AU720176B2

AU720176B2 - Bicyclic amines as insecticides

Info

Publication number: AU720176B2
Application number: AU36832/99A
Authority: AU
Inventors: Martin Stephen Clough; Christopher Richard Ayles Godfrey; Terence Lewis; Roger Salmon; Christopher John Urch
Original assignee: Zeneca Ltd
Current assignee: Syngenta Ltd
Priority date: 1995-05-24
Filing date: 1999-06-29
Publication date: 2000-05-25
Anticipated expiration: 2016-05-13
Also published as: AU3683299A

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Zeneca Limited Actual Inventor(s): Christopher John Urch Roger Salmon Terence Lewis Christopher Richard Ayles Godfrey Martin Stephen Clough Address for Service:

A

i a. PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: BICYCLIC AMINES AS INSECTICIDES Our Ref 589492 POF Code: 207385/192132 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1A- BICYCLIC AMINES AS INSECTICIDES The present application is a divisional application from Australian Patent Application Number 56988/96, the entire disclosure of which is incorporated herein by reference.

This invention relates to novel bicyclic amines, to processes for preparing them, to insecticidal compositions comprising and to methods of combating and controlling insect pests therewith.

The invention provides compounds of formula wherein R 1 represents a group of formula where each of W, X, Y and Z and Z represents either a group CR or the nitrogen atom, provided that no 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, heterocyclyalkyl, carbamyl or dithiocarboxyl groups, said groups comprising from 1 to 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 Noxides derived therefrom. R 1 is preferably a halo-substituted phenyl, pyridyl or diazinyl group.

25 In a preferred aspect invention provides compounds of formula where R 1 represents an optionally halogen substituted phenyl group or an optionally halogen substituted pyridyl, pyridazinyl or pyrazinyl group and R 2 represents hydrogen or a C1-6 alkyl, alkenyl, alkynyl, phenyl, benzyl, pyridylmethyl, thienylmethyl, thiazolylmethyl group which may be optionally substituted with one or more alkyl, alkoxy, alkoxycarbonyl, 30 cyano, optionally substituted alkane sulphonyl groups or halogen atoms; and acid addition salts thereof.

One particularly preferred group of compounds are those wherein R 1 represents an optionally halogen substituted phenyl or pyridyl group and R represents an alkyl group containing up to 4 carbon atoms which may optionally be substituted with one or S35 more halogen atoms.

C:WINWORD ANNA\NODELETE\SPECIES\POV56988.00C 2.- .An especially preferred group of compounds are those wherein R' represents a halopyrid-3-yI group and R 2 represents hydrogen or a haloalcyl, haloalkenyl or halobenzyl group.

Specific compounds of formula I according to the invention include those set out in I below in which the groups represented by R' and R' are given for each compound, togethe r with the melting point 0 C) or an indication of the physical state of the compound.

TABLE I Compound No 1 2 3 4 6 7 3,5-dichlorophenyl 3,5-difluorophenyl 2,3-difluorophenyl pentafluorophenyl 2,3-dichiorophenyl 4-methoxyphenyl 4-methoxyphenyl 3.5-difluorophenyl 3,5-difluorophenyl 3,5-dffluorophenyl 3,5-difluorophenyl methyl methyl methyl methyl methyl benzyl (Isomer A) benzyl (Isomer B) S.

S

9.

H

benzyl 5,6-dichloropyrid-3ylmethyl pyrid-2-ylmethyl 3-methylbenzyl- 4-chlorobenzyl pyrid-3-ylmethyl- 3,4-methylenedioxybenzyl 3,5-dichlorobenizyl 3,3-difluoroprop-2-en- I -yI 2-hydroxy-2-phenylethyl I-phenyl-2-hydroxyethyl allyl propargyl 2-fluoroethyl 2-hydroxyethyl 2-methoxyethyl 2-cyanoethyl 5-chlorothien-2-yhmethyl 6-chloropyrid-2-yl 2-methylthiazol-5-ylnethyl 2-iminyl-2-methoxyethyl Melting Point 145-146 0

C

93-94 0

C

oil oil solid 178.4 0

C

95- 100 0

C

112.1 0

C

85.2 0

C

143.2-144.2 0

C

127.9-128.5 OC 95.9*96.l 0

C

95.5-96.7 0

C

78.2 OC oil 154.1 0

C

94.6 0

C

120.8 OC 168.8 OC 70.5 OC 108.4 0

C

oil 100.4 0

C

54.8 0

C

115 OC 114 0

C

gum 140 0

C

109 OC pyrid-3-yI Methyl87C 87 OC -3 Compound No 34 36 37 38 39 41 42 43 44 46 47 48 49 51 52 53 54 56 57 58 59.

61 62 63 64 66 67 68 69 71 72 73 74 75 76 pyrid-3-yl pyrid-3-yl pyrid-3-yl pyrid-3-yl pyrid-3-yl pyrid-3-yl N-methylpyridiniuun-3-yI 6-chloropyridazin-3-yl pyrid-3-yl 6-chloropyrazin-2-yl pyrid-3-yl pyrid-3-yl 6-chloropyrid-3-yl pyrid-3-yl pyrid-3-yl pyrid-3-yl pyrid-3-yl pyrid-3-yl 2-fluoro-4-nitrophenyl 3-fluorophenyl pyrid-3-yl 5,6-dichloropyrid-3-yl pyrid-3-yl pyrid-3-yl pyrid-3-yl 3,5-dfluorophenyl 5-chloropyrid-3-Yl pyrid-3-yl pyrazin-2-yl 2,6-dichloropyrixnid-4-yl 5-chloropyrid-3-yl 2,6-dichloropyrid-4-yl 2-chloro-6hydrazinopyrid-4-yl pyrid-4-yl 5-bromnopyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 6-chloropyrid-2-yl 5-chloropyrid-3-yl 3,5-difuorophenyl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yI 2-fluoroethyl allyl

H

benzyl ethyl t-butoxycarbonylmethyl 1-butoxyc arbonyl (iodide) methiyl propyl.

methyl methanesulphonylmethylsulphonyl methane-suiphonyl methyl methoxymethyl ethoxymethyl cyanomnethyl ethoxycarbonylniethyl methoxycarbonylxnethyl methyl methyl 2-hydroxyethyl methyl propargyl methyl but-2-en-1I-yl 4-nitrophenyl methyl phenyl methyl methyl 2-fluoroethyl methyl methyl methyl methyl vinyloxycarbonyl

H

methyl 2,2,2-trifluoroethyl pyrid-2-yl phenyl propargyl ailyl Melting Point 86-88 0

C

90-92 0

C

80-81 0

C

119-120 0

C

-Oil gum.

