1.3.4-thiadiazole-2(3H)-thione. lvr=130: (oil).
(vii) 5-{4-pyridyl)-1.3.4-thiadiazole-2(3H)-thione. M= 179: Ή NMR: δ 7.75(2Rd);
8.75(2Rd); (solid).
(viii) 5-butyl-l,3,4-thiadiazole-2(3H)-thione. Ή NMR: δ 0.95(3Rt): 1.35-1.50(2Rm):
1.65-1.75(2Rm); 2.70(2Rt): 2.90(lRbr s); (oil).
(ix) 5-pentvl-l,3,4-thiadiazole-2(3H)-thione. !H NMR; δ 0.90(3Rt); 1.25-1.45(4Rm):
1.75(2H,m); 2.70(2Rm); (oil).
(x) 5-(4-nitrobenzyl)-1.3,4-thiadiazole-2(3H)-thione. M*=237; Ή NMR; δ 4.20(2Rs):
7.50(2H,d); 8.25(2Rd); (solid).
(xi) 5-(2.6-difluorobenz\'l)-l,3,4-thiadiazole-2(3H)-thione. ‘HNMR: 64.10(2Rs); 6.907.00(2Rm); 7.25-7.40( IRm); (solid).
(xii) 5-(4-methox>phenyl)-l,3,4-thiadiazole-2(3H)-thione. Ή NMR: δ 3.8O(3Rs);
7.10(2Rd); 7.75(2Rd); (solid).
(xiii) 5-(2-methylphenyl)-l,3,4-thiadiazole-2(3H)-thione. lH NMR; δ (DMSO-d^)
2.50(3H,s); 7.3O-7.40(2Rm); 7.40-7.50(IRm); 7.55(lRbr d); (solid).
(xiv) 542-methoxyphenyl)-1.3,4-thiadiazole-2(3H)-thione. MT=208; (solid).
(xv) 5-(4-nitrophenvl)-1.3,4-thiadiazole-2(3H)-thione. M”=223; 'H NMR: δ 8.05(2Rd);
8.30(2Rd); (solid).
(xvi) 5-benzvl-l,3,4-oxadiazole-2(3H)-thione. Ή NMR: δ 4.00(2H,s); 7.25-7.40(5Rm);
(solid).
EXAMPLE ΧΠ.2
This Example illustrates a prepar ation of 2-(4,4-difluorobut-3-enylthio)-5-phenyl-1,3,4oxadiazole (Compound ΧΠ.3).
To a solution of 2-mercapto-5-phenyl-l,3,4-oxadiazole (0.499g) in acetone (15cm3) was added potassium carbonate (0.3 87g) and 4,4-difluorobut-3-enyl 4-methylbenzenesulfonate (0.7g) and the mixture was heated under reflux for 1.5 hours after which time all starling material had been consumed. The reaction was poured into diethyl ether and water and the layers separated. The aqueous layer was extracted with ether and the combined organic layers were washed with water and dried (MgSO4). Evaporation of solvent under reduced pressure gave a pale yellow liquid which was purified by flash chromatography to give Compound XII.3 as a colourless oil that solidified on standing (0.293g). M=268: Ή NMR: δ 2.58(2Rm); 3.32(2Rt); 4.31(lRm); 7.45-7.57(3Rm);
AP.00649
- 121 8.01 (2Rd); (mp 384O°C).
The following compounds according to the invention were prepared from the appropriate intermediate (either known compounds or prepared as in Example ΧΠ.1) using the above method but with 4-bromo-l.l-difluorobut-l-ene as alkylating agent instead of 4.4-difluorobut-3-envl 4-methyl-benzenesulfonaie.
(i) 5-cvclopropyl-2-(4,4-dif]uorobut-3-enylthio}-1.3.4-oxadia2ole (Compound ΧΠ.1). Ή
NMR δ 1.10-1.15(4Rm); 2.10-2.20( IRm); 2.45-2.55(2Rm); 3.20(2H,t); 4.30(lRm);
(oil).
(ii) 2-(4,4-difluorobut-3-enylthio>-5-isopropyl-1.3,4-oxadiazole (Compound XH.8).
M*=234; Ή NMR δ 1.19(6Rd); 2.50-2.60(2Rm); 3.15(lRseptet); 3.30(2Rt);
4.30(lRm); (oil).
(iii) 5-(2,6-difluorobenzyl)-2-(4,4-difluorobut-3-enylthio)-l,3,4-oxadiazDle (Compound
ΧΠ.11). Ή NMR δ 2.45-2.55(2Rm); 3.25(2Rt); 4.20(2Rs); 425(lH,m); 6.907.00(2Rm); 7.25-7.35(lRm); (oil).
(iv) 2-{4.4-difluorobut-3-enylthio)-5-(4-nitrobenzyl)-l,3,4-oxadia2ole (Compound XU. 12).
Ή NMR δ 2.50-2.60(2Rm); 3.30(2H,t); 4.20(lRm); 4.30(2H,s); 7.50(2H,d);
8.20(2Rd); (oil).
(v) 2-{4,4-difiuorobut-3-enylthio)-5-isoburyl-l,3,4-oxadiazole (Compound ΧΠ.23). Ή
NMR δ 1.00(6Rd); 2.10-2.20(IRm); 2.50-2.60(2Rm); 2.70(2H,d); 325(2H,t);
4.30(IRm); (oil).
(vi) 2-(4,4-difluorobut-3-enylthio)-5-pentyl-l,3,4-oxadiazole (Compound ΧΠ25). Ή
NMR δ 0.90(3Rt); 1.30-1.40(4H,m); 1.70-1.80(2Rm); 2.50-2.55(2Rm); 2.80(2H,t);
3.25(2Rt); 4.30(lRm); (oil).
(vii) 5-butv 1-2-(4,4-difluorobut-3-enylthio)-l.3,4-oxadiazole (Compound XH.28). Ή NMR
60.95(3Rt); 1.35-1.50(2Rm); 1.70-1.80(2Rm); 2.50-2.60(2Rm); 2.80(2H,t);
3.25(2Rt); 4.30(IRm); (oil).
(viii) 2-(4,4-difluorobut-3-enylthio)-5-propyl-l,3,4-oxadiazole (Compound ΧΠ.31). ‘H
NMR δ 1.00(3Rt); 1.75-1.90(2Rm); 2.50-2.60(2Rm); 2.80(2H,t); 325(2H,t);
4.30(IRm); (oil).
(lx) 2-{4,4-difluorobut-3-enylthio)-5-ethyl-l,3,4-oxadiazole (Compound ΧΠ.35). Ή NMR δ 1.40(3Rt); 2.50-2.60(2Rm); 2.85(2H,t); 3.25(2H,t); 4.30(lRm); (oil).
(x) 2-(4,4-difluorobut-3-enylthio)-5-methyl-1.3,4-oxadiazole (Compound ΧΠ.49).
M~=206; Ή NMR δ 2.51(2Rm); 2.73(3Rs); 3.27(2Rt); 4.25(lRm); (oil).
AP/P/ 9 6 / 0 0 8 6 2
- 122 (xi) 2-(4.4-difluorobut-3-enylthio)-1.3.4-oxadiazole-5-carboxamide (Compound ΧΠ.55).
NT-235; Ή NMR: δ 2.50-2.60(2Rm); 3.35(2Rt); 4.30(lRm): (mp 113°C).
(xii) 2-(4,4-difluorobut-3-envlthio)-5-(2-methylphenyl)-1.3,4-oxadiazole (Compound
ΧΠ.128). *H NMR: δ 2.55-2.65(2H.m); 2.70(3Rs); 3.35(2Rt); 4.30(lRm): 7.307.45(3Rm); 7.90(lRd); (oil).
(xiii) 2-(4.4-difluorobut-3-enylthio)-5-(2-furyl)-1.3,4-oxadiazole (Compound XU. 131).
NT-258: Ή NMR; δ 2.50-2.60(2Rm); 3.35(2Rt); 4.30(lRm); 6.60(lRm);
7.10(lRd); 7.60(lRd); (oil).
(xiv) 2-{4,4-difiuorobut-3-envlthio)-5-(2-methoxyphenyI)-l,3,4-oxadiazole (Compound
ΧΠ.132). Ή NMR; δ 2.50-2.60(2Rm); 3.30(2Rt); 3.95(3H,s); 4.30(lRm);
7.10(2Rm); 7.50(lRdt); 7.90(lRdd); (mp 35-37°C).
(xv) 2-(4,4-<iifluorobut-3-enylthio)-5-(2-thienyl)-l,3,4-oxadiazole (Compound XU. 133).
NT-274; Ή NMR; δ 2.50-2.60(2Rm); 3.30(2Rt); 4.30(lRm); 7.10-7.20(lRm);
7.55(lRd); 7.70(lRd); (oil).
(xvi) 2-{4,4-difluorobut-3-enylthio)-5-(3-ftryl)-L3,4-oxadiazole (Compound ΧΠ. 134). *H
NMR; δ 2.50-2.60(2Rm): 3.30(2Rt); 4.30(lRm); 6.90(lRm); 7.50-7.55(1Hun);
8.05(lRbr s); (oil).
(xvii) 2-(4,4-difluorobut-3-enylthio)-5-(4-methoxyphenyl)-l,3,4-oxadiazo]e (Compound
ΧΠ.144). *H NMR; δ 2.50-2.60(2Rm); 3.30(2Rt); 3.90(3H,s); 4.30(lRm);
7.00(2Rd); 8.00(2Rd); (oil).
(xviii) 2-(4.4-difluorobut-3-envlthio)-5-(4-pyridyl)-l,3,4-oxadiazole (Compound ΧΠ.148).
NT-269: Ή NMR; δ 2.50-2.65(2Rm); 3.40(2H,t); 4.30(lRm); 7.90(2Rd);
8.80(2Rd); (oil).
_ EXAMPLE ΧΠ.3
This Example illustrates a preparation of 2-(4,4-difluorobut-3-enylsuIfinyl)-5-phenyl1.3,4-oxadiazole (Compound XII.4).
To a solution of Compound ΧΠ.3 (lg) in dry dichloromethane stirring at 0°C was added 3-chloroperbenzoic acid (1.3g of a 50% by weight solid, 1 equivalent). The reaction was allowed to warm to ambient temperarure. stirred for 3 hours and left overnight Tic indicated complete consumption of starting material. The reaction mixture was filtered and the filtrate partitioned between dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with di chloromethane and the combined organic phases were dried over magnesium sulfate. Evaporation of solvent under reduced pressure gave a yellow
AP.00649
- 123 oil which was purified by flash chromatography on silica gel. eluting with 25% ethyl acetaie in hexane to give Compound ΧΠ.4 (0.474g). M=284: *H NMR δ 2.67(2H.m): 3.52(2H.m); 4.32( lH.m); 7.50(3H.m): 8.12(2H.d): (oil).
The following compounds according to the invention were prepared from the appropriate thioether using the above method (i) 2-(4,4-difluorobut-3-enylsulfinvl)-5-(4-methoxybenzyl)-l,3,4-oxadiazole (Compound
ΧΠ.14). Ή NMR δ 2.45-2.70(2Hm); 3.30-3.50(2H,m); 3.80(3H,s); 4.25(lH.m);
4.25(2H,s); 6.90(2H.d); 7.25(2H.d); (oil).
(ii) 2-(4,4-difluorobut-3-enylsulfinyl)-5-pentyl-l,3,4-oxadiazole (Compound ΧΠ.26). *H
NMR δΟ.95(3Η,ΐ); 1.30-1.40(4H.m); 1.80-1.90(2H.m); 2.50-2.75(2H.m); 2.95(2H,t);
3.35- 3.55(2H.m); 4.30(lH.m); (oil).
(iii) 5-buryl-2-(4,4-difluorobut-3-enylsulfinyl)-l,3,4-oxadiazole (Compound ΧΠ.29). Ή
NMR δ l.OO(3H,t); 1.40-1.50(2H.m); 1.8G-1.90(2Hfm); 2.50-2.75(2H,m); 3.00(2H,t);
3.35- 3.55(2H,m); 4.30(lH,m); (oil).
(iv) 2-(4,4-difluorobut-3-enylsulfmyl)-5-propyl-l,3,4-oxadiazole (Compound ΧΠ.32). Ή
NMR δ 1.05(3H,t); 1.80-1.95(2H.m); 2.50-2.75(2H.m); 2.95(2H,t); 3.35-3.55(2H.m);
4.30( lH,m); (oil).
(v) 2-{4.4-difluorobut-3-enylsulfinyl)-5-(2-methylphenyl)-l)3,4-oxadiazole (Compound
ΧΠ.129). Ή NMR δ 2.55-2.80(2H.m); 2.70(3H.s); 3.40-3.60(2ilm); 4.30(lH,m);
7.30-7.40(lH,m); 7.45-7.50(lH,m); 8.00(lH,d); (oil).
(vi) 2-(4,4-difluorobut-3-envlsulfinyl)-5-(4-nitrophenyl>-l,3,4-oxadiazole (Compound
ΧΠ.142). Ή NMR δ 2.55-2.80(2H,m); 3.45-3.70(2H,m); 4.35(lHjn); 8.35(2H,d);
8.45(2H,d); (oil).
(vii) 2-(4,4-difluorobut-3-envlsulfmyl>5-(4-methoxyphenyI)-l,3,4-oxadiazole (Compound
ΧΠ.145). Ή NMR δ 2.50-2.80(2H,m); 3.40-3.60(2Iim); 3.90(3H,s); 4.30(lH,m);
7.05(2H.d); 8.05(2H.d); (oil).
The following compounds according to the invention were prepared from the appropriate thioether using the general method described above but with 2 equivalents of 3chloroperbenzoic acid as oxidant.
(viii) 2-(4,4-difluorobut-3-enylsulfonyl)-5-phenyM,3,4-oxadiazole (Compound XH.5).
M*=300; Ή NMR δ 2.71(2H.m); 3.67(2H.m); 4.33(lH.m); 7.52-7.70(3H.m); ’
8.25(2H.d); (mp 1W-1O6°C).
(lx) 2-(4.4-difluorobut-3-enylsulfonyl)-5-isopropyl-1.3.4-oxadiazole (Compound ΧΠ.9). *H
AP/P/ 9 6 / 0 0 8 6 2
- 124 NMR δ 1.50(6Rd): 2.60-2.70(2Rm): 3.20-3.40( IRm): 3.60(2Rt); 4.30(lRm): (gum).
(x) 2-(4.4-difluorobut-3-enylsulfonyl)-5-(4-nimobenz>'l)-1.3.4-oxadiazole (Compound ΧΠ.13). Ή NMR δ 2.60-2.70(2Rm); 3.60(2Rt); 4.30(lRm); 4.40(2Rs); 7.55(2Rd); 8.25(2Rd); (oil).
(xi) 2-(4,4-difluorobut-3-enylsulfonyl)-5-(4-methoxybenzyl)-1.3.4-oxadiazole (Compound ΧΠ.15). lH NMR δ 2.60-2.70(2Rm); 3.65(2Rt); 3.8O(3Rs); 4.20( IRm); 4.25(2Rs); 6.90(2Rd); 7.25(2Rd); (mp 60-63°C).
(xii) 5-benzyI-2(4,4-difuorobut-3-envlsulfonyl)-L3,4-oxadiazole (Compound ΧΠ.19). Ή NMR δ 2.60(2Rm); 3.60(2Rt); 4.25(lRm); 4.30(2Rs); 7.25-7.40(5Rm); (oil).
(xiii) 2-(4,4-difluorobut-3-enylsulfonyl}-5-pentyl-l,3.4-oxadiazole (Compound ΧΠ.27). Ή NMR δ 0.95(3Rt); 1.30-1.45(4Rm); 1.80-1.90(2Rm); 2.60-2.70(2Rm); 3.00(2Rt); 3.60(2Rt); 4.30(lRm); (oil).
(xiv) 5-butvl-2-(4,4-difluorobut-3-enylsulfonyl)-l,3,4-oxadiazole (Compound ΧΠ.30). Ή NMR δ 1.00(3Rt); 1.40-1.50(2Rm); 1.80-1.90(2Rm); 2.60-2.70(2Rm); 3.00(2Rt); 3.60(2Rt); 4.30(lRm); (oil).
(xv) 2-(4,4-difluorobut-3-envlsulfonyl]-5-propyl-l,3,4-oxadiazole (Compound ΧΠ.33). Ή NMR δ 1.10(3Rt); 1.85-2.00(2Rm); 2.60-2.70(2Rm); 2.95(2Rt); 3.60(2H,t); 4.30(lRm); (oil).
(xvi) 2-(4.4-difluorobut-3-enylsulfonvl)-5-methyl-l,3,4-oxadiazoie (Compound XH.51). Ή NMR δ 2.20-2.30(2Rm); 2.30(3Rs); 3.60(2Rt); 4.30(lRm); (oil).
(xvii) 2-(4.4-difluorobut-3-enylsulfonyl>-5-(2-methylphenyl)-l,3,4-oxadiazole (Compound ΧΠ.130). Ή NMR δ 2.70-2.80(2Rm); 2.75(3Rs); 3.70(2Rt); 4.30(lRm);
7.40(lRd); 7.50(lRd); 8.00(lRd); (mp 90-93°C).
(xviii) 2-(4,4-difluorobut-3-enylsulfonyl)-5-(4-nitrophenyl}-l,3,4-oxadiazole (Compound ΧΠ.143). M*=345;‘H NMR δ 2.70-2.80(2Rm); 3.70(2H,t); 4.35(lH,m); 8.35(2Rd); 8.45(2Rd); (oil).
(xix) 2-{4.4-difluorobut-3-enylsulfonyl)-5-(4-methoxyphenyl)-l,3,4-oxadiazole (Compound XII.146). Ή NMR· δ 2.70-2.80(2Rm); 3.65(2Rt); 3.90(3Rs); 4.30(lRm); 7.05(2Rd); 8.10(2Rd); (mp 60°C).
EXAMPLE XIII· 1
This Example illustrates a general procedure for the preparation of 2-(4,4-difluorobui3-envlthio)-5-substituted-L3.4-thiadiazoles from the corresponding thiadiazole-2(3H)-thione, _ 0 0 6 4 9
-125 · compounds which are well known in the art. The process is illustrated by the preparation of
2-(4,4-difluorobut-3-enylthio}-5-methylamino-1.3.4-thiadiazole (Compound ΧΓΠ.70) from the corresponding thione and 4.4-difluorobut-3-enyl 4-methvl-benzenesulfonate. Other alkylating agents, for example 4-bromo-1.1-difluorobut-1-ene may also be used.
