GB2301819A - Insecticidal bicyclic amines - Google Patents

Insecticidal bicyclic amines Download PDF

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Publication number
GB2301819A
GB2301819A GB9609978A GB9609978A GB2301819A GB 2301819 A GB2301819 A GB 2301819A GB 9609978 A GB9609978 A GB 9609978A GB 9609978 A GB9609978 A GB 9609978A GB 2301819 A GB2301819 A GB 2301819A
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United Kingdom
Prior art keywords
cyano
chloropyrid
azabicyclo
octane
mixture
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Granted
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GB9609978A
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GB9609978D0 (en
GB2301819B (en
Inventor
Christopher John Urch
Roger Salmon
Terence Lewis
Christopher Richard Ay Godfrey
Martin Stephen Clough
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Syngenta Ltd
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Zeneca Ltd
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Priority to GB9816362A priority Critical patent/GB2324795B/en
Publication of GB9609978D0 publication Critical patent/GB9609978D0/en
Publication of GB2301819A publication Critical patent/GB2301819A/en
Priority to BR9708947A priority patent/BR9708947A/en
Priority to AU27082/97A priority patent/AU722015B2/en
Priority to HU9902111A priority patent/HUP9902111A3/en
Priority to KR1019980709121A priority patent/KR20000010972A/en
Priority to AT97920866T priority patent/ATE263765T1/en
Priority to JP09540631A priority patent/JP2000510144A/en
Priority to EP97920866A priority patent/EP0901490B1/en
Priority to ES97920866T priority patent/ES2218676T3/en
Priority to EA199801006A priority patent/EA001422B1/en
Priority to IL12688297A priority patent/IL126882A0/en
Priority to PCT/GB1997/001259 priority patent/WO1997043286A1/en
Priority to DE69728531T priority patent/DE69728531T2/en
Priority to CA002251851A priority patent/CA2251851A1/en
Priority to CN97194560A priority patent/CN1067069C/en
Priority to CZ19983660A priority patent/CZ287821B6/en
Priority to ZA9704089A priority patent/ZA974089B/en
Priority to US08/855,521 priority patent/US5859024A/en
Application granted granted Critical
Publication of GB2301819B publication Critical patent/GB2301819B/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/16—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof the nitrogen atom being part of a heterocyclic ring
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/22—O-Aryl or S-Aryl esters thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/38—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the group >N—CO—N< where at least one nitrogen atom is part of a heterocyclic ring; Thio analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

Compounds of formula (I): wherein R 1 represents a group of formula (A) where each of W, X, Y and Z represents either a group CR or the nitrogen atom, provided that not more than two of W, X, Y and Z represent the nitrogen atom and where each R present is independently selected from hydrogen and halogen atoms and cyano, amino, hydrazino, acylamino, hydroxy, alkyl, hydroxyalkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkenyloxy, alkoxyalkenyl, alkynyl, carboxylic acyl, alkoxycarbonyl, aryl and heterocyclyl groups, said groups comprising up to 6 carbon atoms, and wherein R 2 represents hydrogen or cyano or a group selected from alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, aralkenyl, alkynyl, alkoxycarbonyl, alkanesulfonyl, arenesulfonyl, alkanyloxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, heterocyclylalkyl, carbamyl or dithiocarboxyl groups, said groups comprising from 1 to 15 carbon atoms, said groups being optionally substituted with one or more substituents selected from, halogen, cyano, carboxyl, carboxylic acyl, carbamyl, alkoxycarbonyl, alkoxy, alkylenedioxy, hydroxy, nitro, haloalkyl, alkyl, amino, acylamino, imidate and phosphonato groups; and acid addition salts and quaternary ammonium salts and N-oxides derived therefrom, are useful as insecticides, acaricides and nematicides. Intermediates of the formula: are novel when R 2 is other than methyl, benzyl or trichloroethyl.

Description

BICYCLIC ABETS This invention relates to novel bicyclic amines, to processes for preparing them, to insecticidal compositions comprising and to methods of combatting and controlling insect pests therewith.
The invention provides compounds of formula (I) wherein R' represents a group of formula (A) where each of W, X, Y and Z and Z represents either a group CR or the nitrogen atom, provided that not more than two of W, X, Y and Z represent the nitrogen atom and where each R present is independently selected from hydrogen and halogen atoms and cyano, amino, hydrazino, acylamino, hydroxy, alkyl, hydroxyalkyl, alkoxy, haloallcyl, haloalkoxy, alkenyl, alkenyloxy, alkoxyalkenyl, alknyl, carboxylic acyl, alkoxycarbonyl, aryl and heterocyclyl groups, said groups comprising up to 6 carbon atoms, and wherein R2 represents hydrogen or cyano or a group selected from alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, aralkenyl, alkynyl, alkoxycarbonyl, alkanesulfonyl, arenesulfonyl, allranyloxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, heterocyclylalkyl, carbamyl or dithiocarboxyl groups, said groups comprising from 1 to 15 carbon atoms, said groups being optionally substituted with one or more substituents selected from, halogen, cyano, cartoxyl, carboxylic acyl, carbamyl, alkoxycarbonyl, alkoxy, alkylenedioxy, hydroxy, nitro, haloalkyl, alkyl, amino, acylamino, imidate and phosphonato groups; and acid addition salts and quaternary ammonium salts and Nsxides derived therefrom. Rl is preferably a halosubstituted phenyl, pyridyl or diazinyl group.
In a preferred aspect invention provides compounds of formula (T) where R1 represents an optionally halogen substituted phenyl group or an optionally halogen substituted pyridyl, pyridazinyl or pyrazinyl group and R2 represents hydrogen or a Clo alkyl, alkenyl, alkynyl, phenyl, benzyl, pyridylmethyl, thienylmethyl, thiazolylmethyl group which may be optionally substituted with one or more alkyl, alkoxy, alkoxycarbonyl, cyano, optionally substituted alkane sulphonyl groups or halogen atoms; and acid addition salts thereof.
One particularly preferred group of compounds are those wherein R' represents an optionally halogen substituted phenyl or pyridyl group and R2 represents a allcyl group containing up to 4 carbon atoms which may optionally be substituted with one or more halogen atoms.
An especially preferred group of compounds are those wherein R' represents a 5halopyrid-3-yl group and R2 represents hydrogen or a haloalkyl, haloalkenyl or halobenzyl group.
Specific compounds of formula I according to the invention include those set out in Table I below in which the groups represented by Rl and R2 are given for each compound, together with the melting point ( C) or an indication of the physical state of the compound.
TABLE I Compound Rl R2 Melting Point No 1 3,5-dichlorophenyl methyl 145-146 C 2 3,5-difluorophenyl methyl 93-94 C 3 2,3-difluorophenyl methyl oil 4 pentafluorophenyl methyl oil 5 2,3-dichlorophenyl methyl solid 6 4-methoxyphenyl benzyl (Isomer A) 178.4 C 7 4-methoxyphenyl benzyl (Isomer B) 95-100 C 8 phenyl benzyl 90-90.5 C 9 3.5-difluorophenyl H 112.1 C 10 3.5-difluorophenyl benzyl 85.2 C 11 3,5-difluorophenyl 5,6-dichloropyrid-3- 143.2-144.2 C ylmethyl 12 3,5-difluorophenyl pyrid-2-ylmethyl 127.9-128.5 C 13 3,5-difluorophenyl 3-methylbenzyl 95.9-96.1 C 14 3,5-difluorophenyl 4chlorobenzyl 95.5-96.7 C 15 3,5-diiluorophenyl pyrid-3-ylmethyl 78.2 C 16 3,5-difluorophenyl 3,4methylenedioxybenzyl oil 17 3,5-difluorophenyl 3,5-dichlorobenzyl 154.1 C 18 3,5-difluorophenyl 3,3-difluoroprop-2-en-1-yl 94.6 C 19 3,5-difluorophenyl 2-hydroxy-2-phenylethyl 120.8 C 20 3,5-difluorophenyl 1-phenyl-2-hydroxyethyl 168.8 C 21 3,5-difluorophenyl allyl 70.5 C 22 3,5-difluorophenyl propargyl 108.4 C 23 3,5-difluorophenyl 2-fluoroethyl oil 24 3,54ifluorophenyl 2-hydroxyethyl 100.4 C 25 3,5Zifluorophenyl 2-methoxyethyl 54.8 C 26 3,5-difluorophenyl 2-cyanoethyl 115 C 27 3,5-difluorophenyl 5-chlorothien-2-ylmethyl 114 0C 28 3,5-difluorophenyl 6-chloropyrid-2-yl gum 29 3,5-difluorophenyl 2-methylthiazol-5-ylmethyl 140 C 30 3,5-difluorophenyl 2-iminyl-2-methoxyethyl 109 C 31 phenyl benzyl (exo-isomer) 115-116 C 32 phenyl benzyl (endisomer) 97 C 33 pyrid-3-yl methyl 87 C Compound Rl R2 Melting Point No 34 pyrid-3-yl 2-fluoroethyl 86-88 C 35 pyrid-3-yl allyl 90-92 C 36 pyrid-3-yl H 80-81 C 37 pyrid-3-yl benzyl 119-120 C 38 pyrid-3-yl ethyl oil 39 pyrid-3-yl -butoxycarbonylmethyl gum 40 N-methylpyridinium-3-yl t-butoxycarbonyl (iodide) 185-187 CC 41 6-chloropyridazin-3-yl methyl 119-120 C 42 pyrid-3-yl propyl oil 43 6-chloropyrazin-2-yl methyl 80 C 44 pyrid-3-yl methane- 163-164 C sulphonylmethylsulphonyl 45 pyrid-3-yl methane-sulphonyl 135 C 46 6-chloropyrid-3-yl methyl gum 47 pyrid-3-yl methoxymethyl oil 48 pyrid-3-yl ethoxymethyl oil 49 pyrid-3-yl cyanomethyl 90-91 C 50 pyrid-3-yl ethoxycarbonylmethyl gum 51 pyrid-3yl methoxycarbonylmethyl gum 52 2-fluoro-4-nitrophenyl methyl 100-102 C 53 3-fluorophenyl methyl oil 54 pyrid-3-yl 2-hydroxyethyl 155.2-156.8 C 55 5,6-dichloropyrid-3-yl methyl 110.1-111.4 C 56 pyrid-3-yl propargyl 119-8-121.1 C 57 pyrid-3-yl methyl gum 58 pyrid-3-yl but-2-en-1-yl 193-194 C 59 3,5-difluorophenyl 4-nitropheny 96.9-97.9 C 60 5-chloropyrid-3-yl methyl 152.8-154.5 C 61 pyrid-3-yl phenyl 136-137 C 62 pyrazin-2-yl methyl 76-76.9 C 63 2,6-dichloropyrimid-4-yl methyl 95.3-96.8 C 64 5-chloropyrid-3-yl 2-fluoroethyl 125.9-126.9 C 65 2,6-dichloropyridXyl methyl 165-165.8 C 66 2-chloro-6- methyl 72-73 C hydrazinopyridXyl 67 pyrid-4-yl methyl 74.5-76.1 C 68 5-bromopyrid-3-yl methyl 144.1-145.2 C 69 5whloropyrid-3-yl vinyloxycarbonyl gum 70 5-chloropyrid-3-yl H 85-87 C 71 6-chloropyrid-2-yl methyl 103.9-104.8 C 72 5-chloropyrid-3-yl 2,2,2-trifluoroethyl 109.5-111.5 CC 73 3,5-difluorophenyl pyrid-2-yl oil 74 5-chloropyrid-3-yl phenyl 122-123 C 75 5-chloropyrid-3-yl propargyl 110-112 C 76 5-chloropyrid-3-yl allyl 78-80 C Compound R' R2 Melting Point No 77 5-methoxypyrid-3-yl methyl 112.2-113.1 C 78 5-chloropyrid-3-yl ethyl 116-118 C 79 5-chloropyrid-3-yl butyl 48-50 C 80 5-ethoxypyrid-3-yl methyl 567.2-57 C 81 5-chloropyrid-3-yl hexyl resin 82 5-chloropyrid-3-yl phenoxycarbonyl 117-123 C 83 5-chloropyrid-3-yl 2,2,2- oil - ~- trichioroethoxycarbonyl 84 5-chloropyrid-3-yl ethoxycarbonyl oil 85 5-chloropyrid-3-yl fluoren-9- 68-70 C ylmethyloxycarbonyl 86 5-chloropyrid-3-yl ethoxycarbonylmethyl gum 87 5-chloropyrid-3-yl isopropyl oil 88 5-chloropyrid-3-yl 4,4,4-trifluorobut-3-on- 1 - 143.9-145.1 C en-1-yl 89 5-chloropyrid-3-yl 1-methyl-2,2,2- 152-155 C trichioroethoxycarbonyl 90 5-chloropyrid-3-yl allyloxycarbonyl oil 91 5-chloropyrid-3-yl benzyloxycarbonyl oil 92 5-chloropyrid-3-yl 2-chloroethoxycarbonyl gum 93 5-chloropyrid-3-yl pentafluorobenzyl 143-144 C 94 5chloropyrid-3-yl 4-nitrophenyl 213-214.5 C 95 5-chloropyrid-3-yl acetyl 162-165 C 96 5-chloropyrid-3-yl trifluoroacetyl 121-124 C 97 5-chloropyrid-3-yl 4-chlorobenzoyl 175-177 C 98 5-chloropyrid-3-yl 4-fluorobenzoyl 200-204 C 99 5-chloropyrid-3-yl 3-fluoropropyl oil 100 5-chloropyrid-3-yl 2,4-bis(trifluorb 112-114 CC methyl)benzyl 101 5-chloropyrid-3-yl 4-carboxybeazyl gum 102 5-(prop-1-enyloxy)pyrid- methyl gum 3-yl 103 5-chloropyrid-3-yl 2,3-difluorobenzyl 102-103 C 104 5-chloropyrid-3-yl 2-phenylethyl oil 105 5-chloropyrid-3-yl 4-cyanophenyl 201-204 C 106 5-chloropyrid-3-yl 3,3-difluoroprop-2-en-1-yl oil 107 5-chloropyrid-3-yl carboxymethyl 165-167 C 108 5-chloropyrid-3-yl 3,5-dibromobenzyl 194-196 0C 109 5-chloropyrid-3-yl 3-chloro-4-fluorobenryl 95-97 C 110 5-chloropyrid-3-yl formyl 141-142 C 111 5-chloropyrid-3-yl isopropoxycarbonyl gum 112 5-chloropyrid-3-yl benzenesulfonyl 210-211 C 113 5-chloropyrid-3-yl 2,4,6-trifluorobenzyl 106-107 C 114 5-chloropyrid-3-yl 2,3,6-trifluorobenzyl 125-127 C 115 5-chloropyrid-3-yl l-cyano-1-phenylmethyl 141-142 C 116 5-chloropyrid-3-yl methoxycarbonyl oil Compound R' R2 Melting Point No 117 5-chloropyrid-3-yl pyrid-2-ylmethyl 123-125 C 118 5-chloropyrid-3-yl pyrid-3-ylmethyl 105-107 C 119 5-chloropyrid-3-yl pyrid-4-ylmethyl 111-114 CC 120 pyrid-2-yl 2-fluoroethyl 82-84 C 121 5-chloropyrid-3-yl (R)-1-phenylethyl 115.6-116.7 C 122 5-chloropyrid-3-yl (S)-1-phenylethyl 113.4-115 C 123 5-chloropyrid-3-yl 2-methylthiazol-4-ylmethyl 81-83 C 124 5-chloropyrid-3-yl 3,5-dimethylisoxazol-4- 95-99 C ylmethyl 125 5-chloropyrid-3-yl 5-chlorothien-2-ylmethyl 119-121 C 126 5-chloropyrid-3-yl 5-trifluoromethylpyrid-2-yl 124.5-125.5 C 127 pyrid-3-yl 2-methoxyethyl 251-253 C 128 5-chloropyrid-3-yl 6-fluoropyrid-2-yl 131.5-132.5 C 129 5-chloropyrid-3-yl 4-fluorophenyl solid 130 5-chloropyrid-3-yl 2,2,3,3,3-pentafluoropropyl oil 131 5-chloropyrid-3-yl 2,2,3,3-tetrafluoropropyl 110113 0C 132 5-chloropyrid-3-yl 2,2,3,3,4,4,4- oil heptafluoropropyl 133 5-chloropyrid-3-yl 2,2,3,3,4,4,5,5- oil octafluoropropyl 134 5-aminopyrid-3-yl methyl 188-190 C 135 5-chloropyrid-3-yl l-phenyl-l- 193-195 C cartoxamidomethyl 136 5-chloropyrid-3-yl 6-trifluoromethylpyrid-2-yl 117.5-118.5 C 137 5-chloropyrid-3-yl 6-chloropyrid-2-yl 176-177 C 138 5-chloropyrid-3-yl mercaptothiocarbonyl 224 C 139 5-chloropyrid-3-yl t-butyl 127-129 C 140 5-chloropyrid-3-yl 2-(ethoxycarbonyl)ethyl gum 141 5-chloropyrid-3-yl 2-carboxyethyl 180-181 C 142 5-chloropyrid-3-yl 2,2-difluoroethyl 101-104 C 143 5-bromopyrid-3-yl 2,2,2-trifluoroethyl 105-110 C 144 5-chloropyrid-3-yl fluorocartonyl 165-167 C 145 5-chloropyrid-3-yl N-methyl-N-phenyl 108-110 C carbamyl 146 5-chloropyrid-3-yl N-t-butylcarbamyl 62-65 C 147 5-iodopyrid-3-yl methyl 144-145 C 148 5-hydroxypyrid-3-yl methyl 170.9-171.7 C 149 5-chloropyrid-3-yl 4-morpholinocarbonyl 143-145 C 150 5-chloropyrid-3-yl N,Ndiisopropylcarbamyl 118-121 CC 151 5chloropyrid-3-yl pentafluorophenyl gum 152 5-chloropyrid-3-yl 6-chloropyrimin-4-yl 174-176 C 153 Schloropyrid-3-yl 2-acetamidothiazol-4- solid ylmethyl 154 5chloropyrid-3-yl N-(3chloro4- 216-218 C fluorophenyl) carbamyl 155 5-chloropyrid-3-yl 5-chloropyrid-3-yl gum Compound Rl R2 Melting Point No 156 5-chloropyrid-3-yl 4-trifluoromethylpyrid-3- 149.3-150.4 C carboxamidomethyl 157 5-chloropyrid-3-yl 4-trifluoromethylpyrid-3- 80.3-81.9 C ylcarbonyl 158 5chloropyrid-3-yl 5-chloro-1,2,3-triadiazol-4- oil ylmethyl 159 5-chloropyrid-3-yl 1-formyl-1-phenylethyl 124-126 C 160 5-chloropyrid-3-yl -- 4,4,4-trifluorobutyl oil 161 5-methoxypyrid-3-yl 2,2,2-trifluoroethyl 88-90 C 162 5-chloropyrid-3-yl 4-ethoxycarbonylphenyl 131.5-132.5 C 163 5-chloro-6-fluoro pyrid- 2,2,2-trifluoroethyl 121-122 C 3-yl 164 5-chloropyrid-3-yl vinyloxycarbonyl gum 165 5.acetnmidopyrid-3-yl methyl 195-197 C 166 5-methoxypyrid-3-yl- cyanomethyl solid 167 5-chloropyrid-3-yl 3-chloromethyl-1,2,4- gum thiadiazol-5-yl 168 5-chloropyrid-3-yl 5-chlorothiazol-2-yl 111-112 C 169 5-chloropyrid-3-yl cyano 168-170 C 170 5-chloropyrid-3-yl 4-carboxyphenyl solid 171 5-methoxypyrid-3-yl vinyloxycarbonyl gum 172 5-methoxypyrid-3-yl H 112-114 C 173 5-chloropyrid-3-yl 4-chlorophenyl 137.5-138 C 174 5-trifluoromethylpyrid-3- methyl 118.2-118.5 C yl 175 5-chloropyrid-3-yl 2-phenylbut-3-en-2-yl gum 176 5-chloropyrid-3-yl 3-hydroxy-2-phenylprop-2- 124-126 C yl 177 5-trifluoromethylpyrid-3- formyl 117-121 0C yl 178 5-chloropyrid-3-yl 3-acetoxy-2-phenylprop-2- 130-131 C yl 179 5hloropyrid-3-yl 2-fluoro2-phenylpro1-yl gum 180 5-chloropyrid-3-yl 3,3,5-trimethylhexyl 181 5-bromopyrid-3-yl vinyloxycarbonyl 63-66 C 182 5-chloropyrid-3-yl pyrimid-2-yl; 148.5-149.5 C 183 5-trifluoromethylpyrid-3- vinyloxycarbonyl resin yl 184 5-trifluoromethylpyrid-3- H resin yl 185 pyrid-3-yd vinyloxycarbonyl gum 186 5-trifluoromethylpyrid-3- 3-chlorobenzyl oil yl 187 5-chloropyrid-3-yl 2-chloropyrimid-4-yl 210-212 C 188 5-chloropyrid-3-yl 4-trifluoromethylphenyl 131-132 C 189 5-(pyrrol-1-yl)pyrid-3-yl methyl gum Compound R' R2 Melting Point No 190 N-oxidopyrid-3-yl t-butoxycarbonyl 55-57 C 191 5-chloropyrid-3-yl 2-phenyl-2- gum isopropylaminoprop-1-yl 192 5-chloropyrid-3-yl 2-phenyl-3-hydroxy-3- 172-175 C cyanoprop-2-yl 193 5-ethynylpyrid-3-yl methyl solid 194 pyrimid-4-yl methyl solid 195 5-(1-ethoxyvinyl)pyrid-3- methyl - gum yl 196 pyrid-3-yl 1,1-dimethylpropyl gum 197 5-chloropyrid-3-yl 1-ethoxycarbonylethyl gum 198 5-bromopyrimid-4-yl methyl 141-145 C 199 5-trifluoromethylpyrid-3- 2,2,2-trifluoroethyl gum yl 200 6-pyrimid-4-ylpyrimid-4- methyl 136-154 C yl 201 5-acetylpyrid-3-yl methyl gum 202 5-fluoropyrid-3-yl methyl 135-137 C 203 5-bromopyrid-3-yl H 128-130 C 204 5-bromopyrid-3-yl 2-chlorobenzyl 109-111 C 205 5-chloropyrid-3-yl 2-(3-chlorophenyl)prop-2- gum yl 206 5-(2-hydroxyprop-2- methyl gum yl)pyrid-3-yl 207 5-chloropyrid-3-yl 2-methylbut-3-yn-2-yl 107-110 C 208 5-bromopyrid-3-yl ethoxycarbonyl 92-94 C 209 5-chloropyrid-3-yl 2-methyl-1,1,1- 97-99 C trifluoroprop-2-yl 210 5-bromopyrid-3-yl 2-methylpropyl oil 211 5-chloropyrid-3-yl 1-methoxycarbonylethyl