185-187 0

C

119-120 0

C

Oil 80 0

C

163-164 0

C

135 0

C

gum oil oil 90-91 OC gum gum 100- 102 0

C

Oil 155.2-156.8 0

C

110. 1- 111.4 OC 119-8-121.1 0

C

gum 193-194 0

C

96.9-97.9 0

C

152.8-154.5 0

C

136-137 0

C

76-76.9 0

C

95.3-96.8 0

C

125.9-126.9 0

C

165-165.8 0

C

72-73 0

C

74.5-76.1 0

C

144.1-145.2 OC gum 85-87 0

C

103.9-104.8 0

C

109.5-111.5 OC Oil 1224123 0

C

110-1 12C 78-80 0

C

*9 .9 .9 9 0 9* -4 Compound No 77 78 79 81 82 83 84 86 87 88 89 91 92 93 94 96 97 98 99 100 5-methoxypyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-ethoxypyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yI 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5.-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-(prop-l -enyloxy)pyrid- 3 -yI 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl methyl ethyl butyl methyl hexyl phenioxycarbonyl 2,2,2trichloroethoxycarbonyl ethoxycarbonyl fluoren-9ylmethyloxycarbonyl ethoxycarbonylmethyl isopropyl 4,4,4-trifluorobut-3-on- 1 en- l-yl 1 -methyl-2,2,2trichioroethoxycarbonyl allyloxycarbonyl benzyloxycarbonyl 2-chloroethoxycarbonyl pentafiuorobenzyl 4-nitrophenyl acetyl trifluoroacetyl 4-chlorobenzoyl 4-fluorobenzoyl 3-fluoropropyl 2,4-bis(trifluoromethyl)benzyl 4-carboxybenzyl methyl 2,3-difluorobenzyl 2-phenylethyl 4-cyanophenyl 3,3-difluoroprop-2-en- 1-yl carboxymethyl 3,5-dibromobenzyl 3-chloro-4-fluorobenzyl formyl isopropoxycarbonyl benzenesulfonyl 2,4,6-trifluorobenzyl 2,3,6-trifluorobenzyl 1-cyano- 1-phenyimethyl inethoxycarbonyl Melting Point 112.2-113.1 "C 116-118 0

"C

48-50 0

C

567.2-57 0

C

resin 117-123 0

C

Oil Oil 68-70 0

C

gum Oil 143.9-145.1 0

C

152-15 0

C

oil Oil gum 143-144 0

C

213-214.5 0

C

162-165 0

C

121-124 0

C

175-177 0

C

200-204 0

C

Oil 112-114 0

C

gum gum 102-103 0

C

Oil 201-204 0

C

oil 165-167 0

C

194-196 0

C

95-97 0

C

141-142 0

C

gum 210-211 0

C

106-107 0

C

125-127 0

C

14 1-142 OC a 4 4* a. a.

#a.q 9 101 102 103 104 105 106 107 108 109 110 ill.

112 113 114 115 Compound No 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl pyrid-2-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-'yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl pyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-aminopyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-bromopyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-iodopyrid-3-yl 5-hydroxypyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-c6hloropyrid-3-yl 5-chloropyrid-3-yl pyrid-2-ylmethyl pyrid-3-ylnethyl pyrid-4-yhnethyl 2-fluoroethyl (R)-1-phenylethyl 1-phenylethyl 2-methylthiazol-4-ylnethyl 3,5-dimdthylisoxazol-4ylmethyl 5-chlorothien-2-ylmethyl 5-trifluoromethylpyrid-2-yl 2-methoxyethyl 6-fluoropyrid-2-yl 4-fluorophenyl 2,2,3,3,3-pentafluoroprop yl 2,2,3,3-tetrafluoropropyl 2,2,3,3,4,4,4heptafluoropropyl 2,2,3,3,4,4,5,5octafluoropropyl methyl 1-phenyl- 1carboxamidomethyl 6-trifluoromethylpyrid-2-yl 6-chloropyrid-2-yl mercaptothiocarbonyl 1-butyl 2-(ethoxycarbonyl)ethyl 2-carboxyethyl 2,2-difluoroethyl 2,2,2-trifluoroethyl fluorocarbonyl N-methyl-N-phenyl carbamyl N-1-butylcarbamnyl methyl methyl 4-morpholinocarbonyl N,N-diisopropylcarbamyl pentafludrophenyl 6-chloropy&&mn-4-yl 2-acetamidothiazol-4ylmethyl N-(3-chloro-4fluorophenyl) carbamnyl 5-chloropyrid-3-yl Melting Point 123-125 OC 105-107 OC 111-114 0

C

82-84 OC 115.6-116.7 0

C

113.4-115 0

OC

81-83 0

C

95-99 OC 119-121 0

C

124.5-125.5 0

C

251-253 OC, 13 1.5-132.5 0

C

solid oil 110-113 0

C

Oil Oil 188-190 0

C

193-195 OC 117.5-1 18.5 OC 176-177 0

C

224 0

C

127-129 OC gum 180-181 0

C

101-104 0

C

105-110 OC 165-167 0

C

108-110 0

C

62-65 0

C

144-145 0

C

170.9-17 1.7 0

C

143-145 0

C

118-121 0

C

gum 174-176 0

C

solid 216-218 OC 9. 9 .9 4 9 9.99 gum -6 Compound No 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 Melting Point 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-y-l 5-methoxypyrid-3-yl 5-chloropyrid-3-yl 5-chloro-6-fluoro pyrid- 3 -y 1 5-chloropyrid-3-yl 5-acetamridopyrid-3-yI 5-methoxypyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-methoxypyrid-3-yl 5-methoxypyrid-3-yl 5-chloropyrid-3-yl 5-trifluoromethylpyrid-3yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-trifluoromethylpyrid-3yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-bromopyrid-3-yl 5-chloropyrid-3-yl 5-trifluoromethylpyrid-3yl 5-trifluoromethylpyrid-3y 1 pyrid-3-yd 5-trifluoromethylpyrid-3yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl S-(pyrrol-1 -yl)pyrid-3-yI 4-trifluoromethylpyrid-3carboxamidomethyl 4-trifluoromethylpyrid-3ylcarbonyl 5-chioro- 1,2,3-triadiazol-4ylmethyl 1 -formiyl-i1-phenylethyl 4,4,4-trifluorobutyl 2,2,2-trifluoroethyl 4-ethoxycarbonylphenyl 2,2,2-trifluoroethyl vinyloxycarbonyl methyl cyanoxuethyl 3-chioromethyl- 1,2,4- 5-chlorothiazol-2-yl cyano 4-carboxyphenyl vinyloxycarbonyl

H

4-chlorophenyl methyl 2-phenylbut-3-en-2-yl 3-hydroxy-2-phenylprop-2yl formyl 3-acetoxy-2-phenylprop-2yI 2-fluoro-2-phenylprop- l-yl 3,3,5-trimethylhexyl vinyloxycarbonyl pyrimid-2-yl; vinyloxycarbonyl

H

vinyloxycarbonyl 3-chlorobenzyl 2-chloropyrimid-4-yl 4-trifluoromethylphenyl methyl 149.3-150.4 OC 80.3-81.9 0

C

oil 124-126 0

C

Oil 88-90 0

C

131.5-132.5 OC 121-122 OC gum 195-197 0

C

solid gum 111-112 0

C

168-170 OC solid gum 112-114 0

C

137.5-138 0

C

118.2-118.5 0

C

gum 124-126 0

C

117-121 0

C

130-131 OC gum 63-66 0

C

148.5-149.5 0

C

resin resin gum Oil 210-212 0

C

13 1-132 0

C

gum 9 .9 9 .9 -9 9 .9 a.