Preparation of Compound ΧΓΠ.70,
To a solution of 5-methylamino-1.3.4-thiadiazole-2(3H>thione (0.393g) in acetone (10cm3) was added potassium carbonate (0.369g) and 4,4-difluorobut-3-enyl 4-methylbenzenesulfonate (0.7g) and the mixture was heated under reflux for 3 hours after which gc analysis indicated complete consumption of starting material. The reaction mixture was filtered through hi-flo filter aid and the pad washed thoroughly with diethyl ether. The filtrate was poured into ether and waier and the layers were separated. The aqueous layer was extracted twice with ether and the combined organic phases were dried (MgSO4). Evaporation of solvent under reduced pressure gave a brown oil which was purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate : hexane to give Compound ΧΓΠ.70 (0.273g) M*=237; Ή NMR: 52.43(2H,m); 3.04(3H,s); 3.15(2H,t); 429(lH,m);
5.36(lH.br s); (mp 52.5-53.5°C).
The following compounds according to the invention were prepared by the above general method using the appropriate mercapto thiadiazoles and in some cases 4-bromo-l,ldifluorobut-1-ene as alkylating agent (i) 5-cyclopropvl-2-(4.4-difluorobut-3-enylthio)-1.3.4-thiadiazole (Compound ΧΠΙ.6).
M=248; ‘HNMR δ 1.10-1.30(4ELm); 2.30-2.40( IRm); 2.45-2.55(2Rm);
3.30(2H,t); 4.30(lRm); (oil).
(ii) 2-(4,4-difluorobut-3-enylthio)-5-phenyl-l,3,4-thiadiazole (Compound Xffl.9). NT=284;
>H NMR: δ 2.50-2.65(2Rm); 3.40(2Rt); 4.50(lRm); 7.40-7.50(3Rm); 7.857.95(2Rm); (mp 39°C).
(iii) 2-(4,4-difluorobut-3-enylthio)-5-isopropyl-1,3,4-thiadiazole (Compound ΧΙΠ.16).
M*=250; ‘HNMR; δ 1.40(3Rs); 1.45(3Rs); 2.45-2.60(2Rm); 3.35(2H,t); 3.353.50(lRm); 4.30 (IRm); (oil).
(iv) 5-benzyl-2-(4,4-difluorobut-3-enylthio)-1.3.4-thiadiazole (Compound XEDL20).
M*=298; ‘HNMR· δ 2.45-2.55(2Rm); 3.30(2Rt); 4.30(lRm); 4.40(2H,s); 7.257.40(5Rm): (oil).
(v) 2-(4.4-difluorobut-3-enylthio)-5-methyl-1.3,4-thiadiazoIe (Compound ΧΠΙ.40).
M-=222; Ή NMR δ 2.50(2Rm); 2.73(3Rs); 3.35(2Rt); 4.29( IRm); (oil).
AP/P/ 9 6 / 0 0 8 6 2
- 126 (vi) 2-{4.4-difiuorobut-3-enylthio)--1.3.4-thiadiazole-5-carboxamide (Compound ΧΠΙ.45).
M=151; ‘H NMR δ 2.50-2.60(2Rm): 3.45(2Rt); 4.30(lRm): 6.80( 1 Rbr s):
7.15(1 Rbr s); (mp 168°C).
(vii) 2-(4,4-difluorobut-3-envlthio)-l,3.4-thiadiazole (Compound ΧΠΙ.63). M*=208; Ή
NMR δ 2.54{2Rm); 3.43(2Rt); 4.30(lRm); 9.03(lRs); (oil).
(viii) 5-amino2-(4,4-difluorobut-3-enylthio)-l,3,4-thiadiazole (Compound ΧΓΠ.69).
ΜΓ=223; ‘H NMR 62.45(2Rm); 3.20(2Rt); 4.30(IRm); 5.20(2Rbr s); (mp 138°C).
(ix) 2-(4.4-difluorobut-3-envlthio)-5-(3-trifluoromethylbenzylthio)-1.3.4-thiadiazole (Compound ΧΠΙ.110). M*=304; Ή NMR δ 2.51 (2Rm); 3.31 (2Rt); 4.27( IRm);
4.56(2Rs); 7.42-7.70(4Rm); (oil).
(x) 5-cyclopropylmethylthio-2-(4.4-difluorobut-3-enylthio)-l,3,4-thiadiazole (Compound
Xm.114). M*=294: Ή NMR δ 0.35(2Rm); 0.65(2Rm); 1.25(lRm); 2.50(2Rm);
3.25(2Rd); 3.30(2Rt); 4.25(lRm); (oil).
(xi) 2,5-bis-(4,4-difluorobut-3-enylthio)-1.3,4-thiadiazole (Compound ΧΠΙ.117). M*=330;
Ή NMR δ 2.51(4Rm); 3.32(4Rt); 4.29(2Rm); (oil).
(xii) 2-(4,4-difluorobut-3-enylthio)-5-methylthio-l,3,4-thiadiazole (Compound ΧΓΠ.119).
M*=254; Ή NMR δ 2.51 (2Rm); 2.77(3Rs); 3.31(2H,t); 4.20(lRm); (oil).
(xiii) 2-(4,4-difluorobut-3-enylthio)-5-(sulfonamidophenyl)-l,3,4-thiadiazole (Compound
Xm.143). M*=363; *H NMR δ 2.55-2.65(2Rm); 3.50(2Rt); 4.30(IRm); 4.95(2Rbr s); 8.05(4Rm); (mp 154°C).
EXAMPLE XHI.2
This Example illustrates a general procedure for the preparation of 2-(4,4-difluorobut3-enylthio)-5-substituted-1.3,4-thiadiazoles from 2-amino-5-substituted thiadiazoles. The process is illustrated by the preparation of 2-(4,4-difluorobut-3-enylthio)-5-ethyl-1,3,4thiadiazole (Compound ΧΠΙ.27) from 2-amino-5-ethyl-l,3,4-thiadiazole.
Preparation of Compound ΧΓΠ.27.
A solution of 2-amino-5-ethyl-l,3,4-thiadiazole (0.786g) and di-4,4-difluorobut-3-enyl disulfide (1.5s) in dichloromethane (25cm3) was stirred and cooled in an ice-water bath.
Tert, butyl nitrite (1.2g) was added, the cold bath removed and the reaction heated under reflux for 1.3 hours. The mixture was then poured into diethyl ether/water and the layers separated. The aqueous layer was extracted with ether and the combined organic phases were dried (MgSOJ, filtered, and evaporated under reduced pressure to give a brown oil. Purification by column chromatography on silica gel using 1:9 and 2:8 ethyl acetate : hexane
AP. Ο Ο 6 4 9
- 127as eluant eave Compound XHI.27 (O.959g). M‘=236: Ή NMR δ 1.40(3Rt): 2.452.60(2Rm); 3.10(2Rq); 3.35(2Rt); 4.30(lRm); (oil).
The following compounds according to the invention were prepared by the above procedure, using the appropriate intermediates:
(i) 5-bromo-2-(4,4-difluorobut-3-enylthio)-l,3,4-thiadiazole (Compound XHI.l). M'=286:
Ή NMR δ 2.45-2.60(2Rm); 3.40(2Rt); 4.30( IRm); (oil).
(ii) 2-(4,4-difluorobut-3-enylthio)-5-tert.-butyl-l,3,4-thiadiazole (Compound XHI.3).
M“=264; Ή NMR δ 1.48(9Rs); 2.45-2.60(2Rm); 3.35(2H,t); 4.30(lRm); (oil).
(iii) 2-(4,4-difluorobut-3-envlthio)-5-trifluoromethyl-1.3,4-thiadiazole (Compound ΧΙΠ.14).
M*=276; Ή NMR δ 2.50-2.60(2H,m); 3.45(2Rt); 4.30(lRm); (oil).
EXAMPLE ΧΠΙ.3
This Example illustrates a preparation of 2,5-bis-(4,4-difluorobut-3-enylsulfinyl)1.3,4-thiadiazole (Compound XHL133) using 3-chloroperbenzoic acid as the oxidant.
A solution of Compound XHI.117 (0.49g) in dichloromethane (30cm3) was cooled in a methanol ice bath to - -10°C, 3-chloroperbenzoic acid (lg of a 50% by weight solid, 2 equivalents) was added and the reaction was allowed to stir and gradually warm to the ambient temperature, then stirred for 7 hours and left to stand for 18 hours. The mixture was then poured into sodium bicarbonate solution and the product extracted into diethyl ether.
The combined organic phases were washed with sodium bicarbonate solution and dried (MgSOJ. Evaporation of solvent under reduced pressure gave a pale yellow liquid which was purified by flash chromatography on silica gel, eluting with 30% ethyl acetate in hexane to give Compound XHI.133 (0.168g). M*=362; ‘HNMR 02.58(4Rm); 336(4H,m); 4.26(2Rm). (mp 4648°C).
The following compounds according to the invention were prepared by the above general procedure, using the appropriate number of equivalents of 3-chloroperbenzoic acid as oxidant.
(i) 2-(4,4-difluorobut-3-envlsuIfinyl)-5-phenyI-l,3,4-thiadiazoIe (Compound XHI.10).
M*=300; Ή NMR δ 2.40-2.80(2Rm); 3.30-3.40(2H,m); 4.30(lH,m); 7.457.60(3Rm); 7.95-8.OO(2Rm); (mp 67°C).
(ii) 2-(4,4-difluorobut-3-envlsulfonyl)-5-phenyl-l,3,4-thiadiazole (Compound ΧΠΙ.11).
M*=316; Ή NMR δ 2.60-2.75(2Rm); 3.65(2H,t); 4.30(lRm); 7.45-7.65(3Rm);
7.95-8.05(2Rm); (mp 80°C).
(iii) 2-(4,4-difluorobut-3-enylsulfinyl)-5-methyl-l,3,4-thiadiazole (Compound XHI.41).
AP/P/ 9 6 / 0 0 8 6 2
- 128M*=238: ‘H NMR δ 2.35-2.55(IRm): 2.55-2.75( IRm): 2.90(3Rs): 3.20-3.40(2Rm):
4.30(IRm): (oil).
(iv) 2<4.4-difluorobut-3-enylsulfonyl)-5-methyl-1.3,4-thiadiazole (Compound ΧΕΠ.42).
M=255; Ή NMR δ 2.55-2.70(2Rm); 2.95(3Rs): 3.60(2Rt); 4.30(lRm); (oil).
(v) 2-(4.4-difluorobut-3-envlsulfinyl)-1.3.4-thiadiazole (Compound ΧΓΠ.64). M*=225: Ή
NMR δ 2.35-2.50(lRm); 2.60-2.75(IRm): 3.25-3.45(2Rm); 4.30(lRm); 9.35(lRs):
(oil).
(vi) 2-(4.4-difluorobut-3-enylsulfonvl)-1.3,4-thiadiazole (Compound ΧΕΠ.65). MH=241;
'HNMR δ 2.60-2.70(2Rm); 3.70(2Rt); 4.30(lRm); 9.40(lRs); (oil).
(vii) 2,5-bis-(4.4-difluorobut-3-enylsulfonyl)-l,3,4-thiadiazole (Compound XUI. 124).
M*=394; Ή NMR· δ 2.69(4Rm); 3.70(4Rt); 4.30(2Rm); (mp 88-91 °C).
(viii) 2-(4.4-difluorobut-3-enylsulfonvl)-5-(4,4-difluorobut-3-enylsulfinyl)-L3,4-thiadiazole (Compound ΧΠΙ.134). NT=378; 'HNMR· δ2.38-2.55(lRm); 2.60-2.79(3Rm);
3.38(2Rm); 3.62-3.74(2Rm); 4.194.39(2Rm); (mp 45-47°C).
The following compounds according to the invention were prepared by the above general procedure but using the appropriate number of equivalents of magnesium monoperoxyphthalate as oxidant.
(ix) 5-bromo-2-(4,4-difluorobut-3-enylsulfonyl)-l,3,4-thiadiazole (Compound XHI.2).
MH*=319; Ή NMR δ 2.60-2.70(2Rm); 3.65(2Rt); 4.30(lRm); (oil).
(x) 2-(4,4-difluorobut-3-envlsulfonyl)-5-terL-butyl-l,3,4-thiadiazole (Compound XHI.4).
MR=297; 'HNMR δ 1.55(9Rs); 2.60-2.70(2Rm); 3.65(2Rt); 4.30(lRm); (mp
37°C).
(xi) 5-cvclopropyl-2-(4,4-difluorobut-3-enylsulfonyl)-l,3,4-thiadiazole (Compound ΧΙΠ.7).
MH*=281; Ή NMR δ 1.25-1.45(4Rm); 2.40-2.55(IRm); 2.55-2.65(2Rm);
3.60(2Rt); 4.30(lRm); (gum/ (xii) 2-(4.4-difluorobut-3-enylsulfonyl)-5-trifluoromethyl-l,3,4-thiadiazole (Compound
ΧΠΙ.15). M-SaR=243; 'HNMR δ2.60-2.75(2Rm); 3.75(2Rt); 4.204.40( IRm);
(gum).
(xiii) 2-{4,4-difluorobut-3-envlsulfonyl)-5-isopropyl-l,3,4-thiadiazole (Compound XEH. 17).
M*=283; 'HNMR δ 1.50(3Rs); 1.55(3Rs); 2.60-2.70(2Rm); 3.5O-3.7O(3Rm);
4.30(IRm); (mp 43°C).
(xiv) 2-(4,4-difluorobut-3-enylsulfinyl)-5-ethyI-l,3,4-thiadiazole (Compound ΧΕΠ.28). Ή
NMR δ 1.50(3Rt): 2.40-2.50(IRm); 2.60-2.70(IRm); 3.20(2Rq); 3.25-3.35(2Rm);
AP .0 0 6 4 9
- 129 4.25( lH.m); (gum).
(xv) 2-(4,4-difluorobut-3-enylsulfonyl)-5-ethyl-1.3.4-thiadiazole (Compound XE29).
M=269; Ή NMR δ 1.5O(3H,t); 2.60-2.70(2H.m); 3.20(2H.q): 3.65(2H.t):
4.30( lH,m); (gum).
EXAMPLE XE.4
This Example illustrates a preparation of 2-(4,4-difluorobut-3-envlthio}-5-methoxy1.3.4-thiadiazole (Compound XE.101) from Compound XE.l.
To a stirred suspension of sodium hydride (0.030g) in toluene (3cm3) was added methanol (0.022g), resulting in effervescence. After stirring for 10 minutes. Compound XE.l (0.20g) was added and the reaction was stirred at the ambient temperature for 18 hours. The reaction was analysed by gc and further portions of sodium hydride and methanol added until complete loss of starting material was observed. The reaction was poured into water and the layers separated. The product was extracted into diethyl ether and the combined organic phases were dried (MgSOJ filtered and evaporaied under reduced pressure to give a pale yellow oil. Purification by column chromatography on silica gel using 3:17 ether : hexane as the eluant gave Compound XE.101 (0.069g). M*=238; Ή NMR δ 2.402.55(2H.m); 3.25(2H,t); 4.20(3H.s); 4.30(lH,m); (oil).
EXAMPLE XIV.l
This Example illustrates the preparation of 5-(4,4-difluorobut-3-enylthio)-lmethyltetrazole (Compound XIV.l).
The sodium salt of 5-mercapto-l-methyltetrazole was alkylated with 4-bromo-1,1difluorobut-l-ene using the procedure of Example XE.l to give Compound XIV.l. lvT=206; Ή NMR δ 2.53(2H,m); 3.38(2H,t); 3.92(3H,s); 4.28(lH,m); (oil).
EXAMPLE, XV.l
This example illustrates a preparation of l-(4,4-difluorobut-3-enylthio)-4-nitrobenzene (Compound XV. 1).
4-Nitro-thiophenol (0.5g), potassium carbonate (0.448g), 4,4-difluorobut-3-enyl 4methvl-benzenesulfonaie (0.846g) and potassium iodide (0.388g) were heated and stirred under reflux in acetone (15cm3) for a total of 6 hours after which none of the starting tosvlaie was detectable by tic. The reaction mixture was poured into water and extracted with 3 portions of ethyl acetate. The combined organic phases were washed 3 times with 2M NaOH. and saturated aqueous brine and then dried (MgSO4). Removal of solvent by evaporation under reduced pressure gave a dark yellow oil which was purified by flash
AP/P/ 9 6 / 0 0 8 6 2
- 130chromaiography on silica gel using 5% ethyl acetaie in hexane as eluant to give Compound XV.l (0.4742). M*=245: Ή NMR; δ 2.42(2H.m); 3.09(2H.t); 4.30(lH.m); 7.35(2H.d): 8.14(2H.d); (oil).
EXAMPLE XVI. 1
This Example illustrates a preparation of 2-chloro-4-(4.4-difluorobut-3-enylthio)pvridine (Compound XVI. 1).
Ten-butyl nitrite (0.442g) in dichloromethane (20cm3) was added dropwise to a solution of 4-amino-2-chloropyridine and bis-(4,4-difluorobut-3-enyl)disulfide (1.9g) in di chloromethane (20cm3) while stirring the mixture at 0°C. The reaction mixture was stirred for 4 hours and then allowed to stand at the ambient temperarure for 18 hours. Water was added and the product extracted into ethyl acetate. The combined organic phases were washed with saturated brine, dried (MgSO4), filtered and evaporated under reduced pressure to give an orange-brown gum. Chromatography on sorbsil-C30 using 4% ethyl acetaie in hexane as eluant gave Compound XVI. 1 (0.134g). M*=235; *H NMR; δ 2.35-2.46(2H.m); 2.98-3.7(2H,t); 4.18(lH,m); 7.02(lH,d); 7.1l(lH,d); 8.14-8.21(lH,d); (oil).
EXAMPLE. XVL2
This Example illustrates a 2-step preparation of 4-(4,4-difluorobut-3-enylthio)-2,3,5,6tetrafluoropyridine (Compound XVI.2).
Step 1: Preparation of the sodium salt of 2.3.5.6-tetrafluoropyridine-4-thiol
4-Chloro-2,3,5,6-tetrafluoropyridine (2g) and sodium hydrosulfide dihydrate were stirred and heated under reflux in iso-propanol (40cm3) for 3 hours. The mixture was then stirred at the ambient temperarure for 18 hours. The precipitated solid was removed by filtration, washed with diethyl ether and discarded. The combined organic solutions were evaporated under reduced pressure to give 2,3,5,6-tetrafluoropvridine-4-thiol as its sodium salt (2.2 lg), which was used without further purification in the second step.