gum (Isomer A) 212 5-chloropyrid-3-yl 1-methoxycarbonylethyl 105-106 C (racemate) 213 5-chloropyrid-3-yl 1-methoxycarbonylethyl gum (Isomer B) 214 6-methoxypyrazin-2-yl methyl gum 215 5-chloropyrid-3-yl 1-cyano-1-(3- foam chlorophenyl)methyl 216 5-chloropyrid-3-yl 1-cyanoethyl gum 217 5-phenylpyrid-3-yl vinyloxycarbonyl gum 218 5-chloropyrid-3-yl 4,4-difluorobut-3-en-1-yl oil 219 5-chloropyrid-3-yl 1-cyano-2-methylprop-1-yl gum 220 5-phenylpyrid-3-yl H gum 221 5-methylpyrid-3 -yl vinyloxycarbonyl gum 222 5-ethoxycarbonylpyrid-3- vinyloxycarbonyl solid yl 223 5-chloropyrid-3-yl 2-cyanoprop-2-yl solid Compound Rl R2 Melting Point No 224 Gethynylpyrazin-2-yl methyl solid 225 5-ethoxycarbonylpyrid-3- H gum yl 226 5-(2,2,2- trifluoroethyl oil - trifluoroethoxy)pyrid-3-yl 227 5-chloropyrid-3-yl 3,5 bis(trifluoromethyl)benzyl 228 5-chloropyrid-3-yl 2,6-difluorobenzyl 229 5-chloropyrid-3-yl 3-phenoxybenzyl 230 5-chloropyrid-3-yl 3-bromo-4-fluorobenzyl 231 5-chloropyrid-3-yl 3-benzoylbenzyl 232 5-chloropyrid-3-yl 3-(2,6 dichlorobenzoyl)benzyl 233 5-chloropyrid-3-yl 3-(2,6 difluorobenzoyl)benzyl 234 5-chloropyrid-3-yl 4-allyl-2,3,5,6 tetrafluorobenzyl 235 5-chloropyrid-3-yl 3-trifluoromethoxybenzyl 236 5-chloropyrid-3-yl naphth-1-ylmethyl 237 5-chloropyrid-3-yl benzyl 238 5-chloropyrid-3-yl 2-bromobenzyl 239 5-chloropyrid-3-yl 2-methylbenzyl 240 5-chloropyrid-3-yl 3-bromobenzyl 241 5-chloropyrid-3-yl 3-methoxycarbonylbenzyl 242 5-chloropyrid-3-yl 3-methylbenzyl 243 5-chloropyrid-3-yl 4-bromobenzyl 244 5-chloropyrid-3-yl 4-methoxycarbonylbenzyl 245 5-chloropyrid-3-yl 4-t-butylcarbonylbenzyl 246 5-chloropyrid-3-yl 4-t-butylbenzyl 247 5hloropyrid-3-yl 4-isopropylbenzyl 248 5-chloropyrid-3-yl 4-methylbenzyl 249 5-chloropyrid-3-yl 3,4-difluorobenzyl 250 5-chloropyrid-3-yl 2-fluorobenzyl 251 5-chloropyrid-3-yl 3-bromo-5-fluorobenzyl 252 5-chloropyrid-3-yl 2,4-difluorobenzyl 253 5-chloropyrid-3-yl 3-fluorobenzyl 254 5-chloropyrid-3-yl 4-fluorobenzyl 255 5-chloropyrid-3-yl 3-trifluoromethylbenzyl 256 5-chloropyrid-3-yl 4-trifluoromethylbenzyl 257 5-chloropyrid-3-yl 2-fluoro-3-chlorobenzyl 258 5-chloropyrid-3-yl 2-chloro-3,6-difluorobenzyl 259 5-chloropyrid-3-yl 2chlorobenzyl 260 5-chloropyrid-3-yl 2,6-dichlorobenzyl 261 5-chloropyrid-3-yl 3-chlorobenzyl 262 5-chloropyrid-3-yl 2-iodo-4-fluorobenzyl 108-109 C 263 5-chloropyrid-3-yl 2-fluoro-3-methylbenzyl 264 5-chloropyrid-3-yl 2-(N-succinimido)benzyl Compound R' R2 Melting Point No 265 5-chloropyrid-3-yl 2-fluoro-5 triflurormethylbenzyl 266 5-chloropyrid-3-yl biphenyl-2-ylmethyl 267 5-chloropyrid-3-yl 2-cyanobenzyl 268 5-chloropyrid-3-yl 4-(1,2,3-thiadiazolX yl)benzyl 269 5-chloropyrid-3-yl 3-(4-fluorophenoxy)benzyl 270 5-chloropyrid-3-yl - 4cyanobenzyl 271 5-chloropyrid-3-yl 2,3,4-trifluorobenzyl 272 5-chloropyrid-3-yl 2-nitrobenzyl 273 5-chloropyrid-3-yl 2-nitro-6-fluorobenzyl 274 5-chloropyrid-3-yl 3-nitrobenzyl 275 5-chloropyrid-3-yl 4-nitrobenzyl 276 5-chloropyrid-3-yl 2-methylprop-1-yl 277 5-chloropyrid-3-yl decyl 278 5-chloropyrid-3-yl 2-phenoxyethyl 279 5-chloropyrid-3-yl 2-ethoxyethyl 280 5-chloropyrid-3-yl 3-methylbut-1-yl 281 5-chloropyrid-3-yl 3-methoxycarbonylprop-1 yl 282 5-chloropyrid-3-yl 3-phenylprop-1-yl 283 5-chloropyrid-3-yl cyclohexylmethyl 284 5-chloropyrid-3-yl 2cyanoethyl 285 5-chloropyrid-3-yl 3-cyanoprop-1-yl 286 5-chloropyrid-3-yl 2-hydroxyprop-1-yl 287 5-chloropyrid-3-yl 2-propenoyloxyethyl 288 5-chloropyrid-3-yl 2-methoxyethyl 289 5-chloropyrid-3-yl tetrahydropyran-2-ylmethyl 290 5-chloropyrid-3-yl 2-hydroxymethylprop- 1 -yl 291 5-chloropyrid-3-yl diethylphosphonomethyl 69-70 C 292 5-chloropyrid-3-yl phosphonomethyl 242-245 C 293 5-chloropyrid-3-yl methyl (N-oxide) 153-155 C 294 pyrid-3-yl t-butoxycarbaryl 295 6-choloropyrid-3-yl H 296 5-chloropyrid-3-yl methoxy 297 2-chloropyrimid-4-yl 2,2,2-trifluoroethyl 298 6-chloropyrazin-2-yl vinyloxycarbonyl 299 6-chloropyrazin-2-yl H 300 6-chloropyrazin-2-yl 3-chlorobenzyl 301 6-chloropyrazin-2-yl cyanomethyl 302 5-chloropyrid-3-yl 1 -(3chlorophenyl)ethyl 303 5whloropyrid-3-yl 4-methoxyphenyl 304 5-cyanopyrid-3-yl methyl 305 2-chloropyrid-4-yl methyl 306 5-chloropyrid-3-yl 2-phenylprop-1-en-1-yl 307 5-chloropyrid-3-yl methylmercaptothio carbonyl Compound Rl R2 Melting Point No 308 5-(2,2,2-trifluoro- methyl ethoxy)pyrid-3-yl 309 5-iodopyrid-3-yl vinyloxycarbonyl It will be appreciated that the bicyclic amine compounds of formula I are capable of existing in more than one isomeric form since the groups R' and R2 may be positioned in either an exo or endo relationship, and the present invention embraces within its scope both exo and endo forms and mixtures thereof and also any further isomeric variants arising from cis and trans substitution patterns or chiral centres present in either of Rl or R2.
Suitable acid addition salts include those with an inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, or an organic carboxylic acid such as oxalic, tartaric, lactic, butyric, toluic, hexanoic and phthalic acids, or sulphonic acids such as methane, benzene and toluene sulphonic acids. Examples of salts of compound 72 (Table I) with some less common acids are given in Table IA.
TABLE IA Compound No Acid Component 310 2-chlorobenzoic acid 311 Schlorophenoxyacetic acid 312 2P,6-trimethylbenzoic acid 313 3-benzylbenzoic 314 4hydroxybenzoic acid 315 1-phenylpropionic acid 316 3-(4-hydroxyphenyl)propenoic acid 317 undecanoic acid 318 4-(4-hydroxyphenyl)butyric acid 319 2-hydroxy-5-nitrobenzoic acid 320 2-nitro-5-N-methylformamidobenzoic acid 321 2,2,3,3-tetramethylcyclopropanoic acid The preparation of the compounds of formula (I) may be accomplished by use of one or more of the following synthetic techniques described below and further illustrated in the Examples.
The compounds of general formula (')can be prepared from compounds of general formula (11) by treating them with a suitable base, such as potassium carbonate, in the presence of compound of formula R2 where L is a suitable leaving group such as a halide or triflate.
Alternatively, compounds of general formula (I) can be prepared from compounds of general formula (n) by reductive amination with an aldehyde (R3CHO; where R3CH2=R2) in the presence of a suitable reducing agent such as formic acid.
Compounds of general formula (11) can be prepared by demethylating compound of general formula (m) by, for instance, treating them first with a chloroformate ester (such as vinyl chloroformate) to produce a carbamate, followed by acid hydrolysis.
Compounds of general formula (III) can be prepared by treating 3cyano8-methyl-8- azabicyclo[3.2.1]octane (IV) first with a suitable base, such as lithium diisopropylamide (LDA), followed by reaction with an aryl or heteroaryl halide (R1Hal).
3-Cyano8-methyl-8-azabicyclo[3.2.1]octane (IV) can be prepared by treating tropinone (V) with tosylmethyl isocyanide in the presence of a suitable base, such as potassium ethoxide. As an alternative 3-cyano-8-methyl-8-azabicyclo[3.2.1loctane (IV) can be prepared from tropine (XE) by treatment with thionyl chloride to give alternative 3-chloro8-methyl-8-azabicyclo[3.2.1]octane (XIII) followed by treatment with cyanide as described in J. Am. Chem. Soc., 1958 80, 4677.
As an alternative, compounds of general formula (I) can be prepared from compounds of general formula (VI) by treatment with a suitable base, such as lithium diisopropylamide (LDA), followed by reaction with an aryl or heteroaryl halide (R'Hal).
Compounds of general formula (VI) can be prepared from 3-cyano-8- azabicyclo[3.2.l]octane (V) by treatment with a suitable base, such as potassium carbonate, in the presence of an alkyl halide (R2Hal).
3-Cyano-8-azabicyclo[3.2.1]octane (VII) can be prepared by demethylating 3cyano-8methyl-8-azabicyclo[3.2.1]octane (IV) by, for instance, treatment first with a chloroformate ester (such as vinyl chloroformate) to produce a carbamate, followed by acid hydrolysis.
As a further alternative, compounds of general formula (VI) can be prepared by treating compounds of general formula (Vm) with tosylmethyl isocyanide in the presence of a suitable base, such as potassium ethoxide.
Compounds of general formula (Vm) can be prepared by the Robinson tropinone synthesis, see, for instance, J. Chem. Soc., 1917, 111, 762. As an alternative compounds of general formula (Vm) can be prepared from cyclohepta-2,6-dienone (XI) by reaction with an amine (R2NH2) as described in, for instance, Tetrahedron, 1973, 155, Bull, Chem, Chem, Soc, Jpn., 1971, 44, 1708 and J. Org. Chem., 1971, 36, 1718.
As yet a further alternative, compounds of general formula (I) can be prepared by treatment of a compound of general formula (DC) with an aryl- or heteroaryl-acetonitrile of general formula (x) in the presence of a suitable base, such as sodium hydride, as described in J. Med. Chem., 1975, 18, 496.
The compounds of general formula (VI) (except those where R2 represents methyl, benzyl or trichloroethyl are believed not to have been previously described. Accordingly in a further aspect the invention provides compounds of formula (VI) wherein R2 has any of the meanings given hereinabove except that R2 cannot be methyl, benzyl or trichloroethyl.
In a further aspect the invention provides a method of combating insect and like pests at a locus by applying to the locus or the pests an insecticidallyeffective amount of an insecticidal composition comprising the compounds of Formula I or an acid addition salt thereof.
The compounds of Formula I and acid addition salts thereof may be used to combat and control infestations of insect pests such as Lepidoptera, Diptera, Homoptera and Coleoptera (including Diabrotica i.e. corn rootworms) and also other invertebrate pests, for example, acarine pests. The insect and acarine pests which may be combated and controlled by the use of the invention compounds include those pests associated with agriculture (which term includes the growing of crops for food and fibre products), horticulture and animal husbandry, forestry, the storage of products of vegetable origin, such as fruit, grain and timber, and also those pests associated with the transmission of diseases of man and animals.Examples of insect and acarine pest species which may be controlled by the compounds of Formula I include: Myzus persicae (aphid), Aphis gossypii (aphid), Aphis fabae (aphid), Aedes aegvpti (mosquito), Anopheles spp. (mosquitos), Culex spp. (mosquitos), Dysdercus fasciatus (capsid), Musca domestica (housefly), Pieris brassicae (white butterfly), Plutella xylostella (diamond back moth), Phaedon cochleariae (mustard beetle), Aonidiella spp. (scale insects), Trialeurodes spp. (white flies), Bemisia tabaci (white fly), Blattella germanica (cockroach), Periplaneta americana (cockroach), Blatta orientalis (cockroach) Spodoptera littoralis (cotton leafworm), Heliothis virescens (tobacco budworm) Chortiocetes terminifera (locust), Diabrotica spp. (rootworms), Agrotis spp. (cutworms), Chilo partellus (maize stem borer), Nilaparvata lugens (planthopper), Nephotettix cincticeps (leafhopper), Panonychus ulmi (European red mite), Panonychus citri (citrus red rnite), Tetranychus urticae (two-spotted spider mite), Tetranvchus cinnabarinus (carmine spider mite), Phyllcoptruta oleivora (citrus rust mite), Polyphagotarsonemus latus (broad mite) and Brevipalpus spp. (mites).
In order to apply the compounds of Formula I to the locus of the nematode, insect or acarid pest, or to a plant susceptible to attack by the nematode, insect or acarid pest, the compound is usually formulated into a composition which includes in addition to the the compounds of Formula I suitable inert diluent or carrier materials, andlor surface active agents. The amount of composition generally applied for the control of nematode pests gives a rate 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 or seed, 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, sulphur, 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 corn cobs, and the like, or on to hard core materials such as sands, silicates, mineral carbonates, sulphates, 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 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-volatile 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.
Suitable liquid solvents for ECs include methyl ketone, methyl isobutyl ketone, cyclohexanone, xylenes, toluene, chlorobenzene, paraffins, kerosene, white oil, alcohols, (for example, butanol), methylnaphthalene, trimethylbenzene, trichloroethylene, N-methyl-2-pyrrolidone and tetrahydrofurfuryl alcohol (I ;A).
Wetting agents, dispersing agents and emulsifying agents may be of the cationic, anionic or non-ionic type. Suitable agents of the cationic type include, for example, quaternary ammonium compounds, for example cetyltrimethyl ammonium bromide. Suitable agents of the anionic type include, for example, soaps, salts of aliphatic monoesters of sulphuric acid, for example sodium lauryl sulphate, salts of sulphonated aromatic compounds, for example sodium dodecylbenzenesulphonate, sodium, calcium or ammonium lignosulphonate, or butylnaphthalene sulphonate, and a mixture of the sodium salts of diisopropyl- and trlisopropylnaphthalene sulphonates.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 10-858 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.
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 suspension CS) for use in seed treatments.
In use the compositions are applied to the insect pests1 to the locus of the pests, to the habitat of the pests, or to growing plants liable to infestation by the pests, by any of the known means of applying pesticidal compositions, for example, by dusting, spraying, or incorporation of granules.
The compound of Formula I may be the sole active ingredient of the composition or they may be admixed with one or more additional active ingredients such as insecticides, synergists, herbicides, fungicides or plant growth regulators where appropriate.
Suitable additional active ingredients for inclusion in admixture with a compound of Formula I may be compounds which will broaden the spectrum of activity of the compositions of the invention or increase their persistence in the location of the pest. They may synergise the activity of the compound of Formula I 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 type of complementary action required.Examples of suitable insecticides include the following: a) Pyrethroids such as permethrin, esfenvalerate, deltamethrin, cyhalothrin in particular lambda-cyhalothrin, biphenthrin, fenpropathrin, cyfluthrin, tefluthrin, fish safe pyrethroids for example ethofenprox, natural pyrethrin, tetramethrin, s-bioallethrin, fenfluthrin, prallethrin and 5-benzyl-3-fiirylmethyl-(E)-( 1 R,3S)-2,2imethyl- 3-(2-oxothiolan-3-ylidenemethyl) cyclopropane carboxylate; b) Organophosphates such as profenofos, sulprofos, methyl parathion, azinphos-methyl, demeton-s-methyl, heptenophos, thiometon, fenamiphos, monocrotophos, profenophos, triazophos, methamidophos, dimethoate, phosphamidon, malathion, chloropyrifos, phosalone, terbufos, fensulfothion, fonofos, phorate, phoxim, pyrimiphos-methyl, pyrimiphosethyl, fenitrothion or diazinon; c) Carbamates (including aryl carbamates) such as pirimicarb, cloethocarb, carbofuran, furathiocarb, ethiofencarb, aldicarb, thiofurox, carbosulfan, bendiocarb, fenobucarb, propoxur or oxamyl; d) Benzoyl ureas such as triflumuron, or chlorfluazuron; e) Organic tin compounds such as cyhexatin, fenbutatin oxide, azocyclotin; f) Macrolides such as avermectins or milbemycins, for example such as abamectin, ivermectin, and milbemycin; g) Hormones and pheromones; h) Organochlorine compounds such as benzene hexachloride, DDT, chlordane or dieldrin; i) Amidines, such as chlordimeform or amitraz; j) Fumigant agents; k) 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 ovo-larvicides such as chlofentezine, flubendmine, hexythiazox and tetradifon, motilicides such as dicofol or propargite, acaricides such as bromopropylate, chlorobenzilate, or growth regulators such as hydramethylron, cyromazine, methoprene, chlorofluazuron 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 herbicide 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 compounds of Formula I 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 rate if synergism occurs.
The invention is illustrated by the following examples. Examples 1 to 86 illustrate the preparation of a range of compounds of formula (I).
Examples 87 - 104 illustrate formulations suitable for the application of the the compounds of Formula I according to the invention. The following ingredients are referred to by their Registered Trade Marks and have the composition as shown below.
Registered Trade Mark Composition Synperonic NP8 ) Nonylphenolethylene oxide Synperonic NP13 } condensate Synperonic OP10 } Aromasol H Alkylbenzene solvent Solvesso 200 Inert organic diluent Keltrol Polysaccharide EXAMPLE 1 This example illustrates the preparation of exo-3-(pyrid-3-yl)-endo-3-cyano-8-methyl-8- azabicyclo[3.2. 1 ]octane.