177 178 179 180 181 182 183 184 185 186 187 188 189 7- Compound No 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 N-oxidopyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-ethynylpyrid-3-yl pyrimid-4-yl 1-ethoxyvinyl)pyrid-3- 34 pyrid-3-yl 5-chloropyrid-3-yl 5-bromopyrimid-4-yl 5-trifluoromethylpyrid-3- 34 6-pyriid4-ylpyrimid- 34 5-acetylpyrid-3-yl 5-fluoropyrid-3-yl 5-bromopyrid-3-yl 5-bromopyrid-3-yl 5-chloropyrid-3-yl 5-(2-hydroxyprop-2yl)pyrid-3-yl 5-chloropyrid-3-yl 5-bromopyrid-3-yl 5-chloropyrid-3-yl 5-bromopyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 6-methoxypyrazin-2-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-phenylpyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-phenylpyrid-3-yl 5-methylpyrid-3-yl 5-ethoxycarbonylpyrid-3- 34 5-chloropyrid-3-yl t-butoxycarbonyl 2-phenyl-2isopropylaniinoprop- l-yl 2-phenyl-3-hydroxy-3cyanoprop-2-yl methyl methyl methyl 1 .1-dimethyipropyl 1 -ethoxycarbonylethyl methyl 2,2,2-trifluoroethyl methyl methyl methyl

H

2-chlorobenzyl 2-(3-chlorophenyl)prop-2- 34 methyl 2-methylbut-3-yn-2-yl ethoxycarbonyl 2-methyl-i, 1,1trifluoroprop-2-yl 2-methyipropyl 1-methoxycarbonylethyl (Isomer A) 1-methoxycarbonylethyl (racemate) 1-methoxycarbonylethyl (Isomer B) methyl 1-cyano-l1-(3chlorophenyl)methyl 1-cyanoethyl vinyloxycarbonyl 4,4-difluorobut-3-en- l-yl 1-eyano-2-methylprop-1-yl

H

vinyloxycarbonyl vinyloxycarbonyl Melting Point 55-57 0

C

gum 172-175 0

C

solid solid gum gum gum 141-145 0

C

gum 136-154 0

C

gum 135-137 0

C

128-130 0

C

109-111 OC gum gum 107-110 0

C

92-94 0

C

97-99 0

C

Oil gum 105-106 0

C

gum gum foam gum gum Oil gum gum gum solid p p 9* S.

C.

S.

CC

9~ S P 210 211 212 213 214 215 216 217 218 219 220 221 222 223 2-cyanoprop-2-yl solid -8 Compound R' No 224 6-ethynylpyrazin-2-yl 225 5-ethoxycarbonylpyrid-3yl 226 5-(2,2,2- 227 5-chloropyrid-3-yl 228 5-chloropyrid-3' .Yl 229 5-chloropyrid-3-yl 230 5-chloropyrid-3-yl 231 5-chloropyrid-3-yl 232 5-chloropyrid-3-yl 233 5-chloropyrid-3-yl 234 5-chloropyrid-3-yl 235 5-chloropyrid-3-yl 236 5-chloropyrid-3-yl 237 5-chloropyrid-3-yl 238 5-chloropyrid-3-yl 239 5-chloropyrid-3-yl 240 5-chloropyrid-3-yl 241 5-chloropyrid-3-yl 242 5-chloropyrid-3-yl 243 5-chioropyrid-3-yl 244 5-chloropyrid-3-yl 245 5-chloropyrid&3-yl 246 5-chloropyrid-3-yl 247 5-chloropyrid-3-yl 248 5-chloropyrid-3-yl 249 5-chloropyrid-3-yl 250 5-chloropyrid-3-yl 2 51 5-chloropyrid-3-yl 252 5-chloropyrid-3-yl 253 5-chloropyrid-3-yl 254 5-chloropyrid-3-yl 255 5-chloropyrid-3-yl 256 5-chloropyrid-3-yl 257 5-chloropyrid-3-yl 258 5-chloropyrid-3-yl 259 5-chloropyrid-3-yl 260 5-chloropyrid-3-yl 261 5-chloropyrid-3-yl 262 5-cliloropyrid-3-yl 263 5-chloropyrid-3-yl 264 5-chloropyrid-3-yl R 2 methyl Melting Point solid gum trifluoroethyl bis(trifluoromethyl)benzyl 2,6-difluorobenzyl 3-phenoxybenzyl 3-bromo-4-fluorobenzyl 3-benzoylbenzyl 3-(2,6dichlorobenzoyl)benzyl 3-(2,6difluorobenzoyl)benzyl 4-allyl-2,3,5,6tetrafluorobenzyl 3-tnifluoromethoxybenzyl naphth- 1 -ylmethyl benzyl 2-bromobenzyl 2-rncthylbenzyl 3-bromobenzyl 3-methoxycarbonylbenzyl 3-methylbenzyl 4-bromobenzyl 4-methoxycarbonylbenzyl 4-t-butylcarbonylbenzyl 4-t-butylbenzyl 4-isopropylbenzyl 4-methylbenzyl 3,4-.difluorobenzyl 2-fluorobenzyl 2,4-difluorobenzyl 3-fluorobenzyl 4-fluorobenzyl 3-trifluoromethylbenzyl 4-trifluoromethylbenzyl 2-fluoro-3-chlorobenzyl 2-chloro-3,6-difluorobenzyl 2-chloroberizyl 2,6-dichlorobenzyl 3-chiorobenzyl 2-iodo-4-fluorobenzyl 2-fluoro-3-niethylbenzyl 2-(N-succinimido)benzyl 4 4.

4 4 .4 4 4 444* 4 .4 4 .4.

4444 44 4* 4 4. 4 4* 108-109 0

C

9- Compound No 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 Melting Point a.

.i 9 9 *9 9 9 9 i *9 *9 9 99 a. 9 9* 9.* 9S** *9a* 9 9.

9. a a a 9.

282 283 294 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-cbloropyrid-3-yl 5-chloropyrid-3-yl 5-cliloropyrid-3-yl 5-chloropyrid-3 ,yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl pyrid-3-yl 6-choloropyrid-3-yl 5-chloropyrid-3-yl 2-chloropyrimid-4-yl 6-chloropyrazin-2-yl 6-chloropyrazin-2-yl 6-chloropyrazin-2-yl 6-chloropyrazin-2-yl 5-chloropyrid-3-yl 5-chloropyrid!3-yl 5-cyanopyrid-3-yl 2-chloropyrid-4-yl 5-chloropyrid-3-yl 5-chloropyrid-3-yl trifluoromnethylbenzyl biphenyl-2-ylmethyl 2-cyanobenzyl 1,2,3-thiadiazol-4yl)benzyl 3-(4-fluorophenoxy)benzyl 4-cyanobenzyl 2,3,4-trifluorobenzyl 2-nitrobenzyl 2-nitro-6-fluorobenzyl 3-nitrobenzyl 4-nitrobenzyl 2-methylprop- I1-yl decyl 2-phenoxyethyl 2-ethoxyethyl 3-methylbut- l-yl 3-methoxycarbonyiprop- 1yl 3-phenyiprop- Il-yl cyclohexylmethyl 2-cyanoethyl 3-cyanoprop- I -yl 2-hydroxyprop- l-yl 2-propenoyloxyethyl 2-methoxyethyl tetrahydropyran-2-ylmethyl 2-hydroxymethyiprop- l-yl diethyiphosphonomethyl phosphonornethyl methyl (N-oxide) t-butoxycarbaryl

H

methoxy 2,2,2-trifluoroethyl vinyloxycabonyl

H

3-chlorobenzyl cyanomethyl 1-(3-chlorophenyl)ethyl 4-methoxyphenyl methyl methyl 2-phenylprop- 1-en- l-yl rnethylxnercaptothiocarbonyl 69-70 0