Step 2: Preparation of (Compound XVI.2)
The intermediate from step 2 (1.7g), 4-bromo-l,l,-difluorobut-l-ene (1.99g), and potassium carbonate (1.53g), were stirred and heated under reflux in acetone (30cm3) for 18 hours. The inorganic precipitate was removed by filtration and the filtrate evaporated under reduced pressure to give a dark brown oil. Chromatography on sorbsil-C30 using hexane as eluant gave Compound XVI.2 (1.82g). Μτ=273; Ή NMR; δ 2.3-2.42(2H.m); 3.153.25(2H.t); 4.15-4.34(Him); (oil).
The following compounds according to the invention were prepared using the
AP.00649
- 131 procedure of Step 2 above. Tne alkylating agent was 4-bromo-l.l.-difluorobut-l-ene or 4.4difluorobut-3-enyl 4-methvl-benzenesulfonaie.
(i) 444.4-difluorobut-3-enylthio)-pyridine (Compound XVL5). M=201:‘H NMR: δ
2.40(2Rm); 3.04<2Rt): 4.30(lRm): 7.11(2Rd); 8.41(2Rd); (oil) from 4mercaptopyridine.
(ii) 4.4-difluorobut-3-envl 2-(4.4-difluorobut-3-enylthio)pyridine-3-carboxvlaie (Compound
XVI.10). M*=335; ‘H NMR; δ 2.43(4Rm); 3.22(2Rt); 4.29(2Rm); 4.36(2Rt);
7.09(lH,dd); 8.20(lH,dd): 8.57( IRdd); (oil) from 2-mercaptopyridine-3-carboxvlic acid. Potassium iodide was used to convert two equivalents of 4,4-difluorobut-3-eny] 4-methyl-benzenesulfonate to the more reactive 4-iodo-l.I-difluorobut-l-ene in situ in this reaction.
(iii) 2-{4.4-difluorobut-3-enylthio)-5-trifiuoromethylpyridine (Compound XVI. 11). *H
NMR; h2.40(2H.m): 3.25(2Rt); 4.25(lRm); 7.25(lRdd); 7.45(lRdd); 8.40(lH.d);
(oil) from 2-mercapto-5-trifluoromethylpyridine.
(iv) 2-(4.4-difluorobut-3-envlthio)pyridine (Compound XVI. 19). M*=201; Ή NMR; δ
2.40(2Rm); 3.20(2Rt); 4.30(lRm); 6.90(lRdd); 7.20(lRdd); 7.45(lRtd);
8.40(lRdd); (oil).
(v) 2-(4,4-difluorobut-3-enylthio)-5-nitropyridine (Compound XVI.21). M-=246; lH
NMR; h2.45(2Rm): 3.30(2Rt); 4.28(lRm); 7.30(lRd); 8.23(lRdd); 9.25(lRd);
(oil) from 2-mercapto-5-nitropyridine.
EXAMPLE XVI,3
This Example gives a general procedure for the preparation of 2-(4,4-difluorobut-3enylthio)-5-substituted-pyridines from 2-chloro-5-substituted-pyridines. The method is illustrated by the preparation of 5-chloro-2-(4,4-difluorobut-3-enylthio)pyridine (Compound XVI. 13) from 2.5-dichloropyridine.
Sodium hvdrosulfide dihvdrate (0.672g) was added to a solution of 2,5dichloropyridine (1.48g) in dimethylformamide (20cm3), causing the mixture to go blue and then green on healing to 100°C. The reaction was heated for 7 hours and then 4-bromo-l,ldifluorobut-l-ene (1.71g) and potassium carbonate (1.38s) were added. The reaction was heated for 2 hours then allowed to cool. The reaction mixture was poured into diethyl ether and 2M HCI and the layers separated. The aqueous layer was extracted with ether. The combined organic phases were then washed with 2M HCI, water and brine (alternately 3 times each), dried (MgSO4). filtered and evaporaied under reduced pressure to give a brown
Z 9 8 0 0 / 9 6 /d/dV
- 132 oil. Column chromatography on silica gel using 2% dieihyl ether in hexane as eluant gave Compound XV1.13 (0.805°). M‘=235: 'HNMR; b2.40(2H.m): 3.20(2H.t); 4.25(lH.m): 7.15(lH.dd); 7.45(lH.dd); 8.40(lRd); (oil).
The following compound according to the invention was prepared using the above procedure:
(i) 5-cyano-2-(4.4-difluorobut-3-enylthio)pyridine (Compound XVI. 15). Ή NMR: δ 2.40(2HLm); 3.25(2H.t); 4.25(lRm); 7.25(lH.dd); 7.70(lH.dd); 8.65(lH.d); (mp 34°C).
EXAMPLE XVI.4
This Example gives a general procedure for the preparation of 2-(4.4-difluorobut-3enylthio)-3-substituted-pyridines from 2-chloro-3-substituted-pyridines and 4,4-difluorobut-3envlisothiouronium hvdrobromide. The method is illustrated by the preparation of 2-(4,4difluorobut-3-envlthio)-3-nitropyridine (Compound XVI.24) from 2-chloro-3-nitropvridine.
4,4-Difluorobut-3-enylisothiouronium hvdrobromide (1.24g) was added to a solution of sodium hydroxide (0.6g) in water (10cm3) and the reaction was stirred vigorously at the ambient temperature for 20 minutes. A solution of 2-chloro-3-nitropyridine (0.795g) in dichloromethane (10cm3) was added to the reaction followed by tetra-n-butylammonium bromide (catalytic). The reaction was stirred vigorously for 3 hours. The mixture was diluted with dichloromethane and the layers separated. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated under reduced pressure to give a yellow oil. Column chromatography on silica gel using 15% diethyl ether in hexane as eluant gave Compound XVI.24 (0.847g). M*=246; Ή NMR: δ 2.40(2Rm); 3.25(2H,t); 4.30(lH,m); 7.20(lH,dd); 8.50(lH,dd); 8-70(lH,dd); (oil).
The following compound according to the invention was prepared using the above procedure:
(i) 3-cvano-2-(4,4-difluorobut-3-enylthio)pyridine (Compound XVL8). Μτ=226; Ή
NMR; δ 2.40(2H,m); 3.30(2H.t); 425(lH.m); 7.10(lELdd); 7.80(lH,dd); 8.55(lH,dd);
(oil).
EXAMPLE XVI.5 . This Example illustrates a method suitable for the preparation of compounds according to the invention in which the sulfur atom of the 4,4-difluorobut-3-enylthio substituent of the corresponding unoxidised compound (prepared according to the procedures of the preceding Examples) is oxidised to sulfoxide (sulfinyl) or sulfone (sulfonyl).
AP. Ο Ο 6 4 9
- 133 Preparation of Compound XVL? from Compound XVI.2 using one equivalent of oxidant.
Compound XVI.2 (0.818g) was cooled to 0°C in dichloromethane (30cm3) and 3chloroperbenzoic acid (0.99g) was added over a period of five minutes. The mixture was stirred at the ambient temperamre for 6 hour and stood for 40 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonaie and the product was extracted into dichloromethane. The organic layer was washed with water and dried (MgSO4). Evaporation of solvent under reduced pressure gave a yellow oil which was chromaiographed on sorbsilC30. eluting with 15% ethyl acetate in hexane to give 4-(4,4-difluorobut-3-enylsulfinvl)2,3.5,6-tetrafluoropyridine (0.71 lg). Ή NMR: δ 2.45-2.8(2H,m); 3.15-3.3(lH,m); 3.53.65(lH.m): 4.2-4.4( lH.m); (oil).
Preparation of 5-cyant>2-(4.4-difluorobut-3-enylsulfonyI)pyridine (Compound
XVI.16) from Compound XVI, 15 using two equivalents of oxidant,
3-Chloroperbenzoic acid (3.14g of a 50% solid) was added portionwise to a stirred solution of Compound XVI.15 (1.03g) in dichloromethane (30cm3) at 0°C. The reaction was then allow'ed to warm to the ambient temperature and stirred for 4 hours. The mixture was poured into 2M aqueous sodium hydroxide and the layers separated. The aqueous layer was extracted with di chloromethane and the combined organic layers were dried over magnesium sulfate, filtered and evaporaied under reduced pressure to give a yellow oil which crystallised on standing. Column chromatography on silica gel using 3 : 7 ethyl acetate : hexane as eluant gave Compound XVI. 16 (0.785g). *H NMR δ 2.40(2H,m); 325(2H,t); 4.25(lH,m); 7.25(lH.dd); 7.70(lH.dd); 8.65(lH,d); (mp 34°C)
The following compounds according to the invention were prepared using the above procedure:
(i) 4-(4,4-difluorobut-3-enylsulfonyl)pyridine (Compound XVL6). ‘H NMR δ
2.50(2H,m); 3.20(2H,t); 4.25(lH,m); 7.80(2H,d); 8.95(2H,d); (oil).
(ii) 2-(4,4-difluorobut-3-enylsulfonyl)-5-trifluoromethylpyridine (Compound XVI. 12). Ή
NMR 5 2.50(2H.m); 3.50(2H,t); 4.25(lH,m); 8.25(2H,d); 9.00(lH.br s); (mp 60°C).
(iii) 2-(4,4-difluorobut-3-enylsulfonyl)pyridine (Compound XVI20). Ή NMR δ
2.50(2H.m); 3.50(2H,t); 4.25(lHLm); 7.55-7.50(1Hun); 8.00(lH,dt); 8.10(lH,d);
8.75( lELd); (oil).
EXAMPLE XVTI.l
This Example illustrates a 2-step preparation of 3-(4.4-difluorobut-3-enylthio)-6AP/P/ 9 6 / 0 0 8 6 2
- 134 methylpvridazine (Compound XVII. 1).
Step 1: Preparation of ?-mercapto-6-metb)'lp>Tidazine
3-Chloro-6-methylpyridazine (5g) and thiourea (2.96g) were stirred together and heated under reflux in ethanol (50cm3) for 7.5 hours. The reaction was cooled and allowed to stand for 18 hours. The solid precipitaie which had formed was filtered off and washed with diethyl ether to give 3-mercapto-6-methylpyridazine (2.3 g), which was used in the next step without further purification. Ή NMR; δ 2.40(3Rs); 7.30( lRd); 7.63(1 Rd); 14.514.7( lH.br s).
Step 2: Preparation of Compound XVII· 1
A mixture of the product from Step 1 (0.337g), 4,4-difluorobut-3-enyl 4methylbenzenesulfonate (0.70g), potassium iodide (0.444g) and potassium carbonate (0.369g) w-ere stirred together and heated under reflux in acetone (20cm3) for 11 hours. Inorganic solids were removed by filtration and the filtrate evaporated under reduced pressure to give a brown oil. Chromatography on silica gel using 1:4 ethyl acetate: hexane as eluant gave Compound XVH.l (0.15g). Μ*=21ό; Ή NMR: δ 2.48(2Rm); 2.62(3Rs); 3.36(2Rt); 4.204.40(IRm); 7.10(1 Rd); 7.21(lRd); (oil).
The following compounds according to the invention and the corresponding intermediate compounds were prepared using the procedure of Steps 1 and 2 above.
(i) 3-(4.4-difluorobut-3-enylthio)-6-chloropyridazine (Compound XVH.2). M~=236; lH NMR: δ 2.50(2Rm); 3.39(2Rt); 4.20-4.40(IRm); 727(2Rs); (oil) from 3,6dichloropyridazine.
(ii) 3-(4,4-difluorobut-3-enylthio)-6-methoxypyridazine (Compound XVH.3). M*=232; *H NMR: 02.47(2Rm); 3.31(2Rt); 4.09(3Rs); 4.20-4.40(IRm); 6.83(lRd);
7.20(1 Rd); (solid mp 39.340.1 °C) from 3-chloro-6-methoxypyridazine.
(iii) 3-(4.4-difluorobut-3-enylthio)-6-phenylpyridazine (Compound XVH.4). M*=278; *H NMR: fi2.54(2Rm); 3.46(2Rt); 4.254.42(IRm); 7.39(lRd); 7.51(3Rm); 7.69(lRd); 8.05(2Rm); (solid mp 91.7-92.1°C) from 3-chloro-6-phenylpyridazine.
(iv) 1-(4,4-difluorobut-3-enylthio)-phthalazine (Compound XVH.7). M*=252; lH NMR (CDC13): δ2.59(2Ηπι); 3.55(2Rt); 4.284.45(IRm); 7.89(3Rm); 8.12(lRm);
9.25(IRs); (oil) from l(2H)-phthalazinthione using the procedure of Step 2 above.
EXAMPLE XVH.2
This Example illustrates a preparation of Compounds XVH.5 and XVH.6 from
Compound XVn.4.
AP.0 0 6 4 5
- 135 Compound XVD.4 (0.5s) was stirred at ambient temperature in iso-propanol (20cnf) and magnesium monoperoxyphthalic acid hexahydrate (0.89g in lOcnf water) was added.
The mixture was stirred at the ambient temperature for 20 hours. The solid which had precipitated was filtered off and washed with water. The filtrate was poured into a saturated aqueous solution of sodium bicarbonaie and further product was extracted into ethyl acetate. The combined organic layers were washed with saturated brine and dried (MgSOJ. Evaporation of solvent under reduced pressure gave an off-white solid which was combined with the material first precipitated and chromatographed on silica gel, eluting with 30% ethyl acetate in hexane. The first product recovered was 3-(4,4-difluorobut-3-enylsufonyl)-6phenylpyridazine (Compound XVI1.6) (0.2g). M*=310; Ή NMR; δ 2.60(2H.m); 3.75(2H,t); 4.20-4.40(lH,m); 7.60(3H.m); 8.1 l(lH.d); 8.15(2H.m); 8.22(lH,d); (solid mp 141.7-144.3°C). Further elution gave 3-(4,4-difluorobut-3-enylsufmyI)-6-phenylpyridazine (Compound XVII.5) (0.25g). M*=294; Ή NMR; δ 2.40 and 2.65(2H.m); 3.20-3,40(2H.m); 4.18-4.32( IRm); 7.59(3Rm); 8.1 l(lRd); 8.15(2Rm); 8.21(lRd); (mp 133-134°C).
EXAMPLE XVm.1
This Example illustrates a 3-step preparation of 2-(4,4-difluorobut-3-enylthio)quinoxaline (Compound XVm.l).
Step..!; Preparation of quinoxalin-2-thione
2-Quinoxalinol (lOg), phosphorous pentasulfide (16.72g) and pyridine (200cm3) were stirred together and healed under reflux for 7 hours. The reaction mixture was allowed to cool and most of the pyridine was removed by evaporation under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer was separated. The aqueous layer was extracted with three further portions of ethyl acetate and the combined organic phases were washed with saturated aqueous brine, dried (MgSOJ and evaporated under reduced pressure to give a brown oily solid which was triturated with hot ethyl acetate : hexane (1:1) to dissolve the product and leave an insoluble residue. The solvent was removed under reduced pressure and gave an orange solid, part of which was used without further purification in Step 2.
Step 2; Preparation of 2-f4-bromM.4-difluorobutylthio)-quinoxaline
A mixture of the product from Step 1 (lg), 4-bromo-4,4-difluoroburyl methanesulfonare (1.65g) and potassium carbonate (0.852g) were stirred together in acetone (30cm3) ax ambient temperature for 7 hours. Inorganic solids were removed by filtration and the filtrate evaporated under reduced pressure to give a brown oil. Chromatography on silica
AP/P/ 9 6 / 0 0 8 6 2
- 136 eel using 1:4 ethyl acetate: hexane as eluant gave 2-(4-bromo-4.4-difluorobut\,lthio)quinoxaline (1.375g). M*=332: Ή NMR; b2.19(2Rm): 2.50-2.70(2Rm): 3.43(2Rt): 7.607.73(2Rm); 7.93(lRdd); 8.03(lRdd): 8.60(lRs); (oil).
Step 3: Preparation of Compond XVIII. 1
1,8-Diazabicvclo[5.4.0] undec-7-ene (DBU) (1.14cm3) and the product from step 2 (1.275g) were stirred in toluene (30cm3) and healed under reflux for 5 hours. The mixture was cooled, then excess ethyl acetate and 2M aqueous hydrochloric acid were added and the organic phase separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with saruraied brine, dried (MgSO4), filtered and evaporaied under reduced pressure to give a brown oil. Chromaiography on silica gel using 1:4 ethyl acetate : hexane as eluant gave Compound XVELl (0.65g). NT-252; Ή NMR: δ 2.51(2Rm); 3.39(2Rt); 4.30-4.40( IRm); 7.60-7.75(2Rm); 7.90(lRdd); 8.03(lRdd); 8.60(lRs); (oil).
The following compound according to the invention and the corresponding intermediate compound were prepared using the procedure of Steps 2 and 3 above:
(i) 6-chloro-2-(4,4-difluorobut-3-enylthio)-quinoxaline (Compound XVHI.4). M=286; *H
NMR: δ 2.50(2Rm); 3.35(2Rt); 4.20-4.40(IRm); 7.65(lRdd); 7.86(lRd);
8.01(lRd); 8.59(lRs); (oil), from 6-chloroquinoxalin-2-thione via 2-(4-bromo4,4difluorobutvlthio)-6-chJoroquinoxaline. Ή NMR: δ 2.08-2.2l(2Rm); 2.482.68(2Rm); 3.40(2Rt); 7.65(lRdd); 7.88(lH,d); 8.00(lH,d); 8.60(lRs); (oil).
EXAMPLE XVffl.2
This Example illustrates a 2-step preparation of 2-(4,4-difluorobut-3-enylthio)-pyrazine (Compound XVIH.7).
Step 1: Preparation of 2-mercaptopyraaiK
2-Chlorop\Tazme (5g) and thiourea (3.32g) were heated under reflux in ethanol (50cm3) for 8 hours. The reaction mixture was cooled and the ethanol was removed by evaporation under reduced pressure to give a brown gum (8.3lg) which was stirred with 2M aqueous sodium hydroxide (50cm3) for 16 hours. The solid which precipitated was filtered off and washed with water and acetone and vacuum dried. This gave a yellow solid (0.72g); Ή NMR (DMSO-dJ: δ 7.69(1 Rd); 7.89(1 Rd); 8.6(IRs). which was used in the second step without further purification.
Step 2: Preparation of Compound XVIII.7
The product from Step 1 (0.213g), 4.4-difluorobut-3-enyl 4-methvl-benzenesulfonaie
AP . 0 0 6 4 9
- 137 (0.5g). potassium carbonaie (0.263g) and potassium iodide (0.317g) were mixed in acetone (10cm3) and heated under reflux for 9 hours then allowed to cool over a weekend. The precipitate formed was removed by filtration and the filtrate evaporaied under reduced pressure to give a brown oil. Chromaiography on silica gel using 1:4 ethyl acetaie : hexane as eluant gave Compound XVDI.7 (0.3 s). M*=202; Ή NMR: δ 2.40(2Hm); 321(2H.t): 4.204.40( lH.m); 8.20(lH.d): 8.38(lH,t): 8.48(lKs); (oil).