Potassium -t-butoxide (22.4g) was added portionwise to a stirred mixture of tropinone (11.58g) and tosylmethyl isocyanide (21.2g) in dimethoxyethane (240ml) and ethanol (8ml) at 0 C under nitrogen at such a rate to maintain the temperature between 0 C and 10 C. The mixture was then allowed to warm to room temperature and stirred for a further 4 hours. After standing at room temperature for 3 days the mixture was filtered and the solid residue washed with dimethoxyethane. The filtrate was evaporated under reduced pressure and chromatographed [SiO2; dichloronrthar:methanol (90:10)] to give exo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (9.lg).
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (10.0g) in tetrahydrofuran (60ml) was added dropwise to a stirred solution of lithium diisopropylamide [made by adding n-BuLi (29ml of a 2.5M solution in hexane) to diisopropylamine (loll) in tetrahydrofuran (60i)] at -25 C under nitrogen. The mixture was stirred at 25 C for 20 minutes and then cooled to -78 C. 3 Fluoropyridine (1 0.0g) in tetrahydrofuran (60ml) was then added dropwise. The mixture was then allowed to warm to room temperature over 6 hours. The mixture was then poured into water and extracted with dichloromethane.The combined extracts were washed with brine, dried (MgSO4), evaporated under reduced pressure and chromatographed [sio2; dichloromethane:methanol (80:20)] to give a yellow oil which crystallised on standing. The solid was washed with hexane and ether, filtered and air dried to give exo-3-(pyrid-3-yl)-endo-3-cyano-8-methyl-8- azabicyclo[3.2.1]octane (8.2g).
EXAMPLE2 This example illustrates the preparation of exo-3-(pyrid-3-yl)-endo-3-cyano-8-(2-fluoroethyl)-8- azabicyclo[3.2.1]octane.
Vinyl chioroformate (6.0ml) in tetrahydrofuran (lOml) was added dropwise to exo-3-(pyrid-3-yl)- endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (4.0g) in tetrahydrofuran (4Onil) at 0 C under nitrogen. The mixture was then heated at 70 C for 4.5 hours. After cooling to room temperature the mixture was filtered and the solid residue washed with ethyl acetate. The combined filtrates were evaporated under reduced pressure and ciystallised on standing to give exo-3-(pyrid-3-yl)- endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (4.1g).
exo-3-(Pyrid-3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (3.5g) and concentrated hydrochloric acid (3ml) in methanol (25ml) were reflux for 6 hours and then allowed to stand at room temperature overnight. After the mixture had been refluxed for a further 4 hours it was allowed to cool to room temperature and then evaporated under reduced pressure.
The mixture was then partitioned between 2M sodium hydroxide and ethyl acetate and the aqueous layer was separated and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried (MgSO4) and evaporated under reduced pressure to give exo-3- (pyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (1.7g), which crystallised on stanching.
exo-3-(Pyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.2g), 1-bromo-2-fluoroethane (0.21ml), potassium carbonate (0.14g) and tetrahydrofuran (6i) were heated at 60 C for 6.5 hours and then allowed to stand at room temperature overnight. 1-Bromo-2-fluoroethane (0.2ml) was then added and the mixture heated at 60 C for 6 hours, cooled to room temperature, filtered and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (90:10)] gave exo-3-(pyrid-3-yl)-endo-3-cyano-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octane (0.123g) m.p. 84.4 C.
EXAMPLE 3 This example illustrates the preparation of exo-3-(3,5-difluorophenyl)-endo-3-cyano-8-methyl- 8-azabicyclo[3.2.1]octane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (13.6 g in tetrahydrofuran (80 ml) was added dropwise to a stirred solution of lithium diisopropyiarnide [made by adding n-BuLi (40ml of a 2.5M solution in hexane) to diisopropylamine (14.0ml) in tetrahydrofuran (80rnl)] at -25 C under nitrogen. The mixture was stirred at -25 C for 0.5 hours and then cooled to -78"C. 1,3,5 Trifluorobenzene (12.0g) in tetrahydrofuran (80ml) was added dropwise at such a rate to maintain the temperature below -65 C. The mixture was allowed to warm to room temperature overnight and then poured into water and extracted with dichloromethane.The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to give a yellow solid.
This was recrystallised fiom diethyl ether to give exo-3-(3,5-difluorophenyl)-endo-3-cyano-8- methyl-8-azabicyclo[3.2.1]octane. The mother liquor from the recrystallisation was chromatographed [SiO2; dichloromethane:methanol (90:10)] to give further exo-3-(3,5difluorophenyl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (11.2g in total).
EXAMPLE 4 This example illustrates the preparation of exo-3-(pyrid-3-yl)-endo-3-cyano-8-(prop-1-yl)-8- azabicyclo[3.2. 1 ]octane.
Vinyl chloroformste (2.5ml) in diethyl ether (15ml) was added dropwise to a stirred mixture of exo-3eyano-8-methyl-8-azabicyclo[3.2.1]octane (3.0g) in diethyl ether (15rnl) at -5 C under nitrogen. The mixture was then stirred at 0 C for 0.5 hours and at reflux for 5 hours. After cooling to room temperature the mixture was filtered and the solid residue washed with diethyl ether. The combined filtrates were evaporated under reduced pressure to give exo-3-cyano-8- (vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (2.93g).
exo-3-Cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (2.9g), concentrated hydrochloric acid (lml) and methanol (30ml) were refiuxed for 4 hours and then allowed to stand at room temperature overnight. Concentrated hydrochloric acid (lml) was added and the mixture refluxed for 4 hours. After cooling to room temperature the mixture was evaporated under reduced pressure, dissolved in ethyl acetate and washed with 2M sodium hydroxide and brine, dried (MgSO4) and evaporated under reduced pressure to give exo-3-cyano-8-azabicyclo[3.2.1]octane (1.09g) as a dark yellow solid.
exo-3-Cyano-8-azabicyclo[3.2.1]octane (0.5g), 1-bromopropane (0.34ml) and potassium carbonate (1.27g) were stirred in ethanol (5ml) at room temperature for 5 hours. 1 Bromopropane (0.17rnl) was then added and the mixture stirred overnight. 1-Bromopropane (0.17ml) was added and the mixture stirred at room temperature for 6 hours, a further portion of 1-bromopropane (0.17ml) was added and the mixture allowed to stand at room temperature for 3 days and then refluxed for 0.5 hours. The mixture was then cooled to room temperature, filtered and the filtrate evaporated under reduced pressure. Chromatography [SiOz; dichloromethane:methanol (90:10)] gave exo-3cyano-8-propyl-8-azabicyclo[3.2.I]octane (0.39g).
exo-3-Cyano-8-propyl-8-azabicyclo[3.2.1]octane (0.32g) in tetrahydrofuran 92ml) was added dropwise to a stirred solution of lithium diisopropylamide [made by adding n-Bull (0.8ml of a 2.5M solution in hexane to diisopropylamine (0.2rnl) in tetrahydrofuran (2ml)] at -25 C under nitrogen. The mixture was stirred at -25 C for 0.5 hours, cooled to -76 C and 3-fluoropyridine (0.175g) in tetrahydrofuran (2rnl) was added dropwise. The mixture was stirred at -76 C for 1 hour and then allowed to warm slowly to room temperature and allowed to stand overnight.The mixture was poured into water, extracted with ethyl acetate (x3) and the combined extracts washed with brine and water, dried (MgSO and evaporated under reduced pressure.
Chromatography [sio2; dichloromethane:methanol (95:5)] gave exo-3-(pyrid-3-yl)-endo-3qano- 8-(prop-1-yl)-8-azabicyclo[3.2.1]octane (0.35g).
EXAMPLE 5 This example illustrates the preparation of 3-phenyl-3-cyano-8-benzyl-8- azabicyclo[3.2.1]octane.
Sodium hydride (0.75g of a 55% suspension in oil) was carefully added to benzyl cyanide (0.69g) and meso-2,5-bis(chloromethyl)-1-benzylpyrrolidine (1.0g) in N,N-dimethylformamide (30ml) at 0 C under nitrogen The mixture was stirred at room temperature overnight and then poured into icecold water and extracted with dichloromethane. The aqueous layer was allowed to stand at room tenwrahnre overnight and then filtered and the solid residue washed with water and air dried. The solid product was chromatographed [SiO2; hexane:ethyl acetate (80:20)] to give a 10:1 (exo-phenyl):(endo-phenyl) mixture of 3-phenyl-3-cyano-8-benzyl-8-azabicyclo[3.2.1]octane (0.21g).
EXAMPLE 6 This example illustrates the preparation of exo-3-(pyrid-3-yl)-endo-3-cyano-8-benzyl-8- azabicyclo[3.2.1]octane.
Three drops of SM hydrochloric acid was added to a stirred mixture of 2,5dimethoxytetrahydrofuran (16.5g) and water (70ml). After 10 minutes a mixture of benzylamine (13.6ml) and 5M hydrochloric acid (30ml) were added followed by the immediate addition of a mixture of 1,3-acetonedicarboxylic acid (18.2g) and sodium acetate (lOg) in water (lOOml). After stirring at room temperature for 3 days, during which carbon dioxide was evolved, the mixture was basified to pH8 and extracted with ethyl acetate (x3). The combined extracts were dried (MgSO4) and evaporated under reduced pressure. Chromatography [sio2; hexane:ethyl acetate] to give 8benzyl-8-azabicyclo[3.2.1]octan-3-one(11.2g).
Potassium t-butoxide (2.5g) was added portionwise to a stirred mixture of 8-benzyl-8azabicyclo[3.2.1]octan-3-one (2.0g), tosylmethyl isocyanide (2.36g) and ethanol (2ml) in dimethoxyethane (50ml) at 0 C under nitrogen. The mixture was stirred at 0 C for 0.5 hours and then overnight at room temperature. The mixture was then filtered and the solid residue washed with dimethoxyethane. The combined filtrates were evaporated under reduced pressure and chromatographed [SiO2; hexane:ethyl acetate (80:20)] to give 3-cyano-8-benzyl-8- azabicyclo[3.2.1]octane (0.87g).
3-Cyano-8-benzyl-8-azabicyclo[3.2.1]octane (0.5g) in tetrahydrofuran (2ml) was added dropwise to a stirred solution of lithium diisopropylamide [made by adding n-BuLi (1.5ml of a 1 .6M solution in hexane) to diisopropylamine (0.246g) in tetrahydrofuran (2rnl)] at -25 C under nitrogen. After 0.5 hours the mixture was cooled to -76 C and 3-fluoropyridine (0.215g) in tetrahydrofuran (2ml) was added. After 2 hours the mixture was allowed to warm room temperature overnight and water then added The mixture was then extracted with ethyl acetate (x3) and the combined extracts were washed with brine and water, dried (MgSO and evaporated under reduced pressure.Chromatography [SiO2; dichloromethane:methanol (95:5)] gave exo3-(pyrid-3-ylY endo-3cyano-8-benzyl-8-azabicyclo [3.2. I]octane (0.245g) which crystallised on standing mp.
119-120 C.
EXAMPLE 7 This example illustrates the preparation of exo-3-(pyrid-3-yl)-endo-3-cyano-8-(2- methoxyethyl)-8-azabicyclo[3.2.1]octane, exo-3-(Pyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.30g), 2-bron:oethyl methyl ether (0.235g) and potassium carbonate (0.213g) were refluxed in ethanol (3rnl) for 30 hours. The mixture was allowed to cool to room temperature, filtered and washed with ethanol. The filtrate was evaporated under reduced pressure and chromatographed [SiOt; dichloromethane:methanol (95:5)] to give exo-3-(pyrid-3-yl}endo-3-cyano-8-(2-methoxyethyl)-8- azabicyclo[3.2.1]octane (0.223g).
EXAMPLE 8 This example illustrates the preparation of exo-3-(pyrid-2-yl)-endo-3-cyano-8-methyl-8- azabicyclo[3.2.1]octane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.5g) in tetrahydrofuran (3ml) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (1.6ml of a 2.5M solution in hexane) to diisopropylamine (0.4g) in tetrahydrofuran (3ml)] at -25 C under nitrogen.
After 30 minutes a solution of 2-fluoropyndine (0.388g) in tetrahydrofuran (3ml) was added.
After 1 hour the mixture was allowed to warm to room temperature and then stand overnight.
Water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with water (x2), dried (MgSO) ind evaporated under reduced pressure.
Chromatography [sio2; dichloromethane:methanol (90:10)] gave exo-3-(pyrid-2-yl)-endo-3- cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.467g).
EXAMPLE 9 This example illustrates the preparation of exo-3-(pyrazin-2-yl)-endo-3-cyano-8-methyl-8- azabicyclo[3.2. 1]octane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.5g) in tetrahydrofuran (3ml) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (1.6ml of a 2.5M solution in hexane) to diisopropylamine (0.4g) in tetrahydrofuran (3ml)] at -25 C under nitrogen.
After 30 minutes the mixture was cooled to -78"C and a solution of chloropyrazine (0.46g) in tetrahydrofuran (5ml) was added. After 1 hour the mixture was allowed to warm to room temperature and stand overnight. Water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [Siqz; dichloromethane:methanol (95:5) to (90:10)] gave exo-3-(pyrazin-2-yl)-endo-3-cyano-8-methyl-8-azabicylclo[3.2.1]octane (0.368g) m.p. 76-77 C.
EXAMPLE 10 This example illustrates the preparation of exo-3-(6-chloropyrazin-2-yl)-endo-3-cyano-8- methyl-8-azabicyclo[3.2.1]octane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (1.0g) in tetrahydrofuran (5ml) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (2.66ml of a 2.5M solution in hexane) to diisopropylamine (0.673g) in tetrahydrofuran (5ml)] at -25 C under nitrogen.
After 30 minutes the mixture was cooled to -78"C and a solution of 2,6-dichloropyrazine (1.0g) in tetrahydrofuran (5ml) was added. After 1 hour the mixture was allowed to warm to room temperature and stand over the weekend. Water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (95:5)] gave exo-3-(6-chloropyrazin-2-yl)-endo-3-cyano-8-methyl8-azabicyclo[3.2.1]octane (1. lOg) m.p. 79.8-80.1 C.
EXAMPLE 11 This example illustrates the preparation of exo-3-(6chloropyridazin-3-yl)-eho-3cyan methyl-8-azabicyclo[3.2.1]octane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.5g) in tetrahydrofuran (5ml) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (1.4ml of a 2.SM solution in hexane) to diisopropylamine (0.45g) in tetrahydrofuran (2ml)] at -25 C under nitrogen.
After 30 minutes 1,3-dimethyllmidaaolidinone (lml) was added and the mixture cooled to 78 C. A solution of 3,6-dichlorochloropyridazine (0.S0g) in tetrahydrofuran (2ml) was added. After 2 hours the mixture was allowed to warm to room temperature and stand overnight. Water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (95:5)] gave m3-(S chloropyridazin-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.082g).
EXAMPLE 12 This example illustrates the preparation of exo-3-(5,6-dichloropyrid-3-yl)-endo-3-cyano-8methyl-8-azabicyclo[3.2.1]octane.
3-Chloro-2-hydroxy-5-nitropyridine (4.8g) was added to phosphorus oxychloride (l lml) and phosphorus pentachloride (4.45g) and the mixture refluxed overnight. The mixture was then cooled to room temperature and evaporated under reduced pressure. Iced water was added to the mixture and a solid product formed The solid was removed by filtration, washed with water and air-dried to give 2,3-dichloro-5-nitropyridine (3.94g).
2,3-Dichloro-5-nitropyridine (3.9g) and iron powder (3.0g) were added to isopropyl alcohol (40ml) and water (8ml) and the mixture refluxed for 4 hours. The mixture was then cooled to room temperature and filtered (celite). The filtrate was evaporated under reduced pressure and chromatographed [SiO2; hexane:ethyl acetate (80:20) to (50:50)] to give 5-amino-2,3dichloropyridine (1.71g).
5-Amin2,3-dichloropyridine (0.80g) in dichloromethane (lOml) was added to boron trifluoride etherate (0.92ml) at -15 C under nitrogen. Dichloromethane (15ml) was added followed by t-butylnitrite (0.71ml) in dichloromethane (5ml). After 15 minutes the mixture was allowed to warm to -5"C over 20 minutes. Hexane was added and the resulting solid was filtered, air-dried and washed with ether and stored at approximately -20 C overnight. The solid was then heated until gas evolution had ceased and the product kugelrohr distilled to give 2,3-dichloro-5-fluoropyridine (0.104g).
exo-3-Cyano-8-methyl-8-azabicycio [3.2.l]octane (0.10g) in tetrahydrofuran (1ml) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (0.29ml of a 2.5M solution in hexane) to diisopropylamine (0.073g) in tetrahydrofuran (lml)] at -25 C under nitrogen.
After 30 minutes 2,3-dichloro-5-fluoropyridine (0. lOg) in tetrahydrofuran (lml) was added.
After 1 hour the mixture was allowed to warm to room temperature and stand overnight.
Water was added and the resulting mixture extracted with ethyl acetate (x3). The combined extracts were washed with water, dried (MgSO4) and evaporated under reduced pressure.
Chromatography [SiO2; dichloronthane:rnethano1 (95:5) to (90:10)] gave an orange gum which was triturated with hexane to give exo-3-(5,6-dichloropyrid-3-yl)-endo-3-cyano-8- methyl-8-azabicyclo[3.2.1]octane (0.019g) as a yellow solid.
EXAMPLE 13 This example illustrates the preparation of exo-3-(pyrid-3-yl)-endo-3-cyano-8- (methoxycarbonylmethyl)-8-azabicyclo[3.2.1]octane.
exo-3-(Pyrid-3-ylkendo-3-cyano-8-azabicyclot3.2.1]octane (0.20g), ethyl bromoacetate (0.187g) and potassium carbonate (0.155g) were refluxed in ethanol (3ml) for 4 hours. The mixture was then filtered and the filtrate evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (95:5)] gave exo-3-(pyrid-3-yl)-endo-3-cyano-8- (methoxycarbonylmethyl)-8-azabicyclo[3.2.1]octane (0.112g).
EXAMPLE 14 This example illustrates the preparation of exo-3-(pyrid-3-yl)-endo-3-cyano-8- (methylsulphonylmethylsulphonyl)-8-azabicyclo[3.2.1]octane.
exo-3-(Pyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.39g) and triethylamine (15ml) were added to dichloromethane (5ml) and the mixture cooled to -20 C. Methane sulphonyl chloride (0.12ml) was added dropwise and the mixture allowed to warm to room temperature.
After 1 hour the mixture was evaporated under reduced pressure and dissolved in ethyl acetate.
The resulting solution was washed with aqueous sodium bicarbonate solution and water (x2), dried (MgSO,) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (90:10)] gave a gum which formed a solid on trituration with hexane and ether. Chromatography [Si02; hexane:ethyl acetate (80:20)] gave exo-3-(pyrid-3-yl)-endo-3- cyano-8-(methylsulphonylmethylsulphonyl)-8-azabicyclo[3.2.1]octane (0.028g) wimp. 163 164 C.
EXAMPLE 15 This example illustrates the preparation of exo-3-(6-chloropyrid-3-yl)-endo-3-cyano-8- methyl-8-azabicyclo[3.2. 1 joctane.
exo-3-(Pyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.50g) in acetonitrile (3ml) was added dropwise to a stirred solution of di+butyl carbonate (0.512g) in acetonitrile (semi) at 0CC. 4 4-Dimethylaminopyridine (0.02g) was added and after 30 minutes the mixture was warmed to room temperature, stirred for 2 hours and allowed to stand overnight. The mixture was evaporated under reduced pressure and chromatographed [Si02; ethyl acetate:dichloromethane (20:80) to (30:70)] to give exo-3-(pyrid-3-yl)-endo-3-cyano-8-(t- butyloxycarbonyl)-8-azabicyclo [3.2.l]octane (0.602g).
m-Chloroperoxybenzoic acid (0.22g) was added to a solution of exo-3-(pyrid-3-yl)-endo-3- cyano-8-(t-butyloxycarbonyl)-8-azabicyclo[3.2.1]octane (0.20g) in dichloromethane (2ml) at 0 C under nitrogen. After 1 hour the mixture was warmed to room temperature and allowed to stand overnight. The mixture was evaporated under reduced pressure, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution (x2), dried (MgSO4) and evaporated under reduced pressure to give exo-3-(N-oxopyrid-3-yl)-endo-3-cyano-8-(t- butyloxycarbonyl)-8-azabicyclo[3.2.1]octane (0.161g).
exo-3-(N-oxopyrid-3-yl)-endo-3-cyano-8-(t-butyloxycarbonyl)-8-azabicyclo[3.2.1]octane (0.161g) was added to phosphorus oxychloride (lml) and the mixture refluxed for 1 hour.
The mixture was then allowed to cool to room temperature, evaporated under reduced pressure, toluene added and evaporated under reduced pressure. Ethyl acetate was added and the mixture washed with aqueous sodium hydroxide solution and water (x2), dried (MgSO4) and evaporated under reduced pressure to give exo-3-(6-chloropyrid-3-yl)-endo-3-cyano-8- azabicyclo[3.2.1]octane (0.058g).
exo-3-(6-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.05g) and paraformaldehyde (0.50g) were added to formic acid (2ml) and the mixture heated under reflux. After 2 hours the mixture was allowed to cool to room temperature and stand overnight. The mixture was evaporated under reduced pressure and 2M sodium hydroxide added. The mixture was extracted with ethyl acetate (x3) and the combined extracts were washed with brine and water1 dried (MgSO4), evaporated under reduced pressure and chromatographed [sio2; dichloromethane:methanol (95:5)] to give exo-3-(6-chloropyrid-3-yl)- endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.023g).