C

242-245 0

C

153-155 0

C

10 Compound R' No 308 5-( eth 309 5-i Melting Point (2,2,2-trifluoroioxy)pyrid-3-yl odopyrid-3-yl methyl 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 R 2 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 R' or R 2 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 310 311 312 313 314 315 316 317 318 319 320 Acid Component 2-chlorobenzoic acid 4-chlorophenoxyacetic acid 2,4,6-trimethylbenzoic acid 3-benzylbenzoic 4-hydroxybenzoic acid 1-phenylpropionic acid 3-(4-hydroxyphenyl)propenoic -acid undecanoic acid 4-(4-hydroxyphenyl)butyric acid 2-hydroxy-5-nitrobenzoic acid acid 2,2,3,3-tetramethylcyclopropanoic acid a a. *a a a a aa a a, a a .a The preparation of the compounds of formula 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 (II) by treating them with a suitable base, such as potassium carbonate, in the presence of compound formula R2L where L is a suitable leaving group such as a halide or triflate.

11 Alternatively, compounds of general formula can be prepared from compounds of general formula (II) by reductive amination with an aldehyde (R 3 CHO; where R 3

CH

2

=R

2 in the presence of a suitable reducing agent such as formic acid.

Compounds of general formula (II) can be prepared by demethylating compound of general formula (II) 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 (fII) can be prepared by treating 3-cyano-8-methyl-8azabicyclo[3.2.1]octane (IV) first with a suitable base, such as lithium diisopropylamide (LDA), followed by reaction with an aryl or heteroaryl halide (R'Hal).

3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (IV) can be prepared by treating tropinone with tosylmethyl isocyanide in the presence of a suitable base, such as potassium ethoxide. As an alternative 3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (IV) can be prepared from tropine (XIII) by treatment with thionyl chloride to give alternative 3chloro-8-methyl-8-azabicyclo[3.2.1]octane (XII) followed by treatment with cyanide as described in J. Am. Chem. Soc., 1958 80, 4677.

As an alternative, compounds of general formula 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-8azabicyclo[3.2.1]octane (VII) by treatment with a suitable base, such as potassium carbonate, in the presence of an alkyl halide (R 2 Hal).

3-Cyano-8-azabicyclo[3.2. ]octane (VII) can be prepared by demethylating 3-cyano-8methyl-8-azabicyclo[3.2. l]octane (IV) by, for instance, treatment first with a chloroformate ester (such as vinyl chloroformate) to produce a carbamate, followed by acid hydrolysis.

25 As a further alternative, compounds of general formula (VI) can be prepared by treating compounds of general formula (VIII) with tosylmethyl isocyanide in the presence of a suitable base, such as potassium ethoxide.

Compounds of general formula (VIII) can be prepared by the Robinson tropinone synthesis, see, for instance, J. Chem. Soc., 1917, 111, 762. As an alternative compounds of general formula (VIII) can be prepared from cyclohepta-2,6-dienone (XI) by reaction with an amine (R 2

NH

2 as described in, for instance, Tetrahedron, 1973, 155, Bull, Chem, Chem, Soc, Jpn., 1971,44, 1708 andJ. Org. Chem., 1971,36, 1718.

o

*D

-12- As yet a further alternative, compounds of general formula can be prepared by treatment of a compound of general formula (IX) with an aryl- or heteroaryl-acetonitrile of general formula 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 R 2 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

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, heterocyclyalkyl, 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; with the proviso that

R

2 is not methyl, 3-methylbutyl, n-hexyl, cyclohexylmethyl, benzyl, 4-chlorobenzyl, 4methylbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, 3-trifluoromethylbenzyl, 2-phenethyl, 2-thienyl 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 insecticidally-effective 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 Lepidopetera, 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 30 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 carine pest 35 species which may be controlled by the compounds of Formula I include: C:%WINWORDIANNA NODELETSPECIESI588sB98.DOC 12A Myzu perica (apid),A.Ws gossypii (aphid), Aphis fabae (aphid), Aedes aevTi (mosquito), Anopheles spp. (mnosquitos), Culex spp. (mosquitos), Dysdercus fasciatus (capsid), Musca domestica (housefly), Pieris brassicae (white butterfly), Plutela xylostella (diamond back moth), Phaedon cochleariae (mustard beetle), Aonidiella spp. (scale insects), Trialeurodes spp. (white flies), Berrusia tabaci (white fly), Blattella gegrranjca (cockroach), Periplaneta americana (cockroach), Blatta orientalis (cockroach) Spodoptera littoralis (cotton leafworm), Heliothis virescens (tobacco budworm) Chortiocetes terminifea (locust), Diabrotic spp. (rootworms), Agrtis spp. (cutworms), Cbilo patllA (maize stem borer), N-Aavtalgn (planthopper), Ne~oetx icia (leafhopper), Pnnychus ulmi (European red mite), Panonycb1us iti (citrus red mite), Tgmcu uicai (two-spotted C:kW[NV40RDIANNANODELETESPECIESW988.98.00C 13 spider mite), Tetranychus cinnabarinus (carmine spider mite), Phvllcoptruta 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, and/or 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.

20 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 25 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 30 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 14 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, trichioroethylene, N-methyl-2-pyrrolidone and tetrahydrofurfuryl alcohol (THFA).

Wetting agents, dispersing agents and emulsifying agents may be of the cationic, anionic or non-ionic type. Suitable agents of the 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 20 diisopropyl- and triisopropylnaphthalene 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 25 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 10-85% by weight of the active ingredient or 30 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.

15 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 pests, 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: S 20 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-furylmethyl-(E)-(1R,3S)-2,2-dimethyl- 3-(2-oxothiolan-3-ylidenemethyl) cyclopropane carboxylate; 25 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, pyrimiphos-ethyl, fenitrothion or diazinon; 30 c) Carbamates (including aryl carbamates) such as pirimicarb, cloethocarb, carbofuran, furathiocarb, ethiofencarb, aldicarb, thiofurox, carbosulfan, bendiocarb, fenobucarb, propoxur or oxamyl; 16 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, flubenzimine, 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, 20 sesamax, safroxan and dodecyl imidazole.

Suitable herbicides, fungicides and plant-growth regulators for inclusion in the compositions S" 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 25 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.

30 The invention is illustrated by the following examples (except example Examples 1 to 86 illustrate the preparation of a range of compounds of formula -17- Examples 87-104 (except example 101) illustrate formulations suitable for the application of 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 Nonylphenol-ethylene 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-8azabicyclo[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 dirmethoxyethane (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 20 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; dichloromethane:methanol (90:10)] to give exo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (9.1g).

exo-3-Cyano-8-methyl-8-azabicyclo[3.2.1]octane (10.Og) in tetrahydrofuran (60ml) was added S 25 dropwise to a stirred solution of lithium diisopropylamide [made by adding n-BuLi (29ml of a 2* 2.5M solution in hexane) to diisopropylamine (10ml) in tetrahydrofuran (60ml)] at -25 0 C under nitrogen. The mixture was stirred at -25°C for 20 minutes and then cooled to -78"C. 3- Fluoropyridine (10.0g) 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 30 extracted with dichloromethane. The combined extracts were washed with brine, dried (MgSO 4 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 18 and ether, filtered and air-dried to give exo-3-(pyrid-3-yl)-edo-3yano-8-methyl-8azabicyclo[3.2. ]octane (8.2g).