EXAMPLE XVHL3
This Example illustrates a 2-step preparation of 3-chloro-2-(4.4-difluorobut-3envlthio)-pyrazine (Compound XVH1.10).
Step 1: Preparation of 2-chlore-3-mercaptopyrazine and 2.3-diraercaptopyrarine
2,3-Dichloropyrazine (lg) and sodium hydrosulfide dihvdraie (2.5g) were combined in isopropanol (20cm3) and the mixture heated under reflux for 1 hour. The reaction was cooled and allowed to stand for 36 hours. The yellow solid which precipitated was recovered by filtration, washed with diethyl ether and dried under vacuum. The filtrate was discarded.
The solid was dissolved in hot ethanol and on cooling a small amount of sodium hydrosulfide precipitated and was removed by filtration. The remaining ethanol solution was diluted with diethyl ether wherupon a yellow' solid (0.3g) precipitated. This was identified as the bissodium salt of 2.3-dimercaptopyrazine, MH*(FAB)=T 88; Ή NMR (DMSO-dJ: δ 735(lH,d); 7.50(lH,d). Evaporation of the mother liquors gave a yellow solid (0.8g), identified as the sodium salt of 2-chloro-3-mercaptopyrazine, M'(FAB)=145; *H NMR (DMSO-dJ: δ
AP/P/ 9 6 / 0 0 8 6 2
7.35(lH,d); 7.80(lH,d)
Slgp.2; Preparation of 3-chloro-2-(4.4-difluorobut-3-enylthio)-pyrazine
The mono-thiolaie product from Step 1 (0.8g), 4,4-difluorobut-3-enyl 4-methylbenzenesulfonate (1.24g) and potassium carbonate (0.655g) were mixed in acetone (25cm3) containing dimethyl formamide (5cm3) and heated under reflux for 15 hours then allowed to cool. The precipitate was removed by filtration and the filtrate evaporaied under reduced pressure to give a brown oil. Chromatography on silica gel using a 95:5 mixture of hexane : ethyl acetaie as eluant gave Compound XVIII. 10 (0.45g). M*=236; Ή NMR· δ 2.41 (2Hjn); 3.20(2H,t); 4.204.40( lH.m); 8.05(lH.d); 8.30(lH.d) (oil). This contained (ge) 5% of Compound XVIII. 13 as an impurity.
Compound XVIII. 13 was obtained pure in its own right by treatment of the bisthiolated product from Step 1 of the above example with two equivalents of 4,4-difluorobui3-enyl 4-methyl-benzenesulfonate under the same conditions as Step 2 of this Example.
- 138 Chromatography on silica gel using a 4:1 mixture of hexane : ethyl acetate as eluant gave
2.3-bis-(4.4-difluorobut-3-enylthio)-p_\Tazine. M=324: Ή NMR' δ 2.40(4Rm); 3.22(4Rt); 4.204.40(2Rm); 8.07(2Rs) (oil).
The following compound according to the invention was prepared using the above procedure:
(i) 6-chloro-2-(4.4-difluorobut-3-enylthio)-p\tazine (Compound XVHI.14). \T=236: *H
NMR; b2.42(2Rm): 3.21(2Rt); 4.204.40(IRm): 8.20(lRs); 8.35(lRs) (oil) from
2,6-dichioropyrazine.
EXAMPLE XVffl/
This Example illustrates a preparation of Compounds XVHI.2 and XVIH.3 from Compound XVUI.l.
Compound XVUI.l (0.25g) was stirred at ambient temperarure in ethanol (10cm3) and magnesium monoperoxyphthalic acid hexahvdrate (0.589g in 5cmJ water) was added over a period of five minutes. After 30 minutes, the mixture was heated to 70°C for 1 hour. The reaction mixture was cooled, poured into saturated aqueous sodium bicarbonate and the products were extracted into ethyl acetate. The organic layer was washed with water and dried (MgSO4). Evaporation of solvent under reduced pressure gave an off-white solid (0.15g) which was chromatographed on silica gel, eluting with 10% ethyl acetaie in hexane. The main product recovered was 2-(4,4-difluorobut-3-enylsulfonyl)-quinoxaline (Compound XVm.3) (O.lg) mp 86.5-87.5°C. M*=284; Ή NMR δ 2.61(2Rm); 3.62(2H,t); 4204.40(lRm); 8.00(2Rm); 825(2Rm); 9.51(lRs). Tic indicated the presence of a lower rf material, 2-(4,4-difluorobut-3-enylsulfinyl)-quinoxalme (Compound XVIH2) in the crude reaction product but this was not isolated pure.
The following compounds according to the invention were prepared by the above procedure:
(i) 6-chloro-2-(4,4-difluorobut-3-enylsulfinyl)-pyrazine (Compound XVUI.l5). M*=253;
Ή NMR δ 2.30-2.70(2Rm); 3.00-3.30(2Rm); 4.194.35(lH,m); 8.70(lRs);
9.10(lRs) (oil) from Compound XVIII. 14.
(ii) 6-chloro-2-(4,4-difluorobut-3-enylsulfonvl)-pyTazine (Compound XVIH.16). M*=268;
Ή NMR δ 2.55(2Rm); 3.50(2Rt); 4.204.35(lH,m); 8.90(lH,s); 9.19(lRs) (oil) from Compound XVIII. 14.
EXAMPLE VIILI.
This Example illustrates a 3-step preparation of 4-(4,4-difluorobut-3-enylthio]-1,2.3AP . 0 0 6 4 9
- 139 benzotriazine (Compound XIX1).
Step 1: Preparation of 4-mercaptol.2.3-benzotriazine
2-Aminobenzonimle (5g) was stirred in pyridine (30cm3). triethylamine (6cm3) was added and hydrogen sulfide gas was bubbled into the reaction over 4 hours. The mixture was then poured into waier (20cm3) and the oil which separated out on shaking was separated off. and dried by azeotroping with ethanol and toluene. This gave a yellow solid (2aminothiobenzamide. 3g) which was stirred in 2M hydrochloric acid (30cm3) at 0°C. Sodium nitrite (1.65g) in water (10cm3) was added dropwise and the reaction mixture was stirred cold for 1 hour, then allowed to warm to the ambient temperature and stirred for a further 1 hour. The solid which was produced was filtered off, washed with water and dried by washing with diethyl ether, to give a brown solid (2.15g).
5l£R2l Preparation of 4-<4.4-difluorobut-3-enylthio>)-12.3-benzotriazine The product of Step 1 (lg), 4-bromo-4,4-difluoroburyl methanesulfonate (1.65g) and potassium carbonate (0.852g) w’ere stirred together in acetone (30cm3) at ambient temperature for 36 hours. Inorganic solids w’ere removed by filtration and the filtrate evaporated under reduced pressure to give a brown oil. Chromatography on silica gel using 1:4 ethyl acetaie: hexane as eluant gave two yellow oils (ea 0.5g). The first-eluted oil was identified as Nalkvlaied material and the second was the desired S-alkyated intermediate 4-(4-bromo-4,4difluorobutylthio)-l,2,3-benzomazine. Ή NMR: δ 2.18-2.3l(2Hjn); 2.58-2.71(2Hun); 3.63(2H,t); 7.95(lH,t); 8.09(2H.m); 8.40(lH,d).
Step 3: Preparation of Compound XIX1
1,8-Diazabicvclo[5.4.0] undec-7-ene (DBU) (0.45cm3) and the product from step 2 (0.5g) were stirred in toluene (15cm3) and heaxed under reflux for 6 hours. The mixture was cooled, then excess ethyl acetate and 2M aqueous hydrochloric acid were added and the organic phase separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a yellow oil. Chromatography on silica gel using 1:4 ethyl acetate : hexane as eluant gave Compound XIX1 (025g). MH*=254; *H NMR δ 2.60(2H.m); 3.60(2H,t); 4.30-4.40(lH,m); 7.93(lH,t); 8.09(2H,m); 8.39( Hid); (oil).
EXAMPLE XXI
Two methods (A and B) of preparing mercapto-l,2,4-triazines required as intermediates for preparation of compounds of the invention are described below.
AP/P/ 9 6 / 0 0 8 6 2
- 140 METHOD A
A general synthesis of 3-mercapto-1.2.4-triazines is by reaction between thiosemicarbazide and a 1.2 di-carbonvl compound. This is illustrated by the preparation of
3-mercapto-5-methy 1-1,2.4-triazine.
A solution of sodium bicarbonate (8g) in water (100cm3) was added to a suspension of thiosemicarbazide (8g) in water (100cm3). The resulting solution was cooled below 5°C and pyruvic aldehyde (40% weight solution in water, (20cm3)) was added. The solution was kept at 5°C for 18 hours, then washed with chloroform (10 x 50cm3). The pH of the aqueous layer was adjusted to 2 with concentrated hydrochloric acid. The resulting precipitate was filtered off. washed with copious amounts of water and dried, giving an orange solid (4.036g). The 3-mercapto-5-methvl-l,2.4-triazine was used without further purification in subsequent steps.
The following intermediate mercaptotriazines were prepared following the above procedure. In some cases, ethanol was used as solvent in place of water. The starting materials were commercially available.
(i) 3-mercapto-l,2,4-triazine from glyoxal.
(ii) J-mercapto-5-propyI-6-methyl-1.2,4-triazine from hexane-2,3-dione. lHNMR:5
0.98(3H,t); 1.54-1.68(2H.m); 2.08(3H.s); 3.04(2H,t); 8.2(lH,br s).
(iii) 3-mercapto-5-phenyl-6-methyl-l,2,4-triazine from l-phenylpropane-12-dione.
METHQD.B
An alternative method for preparing mercapto-1.2,4-tri azines comprises treatment of a corresponding hydroxvtriazine (which may exist in various tautomeric forms) with a thiolating reagent such as phosphorous pentasulfide. This following illustrates the preparation of 12,4-triazine-3,5(2H,4H)-dithione from l,2,4-triazine-3,5(2H,4H)-dione (6-azauracil).
6-Azauracil (2g), phosphorous pentasulfide (15.72g) and pyridine 50cm3 were stirred together and heated under reflux for 56 hours. The reaction mixture was allowed to cool and most of the pyridine was removed by evaporation under reduced pressure. The residue was agitated with diethyl ether and water and the organic layer was separated. The aqueous layer was extracted with three further portions of diethyl ether and the combined organic phases were washed with saturated aqueous brine, dried (MgSOJ and evaporated under reduced pressure to give a brown oil which was chromatographed on silica gel, using 1:5 ethyl acetate: hexane as eluant. This gave an orange solid (lg) which was used without further purification. Ή NMR (DMSO-d,): δ 7.95(lH.s); 13.8-14.1(lH,br s); 14.3-14.6(lH.br s)
AP .00649
- 141 3-Mercapto-1.2,4-benzotriazine was prepared from 3-hydroxy-12.4-benzotnazme and 6-methvl- 1.2.3-triazine-5(4H)-thione from 6-methvl-1.2.3-triazine-5(4H)-one following essentially the above procedure.
EXAMPLE XX2
This Example illustrates the preparation of compounds according to the invention which contain a 1.2,4-triazine substituted with a 4,4-difluorobut-3-enylthio group in the 3. 5 or 6-position, starting from a correspondingly substituted mercaptotriazine and an appropriate difluorobut-l-ene alkylating agent. This is demonstrated by the following preparation of 3(4.4-difluorobut-3-envlthio>5-hydroxy-1.2,4-triazine (Compound XX.227) from 6-aza-2thiouracil and 4,4-difluorobut-3-envl 4-methvI-benzenesulfonaie.
4.4-Difluorobut-3-enyl 4-methvl-benzenesulfonate (1.5g) and potassium iodide (0.95g) were stirred in ethanol (5cm3) and heated under reflux for three hours then allowed to cool. This part of the procedure converts the starting material to the more chemically reactive and thio-selective alkylating agent, 4-iodo-1.1-difluorobut-l-ene. 6-Aza-2-thiouracil (0.744g) was added as a solution in 1M aqueous sodium hydroxide (5.73cm3) and the reaction mixture stirred at ambient temperature for 70 hours. The reaction was worked φ by addition of an excess of 1M aqueous sodium hydroxide and ethyl acetate. The ethyl acetate layer was separated and the aqueous layer was washed with more ethyl acetate. These extracts were discarded. The aqueous layer was then acidified to pH4 with 2M aqueous hydrochloric acid. The product w-as extracted into ethyl acetate (3 portions) and these combined organic layers were washed with water and saturated aqueous brine and dried (MgSO<). The product was recovered from the solution by evaporation under reduced pressure to give a cream solid (0.659g). A portion was redissolved in hot ethyl acetate and some insoluble material removed by filtration. Compound XX.227 recovered from solution by evaporation had mp 102-103°C. M*=219; Ή NMR (DMSO-dJ: 5 2.41(2H,m); 3.25(2H,t); 4.5S4.75(lRm); 7.69 and 7.79(total IRea s, tautomeric protons)
Compound XX.247 was prepared using a related procedure, as follows.
6-Methvl-1.2.3-triazine-5(4H)-thione (0.5g), 4-bromo-1,1-difluorobut-l-ene (0.673g) and potassium carbonaie (0.543g) were stirred together in acetone (5cm3) for 60 hours at the ambient temperarure. Then inorganic material was filtered off and washed with acetone. Solvent was removed from the combined acetone solutions by evaporation under reduced pressure and the residual brown gum was chromaiographed on silica, eluting with 20% ethyl acetaie in hexane, to give 5-(4.4-difluorobut-3-envlthio)-6-methyl-12,4-triazine (Compound
AP/P/ 96/00862
- 142 XX247) (0.075ε). Μ*=217: Ή NMR: δ 2.45(2H.m); 2.6O(3H.s): 3.29(2PLt): 4.204.40(lH.m): 9.11(lH.s); (oil).
EXAMPLE XX 3
When the mercaptotriazine is fully soluble in acetone and carries no other potentially interfering nucleophilic groups a procedure alternative to that of Example XX.2 may be used.
This is illustrated by the following preparation of 3.5-bis-(4.4-difluorobut-3-enylthio)1.2.4- triazine (Compound XX.231) from 1.2,4-triazine-3.5(2H,4H)-dithione and 4.4-difluoro3-butenvl 4-methvl-benzenesulfonate.
12.4-Triazine-3.5(2K4H)-dimione (lg), 4,4-difluorobut-3-envl 4-methylbenzenesulfonaie (3.6g), potassium iodide (1.14g) and potassium carbonate (0.952g) were stirred and healed under reflux in acetone (20cm3) for 7 hours. The solution was cooled and filtered to remove solids. The filtraie and further acetone washings of the solids were combined and evaporaied under reduced pressure to give a brown oil. Chromatography on silica gel using 15:85 ethyl acetate : hexane as eluant gave Compound XX.231 (lg) as an orange oil. ΝΓ=325; Ή NMR: δ 2.40-2.55(4H.m); 3.25(4H,m); 4.154.40(2H,m);
8.70( lH.s).
EXAMPLE XX4
This Example illustrates a general procedure for the two-step preparation of compounds according to the invention by reaction of a mercapto-substituted 12,4-tri azine with 4-bromo-4,4-difluorobutyl methanesulfonate followed by dehydrobromination of the resulting intermediate as demonstrated by the following preparation of 3-(4,4-difluorobut-3enylthio)-5-phenyl-6-methyl-12,4-triazine (Compound XX4).
Step 1: 344-bromo4.4-difluorobutylthioV5-phenyl-6-methyl-12.4-triazine·
A mixture of 4-bromo-4,4-difluorobutyl methanesulfonate (0.7g), 3-mcrcapto-5phenyl-6-methyl-12,4-triazine (0.5g) and potassium carbonate (0.7g) were stirred together and healed under reflux in acetone (40cm3) for 14 hours. Inorganic solids were removed by filtration and the filtrate evaporated under reduced pressure to give a brown oil (1.058g). Chromatography on silica gel using 1:4 ethyl acetate: hexane as eluant gave an orange oil (0.576g). This was stirred and heated under reflux in trifluoroacetic acid (3cm3) for 6 hours to re-cvclise some material which had undergone partial hydrolysis and ring opening.
Product was recovered by evaporation of the solvent under reduced pressure and chromatography on silica eel and gave 3-{4-bromo-4,4-difluoroburyithio)-5-phenyl-6-methyl12.4- triazine. (0.509g). Ή NMR: δ 2.12-2.24(2H.m); 2.48-2.68(2H,m); 2.78(3H,s);
AP.00649
- 143 3.36(2H.t); 7.5O-7.58(3H.m); 7.6S-7.74(2H.m): (oil).
Step 2: 3-4 Xdifiuorobut-?-env1thioK>-phenyl-6-methyl-1.2.4-tri azine
1.8-Diazabicyclo[5.4.0] undec-7-ene (DBU) (lcrfr) w-as added dropwise to a stirred solution of the product from step 1 (0.5g) in toluene (10cmJ). The mixture was kept at ambient temperature for 20 hours, then excess ethyl acetate and saturated aqueous ammonium chloride were added and the organic phase separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with saturated aqueous ammonium chloride, dried (MgSOJ, filtered and evaporated under reduced pressure to give an orange oil (0.43 g). Chromatography on silica gel using 1:4 ethyl acetate : hexane as eluant gave Compound XX4 (0.281g). M*=293; Ή NMR δ 2.48-2.58(2H.m); 2.76 (3H.s); 3.32(2H,t); 4.224.40(Him); 7.48-7.58(3H.m); 7.68-7.76(2H,m); (oil).
EXAMPLE XX5
This Example illustrates a procedure suitable for the preparation of compounds according to the invention carrying an alkoxy, or substituted alkoxy, group on the 5-position of the triazine ring from a compound carrying alkenylthio groups in both the 3 and 5positions, as demonstrated by the preparation of 3-(4,4-difluorobut-3-enylthio)-5-methoxy1.2,4-triazine (Compound XX221) from Compound XX231.
Compound XX.231 (0.5g) was stirred for one hour with sodium methoxide (0.083g) in methanol (15cm3) ai ambient temperature. The solvent was removed by evaporation under reduced pressure and the residue was chromatographed on silica gel, eluting with 15:85 ethyl acetate : hexane, and eave 0.12g of Compound XX.221. M*=233; *H NMR; δ 2.50(2H,m); 3.29(2H.t); 4.02(3H.s); 4.224.42( lH,m); 8.55(lH.s) as a single isomer whose identity as the 5-methoxy compound was confirmed by nmr.
The following compounds according to the invention were prepared using the above procedure with the appropriate alkoxide in the corresponding alcohol as solvent:
(i) 3-(4,4-difluorobut-3-enylthio)-5-( 1-methyl-ethoxy)-1,2,4-triazine (Compound XX.205).