EXAMPLE 16 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(n- hexyl)-8-azabicyclo[3.2.1]octane.
exo-3-Cyano-8-methyl-8-azabicyclo[3 .2.l]octane (0.5g) in tetrahydrofuran (3ml) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (1.6ml of a 2.5M solution in hexane) to diisopropylamine (0.4g) in tetrahydrofuran (3ml)] at -25 C under nitrogen.
After a further 15 minutes at -25 C 3,5-dichloropyridine (0.588g) in tetrahydrofuran (3ml) was added at -78 C. After 1 hour at the mixture was allowed to warm to room temperature and stand overnight. Water was then added and the resulting mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol [90:10)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.249g).
Vinyl chloroformate (2.6ml) in tetrahydrofuran (5ml) was added to a stirred solution of exo3-(5-chloropyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (2.6g) in tetrahydrofuran (25ml) at 0 C. The mixture was allowed to warm to room temperature over 1 hour, reflux for 2 hours and then allowed to cool to room temperature. After 20 hours the mixture was partitioned between water and ethyl acetate and the organic layer was separated, washed with water and dried (MgSO4). Evaporation under reduced pressure gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (2.0g).
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (2.6g) was dissolved in methanol (50ml) and concentrated hydrochloric acid (7ml) added.
The mixture was refluxed for 3 hours after which the mixture was evaporated under reduced pressure and basified with aqueous sodium carbonate. The resulting mixture was extracted with ethyl acetate and evaporated under reduced pressure to give a brown solid. This was then washed with hexane to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- azabicyclo[3.2.1]octane (1.2g).
n-Hexyl bromide (O.lml) and potassium carbonate (O.lg) were added to exo-3-(5 chloropynd-3-yl)-endo-34yano-8-azabicyclo[3.2.1]octane (0.15g) in ethanol (2ml) and the mixture refluxed for 44 hours. The mixture was then diluted with ethanol, filtered and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (96:4)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(n-hexyl)-8-azabicyclo[3.2.1]octane (0. 123g).
EXAMPLE 17 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-allyl-8- azabicyclo[3.2. octane.
Allyl bromide (62 l) and potassium carbonate (O.lg) were added to exo-3-(5-chloropyrid-3- yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (O.lSg) in ethanol (2ml) and the mixture stirred for 3 hours and then allowed to stand overnight. The mixture was then diluted with ethanol, filtered and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (95:5)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-allyl-8- azabicyclo[3.2.1]octane (0. 167g).
EXAMPLE 18 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2,2,2- trifluoroethyl)-8-azabicyclo[3.2.1]octane.
A few drops of dilute hydrochloric acid were added to a solution of 2,5dimethoxytetrahydrofuran (16.5g) in water (7Oml). After stirring at room temperature for 30 minutes 2,2,2-trifluoroethylamine hydrochloride (16.9g), 1,3-acetonedicarboxylic acid (18.3g) and sodium acetate (10.0g) were added and the mixture stirred at room temperature for 2 days. The mixture was diluted to SOOml with water, saturated with potassium carbonate and extracted with ethyl acetate (x2). The combined organic extracts were washed with aqueous potassium carbonate, dried (MgSO4) and evaporated under reduced pressure. Distillation (90CC; O.lmmHg) gave 8-(2,2,2-trifluoroethyl)-8-azabicyclo[3 .2.1 ]octan-3ne (8.7g).
Potassium t-butoxide (5.4g) was added slowly with cooling to a stirred solution of 8-(2,2,2 trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-one (4.0g) and tosylmethyl isocyanide (4.9g) in dimethoxyethane (80ml) and ethanol (semi) under nitrogen at such a rate so as to keep the temperature below 100C. The mixture was stirred for 18 hours while allowing it to warm to room temperature, evaporated under reduced pressure and added to aqueous potassium carbonate solution. The mixture was extracted with ethyl acetate (x2) and the combined extracts were dried (MgSO4) and evaporated under reduced pressure to give an oil.The mixture was extracted with refluxing hexane and the extracts allowed to cool and evaporated under reduced pressure to give exo-3-cyano-8-(2,2,2-trifluoroethyl)-8- azabicyclo[3.2.1]octane (2.5g) m.p. 9O92CC.
exo-3-Cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1 octane (1 .09g) in tetrahydrofuran (lOml) was added to a stirred solution of lithium diisopropylamide [made by adding n-BuLi (2.4ml of a 2.5M solution in hexane) to diisopropylamine (0.61g) in tetrahydrofuran (lOml)] at -25 C under nitrogen. After 2 hours at -25"C the mixture was cooled to -76 C and 3,5dichloropyridine (0.74g) in tetrahydrofuran (loll) added. The mixture was allowed to warm to room temperature, stirred for 18 hours and evaporated under reduced pressure.The mixture was dissolved in ether, washed with water (x2), dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; diethyl ether hexane (20:80) to (50:50)] gave exo3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane (0.45g) m.p. 109.5-111.5 C.
EXAMPLE 19 This example illustrates the preparation of exo-3-(5-bromopyrid-3-yl)-endo-3-cyano-8- methyl-8-azabicyclo[3.2.1]octane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.Sg) in tetrahydrofuran (3ml) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (1.6ml of a 2.5M solution in hexane) to diisopropylamine (0.4g) in tetrahydrofuran (3ml)] at -25 C under nitrogen.
After 30 minutes the mixture was cooled to -76 C and a solution of 3,5-dibromopyridine (0.94g) in tetrahydrofuran (3ml) added. After 1 hour the mixture was allowed to warm to room temperature and left to stand overnight. Water was added and the resulting mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine (x2) and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (90:10)] gave exo-3-(5-bromopyrid-3-yl)-endo-3-cyano-8-methyl- 8-azabicyclo[3.2.1]octane (0.327g) m.p 144-145 C.
EXAMPLE 20 This example illustrates the preparation of exo-3-(5-cyanopyrid-3-yl)-endo-3-cyano-8-methyl- 8-azabicyclo[3.2.1]octane.
exo-3-(5-Bromopyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.30g) and copper(I) cyanide (0.345g) were heated at 200 C in N-methylpyrrolidinone (lOml) under nitrogen. After 36 hours the reaction was allowed to cool to room temperature and water was added followed by aqueous ammonium hydroxide solution (density=0.88). The mixture was extracted with ethyl acetate (x3) and the combined extracts were washed with brine and water, dried (MgSO4) and evaporated under reduced pressure. The resulting oil was dissolved in ether and washed with brine (x7), dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (95:5)] gave a yellow solid.
This was recrystallised three times (from dichloromethanemexane, ethyl acetate/hexane and dichloromethane'hexane) to give exo-3-(5-cyanopyrid-3-yl)-endo-3-cyano-8-methyl-8- azabicyclo[3 .2.1 joctane (0.49g) m.p. 183.5-1 84CC.
EXAMPLE 21 This example illustrates the preparation of exo-3-(5-ethoxypyrid-3-yl)-endo-3-cyano-8- methyl-8-aaabicyclo[3.2. 1 ]octane.
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2. 1 octane (0.30g) and sodium ethoxide (0.625g) were heated at 80 C in N,N < iimethylformamide (lOml) under nitrogen. After 5 hours the mixture was allowed to cool to room temperature and water added. The mixture was extracted with ethyl acetate (x3) and the combined extracts were washed with brine (x2) and water, dried (MgSO4) and evaporated under reduced pressure.
Chromatography [SiO2; dichloromethane:methanol (90:10)] gave an oil. A small amount of hexane was added and the mixture was allowed to stand at approximately 0 C overnight after which a solid product had formed. The mixture was filtered and the solid washed with a small amount of hexane to give exo-3-(5-ethoxypyrid-3-yl)-endo-3syano-8-methyl-8- azabicyclo[3.2.1]octane (0.105g) m.p. 557CC.
EXAMPLE 22 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- isopropyl-8-azabicyclo[3.2.1]octane.
2M Hydrochloric acid (8 drops) was added to a stirred solution of 2,5dimethoxytetrahydrofuran (16.5g) in water (70ml). After 15 minutes a mixture of diisopropylamine (7.38g) and 2M hydrochloric acid (40ml) was added to the reaction followed by acetonedicarboxylic acid (18.25g) and sodium acetate (10.0g) in water (lOOmI).
After 3 days 1,3-acetonedicarboxylic acid (6.0g) and sodium acetate (3.0g) were added.
After a further 6 days the mixture was basified to pH8 and extracted with ethyl acetate. The extracts were dried (MgSO4) and evaporated under reduced pressure. The aqueous fraction was then extracted with chloroform and the extracts dried (MgSO4) and evaporated under reduced pressure. Distillation of the combined extracts (95-115"C; l8mmHg) gave 8 isopropyl-8-azabicyclo[3 .2.1 ]octan-3-one (3.37g).
Potassium t-butoxide (5.0g) was added slowly with cooling to a stirred solution of 8isopropyl-8-azabicyclo[3.2.1]octan-3-one (3.16g) and tosylmethyl isocyanide (4.80g) in dimethoxyethane (SOml) and ethanol (2.2ml) under nitrogen at such a rate so as to keep the temperature below 10"C. After 1 day tosylmethyl isocyanide (1.0g), potassium t-butoxide (l.Og) and ethanol (lml) were added. After a further day the mixture was filtered and the filtrate evaporated under reduced pressure and chromatographed [SiO2; dichloromethane:methanol (95:5)] to give exo-3-cyano-8-isopropyl-8-azabicyclo[3.2.1]octane (0.90g).
Lithium bis(trimethylsilyl)amide (2.5ml of a 1M solution in tetrahydrofuran) in tetrahydrofuran (5ml) was added to a stirred solution of exo-3-cyano-8-isopropyl-8- azabicyclo[3.2.1]octane (0.38g) and 3,5-dichloropyridine (0.34g) in tetrahydrofuran (semi) at 10"C over 30 minutes. The mixture was then stirred at room temperature for 2 hours and allowed to stand at room temperature overnight. 3,5-Dichloropyridine (0. 15g) was added followed by lithium bis(trimethylsilyl)amide (1.0ml of a 1M solution in tetrahydrofuran) over 30 minutes.After 2 hours lithium bis(trimethylsilyl)amide (1.0ml of a 1M solution in tetrahydrofuran) was added dropwise and after a further 1 hour additional lithium bis(trimethylsilyl)amide (1.0ml of a 1M solution in tetrahydrofuran) was added and the mixture warmed to 50 C. After 5 minutes the reaction was cooled to room temperature and aqueous sodium carbonate solution added. The mixture was extracted with ethyl acetate (x2) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure to give a brown oil. The oil was extracted with boiling hexane and the combined extracts evaporated under reduced pressure to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano- 8-isopropyl-8-azabicyclo[3.2.1]octane (0.60g).
EXAMPLE 23 This example illustrates the preparation of exo-3-(2,6-dichloropyrimid-4-yl)-endo-3-cyano-8- methyl-8-azabicyclo[3 .2.1 joctane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.5g) in tetrahydrofuran (3ml) was added to a solution of lithium dilsopropylathide [made by adding n-BuLi (1.6ml of a 2.5M solution in hexane) to diisopropylamine (0.4g) in tetrahydrofuran (3ml)] at -25 C under nitrogen.
After 30 minutes the mixture was cooled to -78 C and a solution of 2,4,6-trichloropyrimidine (0.728g) in tetrahydrofuran (5ml) was added. After 1 hour the mixture was allowed to warm to room temperature, stirred for 2 hours and allowed to stand overnight. Water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (95:5) to (90:10)] gave exo-3-(2,6-dichloropyrimid4-yl)- endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.087g) m.p. 95-97 C.
EXAMPLE 24 This example illustrates the preparation of exo-3-(2-chloropyrid-4-yl)-endo-3-cyano-8- methyl-8-azabicyclo[3.2.1]octane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.Sg) in tetrahydrofuran (3ml) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (1.6ml of a 2.SM solution in hexane) to diisopropylamine (0.4g) in tetrahydrofuran (3ml)] at -25 C under nitrogen.
After 30 minutes the mixture was cooled to -78"C and a solution of 2,4,6-trichloropyridine (0.724g) in tetrahydrofuran (semi) was added. After 1 hour the mixture was allowed to warm to room temperature and allowed to stand ovemight. Water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (95:5)] gave a solid product which was recrystallised (ethyl acetate/hexane) to give exo-3-(2,6dichloropyrid-4-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.389g) m.p. 165166 C.
exo-3-(2,6-Dichloropyrid-4-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.50g) and hydrazine hydrate (0.106ml) were refluxed in isopropyl alcohol (5ml) for 5 hours and then left to stand overnight. Hydrazine hydrate (0.106ml) was added and the mixture refluxed for 8 hours. More hydrazine hydrate (0.106ml) was added and the mixture reflux for a further 8 hours. After cooling to room temperature the mixture was evaporated under reduced pressure and the residue extracted with dichloromethane.The extracts washed with water (x2), dried (MgSO4), evaporated under reduced pressure and triturated with hexane and ether to give 3-(2hloro6hycirazinopyridyl)endo-3-cyanc-8-methyl-8- azabicyclo[3.2.1]octane (0.205g) m.p. 215-216"C.
Copper(II) sulphate octahydrate (0.36g) was added to a solution of exo-3-(2-chloro-6- hydrazinopyrid-4-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.170g) in water (3ml) and the mixture refluxed for 7 hours. After cooling to room temperature ammonium hydroxide solution (density=0.88) was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (90:10)] gave exo-3-(2-chloropyrid-4-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.052g) m.p. 104-105 C.
EXAMPLE 25 This example illustrates the preparation of exo-3-(pyrid-4-yl)-endo-3-cyano-8-methyl-8- azabicyclo[3.2.1]octane.
exo-3-(2,6-Dichloropyrid-4-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.35g), crushed potassium hydroxide (0.133g) and palladium on charcoal (0.20g) were stirred in methanol (lOml) under hydrogen for 3 hours and then allowed to stand for 3 days. The mixture was filtered (celite), evaporated under reduced pressure and dissolved in ethyl acetate. The resulting solution was washed with aqueous sodium hydroxide and water, dried (MgSO4) and evaporated under reduced pressure to give a solid product which was washed with hexane and ether to give exo-3-(pyrid-4-yl)-endo-3-cyano-8-methyl-8- azabicyclo[3.2.1]octane (0.072g) m.p. 74.5-76 C.
EXAMPLE 26 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(3,3- difluoroprop-2-en-1-yl)-8-azabicyclo[3.2.1]octane.
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.248g), 1-bromo-1,1difluoroprop2-ene (0.314g) and potassium carbonate (0.345g) were stirred in ethanol (2ml) for 2 hours and then allowed to stand for 4 days. The mixture was then evaporated under reduced pressure and water added. The mixture was then extracted with dichloromethane (x3) and the combined extracts were washed with brine, dried (MgS04) and evaporated under reduced pressure. Filtration [SiO2; dichloromethane:methanol (98:2)] gave exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-(3,3-difluoroprop-2-en-1-yl)-8-azabicyclo[3.2.1]octane (0.287g).
EXAMPLE 27 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(3- oxo-4,4,4-trifluorobut-1-en-1-yl)-8-azabicyclo[3.2.1]octane.
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.30g), 4-ethoxy-1,1,1 trifluorobut-3-en-29ne (0.204g) and potassium carbonate (0.20g) were heated under reflux in ethanol. After 4 hours the mixture was allowed to cool to room temperature and water added. The mixture was extracted with ethyl acetate (x3) and the combined extracts were washed with brine (x2) and water, dried (MgSO4) and evaporated under reduced pressure.
Chromatography [SiO2; dichloromethane:methanol (95:5)] gave exa-3-(5-chioropyrid-3-yl)- endo-3-cyano-8-(3sxo4P,4-trifluorobut- 1 -en- 1 -yl)-8-azabicyclo[3.2.1]octane (0.1 62g) m.p.
144-145 C.
EXAMPLE 28 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-acetyl- 8-azabicyclo[3.2.1 ]octane.
N,N-Diisopropylethylamine (0.43ml) and acetyl chloride (0.18ml) were added to exo-3-(5 chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.50g) in dichloromethane (loll) at room temperature. After 10 minutes the mixture was evaporated under reduced pressure and ethyl acetate (SOml) added. The resulting mixture was washed with potassium carbonate solution, dried (MgSO4) and evaporated under reduced pressure. The resulting product was triturated with hot hexane and evaporated under reduced pressure to give exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-acetyl-8-azabicyclo[3.2.1]octane (0.43g) m.p. 162-165 C.
EXAMPLE 29 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- azabicyclo[3.2.1]octane hydroperchlorate.
Perchloric acid (1.19ml) was added dropwise to a stirred suspension of exo-3-(5-chloropyrid- 3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (5.0g) in diethyl ether (lOOml) at room temperature. After 5 hours the mixture was filtered and the precipitate washed with diethyl ether to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane hydroperchlorate (5.36g).
EXAMPLE 30 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(tertbutyl)-8-azabicyclo[3.2.1]octane.
Acetone (0.42ml) was added to a stirred solution of exo-3-(5-chloropyrid-3-yl)-endo-3- cyano8-azabicyclo[3.2.1]octane hydroperchlorate (l.Og) in ethanol (2ml) at room temperature under nitrogen. After 30 minutes the mixture was heated to S0CC. After 1 hour the mixture was evaporated under reduced pressure. Acetone was then added and the mixture heated under reflux for 3 hours and then evaporated under reduced pressure. Diethyl ether (lOml) was added followed by methylmagnesium bromide (4.3ml of a 3.0M solution in diethyl ether). The mixture was then heated under reflux for 6 hours and then allowed to stand at room temperature overnight.Saturated ammonium chloride solution was then added and the mixture extracted with dichloromethane (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane :methanol (95:5)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(tert- butyl)-8-azabicyclo[3.2.1]octane (0.218g) m.p. 127-129 C.
EXAMPLE 31 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2 pbenyl-3-oxo-prop2-yI)-8-azabicyclo [3.2.l]octane.
2-Phenylpropanal (1.08g) was added to a mixture of exo-3-(5-chloropyrid-3-yl)-endo-3- cyanO-8-azbicyclo[3.2.1]octane (2.0g) and ttoluenesulphonic acid (0.15g) in toluene (30ml) and the mixture heated under Dean and Stark reflux for 3 hours. After standing at room temperature overnight the mixture was evaporated under reduced pressure to give exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-(2-phenylprop-1-en-1-yl)-8-azabicyclo[3.2.1]octane which was used without further purification.
Sodium Nchloro-p-toluenesulphonamide (2.3g) was added to the exo-3-(5-chloropyrid-3-yl)- endo-3cyano-8-(2-phenylprop- len-l -yl)-8-azabicyclo[3.2. I]octane from the above reaction in dichloromethane (30ml) and the mixture stirred at room temperature for 5 hours. After standing at room temperature over the weekend the mixture was stirred for 8 hours and then allowed to stand overnight The mixture was then filtered (celite) and the residue washed with dichloromethane. The combined filtrates were washed with sodium hypochlorite (x2) and brine, dried (MgSO4) and evaporated under reduced pressure.Chromatography [SiO2; dichloromethane:methanol (98:2)] followed by chromatography [SiO2; dichloromethane:methanol (99:1)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2- phenyl-3-oxc-pro2-yl)-8-azabicyclo[3 .2.1 ]octane (0.43g) m.p. 124-1 26CC.
EXAMPLE 32 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2- phenylbut-3-en-2-yl)-8-azabicyclo[3.2.1]octane.
Sodium methoxide (0.085g) was added in two portions to a stirred solution of methyltriphenylphosphonium bromide (0.56g) in dimethyl sulphoxide (30ml) at room temperature under nitrogen. The mixture was warmed to 70 C and after 2 hours exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-(2-phenyl-3-oxo-prop-2-yl)-8-azabicyclo[3.2.1]octane (0.30g) in a small volume of dimethyl sulphoxide was added dropwise. After 3 hours the mixture was allowed to cool to room temperature and stand overnight. The mixture was poured into ice/water and the resulting mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine (x2), dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate:hexane (90:10)] gave exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-(2-phenylbut-3-en-2-yl)-8-azabicyclo[3.2.1]octane (0.24g).
EXAMPLE 33 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano- phenyl-3-hydroxyprop-2-yl)-8-azabicyclo[3.2.1]octane.
Sodium borohydride (0.094g) was added to a stirred solution of exo-3-(5-chloropyrid-3-yl)- endo-3-cyano-8-(2-phenyl-3-oxo-prop-2-yl)-8-azabicyclo[3.2.1]octane (0.90g) in ethanol (15ml) under nitrogen. After 2 hours the mixture was poured into brine and the resulting mixture extracted with ethyl acetate (x2). The combined extracts were dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; ethyl acetate:hexane (50:50)] to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2-phenyl-3-hydroxyprop-2-yl)-8 azabicyclo[3.2. 1 ]octane (0.777g) m.p. 124-126 C.