EXAMPLE 2 This example illustrates the preparation of exo- 3 -(pyrid-3-yl)-endo-3-cyano-8-(2-fluoroethyl)-8azabicyclo[3.2. lI]octane.

Vinyl chloroformate (6.ml) in tetrahydrofuran (l10m) was added dropwise to ex-3-(pyrid-3-yl)endo-3-cyano-8-thyl-8-azabicyclo[3.2.1 ]octane (4.0g) in tetrahydrofuran (40ml) at 0 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 crystallised on standing to give exo-3-(pyrid-3-yl)endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2. 1]octane 1 g).

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 refluxed 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 (MgSO 4 and evaporated under reduced pressure to give exo-3- (pyrid- 3 -yl)-endo-3-cyano-8-azabicyclo[3.2.l]octane which crystallised on standing.exo- 3 -(Pyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2. 1]octane l-bromo-2-fluoroethane (0.21ml), potassium carbonate (0.14g) and tetrahydrofuran (6ml) were heated at 60*C for hours and then allowed to stand at room temperature overnight. l-BromD-2-fluoroethane (0.2ml) was then added and the mixture heated at 60 0 C for 6 hours, cooled to room temperature, filtered and evaporated under reduced pressure. Chromatography [SiO 2 dichloromiethane:methanol (90:10)] gave exo-3-(pyrid-3-yl)-endo-3-cyano-8-(2-fluoroethyl)-8-azabicyclo[3.2. 1]octane 123g) mp. 84.4*C.

EXAMPLE 3 This example illustrates the preparation of exo-3-(3,5-difluorophenyl)-endo-3-cyano-8-rmethyl- 30 8-azabicyclo[3.2.1]octane.

3 -Cyano-8-ethyl-8-azabicyclo[3.2.1]octane (13.6 g in tetrahydrofuran (80 ml) was added dropwise to a stirred solution of lithium diisopropylamide [made by adding n-BuLi (40ml of a 19- 2.5L4 solution in hexane) to diisopropylanine (14.Oml) in tetrahydrofuran (80m1)] at -250C under nitrogen. The mixture was stirred at -25*C for 0.5 hours and then cooled to -78 0 C. 1,3,5-' Trifluorobenzene (12.0g) intetrahydrofuran (80rr1) was added dropwise at such a rate to maintain the temper-ature below -65 0 C. The mixture was allowed to warm to room temperature overnight and then poured into water and extracted with dichiorometbane. The combined extracts were washed with brine, dried (MgSQ 4 and evaporated under reduced pressure to give a yellow solid.

T'his was recrystallised from 'diethyl ether to give tx-3-(3,5-dfluorophenyl)-endo-3-cyano-8rrrthyl-8-azabicyclo[3.2. Il]octane. The mother liquor from the recrystallisation was chroinatographed [SiC) 2 dichloronethane:rthanol (90: 10)] to give further exo-3-(3,5difluorophenyl)-end-3-cyano-8-rrtthyl-8-azabicyclo(3.2. f]octane (1 1.2g in total).

EXAMPLE 4 This example illustrates the preparation of ex-3-(pyrid-3-yl)-endo-3-cyano-8-(prop -l-yl)-8azabicyclo[3.2. 1l]octane.

Vinyl chioroformate (2.Srnl) in diethyl ether (l1rnl) was added dropwise to a stirred mixture of exo-3-cyano-8-inethyl-8-azabicyclo[3.2.lI]octane (3.0g) in diethyl ether (i5nmi) at -5*C under nitrogen. The mixture was then stirred at 0 0 T for 0.5 hours and at reflux for 5 hours. After cooling to room tempyerature the mixture was filtered and the solid residue washed with diethyl ether. The combined filtrates were evaporated under reduced pressure to give ex-3-cyano-8- :20 (vinyloxycarbonyl)-8-azabicyclo[3.2. Iloctane (2.93g).

exo-3-Cyano-8-(vinyloxycarbonyl)-8-azabicyclo [3 1 ]octane concentrated hydrochloric acid (lml) and riethanol (30m1) were refluxed for 4 hours and then-allowed to stand at room temperature overnight. Concentrated hydrochloric acid (lmnl) was added and the mixture refluxed for 4 hours. -After cooling to room temperature the mixture was evaporated under reduced 25 pressure, dissolved in ethyl acetate and washed with 2M sodium hydroxide and brine, dried (MgSQ 4 and evaporated under reduced pressure to give exo-3-cyano-8-azabicyclo[3.2. I]octane (1.09g) as a dark yellow solid.

exo-3-Cyano-8-azabicyclo[3.2. 1]octane I-bromnopropane (0.34m1) and potassium carbonate (1.27g) were stirred in ethanol (5mi) at room- temperature for 5 hours. 30 Broimpropane (0.17m1) was then added and the mixture stirred overnight. -Bronxopropane l7rnl) was added and the mixture stirred at room temp3erature for 6 hours, -a futher portion of I -brorropropane 17in1) 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 tenmerture, filtered and the filtrate evaporated under reduced pressure. Chromatography [SiC) 2 dichloronethane:nethanol (90: 10)] gave ex-3-cyano-8-propyl--azabicyclo [3 1]octane (0.39g).

exo-3-Cyano-8-propyl-8-azabicyclo[3.2. 1]octane (0.32g) in tetrahydrofuran 92m1) was added dropwise to a stirred solution of lithium diisopropylarmde [made by adding n-BuUi (0.8xnl of a solution in hexane to diisopropylamine (0.2m1d) in tetrahydrofuiran (2m1)] at -25 0 C under nitrogen. The mnixture was stirred at -25*C for 0.5 hours, cooled to -76*C and 3-fluoropyridine (0.175g) in tetrahydrofuiran (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 (03) and the combined extracts washed- ,with brine and water, dried (MgSO 4 and evaporated under reduced pressure.

Chromatography [SiC) 2 dichloronmthane:methanol gave ex-3-(pyid-3-yl).-gnd-3-cyaino- 8-(prop- 1 -yl)-8-azabicyclo[3.2. 1 ]octane (0.35g).

EXLAMPLE This example illustrates the preparation of 3-phenyl-3-cyano-8-benzyl-8azabicyclo13.2.1 I octane.

Sodium hydride (0.75g of a 55% suspension in oil) was carefulfly added to benzyl cyanide (0.69g) and nps--2,5-bis(chloronthyl)-l-benzylpyrroidine (1.0g) in NN-dinthyformamnide (30ml) at 0 0 C under nitrogen. The mixture was stirred at room temp4erature overnight and then poured into 20 ice-cold water and extracted with dichloromethane. The aqueous layer was allowed to stand at room temperature overnight and then filtered and the solid residue washed with water and air dried. The solid product was chromatographed [SiC) 2 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).

25 EXAMPLE 6 This example illustrates the preparation of exo-3-(pyrid-3-yl)-endo-3-cyano-8-benzyl-8azabicyclo[3.2. 1 ]octane.