M*=261; Ή NMR δ 1.4(6H,d); 2.5(2H,m); 3.25(2H,t); 4.24.4(lH,m); 5.4(lH.m);
8.45( lH,s).
(ii) 3-(4.4-difluorobut-3-enylthio)-5-ethoxy-1,2,4-triazine (Compound XX218). ΙνΓ=247;
Ή NMR δ 1.43(3H.t): 2.50(2H.m); 3.26(2H,t); 4.24.4(lH,m); 4.46(2H,q); 8.5(lH.s)
EXAMPLE XX 6
This Example illustrates a 2-step procedure used for the preparation of Compounds
XX52 and XXI16 as a 1:1 mixture.
AP/P/ 9 6 / 0 0 8 6 2
- 144 Step 1: 3-<~bromMAdifluoroburvlthioK^-methyi-1.2.4-tri3zine and 3-(4bromo-4.4-difluorobutylthio)-6-methyl-1.2.4-tri azine
4-bromo-4,4-difiuorobutyi methanesulfonate (lg) and thiosemicarbazide (0.475s) were stirred together and heated under reflux in ethanol (20cm3) for 5 hours. GC indicated complete consumption of the methanesulfonate. The mixture was allowed to cool and water (3cm3) and sodium bicarbonate (lg) were added (effervescence). A 40% by weight solution of p\Tuvic aldehyde (1cm3) was then added and the mixture stirred at ambient temperature for 4 hours. TLC showed that product had formed. It was extracted into ethyl acetate and the organic layer was dried (MgSO4), filtered and evaporated to give an oil (1.209g). This intermediate product was purified by chromaiography on silica gel, eluting with 1:4 ethyl acetate : hexane and gave a yellow oil (0.464°) which had Ή NMR: δ 2.08-2.20(2ELm); 2.48-2.62(2H.m); 2.52 and 2.66 (total 3H.ea s); 3.28-3.38(2H,m); 8.28 and 8.84 (total IH. ea s). indicating it to be an approximately 1:1 mixture of the 5- and 6-methyl isomers.
Step 2: 3-(4.4-difluorobut-3-enylthioV5-methyl-1.2.4-triazine and 344.4difluorobut-3-enylthioV6-methyl-1.2.4-tri azine
The mixture of products from Step 1 (0.46g) were dehydrobrominated using DBU in a procedure analogous to Step 2 of Example XX.4 and the product (0.253g) was purified by chromatography on silica gel eluting with di chloromethane. Under these conditions the 5and 6-methyl isomers were inseparable and 0.232g of a yellow oil was obtained which had M*=217; Ή NMR: δ 2.44-2.54(2H.m); 2.50 and 2.66 (total 3H,ea s); 3.26-3.34{2H,m); 4.224.40(lH,m); 8.28 and 8.82 (total IH, ea s); this indicated it to be a 1:1 mixture of Compound XX52 and Compound XXI16.
Compound XX251 according to the invention was prepared using the above procedure but taking cyclohexane-1,2-dione in Step 1 in place of pyruvic aldehyde. Ή NMR: δ 1.86-1.98(4H,m); 2.42-2.54(2H.m); 2.84-2.92(2H.m); 3.04-3.12(2H,m); 328(2H,t); 4.224.38(1 Hun); (oil).
EXAMPLE XX7
This Example illustrates an alternative procedure used for the preparation of Compounds XX.52 and XXI16 as a chromatographically separable mixture.
4,4-difluorobut-3-enyl 4-methvl-benzenesulfonaie (lg) and thiosemicarbazide (0.4g) were stirred together and heated under reflux in ethanol (20cm3) for 6 hours. The mixture was allowed to cool overnight, whereupon a crystalline yellow precipitate of the S-alkylated compound was evident. This was not isolated but solvent was removed by evaporation at
AP . 0 0 6 4 9
- 145 reduced pressure and the residue (1.3 s) was treated with sodium bicarbonate (0.928g), water (3cm5) and ethanol (20cm3). A 40% by weight solution of pyruvic aldehyde (0.9cm3) was then added (slight effervescence) and the mixture stirred at ambient temperarure for 1 hour. The reaction was poured into water and the product was extracted into ethyl acetate (3 portions). The combined organic phases were dried (MgSO4), filtered and evaporated to give a brown gum (0.85g). Chromatography on silica gel, eluting with 10% ethyl acetate in hexane gave a fraction which was identified as Compound XX. 116 (0.05g) (containing 10% of Compound XX.52 by NMR). Continued elution gave a mixed fraction containing an approximately 1:1 mixture of Compounds XX52 and XXI16 (0.16g) and then a fraction identified as Compound XX52 (O.lg) (containing 15% of Compound XXI16 by NMR). EXAMPLE XX8
This Example illustrates a general procedure for the two-step preparation of compounds according to the invention by reaction of thiosemicarbazide with 4-bromo-l.ldifluorobut-l-ene and then cyclisation of the intermediate with a 1,2-dicarbonvl compound, as demonstrated by the following preparation of 3-(4,4-difluorobut-3-enylthio)-1,2,4-triazine (Compound XX137).
Thiosemicarbazide (2.6g) was stirred with 4-bromo-l,l-difluorobut-l-ene in ethanol (75cirT) and the mixture heated under reflux for 7 hours and allowed to cool to the ambient temperarure. Glyoxal (4.2g of a 40% aqueous solution) and sodium hydrogen carbonate (7.37g) were added and the resulting mixture was stirred at the ambient temperature for 18 hours. Water was added and the product was extracted into three portions of ethyl acetate. The combined organic phases were washed with saturated brine, dried (MgSOJ, filtered and evaporated under reduced pressure to give a brown gum Chromatography on silica gel, eluting with 20% ethyl acetate in hexane gave Compound XX137. NT-203; ‘H NMR: δ
2.50(2H,m); 3.30(2H,t); 4.20-4.40(lH.m); 8.39(lH,d); 8.95(lH,d) (oil).
The following compounds according to the invention were prepared using the above procedure with the appropriate 1,2-dicarbonyl compound in place of glyoxal:
(i) 3-(4,4-difluorobut-3-enylthio)-5-propy 1-1,2.4-triazine (Compound XX27) from 2-oxopentanal. NT-245; Ή NMR: δ 1.0(3H,t); 1.7-1.85(2H,m); 2.45-2.55(2H,m);
2.6(2H,t); 3.3(2H,t); 4.2-4.4(lH,m); 8.8(lH,s) (oil). This preparation also gave the isomeric Compound XX109; NT-245; ‘HNMR: δ 1.0(3H,t); 1.75-1.9(2H,m); 2.452.55(2H.m): 2.9(2H.t); 3.3(2H.t); 4.2-4.4(lH,m); 8.25(lH,s) (oil), the latter faster running isomer in the chromatography being approximately 8% of the mixture which
96/00862
- 146 was produced.
(ii) 3-(4.4-difluorobut-3-enylthio)-5-ethyl-1.2.4-triazine (Compound XX.30) from 2-oxobuianal. M*=231: ‘HNMR δ 1.3-1,4(3Rt): 2.45-2.55(2Rm): 2.75-2.85(2Rq): 3.253.35(2Rt); 4.24.4(lRm): 8.85(lRs) (oil). The isomeric Compound XXI10 was detected in the reaction mixture but was not isolated. However, it was the major product of the cyclisation when l.l-diethoxy-butan-2-one was used in place of 2-oxobutanal. Initial imine formation in waier followed by cyclisation in aqueous acetone catalysed with pvridinium tosvlaie gave Compound XX. 110. M*=231; ‘H NMR δ 1.4(3Rt); 2.50(2Rm); 2.95(2Rq); 3.3(2Rt); 4.24.4(lRm); 8.29(lRs) (oil).
(iii) 3-(4,4-difluorobut-3-enyithio)-6-methyl-1.2,4-triazine-5(4H)-one (Compound XX226) from pyruvic acid. M*=233; Ή NMR (DMSO-dJ: δ 2.05(3Rs); 2.30(2Rm); 3.12(2Rt); 4.44.6(lRm) (gum).
The following compounds according to the invention were prepared using the above procedure with a 2,2-dichloro aldehyde in place of glyoxal:
(iv) 3-(4,4-difluorobut-3-envlthio)-5-(l-methyl-ethvl)- 1,2,4-triazine (Compound XX.15). M=245; 'HNMR δ 1.32(6Rd); 2.50(2Rm); 3.0(lRm); 3.3(2Rt); 4.204.40(1Rm); 8.82(lRs) (oil) and the c’nromatographically faster-running isomer 3-(4,4-difluorobut3-enylthio)-6-(l-methyl-ethyl)-1.2,4-triazine (Compound XX.98). M’=245; 'HNMR δ 1.4(6Rd); 2.50(2Rm); 3.18-3.35(3Rm); 4.204.40(IRm); 8.3O(lRs) (oil) from 2,2-dichloro-3-methvl-butanal.
EXAMPLE XX9
This Example illustrates a preparation of 5-dichloromethyl-3-(4,4-difluorobut-3envlthio)-1,2,4-triazine (Compound XX65) from Compound XX52.
Compound XX52 (3.1s) and N-chlorosuccinimide (2g) were stirred and healed together under reflux in carbon tetrachloride (40cm3) for 1 hour. The mixiure was allowed to cool and stirred at the ambient iemperarure for 4 hours. Solvent was removed by evaporation under reduced pressure and the black tarry residue was suspended in diethyl ether (40cm3) and passed through a bed of hi-flo filter aid. Insoluble material was washed with further diethyl ether and the combined solutions w'ere evaporated under reduced pressure. The residue was purified by chromatography on silica, eluting with diethyl ether : hexane 1 : 1 and the fractions containing product were evaporaied under reduced pressure and further purified by preparative tic. eluting with 30% diethyl ether in hexane to give Compound XX65 (0.2g). Ή NMR δ 2.50(2Rm): 3.3(2Rt); 4.204.40(IRm); 6.50(lRs); 9.37(lRs);
AP . 0 0 6 4 9
- 147(oil).
EXAMPLE XX10
This Example illustrates a preparation of 3-{4.4-difluorobut-3-enylsulfonyl')-5-propyl12,4-triazine (Compound XX28) from Compound XX27.
Compound XX27 (0.2g) was stirred at 5°C in dichloromethane (5cm3) and 3-chloro perbenzoic acid (0.282g. 2 equiv.) was added. Stirring continued for 18 hours at the ambient temperarure. The reaction was quenched by the addition of a saturated aqueous solution of sodium bicarbonate and the product was extracted into dichloromethane. The organic phase was separated, washed with saturated brine and dried (MgSOJ. After filtration and concentration by evaporation under reduced pressure, there was obtained an oil which was purified by chromatography on silica gel using 3 : 7 ethyl acetate : hexane as eluant to give Compound XX28 (0.187g). M'=277; ’HNMR; δ 1.0-1.l(3H,t); 1.8-1.95(2Hun); 2.62.7(2H,m); 2.9-3.0(2Ht); 3.7-3.8(2H,t); 4.2-4.4( lH.m); 9.3(lH,s); (oil).
The following compounds according to the invention were prepared by the above procedure, using 1.75 equivalents of oxidant:
(i) 3-(4,4-difluorobut-3-enylsulfinyl)-5-methyl-12,4-triazine (Compound XX53);
M=233; Ή NMR; δ 2.35-2.7(2H,m); 2.75(3Hs); 3.2-3.4(2H,m); 4.24.35(lRm);
9.25( lH.s); (oil) and 3-(4,4-difluorobut-3-enylsulfonyl)-5-methyl-l^,4-triazine (Compound XX54); MH‘=250; Ή NMR; δ 2.6-2.7(2H,m); 2.8(3Rs); 3.7-3.8(2H,t);
4.25-4.4(lH.m); 9.35(lHs); (oil) from Compound XX52.
(ii) 3-(4,4-difluorobut-3-envlsulfinyl)-6-methyl-1,2,4-triazine (Compound XX117);
ΜΕΓ=234; Ή NMR; δ 2.3-2.75(2Hm); 2.85(3H,s); 32-3.4(2Rm); 4.154.3(lRm);
8.7(lHs); (oil) and 3-(4,4-difluorobut-3-enyisulfonyl}-6-methyl-l,2,4-triazine (Compound XX118); MH*=250; Ή NMR; δ 2.6-2.7(2Rm); 2.9(3H,s); 3.653.75(2H,t); 4.2-4.4( lH.m); 8.75(lH,s); (oil) from Compound XXI16.
EXAMPLE XXI.l
This Example illustrates a preparation of 2-(4,4-difiuorobut-3-enylthio>-1,3.5-triazine (Compound XXI.l).
(4,4-difluorobut-3-envl)-thiourea (as its 4-methyl-benzenesulfonaie salt) (0.9g) and 1,3,5-triazine (0.216s) were heated together under reflux in ethanol (20cm3) for 4 hours. The reaction mixture was cooled and the solvent was removed by evaporation to give a solid which was triturated with hexane. The hexane-soluble material was recovered by evaporation under reduced pressure. This gave Compound XXI (0.4g). M*=203; *H NMR; δ
AP/P/ 9 6 / 0 0 8 6 2
- 14S 2.45(2Rm); 3.20(2Rt); 4.204.40( IRm); S.S2(2Rs); (oil).
The compounds of formula (I) are nematicidal and can be used to control nemaiodes in plants. Thus, in a further aspect of the present invention, there is provided a method of killing or controlling nematodes, which comprises applying a compound of formula (I) to the nematode.
The term controlling extends to non-lethal effects which result in the prevention of damage to the host plant and the limitation of nematode population increase. The effects may be the result of chemical induced disorientation, immobilisation, or hatch prevention or induction. The chemical treatment may also have deleterious effects on nematode development or reproduction.
The compounds of the present invention can be used against both plant parasitic nemaiodes and nematodes living freely in the soil.
Examples of plant-parasitic nemaiodes are: ectoparasites, for example, Xiphinema spp., Longidorus spp.. and Trichodorus spp.: semi-parasites, for example, Tylenchulus spp.: migrator.’ endoparasites, for example, Pratylenchus spp.. Radopholus spp. and Scutellonema spp.: sedentary parasites, for example, Het erod era spp.. Globodera spp. and Meloidogyne spp.; and stem and leaf endoparasites, for example. Ditylenchus spp.. Aphelenchoides spp. and Hirshmaniella spp.
The compounds of formula (I) also display activity against different types of nemaiodes including cyst nematode.
The compounds of the present invention also exhibit activity against other pests of growing and stored agronomic crops, forestry', greenhouse crops, ornamentals, nursery crops, stored food and fibre products. These pests include:
HeteropteraRomoptera including Myzus persicae. Aphis gossypii. Aphis fabae.
Rhopalosiphum padi. Aonidiella spp.. Trial eurodes spp,. Bgmisia tabaci, Nilaparvata lugens. Nephotettix cincticeps. Nezara viridula. Dysdercus.syrurellus, Dysdercus. fascisms, and Lygus lingQralisDiptera including Ceratitis .eapitata. Iipula spp., Oscinclla. frit, Liriomyza spp., Delia spp., and Peromva spp.
Lepidoptera including Pieris brassicae. Plutella xylostella. Spodoptera littoralis and other Spodoptera spp., Heliothis virescens and other Heliothis and Helicoverpa spp., and Chilo panellus·
Coieoptera including Phaedon cochleariae. Diabrotica spp., Agrotis spp.. and Leptinotarsa
AP. Ο Ο 6 4 9
- 149 decemlineata.
Blanodea including Blanella germanica. Periplaneta americana and Blarta oriental is. Orthoptera including Chortiocetes terminifera- Schistocerca spp.. Locusa spp. and Scapteriscus spp..
Acari including Panonychus ulmi. Panoychus cirri. Tetranychus urticae. Tetranychus cinnabarinus. Phyllocoptruta oleivora and Bre^palpus spp.
The compounds can also be used against livestock, household, public and animal health pests such as:
Siphonaptera including Ctenocephalides felis. Ctenocephalides cards. Xenopsvlla cheopis. and Pulex imtans.
Mallophaga including Menopon gallinae. and Cuclotogaster heterographus.
Anoplura including Pediculus humanus capitis, Pedicuius humanus humanus, and Phthirus pubis.
Diptera including Musca domestica. Aedes aggypiL Anopheles gambiae. Culsx quinqugfasciatus, Chrysops discalis, and Tabanus nigrovinatus.
Sarcophagidae including Sarcophaga haemorrhoidalis and Wohlfahrtia magnifica Calliphoridae including Lucilia CUprina and Cordvlobia anthropophaga .
Oestridae including Oestrus ovis.
Generally, the compounds may be used to combat and control pests injurious to and/or associated with the transmission of diseases of man and animals. The pests which may be combated and controlled by the use of the compounds of the invention parasitic nematodes of animals, including mammals, which may be found in the gastrointestinal tract, the air passages or blood vessels of the respiratory tract and the heart, together with the associated blood vessels.
The compounds of formula (I) may be used to treat vertebrates, such as mammals (for example, man, pigs, sheep, cattle, equines, cats and dogs), birds (for example, chicken, ducks, turkeys, geese, canaries and budgerigars), and fish (for example, salmon, trout and ornamental fish).
The nemaiode and other pests may be killed/controlled by applying an effective amount of one or more of the compounds of the present invention to the environment of the pests, to the area to be protected, as well as directly on the pests.
In order to apply the compound to the locus of the nemaiode. insect or acarid pest, or to a plant susceptible to attack by the nemaiode. insect or acarid pest, the compound
AP/P/ 9 6 / 0 0 8 6 2
- 150 is usually formulaied into a composition which includes in addition to the compound of formula (I) suitable inert diluent or carrier materials, and/or surface active agents. Thus in two further aspects of the invention there is provided a nemaiicidal. insecticidal or acaricidal composition comprising an effective amount of a compound of formula (I) as defined herein and an inert diluent or carrier material and optionally a surface active agent.
The amount of composition generally applied for the control of nematode pests gives a rare of active ingredient from 0.01 to 10 kg per hectare, preferably from 0.1 to 6 kg per hectare.
The compositions can be applied to the soil, plant, seed, or other area to be protected, to the locus of the pests, or to the habitat of the pests, in the form of dusting powders, wettable powders, granules (slow or fast release), emulsion or suspension concentrates, liquid solutions, emulsions, seed dressings, fogging'smoke formulations or controlled release compositions, such as microencapsulated granules or suspensions.
Dusting powders are formulated by mixing the active ingredient with one or more finely divided solid carriers and/or diluents, for example natural clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr. chalk, diatomaceous earths, calcium phosphates, calcium and magnesium carbonates, sulfur, lime, flours, talc and other organic and inorganic solid carriers.