EXAMPLE 34 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2- fluoro-2-phenylprop-1-yl)-8-azabicyclo[3.2.1]octane.
Diethylaminosulphur trifluoride (0.4ml) and exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2- phenyl-3-hydroxyprop-2-yl)-8-azabicyclo[3.2.1]octane (0.10g) were stirred in dichloromethane (0.2ml) at room temperature for 4 hours. The mixture was allowed to stand at room temperature over the weekend and water added. The mixture was extracted with ethyl acetate and the aqueous layer basified with saturated sodium bicarbonate solution. The aqueous layer was then extracted with ethyl acetate (x3) and the combined organic extracts were washed with sodium bicarbonate solution and brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate:hexane (17:83)] gave exo-3 (5-chloropyrid-3-yl)-endo-3-cyano-8-(2-fluoro-2-phenylprop-1-yl)-8-azabicyclo[3.2.1]octane (0.075g).
EXAMPLE 35 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2- phenyl-3-acetoxyprop-2-yl)-8-azabicyclo[3.2.1]octane.
Triethylamine (0.06ml) and acetyl chloride (0.029ml) were added to a stirred solution of exo 3-(Schloropyrid-3-ylendo3cyano8.(2-phenyl-3-hydroxypro2-yl)-8- azabicyclo[3.2.1]octane (0.15g) in dichloromethane (5ml) at room temperature under nitrogen. After 1.5 hours dichloromethane was added and the mixture washed with water (x2) and brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate:hexane (20:80)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2- phenyl-3-acetoxyprop-2-yl)-8-azabicyclo[3.2.1.]octane (0.1 4g) m.p. 130-131 C.
EXAMPLE 36 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- formyl-8-azabicyclo[3.2.1]octane.
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (3.0g) and formic acid (1.14ml) were heated at reflux for 4 hours. The mixture was then heated at 1 10CC overnight and formic acid (1.0ml) added. After 8 hours the mixture was allowed to cool to room temperature and stand overnight. Ethyl acetate was added and the mixture washed with 2M sodium hydroxide solution (x2), water and brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate:methanol (95:5)] gave exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-formyl-8-azabicyclo[3.2.1]octane (1.675g) m.p. 141 142 C.
EXAMPLE 37 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- (diisopropylcarbamyl)-8-azabicyclo[3.2.1]octane.
Triethylamine (0.27ml) followed by diisopropylcarbamyl chloride (0.317g) was added to a stirred solution of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.40g) in dichloromethane (semi) at room temperature. After 2 hours the mixture was allowed to stand at room temperature for 4 days. Dichloromethane was then added and the mixture washed with water (x2) and brine, dried (MgSO4) and evaporated under reduced pressure. Filtration [sio2; ethyl acetate] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- (diisopropylcarbamyl)-8-azabicyclo [3.2.l]octane (0.12g) m.p. 118-121 CC.
EXAMPLE 38 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(tert- butylcarbamyl)-8-azabicyclo[3.2.1]octane.
Triethylamine (0.27ml) followed by tert-butylisocyanate (0.22ml) was added to a stirred solution of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.40g) in dichloromethane (4ml) at room temperature. After 3 hours the mixture was allowed to stand at room temperature overnight and dichloromethane then added. The mixture was then washed with water (x2) and brine, dried (MgSO4) and evaporated under reduced pressure.
Chromatography [SiO2; diethyl ether] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(tert- butylcarbamyl)-8-azabicyclo[3.2.1]octane (0.40g) m.p. 62-65 C.
EXAMPLE 39 This example illustrates the preparation of (R)-exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(1- phenylethyl)-8-azabicyclo[3 .2.l]octane.
Three drops of SM hydrochloric acid were added to a mixture of 2,5dimethoxytetrahydrofuran (16.5g) and water (70ml). A cooled mixture of (R)-amethylbenzylamine (15.125g) and SM hydrochloric acid (30ml) was then added followed by 1,3-acetonedicarboxylic acid (18.26g) sodium acetate (lOg) and water (lOOml). After 5 days the mixture was basified with aqueous sodium carbonate solution and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate:hexane (10:90) to (20:80)] gave (R)-8-(1 phenylethyl)-8-azabicyclo[3.2. I]octan-3-one.
Potassium t-butoxide (13.4g) was added portionwise to a stirred mixture of gave (R)-8-(1- phenylethyl)-8-azabicyclo[3.2.1]octan-3-one (11.45g) and tosylmethyl isocyanide (12.7g) in dimethoxyethane (200ml) and ethanol (6ml) at -5 C at such a rate to maintain the temperature below -2 C. After stirring overnight the mixture was filtered (celite) and the filtrate evaporated under reduced pressure. The residue was then dissolved in ethyl acetate, washed with water, dried (MgSO and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate:hexane (50:50)] gave (E)-eeo-3-cyano-8-( I-phenylethyl)-8-azabicyclo[3.2. I]octane (3.5g) m.p. 138139.5 C.
Lithium bis(trimethylsilyl)amide (4.8ml of a 1.0 solution in tetrahydrofuran) was added to a stirred solution of (R)-exo-3-cyano-8-(1-phenylethyl)-8-azabicyclo[3.2.1]octane (1.0g) and 3,5-dichloropyridine (0.674g) in tetrahydrofuran (20ml) at 0 C under nitrogen. The mixture was allowed to warm to room temperature and stand for 24 hours. Water (20ml) was added and the mixture stirred for 30 minutes and then allowed to stand for 2 days. The mixture was extracted with ethyl acetate and the extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure.Chromatography [sio2; ethyl acetate:hexane (50:50)], preparative thin layer chromatography [SiO2; ethyl acetate:hexane (25:75)] and recrystallisation from hexane gave (R)-exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(1phenylethyl)-8-azabicyclo[3.2.1]octane (0.46g) m.p. 113-115 C.
EXAMPLE 40 This example illustrates the preparation of exo-3-(5-aminopyrid-3-yl)-endo-3-cyano-8- methyl-8-azabicyclo[3.2.1]octane.
Ammonia solution (35%) was added to exo-3-(5-bromopyrid-3-yl)-endo-3-cyano-8-methyl-8- azabicyclo[3.2.1]octane (0.106g) and copper(II) sulphate hydrate (0.001g) and the tube sealed. The mixture was heated at 100 C for 20 hours and then 150 C for 24 hours. The mixture was then cooled and evaporated under reduced pressure. The residue was then dissolved in methanol, charcoal added and the mixture filtered and evaporated under reduced pressure. Water and dichloromethane were added followed by ammonia solution and the resulting mixture was extracted with dichloromethane. The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to give exo-3-(S- aminopyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.045g) m.p. 188190 C.
EXAMPLE 41 This example illustrates the preparation of exo-3-(5-acetylamidopyrid-3-yl)-endo-3-cyano-8- methyl-8-azabicyclo[3.2. 1 joctane.
Acetic anhydride (1.0rnl) was added to exo-3-(5-aminopyrid-3-yl)-endo-3-cyano-8-methyl-8- azabicyclo[3.2.1]octane (0. lOg). After 3 days dilute sodium bicarbonate solution and ethyl acetate were added followed by sodium bicarbonate and potassium carbonate to basify the mixture. The mixture was extracted with ethyl acetate and the extracts dried (MgSO4) and evaporated under reduced pressure to give exo-3-(5-acetylamidopyrid-3-yl)-endo-3-cyano-8- methyl-8-azabicyclo[3.2.1]octane (0.107g).
EXAMPLE 42 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(a- cyanobenzyl)-8-azabicyclo[3 .2.1 ]octane.
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (2.0g) and benzaldehyde (0.89ml) were added to 1M hydrochloric acid (20ml) and the mixture stirred for 20 minutes.
Sodium cyanide (0.549g) in water (6ml) was then added. After 18 hours ethanol (20ml) was added to give one phase. After 6 days the reaction mixture was partitioned between ethyl acetate and water and the inorganic layer was washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol:triethylamine (99.4:0.5:0.1)] gave exo-3-(5chloropyrid-3-yl > endo-3-cyano-8-(a-cyanobenzyl)-8-azabicyclo[3.2.1]octane (0.104g) m.p. 141-142 C.
EXAMPLE 43 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(a- carbamylbenzyl)-8-azabicyclo[3.2.1]octane.
Concentrated sulphuric acid (lOiml) was added to exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- (a-cyanobenzyl)-8-azabicyclo[3.2.1]octane (0.51g) and the mixture stirred for 1 hour. Ice (lOOg) was added and the mixture basified with sodium bicarbonate solution. A precipitate formed which was collected by filtration, dissolved in ethyl acetate, dried (MgSO4) and evaporated under reduced pressure. Chromatography [sio2; dichloromethane methanol (99:1) to (98:2)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(a-carbamylbenzyl)-8- azabicyclo[3.2. 1]octane (0.181g) m.p. 193- 195CC.
EXAMPLE 44 This example illustrates the preparation of exo-3-(5-iodopyrid-3-yl)-endo-3-cyano-8-methyl- 8-azabicyclo[3.2.1 ]octane.
Nickel(II) bromide (1.55ml of a 0.16M solution in N,N-dimethylformamide) was added to a stirred solution of tri(n-butyl)phosphine (0.124ml) in N N,N-dimethylformamide (5ml) under nitrogen. Potassium iodide (3.96g) was then added followed by exo-3-(5-bromopyrid-3-yl)endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (1.522g) and the mixture heated under reflux for 48 hours. The mixture was then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; dichloromethane:methanol (95:5)] to give exo3-(5-iodopyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.399g) m.p. 144 145"C.
EXAMPLE 45 This example illustrates the preparation of exo-3-(5-trifluoromethylpyrid-3-yl)-endo-3-cyano- 8-methyl-8-azabicyclo[3.2.1]octane.
exo-3-(5-Iodopyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.50g) followed by copper(I) iodide were added to a stirred solution of sodium trifluoroacetate (2.6g) in Nmethylpyrrolidinone (5ml) and the mixture heated to 180 C. After 3 hours the mixture was cooled to room temperature, water added and extracted with dichloromethane. The organic layer was filtered and the filtrate dried (MgSO4) and evaporated under reduced pressure.
Diethyl ether was added and the mixture extracted repeatedly with water. The aqueous fraction was evaporated under reduced pressure, basified with potassium carbonate and extracted with diethyl ether. The extracts were washed with 1M hydrochloric acid and the aqueous fraction basified with potassium carbonate and extracted with diethyl ether. The extracts were dried (MgSO4) and evaporated under reduced pressure. Preparative thin layer chromatography [Al2O3; diethyl ether] gave exo-3-(5-trifluoromethylpyrid-3-yl)-endo-3- cyanc-8-methyl-8-azabicyclo[3.2. l]octane (0.027g) m p. 118.2-118.5 C.
EXAMPLE 46 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- (mercaptothiocarbonyl)-8-azabicyclo[3.2.1]octane.
Carbon disulphide (0.12ml) was added to a stirred solution of exo-3-(5-chloropyrid-3-yl)- endo-3-cyano-8-azabicyclo[3.2.1]octane (0.50g) in ethanol (5ml) at room temperature under nitrogen. After 4 hours the mixture was allowed to stand overnight. The precipitate was collected by filtration and washed with hexane to give exo-3-(Schloropyrid-3-yl)-endo-3- cyano-8-(mercaptothiocarbonyl)-8-azabicyclo[3.2.1]octane (0.509g) m.p. 224 C (decomposed).
EXAMPLE 47 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- (fluorocarbonyl)-8-azabicyclo[3 .2.l]octane.
Iodomethane (0.08ml) was added to a stirred mixture of exo-3-(Schloropyrid-3-ylendo-3- cyano-8-(mercaptothiocarbonyl)-8-azabicyclo[3.2.1]octane (0.40g) in dimethyl sulphoxide (3ml) at room temperature. After 3 hours water was added and the mixture extracted with dichloromethane (x3). The combined extracts were washed with water (x2) and brine, dried (MgSO4) and evaporated under reduced pressure. Dichloromethane was added and the mixture washed with brine (x2), dried (MgSO4) and evaporated under reduced pressure to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(methylmercaptothiocarbonyl)-8 azabicyclo[3.2. 1 ]octane (0.1 87g).
Tetra(n-butyl)ammonium dihydrogentrifluoride (0.48g) was added to a solution of exo-3-(Schloropyrid-3-yl)-endo-3-cyano-8-(methylmercaptothiocarbonyl)-8-azabicyclo[3.2.1]octane (0.180g) in dichloromethane at 0 C under nitrogen. N-Bromosuccinimide (0.38g) was then added. After 10 minutes the mixture was warmed to room temperature. After 2 hours the mixture was cooled to 0 C and allowed to stand over the weekend. The mixture was then stirred at room temperature for 8 hours and allowed to stand overnight. The mixture was diluted with dichloromethane and sodium bicarbonate and sodium bisulphite solutions added.
The mixture was extracted with dichloromethane and the extracts dried (MgSO4) and evaporated under reduced pressure. Ethyl acetate was added and the mixture washed with water (x2) and brine, dried (MgSO4) and evaporated under reduced pressure.
Chromatography [sio2; diethyl ether:hexane (80:20)] gave exo-3-(5-chloropyrid-3-yl)-endo- 3-cyano-8-(fluorocarbonyl)-8-azabicyclo[3 I]octane (0.1 Og) m.p. 165-167"C.
EXAMPLE 48 This example illustrates the preparation of exo-3-(S-chloropyrid-3-yl)endo-3-cyano8-(2,2- difluoroethyl)-8-azabicyclo[3.2. l]octane.
2,2-Difluoroethyl bromide (1.08g), potassium carbonate (1.38g), potassium iodide (0.30g) and exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (1.238g) were stirred at 50 C in ethanol (10ml). After 8 hours the mixture was allowed to stand at room temperature for 3 days. 2,2-Difluoroethyl bromide (1.08g), was then added and the mixture heated under reflux for 48 hours. 2,2-Difluoroethyl bromide (1.08g) and potassium carbonate (1.38g) were then added and the mixture heated under reflux for 24 hours. 2,2-Difluoroethyl bromide (1.08g) was then added and the mixture heated under reflux for 24 hours. The mixture was then cooled to room temperature and water added. The mixture was extracted with dichloromethane (x2) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure.Chromatography [SiO2; dichloromethane:methanol (96:4)] gave exo3-(Schloropyrid-3-yl)-endo3-cyano8-(2,2-difluoroethyl)-8- azabicyclo[3.2.1]octane (0.278g) m.p. 101-104"C.
EXAMPLE 49 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2 phenylethyl)-8-azabicyclo[3.2. 1 joctane.
2-Phenylethyl bromide (0.222g), potassium carbonate (0.345g) and exo-3-(5-chloropyrid-3yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.248g) were heated under reflux in ethanol (2ml) for 9 hours. 2-Phenylethyl bromide (O.lg) was added and the mixture refluxed for 5 hours. The mixture was then cooled to room temperature and water added. The mixture was extracted with dichloromethane (x2) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane: methanol (98:2)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2- phenylethyl)-8-azabicyclo[3.2.1]octane (0.08g).
EXAMPLE 50 This example illustrates the preparation of exo-3-(5-hydroxypyrid-3-yl)-endo-3cyano- methyl-8-azabicyclo[3.2.1]octane.
Pyridinium hydrochloride (1.0g) and exo-3-(5-methoxypyrid-3-ylkendo-3-cyano-8-methyl-8- azabicydo[3.2.1]octane (0.20g) were heated together at 150 C for 5 hours. The mixture was then cooled to room temperature, water added and the mixture basified with sodium bicarbonate solution and extracted with ethyl acetate (x3). The aqueous fraction was neutralised with dilute hydrochloric acid and extracted with ethyl acetate (x3). The combined organic extracts were washed with water, dried (MgSO4) and evaporated under reduced pressure.Chromatography [SiO2; dichloromethane:methanol (90:10) to (80:20)] gave a gum which crystallised on addition of diethyl ether to give exo-3-(5-hydroxypyrid-3-yl)-endo-3- cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.049g) m.p. 171-172 C.
EXAMPLE 51 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- benzyl-8-azabicycol[3.2.1]octane.
exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.5g) in tetrahydrofuran (3ml) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (1.6ml of a 2.5M solution in hexane) to diisopropylamine (0.4g) in tetrahydrofuran (3ml)] at -25 C under nitrogen.
After 15 minutes at the mixture was cooled to -78"C and 3,5-dichloropyridine (0.588g) in tetrahydrofuran (3ml) was added. After 1 hour the mixture was allowed to warm to room temperature and stand overnight. Water was then added and the resulting mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine and water, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (90:10)] gave exo-3-(5-chloropynd-3-yl)-endo-3-cyano-8-methyl-8- azabicyclo[3.2. 1]octane (0.249g).
Vinyl chloroformate (2.6ml) in tetrahydrofuran (5ml) was added to a stirred solution of exo 3-(5-chloropyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (2.6g) in tetrahydrofuran (25ml) at OOC. The mixture was allowed to warm to room temperature over 1 hour, refluxed for 2 hours and then allowed to cool to room temperature. After 20 hours the mixture was partitioned between water and ethyl acetate and the organic layer was separated, washed with water and dried (MgSO4). Evaporation under reduced pressure gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (2.0g).
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (2.6g) was dissolved in methanol (50ml) and concentrated hydrochloric acid (7ml) added.
The mixture was refluxed for 3 hours after which the mixture was evaporated under reduced pressure and basified with aqueous sodium carbonate. The resulting mixture was extracted with ethyl acetate and evaporated under reduced pressure to give a brown solid. This was then washed with hexane to give exo3-(Schloropyrid-3-yl)-endo3cyano-8- azabicyclo[3.2. 1 joctane (1 .2g).
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0. 104g) in ethanol (5ml) was added to benzyl bromide (0.079g) and potassium carbonate (0.12g) and the mixture refluxed for 18 hours. After cooling to room temperature the mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was separated and evaporated under reduced pressure. Preparative thin layer chromatography [SiO2; dichloromethane:rxthanol (97:3)] gave 3-(Schloropyrid-3-yl)- endo-3-cyano8-benzyl-8-azabicydo[3.2. 1 ]octane (0.077g).
EXAMPLE 52 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8 (pentafluorophenylmethyl)-8-azabicyclo[3.2. 1 joctane.
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.248g), 2,3,4,5,6pentafluorobenzyl bromide (0.313g), potassium carbonate (0.345g) and ethanol (2ml) were stirred under reflux for 3 hours. The mixture was then evaporated under reduced pressure and water added. The mixture was then extracted with dichloromethane (x3) and the combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to give an oil which crystallised on standing. The crystals were washed with a small volume of ether to - - give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- (pentafluorophenylmethyl)-8-azabicyclo[3.2.1]octane (0.258g) m.p. 143- 1440C.
EXAMPLE 53 This example illustrates the preparation of potassium exo-3-(5-chloropyrid-3-yl)-endo-3- cyano-8-(4-carboxylatobenzyl)-8-azabicyclo[3.2.1]octane.
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.248g) 4 bromomethylbenzoic acid (0.258g), potassium carbonate (0.345g) and ethanol (2ml) were stirred under reflux for 2.5 hours. The mixture was then diluted with ethanol, filtered and the filtrate evaporated under reduced pressure to give potassium exo-3-(5-chloropyrid-3-yl)- endo-3-cyano-8-(4-carboxylatobenzyl)-8-azabicyclo[3.2.1]octane (0.292g).
EXAMPLE 54 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(3- chloro-4-fluorobenzyl)-8-azabicyclo[3.2.1]octane.
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.495g), 3-chloro-4fluorobenzaldehyde (0.317g) and formic acid (96%, 0.230g) were heated under reflux for 5 hours. The mixture was then cooled to room temperature, basified with dilute sodium hydroxide and extracted with dichloromethane (x2). The combined extracts were washed with brine, dried (MgSO4), and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (100:0) to (95:5)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano- (3-chloro4fluorobenzyl)-8-azabicyclo[3.2.1]octane (0.290g) m.p. 95-97"C.
EXAMPLE 55 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(pyrid- 2-ylrnethyl)-8-aaabicyclo[3.2. 1 ]octane.
2-Picolyl chloride hydrochloride (0.361g), potassium carbonate (0.828g) and exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.495g) were heated under reflux in ethanol (4ml) for 2 hours. The mixture was then cooled to room temperature and water added. The mixture was extracted with dichloromethane (x2) and the combined extracts washed with brine, dried (MgS04) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (100:0) to (95:5)] gave exo-3-(5-chloropyrid-3-yl)-endo-3- cyano-8-(pyrid-2-ylmethyl)-8-azabicyclo[3.2.1 loctane (0.447g) m.p. 123-1 25 CC.
EXAMPLE 56 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-((2- methylthiazol-4-yl)methyl)-8-azabicyclo[3.2.1]octane.