Three drops of 5M hydrochloric acid was added to a stirred mixture of dirrethoxytetrahydrofuiran (16.5g) and water (70m1). After 10 minutes a mixture of benzylamine (13.6m1) and SM hydrochloric acid (30m1) were added followed by the irmediate addition of a mixture of 1,3-acetonedicarboxylic acid (18.2g) and sodium acetate (l0g) in water (lO0ml). After stirring at room temperature for 3 days, during which carbon dioxide was evolved, the mixture was 0* a.

a a a i a a.

a a. a.

a a aq a *aa.

a. a a a -21 basifled to pH8 and extracted with ethyl acetate The combined extracts were dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiC) 2 hexane:ethyl acetate] to give 8benzyl-8-azabicyclo [3.2.1I ]octan-3-one (1 1.2g).

Potassium t-butoxide (2.5g) was added portionwise to a stirred mixture of 8-benzyl-8azabicyclo[3.2.1]octan-3-one tosylrxethyl isocyanide (2.36g) -and ethanol (2m1) indimethoxyethane (50m1) at 0 0 T under nitrogen. The mixtur was stirred at 0 0 C for 0.5 hours and then overnight at room temperature- The mixure was then filtered and the solid residue washed with dimethoxyethane. The combined filtrates were evaporated under reduced pressure and chroniatographed [SiQ hexane:ethyl acetate (80:20)] to give 3-cyano-8-benzyl-8azabicyclo[3.2.lI]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 diisopropylaxnide [made by adding n-BuUi (1 .51 of a 1 .6M solution in hexane) to diisopropylamnine (0.246g) in tetrahydrofura (2m1)] at -25*C under nitrogen. After hours the mixture was cooled to -76*C and 3-fluoropyridine (0.2 15g) in tetrahydrofuiran (21) 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 (x0) and the combined extracts were washed with brine and water, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiC) 2 dichlorornethane:inethanol gave exo-3-(pyrid-3-yl)endo-7 3 -cyano-8-benzyl-8.azabicyclo[3.2.lI]octane (0:245g) which crystallised on standing m.p.

119-120 0

C.

.EXAMPLE 7 :This example illustrates the preparation of ex-3-(pyrd-3-yl)-ndo-3-cyano-8-(2methoxyethyl)-8-azabicyclo [3 Il]octane.

*xo3(yi--l-no3-yn--zbcco32 I octane (0.30g), 2-bronxethyl methyl ether (0.235g) and potassium carbonate (0.213g) -were refluxed in ethanol (3m1) 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 chroniatographed (SiC) 2 dichlorornethane:methanol to give ex-o- 3 -(pyrid-3-yl)etndo..3-cyano.8(2..methoxyethyl)-8 azabicyclo[3.2. Ij]octane (0.223g).

EXAMVPLE 8 *This example illustrates. the-.preparation. of exo-3-(pyrid-2-yl)-_end_..3-cyano-8-methyl-g..

azabicyclo[3.2. lI]octane. 11- I- 22 ~x-o-3-Cyano-8-methyl-8-azabicyclo[3.2. I]octane (0.5g) in tetrahydrofuran (3rnl) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (l.6m1d of a 2.5M solution in hexane) to dilsopropylanine (0.4g) in tetrahydrofuran (3m1)I at -25 0 C under nitrogen.

After 30 minutes a solution of 2-fluoropyridine (0.

3 8 8 g) in tetrahydrofuran (3m1) 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 -The combined extracts were washed with water dried (MgSO 4 -and evaporated under reduced pressure.

Chromatography [SiC) 2 dichloronethane:methanol (90:10)] gave ex-3-(pyrid-2-yl)-endo-3cyano-8-methyl-8-azabicyclo[3.2. I ]octane (0.467g).

EXAMPLE 9 This example illustrates the preparation of ex- 3 -(prazin- 2 -yl)-nd-3-cyano-8-methyl-8.

azabicyclo[3.2. 1 ]octane.

exo-3-Cyano-8-methy[-8azabicyclo[3.2 1 ]octane (0.5g) in tetrahydrofuran (3m1) was added to a solution of lithium diisopropylam-ide [made by adding n-BuLi (l.6m1i of a 2.5M solution in hexane) to diisopropylarnine (0.4g) in tetrahydrofuran (3m1d)] at -25*C under nitrogen.

After 30 minutes the mixture was cooled to -78*C and a solution of chloropyrazine (0.46g) in tetrahydrofuran (5mi) was added. After 1 hour the midxture was allowed to warm to room temperature and stand overnight. Water was added and the mixture extracted with ethyl acetate The combined extracts were washed with brine and water, dried (MgSQ 4 and :20 evaporated under reduced pressure. Chromatography [Sick; dichloronethane:nxthanol (95:5) to (90:10)] gave ex--przn2y)-no3cao8mthl8aaiyl[.2. 1 ]octane (0.368g) m.p. 76-771C. EAPE1 This example illustrates the preparation of exo-3-(6-chloropyrazin-2-yl)-endo-3-cyano-8- 25 methyl-8-azabicyclo[3.2. I]octane.

exo- 3 -Cyano-8-methyl-8-azabicyclo[3.2. 1]octane (1.0g) in tetrahydrofuran (5m was added to a solution of lithium diisopropylaxnide [made by adding n-BuLi (2.66m1 of a 2.5M solution in hexane) to diisopropylamine (0.673g) in tetrahydrofuran (5m1)] 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 (5m1) 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 The combined extracts were washed with brine and water, dried 23 (MgSQ 4 and evaporated under reduced pressure. Chromatography [SiC) 2 dichloronetbane:mrthanol gave gx--3-(6-chloopyrazin-2-yl)-nd-3-cyao..8methyl.

8-azabicyclo[3.2. 1 ]octane (1.1 Og) m.p. 79.8-80. 1 TC.

EXAMPLE 11 This example illustrates the preparation of exo3(-hlrprdzn3y)fno3cao8 methyl-8-azabicyclo[3 1 ]octane.

exo-3-Cyano-8-methyl-8-a2zibicyclo[3 .2.1 I octane (0.5g) in tetrahydrofuran (5m1) was added to a solution of lithium diisopropylainide [made by adding n-BuLi (l.4m1 of a 2.5M solution in hexane) to diisopropylamine (0.45g) in tetrahydrofuran (2m1)] at -25'C under nitrogen..

After 30 minutes 1.3-dixnethylimidazolidinone (lml) was added and the mixture cooled to 78*C. A solution of 3,6-dichlorochloropyridazine (0.50g) in tetrahydrofuran (2m1i) 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 The combined extracts were washed with brine and water, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiC) 2 dichloromethane:nwthanol gave ex-3-(6chloropyridazin-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)-Lndo-3-cyano-8methyl-8-azabicyclo 1 ]octane.

3-Chloro-2-hydroxy-5-nitropyridine (4.8g) was added to phosphorus oxychloride (1 imi) and 9. 9.phosphorus pentachioride (4.45g) and the mixture refluxed overnight. The mixture was then *.cooled to room temperature and evaporated under reduced pressure. Iced water was added 99::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 (40m1) and water (8rnil) 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 chromnatographed [SiC) 2 hexane:ethyl acetate (80:20) to (50:50)] to give 5-amino-2,3dichloropyridine (1.7 1ig).