Granules are formed either by absorbing the active ingredient in a porous granular material for example pumice. attapulgite_clays, fuller's earth, kieselguhr, diatomaceous earths, ground com cobs, and the like, or on to hard core materials such as sands, silicates, mineral carbonates, sulfates, phosphates, or the like. Agents which are commonly used to aid in impregnation, binding or coating the solid carriers include aliphatic and aromatic petroleum solvents, alcohols, polyvinyl acetates, polyvinyl alcohols, ethers, ketones, esters, dextrins, sugars and vegetable oils, with the active ingredient. Other additives may also be included, such as emulsifying agents, wetting agents or dispersing agents.
Microencapsulated formulations (microcapsule suspensions CS) or other controlled release formulations may also be used, particularly for slow release over a period of time, and for seed treatment.
Alternatively the compositions may be in the form of liquid preparations to be used as dips, irrigation additives or sprays, which are generally aqueous dispersions or emulsions of the active ingredient in the presence of one or more known wetting agents, dispersing agents or emulsifying agents (surface active agents). The compositions which are to be used in the
AP.00649 • 151 form of aqueous dispersions or emulsions are generally supplied in the form of an emulsifiable concentrate (EC) or a suspension concentrate (SC) containing a high proportion of the active ingredient or ingredients. An EC is a homogeneous liquid composition, usually containing the active ingredient dissolved in a substantially non-volaiile organic solvent. An SC is a fine particle size dispersion of solid active ingredient in water. To apply the concentrates they' are diluted in water and are usually applied by means of a spray to the area to be treated. For agricultural or horticultural purposes, an aqueous preparation containing between 0.0001% and 0.1% by weight of the active ingredient (approximately equivalent to from 5-2000g/ha) is particularly useful.
Suitable liquid solvents for ECs include methyl ketone, methyl isobutyl ketone, cyclohexanone, xylenes, toluene, chlorobenzene, paraffins, kerosene, white oil, alcohols, (for example, butanol), methylnaphthalene. trimethvlbenzene, trichloroethylene,
N-methyI-2-pyrroIidone and tetrahydrofurfuryl alcohol (THFA).
Wetting agents, dispersing agents and emulsifying agents may be of the cationic, anionic or non-ionic type. Suitable agents of the caiionic type include, for example, quaternary ammonium compounds, for example cetvltrimethyl ammonium bromide. Suitable agents of the anionic type include, for example, soaps, salts of aliphatic monoesters of sulfuric acid, for example sodium lauryl sulfate, salts of sulfonated aromatic compounds, for example sodium dodecvlbenzenesulfonate, sodium, calcium or ammonium lignosulfonate, or butvlnaphthalene sulfonate, and a mixture of the sodium salts of diisopropyl- and triisopropylnaphthalene sulfonates. Suitable agents of the non-ionic type include, for example, the condensation products of ethylene oxide with fatty alcohols such as oleyl alcohol or cetyl alcohol, or with alkyl phenols such as octyl phenol, nonyl phenol and octyl cresol. 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.
These concentrates are often required to withstand storage for prolonged periods and after such storage, to be capable of dilution with water to form aqueous preparations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment. The concentrates may contain 1-85% by weight of the active ingredient or ingredients. When diluted to form aqueous preparations such preparations may contain varying amounts of the active ingredient depending upon the purpose for which they are to be used.
AP/P/ 9 6 / 0 0 8 6 2
152
The compounds of formula (I) may also be formulated as powders (dry seed treatment
DS or water dispersible powder WS) or liquids (flowable concentrate FS. liquid seed treatment LS). or microcapsule suspensions CS for use in seed treatments. The formulations can be applied to the seed by standard techniques and through conventional seed treaiers. In use the compositions are applied to the nematodes, to the locus of the nematodes, to the habitat of the nematodes, or to growing plants liable to infestation by the nematodes, by any of the known means of applying pesticidal compositions, for example, by dusting, spraying or incorporation of granules.
The compounds of the invention ma}’ be the sole active ingredient of the composition or they may be admixed with one or more additional active ingredients such as nemaiicides or agents which modify the behaviour of nematodes such as hatching factors, insecticides, s}Tiergists. herbicides, fungicides or plant growth regulators where appropriate.
Suitable additional active ingredients for inclusion in admixture with the compounds of the invention may be compounds which will broaden the spectrum of activity of the compounds of the invention or increase their persistence in the location of the pest. They may svnergise the activity of the compound of the invention or complement the activity for example by increasing the speed of effect or overcoming repellency. Additionally multi-component mixtures of this type may help to overcome or prevent the development of resistance to individual components.
The particular additional active ingredient included will depend upon the intended utility of the mixture and the t}pe of complementary action required. Examples of suitable insecticides include the following;
a) Pyrethroids such as. permethrin, esfenvaieraie, deltamethrin, cyhalothrin in particular lambda-cyhalothrin. bifenthrin, fenpropathrin, cvfluthrin, tefluthrin, fish safe pyrethroids for example ethofenprox, natural pyrethrin, tetramethrin, s-bioallethrin, fenfluthrin, prallethrin and 5-benzyl-3-furylmethvl-(EXlR,3S)-2,2-dimethyl3-(2-oxothiolan-3-ylidenemethyl) cyclopropane carboxylaie;
b) Organophosphates such as profenofos, sulprofos, methyl paraihion, azinphos-methyl, demeton-s-methyl, heptenophos, thiometon. fenamiphos, monocrotophos, triazophos, methamidophos. dimethoate, phosphamidon, malathion, chloropyrifos, phosalone, terbufos. fensulfothion. fonofos, phorate, phoxim. pyrimiphos-methyl, pyrimiphos-ethyl. fenitrothion or diazinon;
c) Carbamates (including aryl carbamates) such as pirimicarb. cloethocarb. carbofuran.
AP.00649
- 153 furaihiocarb. eihiofencarb. aldicarb, thiofurox. carbosulfan. bendiocarb. fenobucarb. propoxur or oxamyl;
d) Benzoyl ureas such as triflumuron. or chlorofluazuron;
e) Organic tin compounds such as cvhexatin. fenbutatin oxide, azocyclotin;
f) Macrolides such as avermectins or milbemvcins. for example such as abamectin. ivermectin and milbemycin;
g) Hormones and pheromones;
h) Organochlorine compounds such as benzene hexachloride, DDT. endosulphan, chlordane or dieldrin;
i) Amidines, such as chlordimeform or amitraz
j) Fumigant agents;
k) Nitromethvlenes such as imidacloprid.
In addition to the major chemical classes of insecticide listed above, other insecticides having particular targets may' be employed in the mixture if appropriate for the intended utility' of the mixture. For instance selective insecticides for particular crops, for example stemborer specific insecticides for use in rice such as cartap or buprofezin can be employed. Alternatively insecticides specific for particular insect species/stages for example ovorlarvicides such as clofentezine, flubenzimine, hexythiazox and tetradifon, motilicides such as dicofol or propargite, general acaricides such as bromopropylate, chlorobenzilaie, or growth regulators such as hydramethylnon, cyromazine, methoprene, chlorfluazuron and diflubenzuron may also be included in the compositions.
Examples of suitable synergists for use in the compositions include piperonyl butoxide, sesamax. safroxan and dodecyl imidazole.
Suitable herbicides, fungicides and plant-growth regulators for inclusion in the compositions will depend upon the intended target and the effect required.
An example of a rice selective herbicides which can be included is propanil, an example of a plant growth regulator for use in cotton is Pix, and examples of fungicides for use in rice include blasticides such as blasticidin-S. The ratio of the compound of the invention to the other active ingredient in the composition will depend upon a number of factors including type of target, effect required from the mixture etc. However in general, the additional active ingredient of the composition will be applied at about the rate as it is usually employed, or at a slightly' lower rare if synergism occurs.
AP/P/ 9 6 / 0 0 8 6 2
- 154 EXAMELEJ.
The activity of compounds of formula (I) according to the invention was determined using a variety of pests. The pests were treated with a liquid composition containing 500 pans per million (ppm) by weight of the compound unless otherwise staled. The compositions were made by dissolving the compound in acetone : ethanol (50:50) mixture and diluting the solutions with water containing 0.05% by weight of a wetting agent sold under the trade name Synperonic NP8 until the liquid composition contained the required concentration of the compound. Synperonic is a Registered Trade Mark.
The test procedure adopted with regard to each pest was basically the same and comprised supporting a number of the pests on a medium which was usually a host plant or a foodstuff on which the pests feed, and treating either or both the medium and the pests with the compositions. The mortality of the pests was then assessed al periods usually varying from one to three days after the treatment.
The results of the tests are presented in Table A for each of the compounds. The results indicate a grading of mortality designated as A, B or C wherein A indicates less than 40% mortality, B indicates 40-79% mortality and C indicates 80-100% mortality; - indicates that either the compound was not tested or no meaningful result was obtained.
Information regarding the pest species, the support medium or food, and the type and duration of the test is given in Table B. The pest species is designated by a letter code.
TABLEA
Compound SPECIES (see Table B)
No. TU MPa MD HV SE
Π.1 B A A A A
Π.2 C c A A A
Π.3 A A A A A
Π.4 A A A A A
Π.5 A C A A A
Π.6 C A A A A
Π.7 A A A B A
Π.8 C C A C B
Π.9 B C A A A
m.i A c A A A
m.2 C c A C A
B
AP.00649
- 155 -
m.3 A c A A A
m.4 A A A A A
m.5 A A A A A
m.6 A A A C A
m.7 A A A B A
m.8 A A A A A
m.9 B C A A A
m.io A C A B A
mil A A A A A
m.i2 B A A A A
IV. 1 C C A C B
IV.2 C C A c B
IV.3 C C A B A
IV.7 C C A C A
IV. 8 C C A c A
rv.9 C C A c A
IV.1O C C - B A
IV.23 C C A C B
IV.24 C C A A A
IV.26 c C A A A
V.2 c C A C C
V.12 c C A c A
V.15 c C A A A
V.I A c A A A
VI.4 A A A A A
V.5 C C A A A
V.6 c A A A A
VL13 B C - A A
VL14 C c - A A
VI.15 A c - A A
V.16 C c - B A
VI. iS C c A B A
Vi. 19 C c B B A
9 8 Ο Ο / 9 6 /d/dV
- 156-
VI.20 C c A A A C
VI.25 C c A B A -
VI.31 C c A A A -
VI.32 C c A A A -
VI.36 C A A A A -
VI.37 C c A A A -
VI.38 C c A A A -
VI.40 C c A C A -
vn.i C c B A A B
VH.2 C c A C B -
Vn.3 C A A B A -
vn.4 A B A A A -
Vn.6 C C A B A -
vn.7 c C A C A -
Vn.8 c C A A A -
VH.9 c C A B A -
vn.io ’ c B A B A -
VH.ll c C A B A -
VH.13 c C A B A -
VH.14 c C A A A -
VH.15 c c A B A -
VH.16 c c A A A -
VH.17 c c A A A C
VH.21 B c A A A -
Vn.23 A B A A A -
Vn.24 A C A A A -
VH.25 C C A C A -
VH.26 c c A B A -
VH.27 c c - A A -
Vn.28 c c - A A -
Vn.32 c c A C A -
VH.36 c c A B A -
VTI.41 c c A C A -
kP . 0 0 6 4 9
- 157-
VH.43 c c A B A
Vn.45 c c A C A -
VH.47 c c A C A -
Vn.52 c c A A B -
\TL53 c c A A A -
VH.56 c c A C A -
VII.82 c c A B A -
VH.83 A c - C A -
Vn.84 A c - A A -
vn.90 C c A B A -
vn.94 c c A C A -
VH.98 c c A C A -
VH.102 A A A A A -
VH.114 c A A A A -
VD.115 A c A A A -
Vn.l 16 B A A A A -
VH.128 C C A A A -
VD.130 C c - A A -
VH.134 A A A C A A
vm.i C C A B A -
vm.2 A C A A A -
vm.3 C C A B A -
vm.4 A A A A C -
vm.5 C C A C A C
vm.7 C c A A A -
vm.8 c A A A A -
vm.9 A A A A A -
vm.io C C A A A -
vm.u c C A B A -
VIII. 12 c c A B A -
vm.n A c A A A -
vm.n c c A A A -
vm.i? c B A A A
AP/P/ 96/00862
- 158 -
\TH.1S c C A A A
vm.19 c C A A A -
VHL20 c c A A A -
vm.21 A A A A A -
VEI.22 c c A A A -
vm.23 c c A A C -
vm.24 c c A A B -
vm.27 c c A B A -
vm.28 A c A A A -
vm.29 c c A C A -
vm.30 A c A A A -
vm.3i c c A A A -
vm.32 B c A A A -
vm.33 c c A A A -
VHI.34 B B A A A -
vm.36 c c A A A -
vm.52- A c - A A -
vm.53 A c A A A -
Vffl.58 c c A C A -
Vffl.59 c c A A A -
vm.6i c c A A A -
vm.63 A A A A C -
vm.64 c c A A A -
vm.65 A B - A A -
vm.66 A A A A A -
vm.67 A A A A A -
vm.68 C C A A A -
vm.151 c C A B A -
vm.152 c c - A A -
1X31 c c A A A -
1X33 A A A A A -
1X34 B c A A A -
1X36 A c A A A -
j\p . 0 0 6 4 9
- 159 -
1X57 C C A A B
ΙΧ4Ο A A A A A
1X42 A A A A A
1X55 C A A A A
1X61 A C A A A
1X73 C C A A C
1X75 C c A A A
1X82 C c A C B
1X84 C A A C A
1X124 C A A A A
1X126 A A A A A
Χ3 C C A C C
Χ26 C C A C A
Χ32 C A A A A
XI.5 C C A C C
XL9 A A A A A
XI.ll C C A C A
ΧΙ.23 c C A c A
ΧΙ.24 A c A A A
ΧΙ.25 C c A B A
ΧΙ.30 A c A A A
ΧΙ.31 A c A A A
XI.34 C c A B A
XI.35 C c A C A
XI.36 C c A C A
XI.38 C c A C A
XI.40 C c A A A
XI.87 C c A C A
XI. 102 B c A A A
X.108 B c A B A
X.109 C A A C B
XI.11O C c A B A
X.125 C c A C A
AP/P/ 9 6 / 0 0 8 6 2
- 160-
XI.127 C c A B B B
ΧΠ.1 C c A C B
ΧΠ.3 C c A C C B
ΧΠ.4 C c A B A C
ΧΠ.5 C c A A A B
ΧΠ.8 C c A A A -
ΧΠ.9 A B A B A -
ΧΠ.11 C c A B A -
ΧΠ.12 c c A B A -
ΧΠ.13 c c A B A -
ΧΠ.14 c c A C A -
ΧΠ.15 c c A A A -
ΧΠ.19 c c A A B -
ΧΠ.23 c c A C A -
ΧΠ.25 c c A C A -
ΧΠ.26 c c A B A -
ΧΠ.27 - c c A A A -
ΧΠ.28 c c A C A -
ΧΠ.29 c c A C A -
ΧΠ.3Ο c c A B A -
ΧΠ.31 c c A A A -
ΧΠ.32 c c A C A -
ΧΠ.33 c c A C A -
ΧΠ.35 c c A A A -
ΧΠ.49 c c A C ' A -
ΧΠ.51 c c A C A -
ΧΠ.54 c c A c A -
ΧΠ.55 c A A c A -
ΧΠ.68 c A A A A -
ΧΠ.128 c c A B C -
XU.129 c c A C A -
ΧΠ.130 B c A A A -
ΧΠ.Ι31 c c A C A .
Ap . 0 0 6 4 9
- 161 -
XH.132 c c A B C
ΧΠ.133 c c A A A -
XU. 134 c c A C B -
ΧΠ.142 c c A c A -
ΧΠ.143 c B A A A -
ΧΠ.144 c c A B A -
ΧΠ.145 c c A C A -
ΧΠ.146 B c A A A -
ΧΠ.147 C c A A A -
XH.148 C c A C A -
xm.i C A A B A -
xm.2 c c A C A -
xm.3 c c A B A -
xm.4 c c A A A -
xm.6 c A A C A -
Xffl.7 c c A c A -
xm.9 c c A c A -
xm.io c c A B A -
xm.n c c A A A -
xm.i4 A A A A A -
xm.15 C c A A A -
xm.i6 c A A B A -
xm.17 c C A C A -
xm.18 c c A B A -
Xffl.20 c c A B A -
xm.24 c c A B A -
xm.27 c A A C A -
xm.28 c c A B A -
xm.29 c c A B A -
xm.4o c c A C A B
xm.41 c c A C A -
xm.4? c c A c A -
Xffi.45 c c A A A .
AP/P/ 9 6 / 0 0 8 6 2
- 162 -
xm.63 A A A A A B
ΧΠΙ.64 c C A C A -
xm.65 c c A C A -
Xffl.66 c c A B A -
xm.69 c B A B A -
xm.70 A c A B A A
xm.ioi c c A A A -
xm.no c c A C A C
xm.114 c c A C A -
xm.115 c c A c A -
xm.ii6 A c A c A -
xm.117 c c B A B B
xm.119 B c C c A C
xm.122 c c A A A -
xm.124 c c B B A B
ΧΠ1.133 c c A C A C
xm,134~ c c A B A B
xm.143 c A A C A -
XIV. 1 c c A C A C
XV. 1 c c A C C c
XVI.l A c A C B -
XVI.2 A A A A A -
XVI.3 c A A C A -
XVI.5 c c A C B -
XVI.6 c c A c A -
XVI.7 A A A A A -
XVI.8 c c A c A -
XVI.9 c B A A A -
XVI. 10 c C A C B c
XVI.l 1 A B A A A A
XVI.12 c C A A C -
XVI.13 A A A A A -
XVI. 14 A A A A A -
AP . 0 0 6 4 9
163 -
XVI.15 B c A A A -
XVI.16 C c A A A -
XVI.17 C c A A A -
XVI.18 C c A A A -
XVI.19 C A A A A B
XVI. 20 A A A A A -
XVI.21 C c A C A -
XVI.22 C A A B A -
XVI .23 A A A B A -
XVI.24 C C A B A -
xvn.i C c A A A C
XVH.2 c c A A A C
XVH.3 B B C C C c
XVH.4 C C A A A B
XVD.5 C C A A A B
XVH.6 A A A A A A
XVH.7 C C A A A C
xvm.i C c A C A C
xvm.3 A c B A A C
xvm.4 C c A A C C
xvm.7 A A A A A C
xvm.io C c A B A -
xvm.13 C c A C C -
xvm.i4 C c A A A -
xvm.15 c c A B A -
xvm.16 c c A B B -
XIX1 c c B C A c
XX4 c B A C A c
XX15 c A A A A -
XX27 c C A B A -
XX.28 c C A A B -
XX3O c c A A A -
XX52 c c A B A
AP/P/ 9 6 / 0 0 8 6 2
- 164
XX.53 C C A C A
XX54 C C A B A -
XX.65 C C A A A -
XX98 C C A A A -
XX109 c C A C A -
XX110 c C A A A -
XX116 c C A B A -
XX117 c c A C A -
XX118 c c A C A -
XX.137 c c A B A -
XX205 c c A C A -
XX218 c c A c A -
XX221 c c A c A -
XX226 c A A c C -
XX227 c c B A A A
XX231 c c A c A -
XX247 c c A c A -
XX251 c c A A A B
XX.l c c B A A A
TABLEB —
CODE TEST SPECIES SUPPORT TYPE OF DURATION
LETTERS TO Tetranvchus urticae MEDIUMTOQD French bean leaf TEST Contact (days) 3
MPa (spider mite) Mvzus persicae Chinese Contact 3
MD (green peach aphid) Musca domestica Cabbage leaf Cotton wool/ Contact 2
HV (houseflies - adults) Heliothis virescens sugar Soya leaf Residual 5
SE (Tobacco bud worm - larva) Spodoptera exigua Cotton leaf Residual 5
(lesser armyworm - larva)
AP.00649
- 165 DB Diabrotica balteata Filter paper/ Residual 2 (banded cucumber beetle maize seed - laiva)
Contact test indicates that both pests and medium were treated, and Residual indicates that the medium was treated before infestation with the pests.