4-Chloromethyl-2-methylthiazole hydrochloride (0.202g), potassium carbonate (0.483g) and exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.247g) were heated under reflux in ethanol (2ml) for 1.5 hours. 4-Chloromethyl-2-methylthiazole hydrochloride (0.40g) was then added and the mixture refluxed for 30 minutes. The mixture was then cooled to room temperature and water added. The mixture was extracted with dichloromethane (x2) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (99: 1) to (95:5)] gave exo-3-(5-chloropyrid-3-ylkendo-3-cyano-8-((2-methylthiazolX yl)methyl)-8-azabicyclo[3.2.1]octane (0.269g) m.p. 81-83 C.
EXAMPLE 57 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-((3,5- dimethylisoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octane.
4-Chloromethyl-3,5-dimethylisoxazole (0.160g), potassium carbonate (0.345g), potassium iodide (0.02g) and exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.247g) were heated under reflux in ethanol (2ml) for 3 hours. The mixture was then cooled to room temperature and water added. The mixture was extracted with dichloromethane (x2) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure. Filtration [SiO2; dichloromethane:methanol (98:2)] gave exo-3-(5-chloropyrid-3-ylf endo-3-cyano-8-((3,5-dimethylisoxazol-4-yl)methyl)-8-azabicyclo[3.2.1]octane (0.258g) m.p.
95-99 C.
EXAMPLE 58 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(5- chlorothiophen-2-yl)-8-azabicyclo[3.2. 1 joctane.
2-Chloro-5-chloromethylthiophene (0.367g), potassium carbonate (0.690g) and exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.495g) were heated under reflux in ethanol (2ml) for 1.5 hours. Potassium iodide (0.02g) was then added and the mixture refluxed for 1.5 hours. The mixture was then cooled to room temperature and water added.
The mixture was extracted with dichloromethane (x2) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (100:0) to (96:4)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano- 8-(5-chlorothiophen-2-yl)-8-azabicyclo[3.2.1]octane (0.37g) m.p. 119-121"C.
- --EXAMPLE 59 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-((5- chloro-1,2,3-thiadiazol-4-yl)methyl)-8-azabicyclo[3.2.1]octane.
5-Chloro-4-chloromethyl-1,2,3-thiadiazole (0.187g), potassium carbonate (0.345g) and exo3-(5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.248g) were heated under reflux in ethanol (2ml) for 4 hours. The mixture was then cooled to room temperature and water added. The mixture was extracted with dichloromethane (x2) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure.
Chromatography [sio2; dichloromethane:methanol (100:0) to (98:2)] gave exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-((5-chloro-1,2,3-thiadiazol-4-yl)methyl)-8azabicyclo[3.2.1]octane (0.148g).
EXAMPLE 60 This example illustrates the preparation of exo-3-(5-fluoropyrid-3-yl)-endo-3-cyano-8- methyl-8-azabicyclo[3.2.1]octane.
exo-3-(5-Aminopyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.40g) in dichloromethane (150ml) was added to boron trifluoride etherate (1.5ml) at -10 to -15 C.
After a few minutes t-butyl nitrite (2ml) was added and the mixture allowed to warm to room temperature and stand overnight. The solid precipitate was collected and heated to cause decomposition. The residue was dissolved in 2M hydrochloric acid, washed with ethyl acetate, basified and extracted with ethyl acetate. The extracts were dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; dichloromethane:methanol (90:10)] to give exo-3-(5-fluoropyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.089g).
EXAMPLE 61 This example illustrates the preparation of exo-3-(5-(pyrrol-1-yl)pyrid-3-yl)-endo-3-cyano-8- methyl-8-azzbicydo[3 .2.1 joctane.
2,5-Dimethoxytetrahydrofuran (0.53ml) was added to a mixture of exo-3-(S-aminopyrid-3- ylkendo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane and acetic acid (13ml). After 5 minutes the mixture was heated at reflux for 1 hour and then allowed to cool to room temperature and stand overnight. Ethyl acetate was added and the mixture extracted with 2M hydrochloric acid and water. The combined extracts were basified with potassium carbonate and extracted with ethyl acetate. The extracts were dried (MgSO4) and evaporated under reduced pressure to give exo-3-(5-(pyrrol-1-yl)pyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.1 05g).
EXAMPLE 62 This example illustrates the preparation of exo-3-(5-(1-ethoxyvinyl)pyrid-3-yl)-endo-3-cyano- 8-methyl-8-azabicyclo[3 .2.1 ]octane.
(1-Ethoxyvinyl)tri-n-butyltin ((0.82ml) was added to a stirred mixture of exo-3-(5-iodopyrid 3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3 .2.1 octane (0.81 7g) and N,N- dimethylformamide (30ml) at room temperature under nitrogen.
Bis(triphenylphosphine)palladium(II) chloride (0.65g) was then added and the mixture heated at 130 C for 3 hours. The mixture was then allowed to cool to room temperature, water added and the mixture extracted with dichloromethane (x3). The combined extracts were washed with brine, dried (MgS04) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (91:9)] followed by chromatography [SiO2; dichloromethane:methanol (98:2) to (92:8] gave exo-3-(5-(1-ethoxyvinyl)pyrid-3-yl)-endo-3- cyano-8-methyl-8-azabicyclo[3.2. I]octane (0.22g).
EXAMPLE 63 This example illustrates the preparation of exo-3-(5-acetylpyrid-3-yl)-endo-3-cyano-8-methyl- 8-azabicyclo[3 .2.1 ]octane.
2M Hydrochloric acid (imi) was added to a stirred mixture of exo-3-(5-(1-ethoxyvinyl)pyrid- 3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.18g) in acetone (2ml). After 3 hours the mixture was allowed to stand overnight. The mixture was poured onto saturated sodium bicarbonate solution and the resulting mixture extracted with dichloromethane (x3).
The combined extracts were dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; dichloromethane:methanol (93:7)] to give exo-3-(S-acetylpyrid-3- ylsendo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.13g).
EXAMPLE 64 This example illustrates the preparation of exo-3-(5-ethynylpyrid-3-yl)-endo-3-cyano-8- methyl-8-azabicyclo[3.2.1]octane.
exo-3-(5-Iodopyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.50g) in tetrahydrofuran (imi) was added dropwise to a stirred mixture of trimethylsilylacetylene (0.22ml), diethylamine (1.13ml), copper(I) iodide (0.Olg) and tetrakis(triphenylphosphine)palladium(0) (0.02g) at room temperature under nitrogen. After 3 hours the mixture was allowed to stand at room temperature for 24 hours and then evaporated under reduced pressure. Dichloromethane (loll) was added followed by tetrabutylammonium fluoride (1.7ml of a 1M solution in tetrahydrofuran) and the mixture stirred at room temperature for 1.5 hours. Water was added and the mixture extracted with dichloromethane (x2).The combined extracts were washed with brine, dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; dichloromethane:methanol (95:5) to (90:10)] to give a crude product. Chromatography [sio2; dichloromethane:methanol (92:8)] followed by dissolving the product in dichloromethane, washing with water (x2) and brine, drying (MgSOs) and evaporating under reduced pressure gave exo-3-(5-ethynylpyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.40g).
EXAMPLE 65 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- (1-hydroxy-1-cyano-2-phenylprop-2-yl)-8-azabicyclo[3.2.1]octane.
Sodium cyanoborohydride (0.033g) was added to a stirred solution of isopropylamine (0.045ml) and exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2-phenyl-3-oxo-prop-2-yl)-8azabicyclo[3.2.1]octane (0.20g) in methanol (2ml). Methanolic hydrogen chloride was then added to give pHS. After 2 hours the mixture was allowed to stand at room temperature for 2 days and isopropylamine (0.045ml) and sodium cyanoborohydride (0.033g) were added.
After stirring at room temperature for 6 hours saturated sodium bicarbonate was added and the mixture extracted with dichloromethane (x3). The combined extracts were washed with brine, dried (MgSO4), evaporated under reduced pressure and chromatographed [Si02; dichloromethane:methanol (100:0) to (90:10)] to give exo-3-(5-chloropyrid-3-yl)-endo-3- cyano-8-(1 -hydroxy- 1 -cyano-2-phenylprop-2-yl)-8-azabicyclo[3.2.1]octane (0.75g) m.p. 172175 C.
EXAMPLE 66 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2- (isopropylamino)-2-phenylprop 1 -yl)-8-azabicycloj3 .2.l]octane.
Triethylamine (0.1ml) and methanesulphonyl chloride (0.053ml) were added to a stirred solution of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2-phenyl-3-hydroxyprop-2-yl)-8azabicyclo[3.2.1]octane (0.25g) in dichloromethane (5ml) at room temperature. After 2 hours isopropylamine (0.65ml) was added. After 2 hours the mixture was allowed to stand at room temperature overnight and dichloromethane then added. The mixture was washed with water (x2) and brine, dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; dichloromethane:methanol (98:2) to (95:5)]to give exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-(2-(isopropylamino)-2-phenylprop-1-yl)-8azabicyclo[3.2.1]octane (0.24g).
EXAMPLE 67 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- cyanomethyl-8-azabicyclo[3.2.1]octane.
Bromoacetonitrile (0.85ml) was added to a mixture of exo-3-(5-chloropyrid-3-yl)-endo-3- cyano-8-azabicyclo[3.2.1]octane (2.0g) and potassium carbonate (2.23g) in ethanol (loci) and the mixture heated at reflux for 3 hours. The mixture was then cooled to room temperature, filtered (celite) and washed through with dichloromethane. The filtrates were evaporated under reduced pressure, chromatographed [SiO2; dichloromethane:methanol (99:1)1 and recrystallised (ethyl acetatelhexane) to give exo-3-(5-chloropyrid-3-yl)-endo-3- cyanc8cyanomethyl-8-azabicyclo[3 .2.1 ]octane (1 .36g). m.p. 149-151 C.
EXAMPLE 68 This example illustrates the preparation of exo-3-(S-chloropyrid-3-yl)-endo-3-cyano-8-(1- (ethoxycarbonyl)ethyl)-8-azabicyclo[3.2.1]octane.
Ethyl 2-bromopropionate (0.29ml) was added to a mixture of exo-3-(S-chloropyrid-3-yl)- endo-3-cyano-8-azabicyclo[3.2.1]octane (O.Sg) and potassium carbonate (0.42g) in tetrahydrofuran (8ml) and the mixture heated at reflux for 24 hours. The mixture was then cooled to room temperature, filtered (celite) and washed through with dichloromethane. The filtrates were evaporated under reduced pressure and chromatographed [SiO2; dichloromethane:methanol (100:0 to (98:2)] to give exo-3-(5-chloropyrid-3-yl)-endo-3- cyano-8-(1-(ethoxycarbonyl)ethyl)-8-azabicyclo[3.2.1]octane (0.49g).
EXAMPLE 69 This example illustrates the preparation of exo3-(Schloropyrid-3-yl)-endo-3cyano-8-(6- fluoropyrid-2-yl)-8-azabicyclo[3.2.1]octane.
2,6-Difluoropyridine (0.37ml), potassium carbonate (1.12g) and exo-3-(S-chloropyrid-3-yl)- endo-3-cyano-8-azabicyclo[3.2.1]octane (1.0g) were heated at 140 C in Nmethylpyrrolidinone (lOml) for a total of 8 hours. The mixture was then cooled to room temperature, poured into water and the resulting mixture extracted with ethyl acetate (x3).
The combined extracts were washed with brine, dried (MgSOs), evaporated under reduced pressure and chromatographed [SiO2; hexane:ethyl acetate (90:10)] to give exo-3-(Schloropyrid-3-yl)-endo-3-cyano-8-(6-fluoropyrid-2-yl)-8-azabicyclo[3.2.1]octane (0.796g) m.p. 131.5-132.5 C.
EXAMPLE 70 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(5- chlorothiazol-2-yl)-8-azabicyclo[3.2.1]octane.
2-Bromo-S-chlorothiazole (2.4g), potassium carbonate (1.67g) and exo3-(S-chloropyrid-3- yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (1.Og) were heated at 140 C in Nmethylpyrrolidinone (10ml) for a total of 10 hours. The mixture was then cooled to room temperature, poured into water and the resulting mixture extracted with ethyl acetate (x3).
The combined extracts were washed with brine, dried (MgSO4), evaporated under reduced pressure and chromatographed [Si02; hexane:ethyl acetate (90:10)]. Recrystallisation (hexane) gave exo3-(Schloropyrid-3-yl)endo3-cyano8-(5chlorothiazol-2-yl)-8- azabicyclo[3.2.l]octane (0.17g) m.p. 111-112"C.
EXAMPLE 71 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- pentafluorophenyl-8-azabicyclo [3.2.l]octane.
Hexafluorobenzene (0.93ml), potassium carbonate (1.12g) and exo-3-(S-chloropyrid-3-yl)- endo-3cyanc-8-azabicyclo[3.2.1]octane (1.0g) were heated at 150 C in Nmethylpyrrolidinone (lOml) for 5 hours. Hexafluorobenzene (0.93ml) and potassium carbonate (1.12g) were added and the mixture heated at 160 C for 7 hours. The mixture was then cooled to room temperature, poured into water and the resulting mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; hexane:ethyl acetate (90:10)] to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-pentafluorophenyl-8azabicyclo[3.2.1]octane (0.55g).
EXAMPLE 72 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-cyano- 8-azabicyclo[3.2.1 ]octane.
Tosyl cyanide (0.88ml) was added dropwise to a stirred mixture of exo-3-(5-chloropyrid-3- yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (1.0g) and N,N-diisopropylethylamine (0.85ml) in tetrahydrofuran (semi) at room temperature. After 6 hours the mixture was allowed to stand at room temperature overnight, poured into water and extracted with ethyl acetate (x3).
The combined extracts were washed with water and brine, dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO2; hexane:ethyl acetate (90:10)].
Recrystallisation (hexane'ethyl acetate) gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- cyano8-azabicyclo[3.2. 1 ]octane (0.20g) m.p. 168-170 C.
EXAMPLE 73 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- methoxy-8-azabicyclo[3.2.1]octane.
N,N-Diisopropylethylamine (14.5ml) was added dropwise to a stirred suspension of O- methylhydroxylamine hydrochloride (2.32g) in isopropyl alcohol (25ml). After 30 minutes cyclohepta-2,6-dienone (3.0g) in isopropyl alcohol (semi) was added dropwise. After 24 hours N,N-diisopropylethylamine (4.9ml) was added. After 6 hours the mixture was allowed to stand at room temperature overnight. The mixture was evaporated under reduced pressure, diethyl ether added and the resulting mixture extracted with 2M hydrochloric acid (x3). The combined aqueous fractions were washed with diethyl ether (x3), neutralised with sodium hydroxide and extracted with diethyl ether (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure.Kugelrohr distillation gave 8-methoxy-8-azabicyclo[3.2.1]octan-3-one (0.86g).
Tosylmethyl isocyanide (2.52g) was added to a stirred suspension of potassium t-butoxide (2.17g) in 1,2-dimethoxyethane (loci) at such a rate to keep the temperature below 10 C.
After 45 minutes 8-methoxy-8-azabicyclo[3.2.1]octan-3-one (1.0g) in 1,2 dimethoxyethane (10ml) was added dropwise. After 30 minutes the mixture was allowed to warm to room temperature. After 4 hours the mixture was allowed to stand at room temperature overnight and water was then added. The resulting mixture was extracted with ethyl acetate (x3) and the combined extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; hexane:ethyl acetate (90:10)] gave exo-3-cyano-8methoxy-8-azabicyclo[3.2.1]octane (0.40g).
Lithium bis(trimethylsilyl)amide (2A2ml of a 1M solution in tetrahydrofuran) was added dropwise to a stirred solution of exo-3-cyano-8-methoxy-8-azabicyclo[3.2. I]octane (0.40g) and 3,5-dichloropyridine (0.358g) in tetrahydrofuran (5ml) at 0CC. After 1 hour the mixture was allowed to warm to room temperature. After S hours water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Preparative thin layer chromatography [SiO2; ethyl acetate] gave exo-3-(S-chloropyrid-3-yl)-endo-3-cyano-8-methoxy-8- azabicyclo[3.2.1]octane (0.192g) m.p. 107.5-108.5 C.
EXAMPLE 74 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2- (ethoxycarbonyl)ethyl)-8-azabicyclo[3.2.1]octane.
Sodium hydride (0.095g of an 80% dispersion in oil) was added to exo-3-(S-chloropyrid-3- yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.75g) and ethyl acrylate (2.0g) in tetrahydrofuran. The mixture was refluxed for 8 hours then allowed to cool to room temperature, water added and the mixture extracted with ethyl acetate (x2). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure.
Chromatography [SiO2; chloroform:methanol (95:5)] followed by chromatography [SiO2; ethyl acetate: dichloromethane (80:20)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2- (ethoxycarbonyl)ethyl)-8-azabicyclo[3.2.1]octane.
EXAMPLE 75 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2- carboxyethyl)-8-azabicyclo[3.2. I]octane.
3M Sodium hydroxide (4ml) was added to a stirred solution of exo-3-(S-chloropyrid-3-yl)- endo-3-cyano-8-(2-(ethoxycarbonyl)ethyl)-8-azabicyclo[3.2.1]octane(0.41g) in ethanol (8ml) at room temperature. After 24 hours the mixture was basified to pH9 and evaporated under reduced pressure. The product was azeotroped with methanol toluene and chromatographed [SiOl; dichloromethane:methanol (75:25)] to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano- 8-(2-carboxyethyl)-8-azabicyclo[3.2.1]octane (0.21g) m.p. 180-181 C.
EXAMPLE 76 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(O,O- diethylphosphonomethyl)-8-azabicyclo[3.2.1]octane.
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.20g), O,Odiethylphosphonomethyl triflate (0.245g) and potassium carbonate (0. 1Sg) were heated under reflux in tetrahydrofuran (8ml). After 3 hours the mixture was cooled to room temperature, filtered and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (96:4)] followed by high pressure liquid chromatography [SiO2; dichloromethane:methanol (96:4)] gave exo-3-(5-chloropyrid-3-yl)-endo-cyano-8-(O,O- diethylphosphonomethyl)-8-azabicyclo[3.2.1]octane m.p. 69-70 C.
EXAMPLE 77 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- phosphonomethyl-8-azabicyclo[3.2.1]octane.
Trimethylsilyl bromide (1.5ml) was added dropwise to a stirred solution of exo-3-(Schloropyrid-3-yl)-endo-3-cyano-8(O,O-diethylphosphonomethyl)-8-azabicyclo[3.2.1]octane (0.56g) in dichloromethane (30ml) at 0CC. After 30 minutes the mixture was allowed to warm to room temperature. After 7 hours trilnethylsilyl bromide (0.8ml) was added, after 23 hours more trimethylsilyl bromide (0.5ml) was added and after 18 hours further trimethylsilyl bromide (O.5ml) was added. After 24 hours the mixture was evaporated under reduced pressure, water added and the mixture filtered.After 10 minutes the filtrate was azeotroped with methanol/toluene to give exo-3-(S-chloropyrid-3-yl)-endo-3-cyano-8-phosphonomethyl- 8-azabicyclo[3.2.1]octane (0.49g) m.p. 242-245 C.
EXAMPLE 78 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2- cyanoethyl)-8-azabicyclo[3.2.1]octane.
3-Bromopropionitrile (0.174ml) was added to exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- azabicyclo[3.2.1]octane (0.40g) and potassium carbonate (0.45g) in ethanol (loll) and the mixture heated under reflux for 16 hours. 3-Bromopropionitrile (0.13ml) was added and the mixture refluxed for 3 hours and allowed to cool to room temperature. Water was added and the mixture extracted with dichloromethane (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (100:0) to (98:2] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano- 8-(2cyanoethyl)-8-azabicyclo[3.2. 1 octane (0.343g).
EXAMPLE 79 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(1,1- dimethyl-2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane.
4A Molecular sieves (1.Og) were added to a suspension of exo-3-(5-chloropynd-3-yl)-endo-3- cyano-8-azabicyclo[3.2.1]octane hydroperchlorate (3.42g) in acetone (30ml) and the mixture heated under reflux for S hours. The mixture was then allowed to cool to room temperature and filtered to give exo-3-(5-chloropynd-3-ylkendo-3-cyano-8-isopropylene-8- azabicyclo[3.2.1]octanium perchlorate (0.279g).
Trimethyl(trifluoromethyl)silane (5.2ml of a O.5M solution in tetrahydrofuran) was added to a suspension of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-isopropylene-8 azabicyclo[3.2.1]octanium perchlorate (0.50g) in tetrahydrofuran (Sml). Cesium fluoride (0.39g) was added and the mixture placed in an ultrasound bath for 2.5 hours. The mixture was then added to water and the resulting mixture extracted with dichloromethane (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure.Chromatography [sio2; dichloromethane:methanol (97:3)] followed by preparative thin layer chromatography [SiO2; dichloromethane:rnethanol (98:2)] gave exo-3-(5chloropyrid-3-yl)-endo-3-cyano-8-(1,1-dimethyl-2,2,2-trifluoroethyl)-8azabicyclo[3.2.1]octane (0.02g).