5-Amino-2,3-dichloropyridine (0.80g) in dichioromethane -(10ml) was added to, boron trifluoride etherate (0.92m1) at -15*C under nitrogen. Dichioromethane (15m1) was-added followed by 1-butylnitrite (0.7 lml) in dichloromethane (5mi). After 15 minutes the mixture -24was 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 stor ed 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 104g).

exo-3-Cyano-8-methyl-8-azabiicyclo[3.2.1I]octane 0g) in tetrahydrofuran (Imi) was added to a solution of lithium dilsopropylainide [made by adding n-BuLi (0.29m1 of a 2.5M- solution in hexane) to diisopropylamine (0.073g) in tetrahydrofuran (lml)I at -25"C under nitrogen.

After 30 minutes 2,3-dichloro-5-fluoropyridine (0.10g) in tetrahydrofuran (lml) was added.

After I hour the mixture was allowed to warm to room temperature and stand overnight.

Water was added and the resulting mixture extracted with ethyl acetate The combined extracts were washed with water, dried (MgSO 4 and evaporated under reduced pressure.

Chromatography [SiO 2 dichloromethane:rnethanol (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-8methyl-8-azabicyclo[3.2. 1l]octane (0.0 19g) as a yellow solid.

EXAMPLE 13 This example illustrates the preparation of exo-3-(pyrid-3-yl)-endo-3-cyano-8- (methoxycarbonylmethyl)-8-azabicyclo 1 ]octane.

exo-3-(Pyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2. loctane (0.20g), ethyl bronriacetate 4 187g) and potassium carbonate (0.155g) were refluxed in ethanol (3m1d) for 4 hours. The rnixture-was then filtered and the filtrate evaporated under reduced pressure. Chromatography [SiQ; dichloronrithane:xrethanol gave exo-3-(pyrid-3-yl)-endo-3-cyano-8- (methoxycarbonylmethyl)-8-azabicyclo[3.2. 1 ]octane 1 12g).

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. iloctane (0-39g) and triethylamine (15m1d) were added to dichloronethane (5m1) and the mixtture cooled to -20*C. Methane suiphonyl chloride (0.12m1) was added dropwise and the rmture allowed to warm to room temperature.

After 1 hour the mixture was evaporated under reduced pressure and dissolved in ethyl acetate.

25 The resulting solution was washed with aqueous sodium bicarbonate solution and water dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiO 2 dichloromethane:methanol (90:10)] gave a gum which formed a solid on trituration with hexane and ether. Chromatography [SiO 2 hexane:ethyl acetate (80:20)] gave exo-3-(pyrid-3-yl)-endo-3cyano-8-(methylsulphonylmethylsulphonyl)-8-azabicyclo[3.2. 1]octane (0.028g) m.p. 163- 164 0

C.

EXAMPLE This example illustrates the preparation of exo-3-(6-chloropyrid-3-yl)-endo-3-cyano-8methyl-8-azabicyclo[3.2.1 ]octane.

exo- 3 -(Pyrid-3-yl)-endo-3cyano-8-azabicyclo[3.2. 1]octane (0.50g) in acetonitrile (3ml) was added dropwise to a stirred solution of di-t-butyl carbonate (0.512g) in acetonitrile (5ml) at OC. 4 -Dimethylamniinopyridine (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 [SiO 2 ethyl acetate:dichloromethane (20:80) to (30:70)] to give exo- 3 -(pyrid-3-yl)-endo-3-cyano-8butyloxycarbonyl)-8-azabicyclo[3.2. I]octane (0.602g).

m-Chloroperoxybenzoic acid (0.22g) was added to a solution of exo-3-(pyrid-3-yl)-ndo-3cyano-8-(-butyloxycarbonyl)-8-azabicyclo[3.2. I]octane (0.20g) in dichloromethane (2ml) at 0 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 dried (MgSO 4 and evaporated under reduced pressure to give exo-3-(N-oxopyrid-3-yl)-endo-3-cyano-8-tbutyloxycarbonyl)-8-azabicyclo[3.2.1]octane (0.161g).

exo-3-(N-oxopyrid-3-yl)-endo-3-cyano-8-C-butyloxycarbonyl)-8-azabicyclo[3.2.I]octane (0.161g) was added to phosphorus oxychloride (Iml) 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 dried (MgSO 4 and evaporated under reduced pressure to give xQ-3-(6-chloropyrid-3-yl)-endo-3-cyano-8azabicyclo[3.2. 1 ]octane (0.058g).

26 exo-3-(6-Chloropyrid-3-y1)-tndo-3-cyano-8-azabicyclo[3 1 ]octane (0.05g) and paraformaldehyde (0.50g) were added to formic acid (2m1) 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 water, dried (MgSO 4 evaporated under reduced. pressure and chromnatographed [SiQ; dicliloronethane:nthanol to give ex-3-(6-chloropyrid-3-y1)endo-3-cyano-8-methyl-8-azabicyclo[3.2. 1 ]octane (0.023g).

E-XANvPLE 16 This example illustrates the preparation of ex-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(nhexyl)-8-azabicyclo[3 .2.1I ]octane.

exo-3-Cyano-8-methyl-8-azabicyclo(3.2.1 I]octane (0.5g) in tetrahydrofuran (3m1i) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (1.6m1 of a 2.5M solution in hexane) to diisopropylanine (0.4g) in tetrahydrofuran (3m1)] at -25*C under nitrogen.

After a further 15 minutes at -25*C 3,5-dichloropyridine (0.588g) in tetrahydrofuran (3m1) was added at -781C. 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 The combined extracts were washed with brine and water, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiO2; dichloromethane:methanol (90:10)1] gave ex-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.- 1]octane (0.249g).

Vinyl chloroformate (2.6m1) in tetrahydrofuran (5nI) was added to a stirred solution of exo- .3-(5-chloropyrid-3-yl)-gnd-3-cyano-8-methyl-8-azabicyclo[3.2. I ]octane (2.6g) in tetrahydrofuran (25ml) at 0 0 C. The mixture was allowed to warm to room-Atemperature over 2s 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 (MgSO 4 Evaporation under reduced pressure gave exo-3-(5-chloropyrid-3-yl)-end4-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo 1 ]octane exo-3-(5-Chloropyrid-3-yl)-tnd-3-cyano-8-(vinyoxycarbony)-8-azabicyclo[3.2. 1l]octane (2.6g) was dissolved in methanol (50mi) and concentrated hydrochloric acid (7m1) added.

The mixture was refluxed for 3 hours after which the mixture was evaporated under reduced 27 pressure and basifled 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-choropyrid-3-yl)-end-3-cyano-8azabicyclo[3.2. lloctane (1 .2g).

n-Hexyl bromide (O.lml) and potassium carbonate (0.1g) were added to chloropyrid-3-yl)-ando-3-cyano-8-azab icyclo[3.2. I]octane (0.15g) in ethanol (2m1) and the mixture refluxed for 44 hours. The mixture was then diluted with ethanol, filtered and evaporated under reduced pressure. Chromatography [SiO 2 dichloromethane:methanol gave ex-3-(5-chloropyrid-3-yl)-nd-3-cyano-8-(n-hexyl)-8-azabicyclo[3.2. 1 ]octane 123g).

EXAMPLE 17 This example illustrates the preparation of ex-3-(5-chloropyrid-3-yl)-ndo-3-cyano-8-allyl-8azabicyclo[3.2. 1 ]octane.