EXAMPLE 2
This Example further illustrates the pesticidal activity of compounds of formula (I) according to the invention.
In Table C, further results are given for the activity of test compounds against four species, at various rates of application. The test procedures and details for tests TU (Tetranychus urticae. contact). MPa (Mvzus persicae. contact) and DB (Diabrotica balteata contact) are as described in Example 1 and Table B. Application rates are shown in the Table heading for each test type. The test procedure for test MPb (Myzus persicae. systemic) was as follows:
Upward systemicitv of the test compounds was evaluated against the peach potato aphid, Mvzus persicae by soil drenching 2-3 week old radish plants (cv. Cherrybelle) al lOppm or 2.5ppm. Plants with 1st true leaves approximately 2 χ 1 cm were used. The cotyledons, growing point and 1 true leaf were removed The soil was covered with a clear lid. 12-18 mature aphids were added to each plant 1 day before treatment On the treatment day, each pot was placed in a 250cm3 plastic pot with a fluon band to prevent aphid escape. Each pot was treated with 10cm3 of chemical in aqueous solution (prepared in 1 % ethanol and acetone (1:1) and 0.01% Synperonic NP8 - ICI Chemicals and Polymers). Each treatment was replicated 3 times. The treated plants were transferred to a constant environment room at 20°C, 60% relative humidity and a 16 hour photoperiod. The mortality was assessed ar 3 and 5 days after treatment.
Activity against the root knot nemaiode, Meloidogvne incognita (MI), was evaluated by applying the candidate nematicide as a drench solution to 2 week old cucumber plants (cultivar Telegraph) and infesting the soil with nematodes. 10 cm3 of an aqueous solution of the test compound, (prepared in 1% ethanol and acetone (1:1) and 0.05% Synperonic NP8 ICI Chemicals &. Polymers) was added to each plant such that the final soil concentration was 2 ppm. Each treatment was replicated twice. The cucumber plants were inoculated 48 hours after treatment with a 2 cmJ suspension of freshly haxched juveniles at a concentration
AP/P/ 9 6 / 0 0 8 6 2
- 166 of 350 nematodes per cm3. The test was maintained at 25°C with a 16 hour photoperiod for 9 days. The roots of each plant were assessed for percentage root-knot reduction relative to an untreated, infested control and the results are recorded in Table C as % knot reduction compared to the control.
The results in Table C for the four species other than MI are expresed as % Control observed. A dash indicates that either the compound was not tested or that no meaningful result was obtained.
AP . 0 0 6 4 9
Compound TU
No. 100 ppm
Π.1 -
Π.2 88
Π.3 -
Π.4 -
Π.5 -
Π.6 39
Π.7 -
Π.8 74
Π.9 -
m.i -
m.2 60
m.3 -
m.4 -
m.5 -
m.6 -
m.7 -
m.8 -
m.9 -
m.io -
m.ii -
ΠΙ.12 -
IV. 1 100
IV.2 94
IV.3 60
IV.7 100
IV.8 92
IV.9 93
rv.io -
IV.23 -
IV.24
- 167 TABLE C
MPa MPa MPb 100 ppm 27 ppm lOppm
92
84
100
100
MPb DB MI
2.5ppm 25 ppm 2ppm
1 - 95
100 - 100
- - 0
4 - 96
- - 96
- - 88
4 - 98
100 - 97
100 - 98
- - 98
97 - 93
41 - 83
- - 0
- - 30
- - 47
- - 48
- - 0
- - 88
- - 51
- - 0
- - 0
- 80 0
- 17 0
- - 96
100 - 100
23 - 0
50 - 0
- - 11
- - 99
• - 88
AP/P/ 9 6 / 0 0 8 6 2
168-
V.2 100 - 84 - 55 - 0
V.6 - - - - - - 72
V.12 100 - 100 - 10 - 0
V.15 49 - 50 - 100 - 92
VI. 1 - - - - - 99
VI.4 - - - - 5 - 98
VI.5 84 95 - - 100 - 100
VI.6 - - - 97 - - 77
VI.13 - - - - - - 22
VI.14 - - - - - - 0
VI.15 - - - - - - 72
VI.16 - - - - - - 55
VI.18 73 - 65 60 - 100 95
VI.19 74 - 100 99 - - 100
VI.20 97 - 100 95 97 53 98
VI.25 77 - 15 - 46 - 88
VI.32 28 - 12 - 28 - 100
VI.36 - - - 79 - - 17
VI.37 93 - 100 - 86 - 97
VI.40 92 - 98 - 100 - 92
VH.l 38 - 0 - 51 - 99
VH.2 36 - 39 - 100 - 99
Vn.3 45 - - - - - 0
VH.4 - - 7 - - - 0
VH.6 100 - 98 - 65 - 95
VH.7 99 - 100 - 45 - 98
vn.8 46 - 16 - 4 - 86
vn.9 90 6 - - - - 0
vn.io 37 7 - - - - 0
vn.12 - - - 96 - - 0
VH.14 - - - - - - 91
Vn.15 - - - - - - 100
VH.16 88 100 . . 96 . 100
AP.00649
- 169·
Vn.17 90 - 9 - - 60 0
VH.22 - - - - - - 76
Vn.23 - - - - - - 68
Vn.24 - - 17 - 50 - 98
νΠ.25 - - - - 98 - 99
νΠ.26 95 - 30 - 96 - 100
VI1.27 - - - - - - 83
VH.28 - - - - - - 66
VD.32 99 - 79 - 49 - 97
νπ.36 100 - 100 - 90 - 92
VH.41 100 - 100 - 49 - 96
νπ.43 85 100 - - - - 86 CM <X?
VH.45 100 99 - - - - 95 CO
Vn.47 - - - - - - 94 o o
VII.52 - - - 41 - - 94
VH.53 - - - 67 - - 99 CC
νΠ.56 - - - 56 - - -
νπ.83 - - - - - - 66 L
νΠ.84 - - - - - - 0 ix <
VD.90 97 - 92 - 93 - 95
VH.94 72 - 5 - - - 0
VH.98 56 - 11 - - - 0
νπ.102 - - - - - - 0
VH.114 - - - 28 - - 50
VH.115 - - - - - - 50
VE.116 - - - - - - 33
Vn.128 - - - 44 - - 66
VH.130 - - - - - - 28
νΠ.134 - - - - - - 100
νπυ- 100 100 - - 100 - 98
vm.2 - 93 - - 98 - 99
vm.3 - - - - - - 88
VE.4 18 . . 39
- 170 -
vm.5 45 - 26 - 96 87 98
vm.7 43 90 - - 90 - 100
vm.s - - - - - - 59
vm.9 - - - - - - 65
vm.io - - - 42 - - 39
vm.12 - - - - - - 48
vm.13 - 4 - - - - 86
vm.14 - - - - - - 90
vm.15 - - - - - - 97
vm.i8 97 100 - - - - 94
vm.19 - - - - - - 66
vm.20 - - - 4 - - 0
VHL21 - - - - - - 0
vm.22 - - - - - - 72
vm.23 - - - 76 - - 44
vm.24 - - - 0 - - 50
vm.27- - - - 0 - - 0
vm.29 - - - - - - 11
VTII.30 - - - 29 - - 44
vm.31 - - - - - - 49
vm.32 - - - - - - 99
vm.33 - - - - - - 0
vm.34 - - - - - - 22
vm.36 - - - - - - 66
vm.52 - - - - - - 22
vm.59 - - - - - - 65
vm.61 - - - - - - 66
vm.63 - - - - - - 99
VHI.64 - - - 29 - - 0
vm.65 - - - 48 - - 72
vm.66 - - - 16 - - -
vm.67 - - - - - - 0
VUI.151 100 100 • 30 . 99
AP . 0 0 6 4 9
- 171 -
vm.152 - - - - - - JO
1X33 - - - 0 - - 44
1X34 - - - 0 - - 94
1X56 - - - Ί - - 0
1X37 - - - - - - 61
IX4O - - - 30 - - 50
1X42 - - - 9 - - 72
1X55 - - - - - - 83
1X61 - - - 86 - - 61
1X73 - - - 100 - - 72
1X75 - - - - - - 99
1X82 91 100 - - - - 3
1X84 97 - - - 100 - 97 CM CO
1X124 - - - - - - 65 CO
1X126 - - - - - - 94 O
1X127 - - - - - - 50 o
X3 100 - 100 52 - - 94 co
X26 - - - 82 - - 88 cn
X32 54 - - - - - 96 CL
XI.5 100 - 100 30 - 13 100 CL <
X.9 - - - - 26 - 99
XI.ll 84 100 - - 100 - 95
XI.23 40 14 - - 48 - 98
XI .24 - - - - 95 - 86
XI.25 41 100 - - - - 97
XI.30 - 81 - - - - 4
XI.31 - 29 - - - - 14
XI.34 100 100 - - 99 - 100
XI.35 97 . 100 - - 98 - 98
XI.36 100 100 - - 100 - 92
XI.38 100 100 - - 52 - 93
XI.40 36 - 100 100 95 77 100
X.87 82 100 . . 92 • 100
- 172
XI. 102 - - - - - 0
XI.108 - 100 - - 93 - 92
XI.109 100 - - - 35 - 93
XI.110 70 - 96 - 59 - 90
XI. 125 100 100 - - 80 - 97
XI.127 100 - 100 26 - - 0
ΧΠ.1 86 - 9 - 100 - 95
ΧΠ.3 100 - 46 9 65 - 88
xn.4 100 - 93 49 - 67 ’ 98
ΧΠ.5 37 - 0 72 - - 89
ΧΠ.8 59 - 4 - 100 - 96
ΧΠ.9 - 42 - - - - 68
ΧΠ.11 81 100 - - 50 - 100
ΧΠ.12 73 100 - - - - 97
ΧΠ.13 43 20 - - - - 76
ΧΠ.14 93 100 - - 95 - 93
ΧΠ.15 - 47 11 - - - - 94
ΧΠ.19 50 30 - - - - 69
ΧΠ.23 95 100 - - 97 - 97
ΧΠ.25 100 100 - - 56 - 99
ΧΠ.26 73 100 - - 77 - 99
ΧΠ.27 - 98 - - - - -
ΧΠ.28 100 100 - - - - 84
ΧΠ.29 - 100 - - 100 - 99
ΧΠ.30 15 100 - - - - 94
ΧΠ.31 73 - 22 - 100 - 95
ΧΠ.32 100 100 - - 98 - 99
ΧΠ.33 45 3 / - - - - -
ΧΠ.35 100 87 - - 95 - 98
ΧΠ.49 38 - 18 - 97 - 95
ΧΠ.51 40 s - - 51 - 91
XU.54 100 80 - - 100 - 98
ΧΠ.55 96 - . 100 - 90
AP.00649
- 173 -
ΧΠ.68 53 - - - - - 0
ΧΠ.128 100 100 - - 26 - 61
ΧΠ.129 100 100 - - 86 - 89
ΧΠ.13Ο - 77 - - 5 - 87
XH.131 87 - 26 - 54 - 86
ΧΠ.132 98 100 - - - - 31
ΧΠ.133 99 - 85 - 6 - 0
ΧΠ.134 75 - 88 - 97 - 0
ΧΠ.142 54 100 - - 92 - 95
XH.143 48 39 - - 65 - 94
ΧΠ.144 100 100 - - - - 53
ΧΠ.145 - 100 - - 32 - 97
ΧΠ.146 - 45 - - - - 69
ΧΠ.147 39 56 - - - - 37
ΧΠ.148 97 97 - - - - 84
xm.i 35 - - - - - 89
xm.2 95 100 - - 100 - 98
xm.3 79 84 - - 88 - 99
xm.4 100 100 - - 100 - 96
xm.6 79 - - - 96 - 100
xm.7 88 100 - - 100 - 99
xm.9 91 - 100 - 18 - 93
xm.io 94 - 100 - 32 - 96
xm.u 94 - 83 - 96 - 92
xm.i4 - - - - 7 - 95
xm.15 43 77 - - - - 94
xm.i6 89 - - - 89 - 96
xm.n 74 100 - - 100 - 97
xm.is 85 100 - - 96 - 99
xm.20 94 - 90 - 48 - 0
xm.24 89 100 - - 45 - 100
Xffl.27 69 - - - 77 - 99
xm.28 100 100 . • 100 96
AP/P/ 96/00862
174 -
xm.29 95 100 - - 100 - 97
xm.40 100 - 5 100 100 - 100
xm.4i 100 - 95 - 100 - 96
ΧΠΙ.42 98 - 35 - 100 - 95
ΧΠ1.45 81 - 44 - 91 - 97
ΧΠΙ.63 - - - 98 - - 100
xm.64 85 - 97 - 98 - 97
xm.65 73 - 42 - 100 - 98
Xffl.66 100 93 - - - - 31
xm.69 84 18 - - - - 63
xm.70 - - 22 - - - 0
xm.ioi 79 98 - - 99 - 100
xm.no 100 - 64 27 - 79 94
xm.114 96 100 - - 18 - 97
xm.115 97 100 - - 45 - 91
xm.116 - 100 - - 19. - 100
xm.iir 100 - 100 77 - - 100
ΧΠΙ.119 - - 13 29 82 53 91
ΧΠΙ.122 95 100 - - 35 - 100
xm.124 78 - 12 - - - 0
xm.133 100 - 100~ 100 - 50 100
xm.134 97 - 100 100 - - 100
xm.143 - - - - - - 41
xrv.i 45 - 15 100 - 0
XV. 1 82 - 18 80 - 70 91
XVI.l - 34 - - - - 50
XVI.2 - - - - 7 - 82
XVI.3 59 - - - 97 - 94
XVI.5 56 - 39 - 62 - 100
XVI.6 88 97 - - 96 - 100
XVI.7 - - - - - - 0
XVI. s 42 100 - - - - 89
X\3 9 68 29 . . 12
AP.00649
XVI.1O 100 65 - 175 - 100 53 100
XVI.ll - - n - - - 0
XVI.12 20 IS - - - - 81
XVI.13 - - - - - - 32
XVL14 - - - - - - 0
XVI.15 - - 53 - 48 - 94
XVL16 100 100 - - - - 94
XVL17 46 45 - - - - 24
XVI.18 25 48 - - - - 43
XVL19 26 - - - - - 0
XVI.20 - - - - - - 42
XVI.21 82 - 100 - 8 - 100
XVI.22 44 - - - - - 41
XVI.23 - - - - - - 38
XVL24 81 100 - - 85 - 97
xvn.i 30 - 7 74 50 0
XVn.2 24 - 1 - - 27 0
XVH.3 - - 0 - - 87 0
XVD.4 11 - 0 - - - 0
XVH.5 32 - 7 - - - 0
XVH.6 - - - - - - 0
XVII.7 49 - 7 - - 30 0
xvm.i 95 - 100 35 - 80 92
XVffl.3 - - 45 100 - 23 98
xvm.4 96 - 100 15 - 93 94
xvm.7 - - - - - 83 0
XVffl.lO 49 - 65 - 29 - 100
XVHL13 100 - 74 - 53 - 0
xvm.14 56 - 7 - - - 0
xvm.15 62 - 38 - 89 - 100
xvm.16 55 - 5 - 94 - 100
XIX1 100 - 15 30 - 100 82
XX4 91 . 71 8 • 97 0
AP/P/ 96/00862
176 -
XX.15 100 - - - 94 - 100
XX27 69 96 - - 91 - 100
XX.28 31 85 - - - - 73
XX30 69 100 - - 91 - 99
XX52 63 - 100 - 93 - 96
XX53 97 100 - - 92 - 100
XX54 43 - - - - 61
XX65 52 34 - - - - 47
XX98 85 - - - 95 - 100
XX109 50 100 - * 100 - 99
XX110 77 100 - - 95 - 99
XX116 68 - 71 - 98 - 96
ΧΧ117 100 98 - - 96 - 100
XX118 34 7 - - - - 21
XX137 47 - 100 - 94 - 95
XX205 79 100 - - .- - 94
XX218- 81 100 - - - - 97
XX221 42 - 79 - 92 - 99
XX226 94 - - - 100 - 97
XX227 86 - 51 100 - - 100
XX231 88 - 100~ - 52 - 100
XX247 90 100 - - 100 - 94
XX251 18 - 79 26 - - 0
XXI. 1 28 - 0 0
EXAMPLE 3
The spectrum of nematicidal activity of compounds according to the invention was investigated in contact assays in the presence of soil and a host plant. Greatest activity was seen against Metoidogyne ingogniia, .Globodsra rosiachimsis. Pratvlenchus brachvurus. Tvlenchorhynchus clavtoni. Hoplolaimus Columbus and Radopholus similis. Adequate activity was seen against Rotvlenchulus reniformis. and Belonolaimus longicaudatus.
The following examples demonstrate formulations suitable for applying the compounds of the present invention. The amount of ingredient is expressed in parts by weight or grams per
AP . 0 0 6 4 9
- 177litre as indicated. A * indicates a trademark.
EXAMPLE 4
This example demonstrates granules suitable for soil application. The granules can be made by standard techniques such as impregnation, coating, extrusion or agglomeration.