EXAMPLE 80 This example illustrates the preparation of exo-3-(5-(2,2,2-trifluoroethoxy)pyrid-3-yl)-endo- 3-cyano-8-methyl-8-azabicyclo [3.2.1]octane.
Sodium (0.46g) was added portionwise to a solution of 2,22,-trifluoroethanol (2.3ml) in Nmethylpyrrolidinone (20ml) under nitrogen. Tetraphenylphosphonium bromide (0.05g) and exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (2.6g) were added and the mixture heated at 110 C for 18 hours and 140 C for 5 hours. Sodium (0.6g) was added to a solution of 2,22,-trifluoroethanol (3ml) in N-methylpyrrolidinone (semi) and after 30 minutes the resulting mixture was added to the reaction mixture. After 6 hours at 140 C the mixture was cooled to room temperature and added to water. The mixture was extracted with diethyl ether (x2) and the combined extracts were washed with water, dried (MgSO4) and evaporated under reduced pressure.The resulting mixture was filtered [SiO2; dichloromethane:methanol (95:5)] and chromatographed [SiO2; dichloromethane:methanol (95:5)] to give exo-3-(5-(2,2,2-trifluoroethoxy)pyrid-3-yl)-endo-3-cyano-8-methyl-8- azabicyclo[3.2.1]octane (0.065g, 80% pure).
EXAMPLE 81 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(1- cyanoethyl)-8-azabicyclo[3.2. 1 joctane.
exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.50g), 2bromopropionitrile (2ml) and potassium carbonate (O.50g) were refluxed in ethanol (5ml).
After 24 hours the mixture was cooled to room temperature, water added and the mixture extracted with dichloromethane (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (100:0) to (98:2)] followed by chromatography [SiO2; ethyl acetate:hexane (80:20)] and preparative thin layer chromatography [A1203; ethyl acetate:hexane (40:60)] gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(1-cyanoethyl)-8- azabicyclo[3.2.1]octane (0.044g, 80% pure).
EXAMPLE 82 This example illustrates the preparation of exo-3-(5-phenylpyrid-3-yl)-endo-3-cyano-8- (vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane.
Vinyl chloroformate (2.17ml) was added a solution of exo-3-(5-iodopynd-3-yl)-endo-3- cyano-8-methyl-8-azabicyclo[3.2.1]octane (3.0g) in tetrahydrofuran (20ml) at 0CC. The mixture was then heated under reflux for 5 hours and then stand at room temperature overnight. Water was then added and the mixture extracted with dichloromethane (x3). The combined extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (98:2)] gave exo-3-(5iodopyrid-3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (3.64g).
Tetrakis(triphenylphosphine)palladium(0) (0.042g) was added to a stirred solution of exo-3 (5-iodopyrid-3-yl)-endo-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (0.50g) in toluene (2ml). To this mixture was added 2M sodium carbonate solution (1.22ml) and phenylboronic acid (0.16g) in ethanol (0.5ml) and the mixture heated under reflux. After 2 hours the mixture was cooled to room temperature, water added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate:hexane (45:55)] gave exo-3-(5-phenylpyrid-3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8 azabicyclo[3.2.1]octane (0.33g).
EXAMPLE 83 This example illustrates the preparation of exo-3-(5-phenylpyrid-3-yl)-endo-3-cyano-8- azabicyclo[3.2.1]octane.
Concentrated hydrochloric acid (0.5ml) was added to a solution of exo-3-(5-phenylpyrid-3yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (0.30g) in methanol (loll) and the mixture heated under reflux. After 5 hours the mixture was allowed to stand at room temperature for 4 days and then heated under reflux for 5 hours. The mixture was then allowed to cool to room temperature, basified with saturated sodium bicarbonate solution and extracted with dichloromethane (x3). The combined extracts were washed with brine and extracted with 2M hydrochloric acid (x2). The acidic extracts were basified and re-extracted with dichloromethane (x3).The combined organic extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to give 3-(S-phenylpyrid-3-yl)-end3- cyano-8-azabicyclo[3.2.1]octane (0.20g).
EXAMPLE 84 This example illustrates the preparation of exo-3-(5-methylpyrid-3-yl)-endo-3-cyano-8- (vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane.
Methyllithium (8.7ml of a l.4M solution in diethyl ether) was added dropwise to a stirred suspension of copper(I) iodide (1.16g) in diethyl ether (loci) at 0 C under nitrogen. After 45 minutes exo-3-(5-iodopyrid-3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8azabicyclo[3.2.1]octane (0.50g) in diethyl ether (semi) was added. After 5 days at room temperature water was added and the mixture extracted with ethyl acetate (x3). The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure. Chromatography [SiO2; ethyl acetate:hexane (60:40)] gave exo-3-(5-methylpyrid- 3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (0.085g).
EXAMPLE 85 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2- cyanoprop2-yl)-8-azabicyclo[3.2. I]octane.
Sodium cyanide (0.069g) was added to a stirred solution of exo3-(5-chioropyrid-3-yl)-endo- 3-cyano-8-isopropylene-8-azabicylco[3.2.1]octanium perchlorate (0.50g) in acetonitrile (semi) at room temperature under nitrogen. After 4 hours the mixture was allowed to stand at room temperature over the weekend, water added and the mixture extracted with dichloromethane (x3). The combined extracts were washed with brine, dried (MgSOs) and evaporated under reduced pressure to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2-cyanoprop-2-yl)-8- azabicyclo[3.2.1]octane (0.38g, 90% pure).
EXAMPLE 86 This example illustrates the preparation of exo3-(5-(ethoxycarbonyl)pyrid-3-yl)-endo-3- cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane.
Potassium carbonate (0.205g) and bis(triphenylphosphine)palladium(u) chloride (0.026g) were added to a stirred solution of exo-3-(5-iodopyrid-3-yl)-endo-3-cyano-8-methyl-8- azabicyclo[3.2.1]octane (0.50g) in ethanol (lOml) under nitrogen. The reaction vessel was then flushed with carbon monoxide, triethylamine (3 drops) added and the mixture heated under reflux. After 3 hours the mixture was cooled to room temperature, water and brine added and the mixture extracted with ethyl acetate (x3). The combined extracts were dried (MgSO4), evaporated under reduced pressure and chromatographed [sio2; ethyl acetate:hexane (35:65)] to give exo-3-(5-(ethoxycarbonyl)pyrid-3-yl)-endo-3-cyano-8- (vinyloxycarbonyl)-8-azabicyclo[3.2. l]octane (0.29g).
Confumation of the structural identity of the compounds prepared in Examples 20 to 106 was obtained by proton magnetic resonance spectroscopy. The results are set out in the following table.
EXAMPLE 'H NMR (270MHz), in CDCI3 unless otherwise stated 1 8.81 (1H, d), 8.56 (1H, dd), 7.85 (1H, dt), 7.30 (1H, dd), 3.44 (2H, m), 2.45-2.15 (8H, m) and 2.33 3H, s).
2 8.80 (1H, d), 8.55 (1H, dd), 7.85 (1H, m), 7.30 (1H, m), 4.55 (2H, dt), 3.4 (2H, m), 2.70 (2H, dt) and 2.4-2.1 (8H, m).
3 7.09 (2H, m), 6.75 (1H, m), 3.31 (2H, m), 2.4-2.1 (8H, m) and 2.35 (3H, s).
4 8.80 (1H, d), 8.54 (1H, dd), 7.83 (1H, dt), 7.29 (1H, dd), 3.40 (2H, m), 2.4-2.0 (10H, m), 1.48 (2H, hex) and 0.91 (3H, s).
5 7.53 (2H, m), 7.4-7.2 (8H, m), 3.59 (2H, s), 3.36 (2H, m) and 2.5-2.15 (8H, m).
6 8.82 (1H, d), 8.58 (1H, dd), 7.86 (1H, dt), 7.4-7.2 (6H, m), 3.59 (2H, s), 3.39 (2H, m) and 2.45-2.15 (8H, m).
7 8.80 (1 H, d), 8.56 (1 H, dd), 7.84 (1 H, dt), 7.31(1 H, dd), 3.50 (2H, t), 3.48 (2H, m), 3.36 (3H, s), 2.61 (2H, t) and 2.4-2.05 (8H, m).
8 8.61 (1H, m), 7.68 (2H, m), 7.20 (1H, m), 3.34 (2H, m), 2.64 (2H, m), 2.5-2.1 (6H, m) and 2.37 (3H, s).
9 8.94 (1H, d), 8.59 (1H, t), 8.53 (1H, d), 3.35 (2H, m), 2.65-2.55 (2H, m), 2.4-2.1 6H, m) and 2.36 (3H, m).
10 8.82 (1H, s), 8.54 (1H, s), 3.37 (2H, m), 2.54 (2H, dd), 2.4-2.1 (6H, m) and 2.35 (3H, s).
11 7.78 (1H, d), 7.55 (1H, d), 3.40 (2H, m), 2.70 (2H, m), 2.5-2.1 (6H, m) and 2.37 (3H, s).
12 8.49 (1H, d), 7.95 (1H, d), 3.34 (2H, m), 2.4-2.15 (8H, m) and 2.35 (3H, s).
13 8.81 (1H, d), 8.56 (1H, dd),.7.84 (1H, dt), 7.31 (1H, dd), 3.72 (3H, s), 3.50 (2H, m), 3.22 (2H, s), 2.5-2.3 (6H, m) and 2.2-2.1 (2H, m).
14 8.89 (1H, d), 8.60 (1H, dd), 7.87 (1H, dt), 7.35 (1H, dd), 4.54 (2H, m), 4.50 (2H, s), 3.22 (3H, s) and 2.6-2.25 (8H, m).
15 8.59 (1H, d), 7.81 (1H, dd), 7.34 (1H, d), 3.33 (2H, m) 2.4-2.15 (8H, m) and 2.35 (3H, s).
16 8.69 (IH, d), 8.51 (1H, d), 7.82 (1H, t), 3.42 (2H, m), 2.4-2.0 (10H, m), 1.5-1.2 (8H, m) and 0.89 (3H, m).
17 8.70 (IH, d), 8.52 (lH, d), 7.83 (IH, t), 5.88 (1H, m), 5.18 (2H, m), 3.42 (2H, m), 3.02 (2H, m) and 2.4-2.05 (8H, m).
18 8.70 (1H, d), 8.55 (1H, d), 7.80 (1H, t), 3.50 (2H, m), 2.90 (2H, q), 2.5-2.2 (6H, m) and 2.10 (2H, m).
19 8.74 (1H, d), 8.61 (1H, d), 8.00 (1H, t), 3.35 (1H, m), 2.4-2.15 (8H, m) and 2.33 (3H, s).
20 9.03 (1H, d), 8.82 (1H, d), 8.15 (1H, t), 3.36 (1H, m), 2.4-2.2 (8H, m) and 2.35 (3H, s).
21 8.40 (1H, d), 8.21 (1H, d), 7.34 (1H, t), 4.10 (2H, q), 3.31 (2H, m), 2.4-2.15 (8H, m), 2.32 (3H, s) and 1.44 (3H, t).
22 8.70 (1 H, d), 8.50 (1 H, d), 7.80 (1 H, t), 3.70 (2H, m), 2.65 (1 H, m), 2.35 (2H, m), 2.25 (4H, m), 2.05 (2H, m) and 1.05 (6H, d).
23 7.47 (2H, s), 3.32 (2H, m), 2.35-2.15 (8H, m) and 2.32 (3H, s).
24 8.39 (1 H, d), 7.51 (1 H, d), 7.40 (1 H, dd), 3.32 (2H, m), 2.4-2.1 (8H, m) and 2.32 (3H, s).
25 8.61 (2H, m), 7.49 (2H, m), 3.33 (2H, m), 2.4-2.1 (8H, m) and 2.32 (3H, s).
26 8.69 (1H, d), 8.51 (1H, d), 7.81 (1H, t), 4.35 (1H, ddt), 3.41 (2H, m), 3.00 (2H, dt) and 2.4 2.1 (8H, m).
27 8.59 (2H, m), 7.98 (1H, d), 7.72 (1H, d), 5.55 (1H, d), 4.36 (1H, m), 4.25 (1H, m), 2.7-2.2 (8H, m).
28 8.65 (1H, d), 8.55 (1H, d), 7.75 (1H, t), 4.95 (1H; m), 4.40 (1H, m), 2.65-2.1 (8H, m) and 2.15 (3H, s).
29 [in DMSO] 8.79 (1H, brs), 8.70 (1H, d), 8.64 (1H, brs), 8.61 (1H, d), 4.16 (2H, m), 2.7-2.6 (2H, m), 2.45-2.25 (4H, m), and 2.15-2.0 (2H, m).
30 8.67 (1H, d), 8.49 (1H, d), 7.80 (1H, t), 3.79 (2H, m), 2.4-2.15 (6H, m), 2.0-1.9 (2H, m) and 1.09 (9H, s).
31 9.56 (1H, s), 8.75 (1H, d), 8.55 (1H, d), 7.89 (1H, t), 7.55-7.3 (5H, m), 3.60 (1H, m), 3.38 (1H, m), 2.6-1.9 (8H, m) and 1.54 (3H, s).
32 8.72 (1H, d), 8.53 (1H, d), 7.89 (1H, t), 7.53 (2H, m), 7.35-7.2 (3H, m), 6.11 (1H, dd), 5.29 (IH, d), 5.19 (1H, d), 3.63 (1H, m), 3.54 (1H, m), 2.45-1.9 (8H, m) and 1.51 (3H, s).
33 8.69 (1H, d), 8.52 (1H, d), 7.82 (1H, t), 7.54 (2H, m), 7.4-7.25 (3H, m), 3.90 (1H, m), 3.70 (1 H, d), 3.65 (1 H, d), 3.31(1 H, m), 2.5-2.0 (8H, m) and 1.49 (3H, m).
34 8.60 (1 H, d), 8.50 (1 H, d), 7.71 (1 H, t), 7.4-7.25 (5H, m), 3.40 (1 H, m), 3.32 (1 H, m), 2.82 (1H, t), 2.66 (1 H, t), 2.3-1.95 (8H, m) and 1.74 (3H, d).
35 8.70 (1H, d), 8.54 (1H, d), 7.85 (1H, t), 7.50 (2H, m), 7.4-7.25 (3H, m), 4.31 (1H, d), 4.19 (IH, d), 3.85 (1H, m), 2.34 (1H, m), 2.5-2.15 (8H, m), 2.00 (3H, s) and 1.56 (3H, s).
36 8.64 (1H, d), 8.56 (1H, d), 8.20 (1H, s), 7.77 (1H, t), 4.86 (1H, m), 4.32 (1H, m) and 2.6 2.1 (8H, m).
37 8.69 (1H, d), 8.52 (1H, d), 7.85 (1H, t), 4.11 (2H, m), 3.65 (2H, hept), 2.55-2.1 (8H, m) and 1.30 (12H, d).
38 8.62 (1H, d), 8.52 (1H, d), 7.75 (1H, t), 4.26 (2H, m), 2.5-2.15 (8H, m) and 1.40 (9H, s).
39 8.71 (1H, d), 8.53 (1H, d), 7.84 (1H, t), 7.4-7.2 (5H, m), 3.71 (1H, m), 3.49 (1H, q), 3.28 (1H, m), 2.4-2.05 (8H, m) and 1.30 (3H, d).
40 8.20 (1H, d), 8.00 (1H, d), 7.11(1H, t), 3.76 (2H, brs), 3.32 (2H, m), 2.4-2.1 (8H, m) and 2.32 (3H, s).
41 8.62 (1H, d), 8.56 (1H, d), 8.22 (1H, t), 7.46 (1H, brs), 3.35 (2H, m), 2.4-2.2 (8H, m), 2.35 (3H, s) and 2.21 (3H, s).
42 8.69 (1H, d), 8.54 (1H, d), 7.81 (1H, t), 7.55-7.35 (5H, m), 4.38 (1H, s), 3.94 (1H, m), 3.29 (1H, m) and 2.6-2.1 (8H. m).
43 8.69 (1H, d), 8.55 (1H, d), 7.81 (1H, t), 7.45-7.3 (5H, m), 6.91 (1H, m), 5.70 (1H, m), 3.96 (1H, s), 3.60 (1H, m), 3.35 (1H, m), 2.5-2.2 (6H, m) and 2.05-1.9 (2H, m).
44 8.77 (2H, m), 8.16 (1H, t), 3.32 (2H, m), 2.4-2.1 (8H, m) and 2.32 (3H, s).
45 9.02 (1H, d), 8.83 (1H, m), 8.07 (1H, m), 3.36 (2H, m) and 2.4-2.05 (11H, m).
46 [in DMSO] 8.72 and 8.62 (1H, m), 8.58 (1H, m), 8.14 and 7.86 (1H, m), 5.39 (1H, m), 4.20 (1H, m) 2.7-2.0 (8H, m).
47 8.65 (1H, d), 8.58 (1H, d), 7.78 (1H, t), 4.51 (2H, m), 2.6-2.2 (8H, m).
48 8.69 (1H, d), 8.52 (1H, d), 7.81 (1H, t), 5.85 (1H, tt), 3.45 (1H, m), 2.71 (2H, dt) and 2.5 2.0 (8H, m).
49 8.69 (1H, d), 8.52 (1H, d), 7.82 (1H, t), 7.35-7.15 (5H, m), 3.45 (2H, m), 2.79 (2H, m), 2.61 (2H, m) and 2.4-2.05 (8H, m).
50 8.39 (1H, m), 8.05 (1H, m), 7.59 (1H, m), 3.43 (2H, m) 2.5-2.1 (8H, m) and 2.40 (3H, s).
51 8.70 (1H, d), 8.52 (1H, d), 7.83 (1H, t), 7.4-7.2 (5H, m), 3.57 (2H, s), 3.40 (2H, m) and 2.45-2.2 (8H, m).
52 8.63 (1H, d), 8.50 (1H, d), 7.77 (1H, t), 3.60 (2H, m), 3.42 (2H, m) and 2.5-2.2 (8H, m).
53 8.71 (1H, d), 8.53 (1H, d), 8.10 (1H, t), 7.90 (2H, m), 7.39 2H, m), 3.45 (2H, m), 3.30 (2H, m) and 2.4-2.2 (8H, m).
54 8.69 (1H, d), 8.53 (1H, d), 7.83 (1H, t), 7.42 (1H, dd), 7.22 (1H, m), 7.09 (1H, t), 3.50 (2H, s), 3.36 (2H, m) and 2.45-2.15 (8H, m).
55 8.71 (1H, d), 8.52 (2H, m), 7.86 (1H, t), 7.69 (1H, dt), 7.54 (1H, d), 7.19 (1H, m), 3.73 (2H,s), 3A3 (2H, m) and 2.5-2.2 (8H, m).
56 8.70 (1H, d), 8.52 (1H, d), 7.85 (1H, t), 7.00 (1H, s), 3.66 (2H, s), 3.49 (2H, m), 2.70 (3H, s) and 2.45-2.15 (8H, m).
57 8.61 (IH, d), 8.52 (1H, d), 7.78 (1H, t), 3.33 (2H, m), 3.29 (2H, s), 2.5-2.1 (8H, m), 2.38 (3H, s) and 2.32 (3H, s).
58 8.70 (1H, d), 8.52 (1H, d), 7.83 (1H, t), 6.74 (1H, d), 6.65 (1H, d), 3.65 (2H, s), 3.46 (2H, m) and 2.45-2.1 (8H, m).
59 8.65 (1H, d), 8.50 (1H, d), 7.80 (1H, t), 3.94 (2H, s), 3.55 (2H, m) and 2.5-2.25 (8H, m).
60 8.65 (1H, d), 8.41 (1H, d), 7b0 (1H, dt), 3.44 (2H, m), 2.4-2.15 (8H, m) and 2.35 (3H, s).
61 8.69 (2H, m), 7.84 (1H, t), 7.10 (2H, m), 6.40 (2H, m), 3.34 (2H, m), 2.4-2.15 (8H, m) and 2.33 (3H, s).
62 8.79 (1H, d), 8.75 (1H, d), 8.05 (1H, m), 4.74 (1H, d), 4.31 (1H, d), 3.94 (2H, q), 3.40 (2H, m), 2.5-2.2 (11H, m) and 1.44 (3H, t).
63 9.09 (1H, d), 8.99 (1H, d), 8.39 (1H, t), 3.37 (2H, m), 2.69 (3H, s), 2.45-2.15 (8H, m) and 2.34 (3H, s).
64 8.76 (1H, d), 8.62 (1H, d), 7.94 (1H, m), 3.34 (2H, m), 3.24 (1H, s), 2.45-2.15 (8H, m) and 2.35 (3H, s).
65 8.80 and 8.70 (1H, m), 8.29 (1H, m), 7.95 (1H, m), 7.71 (1Hm), 7.56 (1H, m), 7.4-7.1 (3H, m), 5.65 and 5.29(1 H, m), 4.91 and 4.75(1 H, m), 4.30 and 4.11(1 H, m), 3.30 (1H, m), 2.8-2.0 (8H, m) and 1.73 and 1.62 (3H, m).