%w/w
Impregnated granule : Active ingredient 5
Wood Rosin 2.5
Gypsum granules 92.5 (20-40 mesh)
Coated granule : Active ingredient 0.5 'Solvesso'* 200 0.4
Calcium carbonate granules 99.1 (30-60 mesh)
Slow release granule : Active ingredient 10
Polyvinylacetate/vinyl 5 chloride copolymer latex Attapulgus granules 85
AP/P/ 96/00862
EXAMPLE 5
This Example demonstrates formulations for use as a spray. The compounds can be formulated as wettable powders, water dispersible granules, suspension concentrates, emulsifiable concentrates, emulsions or microcapsule suspensions for application diluted in water.
Wettable powder
Emulsifiable concentrate:
Active ingredient fid 250
Calcium dodecyl- 50
benzene sulfonate Nonyl phenol ethoxylate 50
Alkylbenzene solvent to 1 litre
Liquid active ingredient %w/w 40
lignosulfonaie dispersant 5
silica 25
- 178 sodium lauryl sulfate 3 china clay (kaolin) 27
Microcapsule suspension: Liquid active ingredient 250 toluene diisocvanate 10 polymethvlene polyphenyl 20 isocyanate nonyl phenol ethoxylate 6 lignosulfonate dispersant 15 xanthan gum 1 bentonite 10 biocide 'ProxeF* 0.1 sodium carbonate 5 water to 1 litre
The microcapsule suspensions can be used as a spray, soil drench or as an intermediate to prepare slow release granules for application to the soil.
Suspension concentrate : Solid active ingredient 400 lignosulfonate dispersant 50 sodium lauryl sulfate 30 xanthan gum 1 biocide 'Proxel'* 0.1 bentonite 10 water to 1 litre
EXAMPLES
This Example demonstrates formulations suitable for use as seed treatments in conventional application machinery.
%w/w
Dry seed treatment : Active ingredient 20 dodecyl benzene 3
Rubine Toner (dyestuff) 2.7
Talc 53.3
Silica to 100%
The suspension concentrate and microcapsule suspension of Example 5 can be used as
AP . 0 0 6 4 8
- 179flowable concentrates for seed treatment.
EXAMPLE 7
This Example demonstrates the formulation of the compounds for electrostatic
spraying.
Active ingredient gd 200
N-methylpyrrolidone 50
Soyabean oil 120
'Solvesso'* 200 to 1 litre
EXAMPLE 8
This Example demonstrates a formulation suitable for use as a bait
Active ingredient %w/w 0.25
Icing sugar 99.65
Butylated hydroxy toluene 0.10
EXAMPLE 9
This Example demonstrates a formulation suitable for use as a bolus.
Active ingredient mg 1300
Sodium starch glycollate 300
Microcrystalline cellulose -1200
Lactose 2920
Povidone 250
Magnesium stearate 30
EXAMPLE 10
This Example demonstrates a formulation suitable for use as an injectable suspension.
Active ingredient mg 40
Sodium metabisulfite 1
Polysorbate 80 1
Sodium methyl hydroxybenzoate 2
Water to 1ml
AP/P/ 96/00862
- 180 EXAMELEIL
This Example demonstrates a formulation suitable for use as an injectable solution.
ms
Active ingredient 20
Sodium citrate 6
Citric acid 1
Sodium chloride 7
Chlorcresol 1 .
Water to 1ml
EXAMPLE 12
This Example demonstrates a formulation suitable for use as an oral suspension.
S
Active ingredient 100.0
Polysorbate 80 2.0
Xanthan gum 5.0
Colloidal silicon dioxide 10.0
Methyl hydroxybenzoate 1.5
Citric acid monohydrate 10.0
Sodium citrate 10.0
Purified water to 1000.0ml
AP.00649
- 181 CHEMICAL FORMULAE (IN DESCRIPTION)
R-S(O)nCH2CH2CH=CF2 (I)
( VIII )
N (IX)
R3 R4
Rs (IV)
(X)
N-N
(XII)
AP/P/ 96/0086 2
182
CHEMICAL FORMULAE (IN DESCRIPTION)
N-N
N (XIV)
R4
(XX) (XXI);
AP,00649
- 1θ3....- ....... .
CHEMI0AL' FORMULAE (IN DESCRIPTION) “ '
R - SH (XXIII)
CF2=CHCH2CH2L (XXIV)
CF2=CHCH2CH2OSO2Rb (XXV) CF2=CHCH2CH2Br (XXVI)
R - L (XXVII)
CF2=CHCH2CH2SH (XXVIII)
R - NH2 (XXIX) (CF2=CHCH2CH2S)2 (XXX,
NP'iPl 9 6 / 0 0 8 6 2
- 184oow partirubrly 3e»rriWI μΛ •*CrT4lllcd lllv.nui i4.J LovcolioU 4*«1 t* *!m (n.i.iiin Uk «η» u m he prri(*rac4 declare that what !/>e tlaua >—
A compound of formula (I),

Claims (12)

1.
R-S(O)nCH,CH:CH=CF, or a salt thereof, wherein n is 0, 1 or 2; and R is a group of formula (H) to (XXI).
AP. Ο Ο 6 4 9
Ν-Ν (XIV) (XXI)
AP/P/ 96/00862 wherein:
the S(O)nCH2CH2CH=CF2 group is at least one of R1 (when attached to a carbon atom), R2. R3. R4. R5 or R6;
R1 (when attached to a carbon atom), R2. R3, R4, R5 and R6 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, cycloalkyl, alkylcvcloalkyl, alkoxy, alkenyloxy, alkynyloxy, hydroxvalkyl, alkoxvalkyl, optionally substituted arvl. optionally substituted arylalkyl. optionally substituted heteroaryl, optionally
- 186 substituted heteroarylalkyl, optionally substituted aryloxy, optionally substituted arylalkoxy. optionally substituted aryloxyalkyl, optionally substituted heteroaryloxy, optionally substituted heteroaiylalkoxy, optionally substituted heteroaryloxyalkyl, haloalkyl. haloalkenyl. haloalkynyl, haloalkoxy, haloalkenyloxy, haloalkynyloxy, halogen, hydroxy, cyano. nitro. -NR7R8, -NR7COR8, -NR7CSR8, -NR7SO2R8. -N(SO2R7/SO2R8), -COR7, -CONR7R8. alkylCONR7R8, -CR7NR8, -COOR7, -OCOR7, -SR7, -SOR7, -SO2R7, -alkvlSR7, alkylSOR7, -alkylSO2R7, -OSO2R7, -SO2NR7R8, -CSNR7R8, -SiR7R8R9, -OCH2CO2R7. -OCH2CH2CO2R7, -CONR7SO2R8, -aIkylCONR7SO2R8, -NHCONR7R8, -NHCSNR7R8. or an adjacent pair of RI, R2, R3, R4, R5 and R6 when taken together form a fused 5- or 6-membered carbocyclic or heterocyclic ring;
RI (when attached to a nitrogen atom) is hydrogen, optionally substituted alkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryloxyalkyl, haloalkyl, hydroxy, cyano, nitro, -NR7R8, -NR7COR8, NR7CSR8, -NR7COOR8, -NR7SO2R8, N(SO2R7XSO2R8), -C0R7, -CONR7R8, -alkylCONR7R8, -CR7NR8, -COOR7, -OCOR7, SOR7, -SO2R7, -alkylSR7, -alkylSOR7, -alkylSO2R7, -OSO2R7, -SO2NR7NR8, -SR7, SOR7, -SO2R7, -CSNR7R8, -SiR7R8R7, -OCH2CO2R7, -OCH2CH2CO2R7, CONR7SO2R8, -alkylCONR7SO2R8, - NHCOR7R8, or -NHCSR7R8; and
R7, R8 and R9 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, optionally substituted aryl or optionally substituted arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, halogen, or hydroxy.
2. A compound according to claim 1, wherein:
the -S(O)nCH2CH2CH=CF2 group is at least one of RI (when attached to a carbon atom), R2, R3, R4, R5 or R6;
RI (when attached to a carbon atom), R2, R3, R4, R5 and R6 are each independently hydrogen, optionally substituted Cl-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, C3-6 cycloalkyl, C4-7 alkylcycloalkyl, Cl-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, Cl-6 hydroxyalkyl, C2-6 monoalkoxyalkyl, C3-6 dialkoxyalkyl, optionally substituted C6-10 aryl, optionally substituted C6-10 aryl-Cl-2 alkyl group, optionally substituted 5 or 6 membered heteroaryl, optionally substituted 5 or 6 membered heteroaryl-Cl-6 alkyl, optionally substituted C6-10 aryloxy, optionally substituted C6-10 arylAP.00649
- 187Cl-2 alkoxy, C6-10 aryloxy-Cl-6 alkyl, optionally substituted 5 or 6 membered heteroarvloxy, optionally substituted 5 or 6 membered heteroaryl-Cl-6 alkoxy. 5 or 6 membered heteroaryloxv-Cl-2 alkyl, Cl-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl.
Cl-6 haloalkoxy, C2-6 haloalkenvloxy, C2-6 haloalkynvloxv, halogen, hydroxy, cyano. nitro. -NR7R8, -NR7COR8, -NR7CSR8, -NR7SO2R8, -N(SO2-R7)(SO2-R8), -COR7, -CONR7R8. -Cl-6 alkylCONR7R8, -CR7NR8. -COOR7, -OCOR7, -SR7, -SOR7, -SO2R7, -Cl-6 alkvlSR7, -Cl-6 alkylSOR7, -Cl-6 alkyl-SO2R7-OSO2R7, -SO2NR7R8, -CSNR7R8, -SiR7R8R9, -OCH2CO2R7, -OCH2CH2CO2R7, -CONR7SO2R8, -Cl-6 alkylCONR7SO2R8. -NHCONR7R8, -NHCSNR7R8 or an adjacent pair of Rl, R2, R3 and R4 when taken together form a fused 5- or 6-membered carbocyclic or heterocyclic ring;
Rl (when attached to a nitrogen atom) is hydrogen, optionally substituted Cl-6 alkyl, C3-6 cycloalkyl, C4-6 alkylcvcloalkyl, Cl-6 hydroxyalkyl, C2-6 monoalkoxyalkyl, C3-6 dialkoxvalkyl, optionally substituted C6-10 aryl, optionally substituted C6-10 aryl-Cl-2 alkyl, optionally substituted C6-10 aryloxy-Cl-6 alkyl, optionally substituted 5 or 6 membered heteroaryl, optionally substituted 5 or 6 membered heteroaryl-Cl-2 alkyl, optionally substituted 5 or 6 membered heteroaryloxy-Cl-2 alkyl, Cl-6 haloalkyl, hydroxy, cyano, nitro, -CONR7R8, -Cl-6 alkylCONR7R8, - NHCOR7R8, -NHCSR7R8, -NR7R8, -NR7COR8, NR7CSR8, -NR7COOR8, -NR7SO2R8, -N(SO2R7)(SO2R8), -COR7, -COOR7, -OCOR7, OSO2R7, -SO2NR7N6, -SO2R7, -SOR7, -CSNR7R8, -SiR7R8R7, -OCH2CO2R7, OCH2CH2CO2R7, -CONR7SO2R8, or -Cl-6 alkylCONR7SO2R8; and
R7, R8 and R9 are each independently hydrogen, optionally substituted Cl-6 alkyl, optionally substituted C2-6 alkenyl, C2-6 alkynyl, Cl-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, optionally substituted C4-6 aryl or optionally substitututed C4-6 aryl-Cl-6 alkyl, halogen or hydroxy.
3. A compound according to claim 2, wherein when any one of Rl to R6 is:
- substituted alkyl, or contains a substituted alkyl moiety, it comprises one or more substituents chosen from halogen, nitro, cyano, -COOR7 or a salt thereof) hydroxy, alkoxy, alkoxyimino. alkoxycarbonyl, carbomyl, mono- or di-alkylcarbamoyl, amino, mono- or dialkylamino. acylamido, alkanesulfonyl and arylsulfonyl;
- substituted alkenyl, or contains a substituted alkenyl moiety, it comprises one or more substituents chosen from halogen, COOR7 or a salt thereof, hydroxy, nitro and cyano;
- substituted aryl or heteroaryl, or contains a substituted sryl or heteroaryl moiety, it
AP/P/ 96/00862
- 188comprises one or more substituents chosen from alkyl, alkoxy, haloalkyl. halogen, hydroxy.
ROOR7 or a salt thereof, aminosulfonvl. cyano and nitro.
4. A compound according to either of claims 2 and 3 wherein when any one of Rl to R6 is -SR7, it is preferably optionally substituted Cl-6 alkylthio, C2-6 alkenylthio, C2-6 alkynylthio, Cl-6 haloalkyl, C2-6 haloalkenylthio. C2-6 haloalkynylthio or C6-10 arylthio.
-T-S
5. A compound according to claim 1 wherein:
at least one of Rl (when attached to a carbon atom) is the -S(O)nCH2CH2CH=CF2 group;
Rl (when attached to a carbon atom) to R6 are each independently hydrogen; nitro; _ halogen; cyano; -CH=NOH; Cl-4 alkyl; Cl-4 haloalkyl; Cl-4 alkenyl; Cl-4 haJoalkenyl; cyclopropyl; hydroxy; Cl-4 alkoxy; C2-4 alkoxvalkyl; -COOH; C2-4 alkoxycaibonyl; C2-4 haloalkenyloxycarbonyl; -C0NH2; mono or di-Cl-2 alkylaminocarbonyl; C2-4 alkanecarbonyl; phenyl optionally mono- or di- substituted with groups independently chosen from halogen, nitro, Cl-4 alkyl, Cl-4 alkoxy or aminosulfonyl; -CONHSO2-C1-4 alkyl; benzyl optionally mono- or di- substituted with groups independently chosen from halogen, nitro, CI-4 alkyl or Cl-4 alkoxy; phenoxy optionally mono- or di- substituted with groups independently chosen from halogen, cyano, Cl-4 alkyl or Cl-4 alkoxy; amino optionally mono- or di- substituted with CI4 alkyl groups; -SH; Cl-4 alkylthio; benzylthio optionally — ί .
mono- or di- substituted with groups independently chosen from halogen or Cl-4 haloalkyl;
Cl-4 alkenylthio; C2-4 haloalkenylthio; a second S(O)nCH2CH2CH=CF2 group; Cl-4 : alkanesulfonyl; Cl-4 haloalkanesulfonyl; fluorosulfonyl; mono- or di- Cl-4 alkylsulfamoyl; a 5 or 6 membered heteroaryl group optionally substituted with halogen; or any adjacent pair forms a fused 5- or 6- carbocyclic or heterocyclic ring; and
Rl (when attached to a nitrogen atom) is hydrogen; nitro; cyano; -CH=NOH; Cl-4 alkyl; Cl-4 haloalkyl; cyclopropyl; hydroxy; -COOH; C2-4 alkoxycarbonyl; C2-4 haloalkenyloxycarbonyl; -CONH2; mono or di-Cl-2 alkylaminocarbonyl; C2-4 alkanecarbonyl; phenyl optionally mono- or di- substituted with groups independently chosen from halogen, nitro, Cl-4 alkyl, Cl-4 alkoxy or aminosulfonyl; -CONHSO2-C1-4 alkyl; benzyl optionally mono- or di- substituted with groups independently chosen from halogen, nitro, Cl-4 alkyl or Cl-4 alkoxy; phenoxy optionally mono- or di- substituted with groups independently chosen from halogen, cyano, Cl-4 alkyl or Cl-4 alkoxy; amino optionally
AP.00649
- 189 mono- or di- substituted with Cl-4 alkyd groups; -SH; CM alkylthio: bcnzylthio optionally mono- or di- substituted with groups independently chosen from halogen or CM haloalkyi; Cl-4 alkenvlthio; C2-4 haloalkenvlthio; CM alkanesulfonvl; CM haloalkanesulfonvl; fluorosulfonyl; mono- or di- CM alkvlsulfamoyl; a 5 or 6 membered heteroarvl group optionally substituted with halogen.
6. A process for the preparation of a compound of any one of claims 1 to 3, where n is
0. comprising reacting a compound of formula (ΧΧΓΠ)
R-SH (ΧΧΙΠ) with a compound of formula (XXTV)
CF2=CHCH2CH2L (XXIV) where R is as defined in any one of claims 1 to 3. and L is a good leaving group.
7. A process for the preparation of a compound of any one of claims 1 to 3, where n is 0, comprising reacting a compound of formula (XXVII)
R-L (XXVH) with a compound of formula (XXVIII) cf2=chch2ch,sh (xxvm) where R is as defined in any one of claims 1 to 3, and L is a good leaving group.
8. A process for the preparation of a compound of any one of claims 1 to 3. when n is 1 or 2, which comprises oxidation of the correspondingly substituted compound of formula (I) when n is 0.
9. An agricultural composition comprising a compound of any one of claims 1 to 3 as the active ingredient in admixture with an agriculturally acceptable diluent or carrier.
10. An agricultural composition according to claim 9, further comprising a surface active material.
11. An agricultural composition according to either of claims 9 and 10, further comprising at least one other active ingredient which is an insecticide, fungicide, bactericide, acaricide or other biologically active compound.
AP/P/ 9 6 / 0 0 8 6 2
- 19012. A process for preparing an agricultural composition of any one of claims 9 to 11, comprising admixing the compound of any one of claims 1 to 3 and the agriculturally acceptable diluent or carrier.
13. A method for killing or controlling nematode, insect or acarid pests comprising applying a compound of any one of claims 1 to 3, or a composition of any one of claims 9 to 11, to the pests, their habitat, or a plant susceptible to attack by the pests.
APAP/P/1996/000862A 1994-03-10 1995-02-27 Heterocyclic and phenyl compounds. AP649A (en)

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GB9404718A GB9404718D0 (en) 1994-03-10 1994-03-10 Aromatic and heterocyclic compounds
GB9404720A GB9404720D0 (en) 1994-03-10 1994-03-10 Heterocyclic compounds
GB9404721A GB9404721D0 (en) 1994-03-10 1994-03-10 Heterocyclic compounds
GB9404719A GB9404719D0 (en) 1994-03-10 1994-03-10 Heterocyclic compounds
GB9404716A GB9404716D0 (en) 1994-03-10 1994-03-10 Heterocyclic compounds
GB9404717A GB9404717D0 (en) 1994-03-10 1994-03-10 Heterocyclic compounds
GBGB9500521.1A GB9500521D0 (en) 1995-01-11 1995-01-11 Heterocyclic compounds
PCT/GB1995/000400 WO1995024403A1 (en) 1994-03-10 1995-02-27 (4,4-difluorobut-3-enylthio)-substituted heterocyclic or carbocyclic ring compounds having pesticidal activity

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