66 8.61 (1H, d), 8.52 (1H, d), 7.79 (1H, t), 7.5-7.15 (5H, m), 3.01 (1H, m), 2.91 (1H, m), 2.79 (1H, m), 2.39 (2H, m), 2.3-1.6 (12H, m), 1.09 (3H, d) and 0.91 (3H, d).
67 8.69 (1H, d), 8.52 (1H, d), 7.81 (1H, t), 3.55 (2H, m), 3.35 (2H, s) and 2.5-2.1 (8H, m).
68 8.69 (1H, d), 8.52 (1H, d), 7.81 (1H, t), 4.20 (2H, m), 3.61 (1H, m), 3.49 (1H, m), 3.23 (1H, q), 2.45-2.0 (8H, m), 1.31 (3H, d) and 1.29 (3H, t).
69 8.50 (1H, d), 8.35 (1H, d), 7.7-7.5 (2H, m), 6.40 (2H, dd), 6.25 (1H, dd), 4.70 (2H, m), 2.6- 2.5 (2H, m) 2.45-2.20 (6H, m).
70 8.51 (1H, d), 8.49 (1H, d), 7.70 (1H, t), 4.45 (2H, m), 2.6-2.5 (4H,m) and 2.4-2.2 (4H, m).
71 8.70 (1H, d), 8.55 (1H, d), 7.85 (1H, t), 4.25 (2H, m) and 2.6-2.2(8H, m).
72 8.29 (1H, d), 8.10 (1H, d), 7.90 (1H, m), 4.15 (2H, m) 2.6-2.25 (8H, m).
73 8.75, 8.65 and 8.50 (1H, m), 7.90 and 7.80 (1H, m), 3.80 and 3.70 (2H, m), 3.6 and 3.5 (3H, m) and 2.7-1.8(8H, m).
74 8.65 (1H, d), 8.51 (1H, d), 7.80 (1H, t), 4.16 (2H, q), 3.41 (2H, m), 2.69 (2H, t), 2.48 (2H, t), 2.4-2.05 (8H, m) and 1.27 (3H, t).
75 8.76 (1H, m), 8.52 (1H, m), 7.98 (1H, m), 3.85 (2H, m), 3.01 (2H, 1), 2.8-2.2 (10H, m).
76 8.64 (1H, d), 8.51 (1H, d), 7.80 (1H, t), 4.18 (4H, m), 3.60 (2H, m), 2.78 (2H, d), 2.45-2.05 (8H, m) and 1.36 (6H, m).
77 [in DMSO] 8.89 (1H, d), 8.62 (1H, d), 8.29 (1H, t), 4.50 (2H, m), 3.48 (2H, d) and 2.85 2.45 (8H, m).
78 8.69 (1H, d), 8.51 (1H, d), 7.80 (1H, t), 3.46 (2H, m), 2.64 (2H, m), 2.51 (2H, m) and 2.45 2.0 (8H, m).
79 9.65 (1H, d), 8.51 (1H, d), 7.79 (1H, t), 3.91 (2H, m), 2.45-2.2 (8H, m) and 1.28 (6H, s).
80 8.55 (1H, d), 8.3 (1H, d), 7.45 (1H, t), 3.35 (2H, m), 2.4-2.1 (8H, m) and 2.3 (3H, s).
81 8.69 (1H, d), 8.52 (1H, d), 7.81 (1H, t), 3.85 (1H, m), 3.60 (1H, m), 3.50 (1H, q), 2.5-2.1 (8H, m) and 1.51 (3H, d).
82 8.81 (1H, d), 8.71 (1H, d), 7.92 (1H, t), 7.6-7.35 (5H, m), 7.25 (1H, dd), 4.80 (1H, dd), 4.61 (2H, m), 4.49 (1H, dd) and 2.55-2.15 (8H, m).
83 8.79 (2H, m), 7.99 (1H, t), 7.6-7.35 (5H, m), 3.75 (2H, m), 2.55-2.2 (6H, m) and 2.05-1.85 (2H, m).
84 8.55 (1H, m), 8.40 (1H, m), 7.55 (1H, m), 7.23 (1H, dd), 4.80 (1H, dd), 4.59 (1H, m), 4.49 (1H, dd), 2.6-2.1 (8H, m) and 2.39 (3H, s).
85 8.64 (1H, d), 8.52 (1H, d), 7.70 (1H, t), 3.91 (1H, m), 2.55-215 (8H, m) and 1.52 (6H, s).
86 9.19 (1H, d), 8.90 (1H, d), 8.31 (1H, t), 7.24 (1H, dd), 4.82 (1H, dd), 4.63 (2H, m), 4.51 (1H, dd), 4.44 (2H, q), 2.6-2.2 (8H, m) and 1.43 (3H, t).
EXAMPLE 87 This Example illustrates an emulsifiable concentrate composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes. The concentrate has the following composition: % Weight Compound No.l 25.5 SYNPEROMC NP13 2.5 Calcium dodecylbenzenenesulphonate 2.5 AROMASOL H 70 EXAMPLE 88 This Example illustrates an emulsifiable concentrate composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes.The concentrate has the following composition: s Weight Compound No.5 50.0 SYNPERONIC NP13 6.0 Calcium dodecylbenzenesulphonate 4.0 AROMASOL H 40.0 EXAMPLE 89 This Example illustrates an emulsifiable concentrate composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes. The concentrate has the following composition: %Weight Compound No.9 1.0 SYNPERONIC OP10 3.0 Calcium dodecylbenzenesulphonate 2.0 AROMASOL H 94.0 EXAMPLE 90 This Example illustrates a wettable powder composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes.The wettable powder has the following composition: 96 Weight Compound No.13 25.0 Silica 25.0 Sodium lignosulphonate 5.0 Sodium lauryl sulphate 2.0 Kaolinite 43.0 EXAMPLE 91 This Example illustrates a wettable powder composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes. The wettable powder has the following composition: %Weight Compound No.17 1.0 Sodium lignosulphonate 5.0 Sodium lauryl sulphate 2.0 Kaolinite 92.0 EXAMPLE 92 This Example illustrates a wettable powder composition which is readily convertible by dilution with water into a liquid preparation suitable for spraying purposes.The wettable power has the following composition: 496 Weight Compound No.21 40.0 Silica 40.0 Calcium lignosulphonate 5.0 Sodium lauryl sulphate 2.0 Kaolinite 13.0 EXAMPLE 93 This Example illustrates a dusting powder which may be applied directly to plants or other surfaces and comprises 1% by weight of Compound No.25 and 99% by weight of talc.
EXAMPLE 94 This Example illustrates a concentrated liquid formulation suitable for application by ultra low volume techniques after mixing with paraffinic diluents.
%Weight Compound No.29 90.0 SOLVESSO 200 10.0 EXAMPLE 95 This Example illustrates a concentrated liquid formulation suitable for application by ultra low volume techniques after mixing with paraffinic diluents.
% Weight Compound No.33 25.0 SOLVESSO 200 75.0 EXAMPLE 96 This Example illustrates a concentrated liquid formulation suitable for application by ultra low volume techniques after mixing with paraffinic diluents.
%Weight Compound No.37 10.0 SOLVESSO 200 90.0 EXAMPLE 97 This Example illustrates a liquid formulation suitable for application (undiluted) by ultra low volume techniques.
% Weight Compound No.41 15 Cotton seed oil 50 SOLVESSO 200 35 EXAMPLE 98 This Example illustrates a capsule suspension concentrate which is readily convertible by dilution with water to form a preparation suitable for application as an aqueous spray.
46 Weight Compound No.45 10.0 Alkylbenzene solvent (e.g. AROMASOL H) 5.0 Toluene di-isocyanate 3.0 Ethylenediamine 2.0 Polyvinyl alcohol 2.0 Bentonite 1.5 Polysaccharide (e.g. KELTROL) 0.1 Water - 76.4 EXAMPLE 99 This Example illustrates a capsule suspension concentrate which is readily convertible by dilution with water to form a preparation suitable for application as an aqueous spray.
% Weight Compound No.49 1.0 Alkylbenzene solvent (e.g. AROMASOL H) 10.0 Toluene di-isocyanate 3.0 Ethylenediamine 2.0 Polyvinyl alcohol 2.0 Bentonite 1.5 Polysaccharide (e.g. KELTROL) 0.1 Water 80.4 EXAMPLE 100 A ready for use granular formulation: % Weight Compound No.4 0.5 SOLVESSO 200 0.2 nonylphenol ethoxylate 0.1 (eg Synperonic NP8) Calcium carbonate granules 99.2 (0.3-0.7 mm) EXAMPLE 101 An aqueous suspension concentrate: 46 Weight Compound No.8 5.0 Kaolinite 15.0 Sodium lignosulphonate 3.0 nonylphenolethoxylate 1.5 (eg Synperonic NP 8) propylene glycol 10.0 Bentonite 2.0 Polysaccharide (eg Keltrol) 0.1 Bactericide (eg Proxel;Proxel 0.1 is a registered Trade Mark) Water 63.3 EXAMPLE 102 A ready for use dust (D.P.) made from a concentrate Concentrate: % Weight Compound No.12 10 Silica 20 Magnesium Carbonate 70 Dust Example containing 1% active ingredient: Above concentrate 10 Talc 90 EXAMPLE 103 This Example illustrates a ready for use granule formulaton.
%Weight Compound No.16 5 Synperonic NP8 2 Pumice granules (20/40 BS Mesh) 93 EXAMPLE 104 This Example illustrates a water dispersible granule formulation.
%Weight Compound No.20 5 Silica 5 Sodium lignosulphate 10 Sodium dioctylsulphosuccinate 5 Sodium acetate 10 Montmorillonite powder 65 EXAMPLE 105 This Example illustrates the insecticidal properties of the compounds of Formula I. The activity of the the compounds of Formula I was determined using a variety of pests. The pests were treated with a liquid composition containing 500 parts per million (ppm) by weight of the compound unless otherwise stated. The compositions were made by dissolving the compound in acetone and 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 substrate, 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 at periods usually varying from two to five days after the treatment.
The results of the tests against peach aphid (Myzus persicae! are presented in Table II.
The results indicate a grading of mortality (score) designated as A, B or C wherein C indicates less than 40% mortality, B indicates 40-79% mortality and A indicates 80-100% mortality; "-" indicates that either the compound was not tested or no meaningful result was obtained. In this test Chinese cabbage leaves were infested with aphids, the infested leaves were sprayed with the test composition, and the mortality assessed after 3 days.
Information regarding the pest species, the support medium or food, and the type and duration of the test is given in Table m. The pest species is designated by a letter code.
TABLE II Comp'd Score Comp'd Score Comp'd Score Comp'd Score No No No No 1 A 2 A 3 A 4 A 5 A 6 C 7 C 8 A 9 A 10 A 11 A 12 A 13 B 14 A 15 A 16 C 17 C 18 A 19 C 20 C 21 A 22 A 23 A 24 A 25 A 26 B 27 A 28 C 29 B 30 A 31 C 32 A 33 A 34 A 35 A 36 A 37 A 38 A 39 C 40 A 41 A 42 A 43 A 44 A 45 C 46 A 47 A 48 A 49 A 50 A 51 A 52 C 53 A 54 A 55 A 56 A 57 A 58 C 59 A 60 A 61 A 62 A 63 C 64 A 65 C 66 C 67 A 68 A 69 A 70 A 71 A 72 A 73 C 74 A 75 A 76 A 77 A 78 A 79 A 80 A 81 A 82 A 83 A 84 A 85 A 86 A 87 A 88 A 89 C 90 A 91 A 92 A 93 A 94 C 95 A 96 A 97 C 98 A 99 A 100 A 101 A 102 A 103 A 104 A 105 B 106 A 107 A 108 A 109 A 110 A 111 A 112 B 113 A 114 A 115 A 116 A 117 A 118 A 119 A 120 A 121 A 122 A 123 A 124 A 125 A 126 C 127 - 128 A 129 A 130 A 131 A 132 A 133 A 134 A 135 A 136 C 137 C 138 A 139 A 140 A 141 A 142 A 143 A 144 A 145 A 146 A 147 A 148 B 149 A 150 A 151 A 152 A 153 A 154 B 155 A 156 A 157 C 158 A 159 A 160 A 161 A 162 C 163 C 164 A 165 A 166 A 167 A 168 A 169 A 170 B 171 A 172 A 173 A 174 A 175 A 176 A 177 A 178 A ' 179 A 180 A 181 A 182 A 183 A 184 A 185 A 186 A 187 C 188 A 189 A 190 - 191 A 192 A 193 A 194 A 195 A 196 A 197 A 198 A 199 A 200 A 201 A 202 A 203 A 204 A 205 A 206 A 207 A 208 A 209 A 210 A 211 A 212 A 213 A 214 A 215 A 216 217 A 218 A 219 - 220 A 221 A 222 C 223 C 224 225 A 226 - 227 A 228 A 229 A 230 A 231 A 232 A 233 A 234 A 235 A 236 A 237 A 238 A 239 A 240 A 241 A 242 A 243 A 245 A 246 A 247 A 248 A 249 A 250 A 251 A 252 A 253 A 254 A 255 A 256 A 257 A 258 A 259 A 260 A 261 A 262 A 263 - -A 264 A 265 A 266 A 267 A 268 A 269 A 270 A 271 A 272 A 273 A 274 A 275 A 276 A 277 A 278 A 279 A 280 A 281 A 282 A 283 A 284 A 285 A 286 A 287 A 288 A 289 A 290 A 291 - 292 A 293 A 294 A 295 - 296 A 297 A 298 A 299 A 300 A 301 A 302 A 303 - 304 A 305 306 - 307 - 308 - 309 A 310 A 311 A 312 A 313 A 314 A 315 A 316 A 317 A 318 A 319 A 320 A 321 A In tests against tobacco budworm (Heliothis virescens, larvae) the following compounds scored A or B.
Compounds 2, 8, 14, 18, 23, 66, 72, 95, 99, 102, 104, 120, 131, 156, 169, 170, 227, 229, 231, 234, 236, 243, 260, 262, 270, 274, 312.
In tests against root knot nematodes (Meloidogyme incognita) the following compounds scored AorB.
Compounds 36, 55, 71, 77, 94, 99, 120, 160, 207, 233, 237, 238, 253, 257, 271, 312, 317, 318.
In tests against red spider mite (Tetranychus urticae) the following compounds scored A or B.
Compounds 12, 13, 22, 23, 25, 34, 37, 39, 47, 53, 63, 64, 66, 87, 90, 99, 101, 106, 120, 135, 142, 186, 193, 195, 199, 201, 207, 208, 236, 237, 239, 245, 247, 249, 280, 283, 310 to 321.
In tests against Whitefly (Bemesia tabaci) the following compounds were particularly effective.
Compounds 33, 34, 36, 56, 64, 68, 69, 70, 72, 74, 76, 77, 81, 90, 93, 99, 227 to 275.
The chemical formulae referred to in the preceding description are set out below.

Claims (17)

1. A compound of formula (I):
wherein Rl represents a group of formula (A)
where each of W, X, Y and Z and Z represents either a group CR or the nitrogen atom, provided that not more than two of W, X, Y and Z represent the nitrogen atom and where each R present is independently selected from hydrogen and halogen atoms and cyano, amino, hydrazino, acylamino, hydroxy, alkyl, hydroxyalkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkenyloxy, alkoxyalkenyl, allcynyl, carboxylic acyl, alkoxycarbonyl, aryl and heterocyclyl groups, said groups comprising up to 6 carbon atoms, and wherein R2 represents hydrogen or cyano or a group selected from alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, aralkenyl, alkynyl, alkoxycarbonyl, alkanesulfonyl, arenesulfonyl, aLkanyloxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, heterocyclylalkyl, carbamyl or dithiocarboxyl groups, said groups comprising from 1 to 15 carbon atoms, said groups being optionally substituted with one or more substituents selected from, halogen, cyano, carboxyl, carboxylic acyl, carbamyl, alkoxycarbonyl, alkoxy, alkylenedioxy, hydroxy, nitro, haloalkyl, alkyl, amino, acylamino, imidate and phosphonato groups; and acid addition salts, quaternary ammonium salts and N-oxides derived therefrom
2. A compound according to claim 1 wherein Rl represents a halo-substituted phenyl, pyridyl or diazinyl group.
3. A compound according to claim 1 where Rl represents an optionally halogen substituted phenyl group or an optionally halogen substituted pyridyl, pyridazinyl or pyrazinyl group and R2 represents hydrogen or a C, alkyl, alkenyl, alkynyl, phenyl, benzyl, pyridylmethyl, thienylmethyl, thiazolylmethyl group which may be optionally substituted with one or more alkyl, alkoxy, alkoxycarbonyl, cyano, optionally substituted are sulphonyl groups or halogen atoms; and acid addition salts thereof.
4. A compound according to claim 1 wherein Rl is a halo-substituted pyridyl group.
5. A compound according to claim 1 wherein R2 is a hydrogen or haloalkyl, haloalkenyl or haloarallyl group.
6. A compound according to claim 4 wherein R2 is a haloalkyl or haloalkenyl group.
7. A compound according to claim 6 wherein R2 is a fluoroalkyl or fluoroalkenyl group.
8. A compound according to claim 4 where R' is a 5-halopyrid-3-yl group.
9. A compound according to claim 8 wherein R2 is fluoroethyl, difluoroethyl or trifluoroethyl.
10. An insecticidal acaricidal and nematicidal composition comprising an insecticidally, acaricidally or nematicidally effective amount of a compound according to claim 1.
11. A method of combating and controlling acerine or nematode pests at a locus which comprises treating the pests or the locus of the pests with an effective amount of a composition according to claim 10.
12. A method according to claim 11 wherein the pests are insect pests of growing plants.
13. A method of preparing a compound of formula (I) where R2 is not hydrogen which comprises reacting a compound of formula (it):
with a compound of formula R2L where L is a leaving group in the presence of a base.
14. A process according to claim 13 wherein L represents halide or triflate.
15. A process of preparing a compound of formula (I) which comprises reacting a compound of formula (VI):
with a compound of formula R'Hal where Hal is a halide in the presence of a base.
16. A process of preparing a compound of formula (VI):
which comprises reacting a compound of formula (Vm):
with a compound of formula R2L where L is a leaving group in the presence of a base.
17. A compound of formula (VI):
wherein R2 has any of the meanings given in claim 1 provided that R2 is not methyl, benzyl or trichloroethyl.
GB9609978A 1995-05-24 1996-05-13 Bicyclic amines Expired - Lifetime GB2301819B (en)

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GB9816362A GB2324795B (en) 1995-05-24 1996-05-13 3-Cyano-8-Azabicyclo[3.2.1]octane derivatives
CZ19983660A CZ287821B6 (en) 1996-05-13 1997-05-09 Bicyclic amines, process of their preparation and insecticidal, acaricidal and nematocidal agent containing thereof
EA199801006A EA001422B1 (en) 1996-05-13 1997-05-09 Bicyclic amines as insecticides
DE69728531T DE69728531T2 (en) 1996-05-13 1997-05-09 BICYCLIC AMINES AS INSECTICIDES
HU9902111A HUP9902111A3 (en) 1996-05-13 1997-05-09 Bicyclic amines and their n-oxides, intermediates, preparation and use thereof, insecticide, acaricide and nematocide compositions containing these compounds
KR1019980709121A KR20000010972A (en) 1996-05-13 1997-05-09 Heterocyclic amine for insecticede
AT97920866T ATE263765T1 (en) 1996-05-13 1997-05-09 BICYCLIC AMINE AS INSECTICIDES
JP09540631A JP2000510144A (en) 1996-05-13 1997-05-09 Bicyclic amines as insecticides
EP97920866A EP0901490B1 (en) 1996-05-13 1997-05-09 Bicyclic amines as insecticides
ES97920866T ES2218676T3 (en) 1996-05-13 1997-05-09 BICYCLE AMINAS AS INSECTICIDES.
BR9708947A BR9708947A (en) 1996-05-13 1997-05-09 Compound insecticidal composition, acaricidal and nematicidal method for combating and controlling pests and process for preparing a compound
IL12688297A IL126882A0 (en) 1996-05-13 1997-05-09 Bicyclic amines as insecticides
PCT/GB1997/001259 WO1997043286A1 (en) 1996-05-13 1997-05-09 Bicyclic amines as insecticides
AU27082/97A AU722015B2 (en) 1996-05-13 1997-05-09 Bicyclic amines
CA002251851A CA2251851A1 (en) 1996-05-13 1997-05-09 Bicyclic amines as insecticides
CN97194560A CN1067069C (en) 1996-05-13 1997-05-09 Bicycle amines as insecticides
ZA9704089A ZA974089B (en) 1996-05-13 1997-05-12 Bicyclic amines.
US08/855,521 US5859024A (en) 1996-05-13 1997-05-13 Insecticidal, acaricidal or nematicidal 3-cyano-8-azabicyclo 3.2.1!octane derivatives

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