Allyl bromide (621) and potassium carbonate 1ig) were added to exo-3-(5-chloropyrid-3yl)--end-3-cyano-8-azabicyclo[3.2. 1]octane (0.15g) in ethanol (2m1d) and the mixture stirred for 3 hours and then allowed to stand overnight. The mixture was then diluted with e thanol, filtered and evaporated under reduced pressure. Chromatography [SiC) 2 dichloromethane:methanol gave ex-3-(5-chloropyrid-3-y)-ndo-3-cyano-8-allyl-8azabicyclo[3.2. Il]octane 167g).

EXAMPLE 18 This example illustrates the preparation of ex-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2,2,2trifluoroethyl)-8-azabicyclo [3.2.1 I octane.

9 e A few drops of dilute hydrochloric acid were. added to a solution of dimethoxytetrahydrofuiran (16.5g) in water (70m1). After stirring at room temperature for minutes 2,2,2-trifluoroethylaimine hydrochloride (I16.9g), 1,3-acetonedicarboxylic acid (I18.3g) and sodium acetate (10.0g) were added and the mixture stirred at room temperature for 2 days. The mixture was diluted to 5O0mI with water, saturated with potassium carbonate and extracted with ethyl acetate The combined organic extracts were washed with aqueous potassium carbonate, dried (MgSO 4 and evaporated under reduced press ure. Distillation 30 (90OC;, 0.lmmHg) gave 8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.l]octan-3-one (8.7g).

Potassium t-butoxide (5.4g) was added slowly with cooling to a. stirred solution of 8-(2,2,2trifluoroethyl)-8-azabicyclo[3.2.lloctan-3-one (4.0g) and tosylmethyl, isocyanide (4.9g) in -28 dimethoxyethane (80m1) and ethanol (5mI) under nitrogen at such a rate so as to keep the temperature below 10*C. 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 (MgSO 4 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~ x-3-cyano-8-(2,2,2-trifluoroethyl)-8azabicyclo[3.2.lI]octane (2.5g) m.p. 90-92*C.

exo-3-Cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2. I ]octane (1 .09g) in tetrahydrofuran (l0ml) was added to a stirred solution of lithium diisopropylarnide [made by adding n-BuLi (2.4m1 of a 2.5M solution in hexane) to diisopropylamiine (0.61ig) in tetrahydrofuran at -25*C under nitrogen. After 2 hours at -25TC the mixture was cooled to -76'C and dichloropyridine (0.74g) in tetrahydrofuran (l0ml) 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 dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiC) 2 diethyl ether:hexane (20:80) to (50:50)] gave exo 3 -(5-chloropyrid-3-yl)-endo-3-cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2. 1 ]octane (0.45g) m.p. 109.5-lll.5*C.

EXAMPLE 19 This example illustrates the preparation of exo-3-(5-brornopyrid-;3-yl)-endo-3-cyano-8methyl-8-azabicyclo[3.2. 1 ]octane.

exo-3-Cyano-8-methyl-8-azabicyclo[3.2. I]octane (0.5g) in tetrahydrofuran (3m1) was added .4 to a solution of lithium diisopropylamide [made by adding n-BuLi (1 .6m1 of a 2.5M solution Sin hexane) to diisopropylamnine (0.4g) in tetrahydrofuiran (3ml)] at -25 0 C Under nitrogen.

**25 After 30 minutes the mixture was cooled to -76*C and a solution of in tetrahydrofuran (3m1) added. After I 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 The combined extracts were washed with brine (x2) and water, dried (MgS 04) and evaporated under reduced pressure. Chromatography [SiC) 2 :.30 dichloromethane:methanol (90:10)] gave ex-3-(5-bomopyrid-3-yl)-eiid-3-cyano-8-methyl- .9 8-azabicyclo[3.2. Ij]octane (0.327g) m~p. l44-l45*C.

-29 EX AMPL E This example illustrates the preparation of ex-3-(5-cyanopyrid-3-yl)-nd-3-cyano--methyl- 8-azabicyclo[3.2. 1 Joctane.

exo-3-(5-Bromopyrid-3-yl)-end4Q-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 (l1in!) 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 (x0) and the combined extracts were washed with brine and water, dried (MgSO 4 and evaporated under reduced pressure. The resulting oil was dissolved in ether and washed with brine dried (MgSO 4 and evaporated under reduced pressure. Chromatography [Si0 2 dichloromethane:methanol gave a yellow solid.

This was recrystallised three times (from dichioromethane/hexane ethyl acetate/hexane and dichioromethane/hexane) to give ex--5caoyi--l-L----yn--ehl8 azabicyclo[3.2.1I]octane (0.49g) mp. 183.5-184 0

C.

EXAMPLE 21 This example illustrates the preparation of exo-3-(5-ethoxypyrd-3-y)- -en-d-3-cyano.8methyl-8-azabicyclo[3.2. 1 ]octane.

exo-3-(5-Cffloropyrid-3-yl)-e~ndo-3-cyano..8-methyl-8azbicyco[3.2. 1 ]octane (0.30g) -and sodium. ethoxide .(0.625g) were heated at _80*C in-NN-dimethylformamide- (10ml) under nitrogen. After 5 hours the mixture was all-owed 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 (MgSO 4 and evaporated under reduced pressure.

**Chromatography [SiO 2 dichloromethane:methanol (90: 10)] gave an oil. A small amount of hexane was added and the mixture was allowed to stand at approximately 0 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 ex-3-(5-ethoxypyrid-3-yl)-Lnd-3-cyano--methyl-8azabicyclo[3.2. 1]octane (0.-105g) Imp. 56-57*C.

EXAMPLE 22 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8isopropyl-8-azabicyclo[3.2."l]octane. 30 2M Hydrochloric acid (8 drops) was added to a stirred solution of dimethoxytetrahydrofuran (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 (100ml).

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 (MgSO 4 and evaporated under reduced pressure. The aqueous fraction was then extracted with chloroform and the extracts dried (MgSO 4 and evaporated under reduced pressure. Distillation of the combined extracts (95-115°C; 18mmHg) gave 8isopropyl-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 (50ml) and ethanol (2.2ml) under nitrogen at such a rate so as to keep the temperature below 10 0 C. After 1 day tosylmethyl isocyanide potassium t-butoxide (1.0g) and ethanol (Iml) were added. After a further day the mixture was filtered and the filtrate evaporated under reduced pressure and chromatographed [SiO 2 dichloromethane:methanol 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-8azabicyclo[3.2.1]octane (0.38g) and 3,5-dichloropyridine (0.34g) in tetrahydrofuran (5ml) 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 25 followed by lithium bis(trimethylsilyl)amide (1.0ml of a IM solution in tetrahydrofuran) over 30 minutes. After 2 hours lithium bis(trimethylsilyl)amide (1.0ml of a IM solution in tetrahydrofuran) was added dropwise and after a further 1 hour additional lithium bis(trimethylsilyl)amide (1.0ml of a lM solution in tetrahydrofuran) was added and the mixture warmed to 50C. After 5 minutes the reaction was cooled to room temperature and 30 aqueous sodium carbonate solution added. The mixture was extracted with ethyl acetate (x2) and the combined extracts washed with brine, dried (MgSO 4 and evaporated under reduced pressure to give a brown oil. The oil was extracted with boiling hexane and the combined -31 extracts evaporated under reduced pressure to give gx-3-(5-coopyrid-3-y1)-end--3-cyaio- 8-isopropyl-8-azabicyclo[3.2.1 ]octane (0.60g).

EXAMPLE 23 This example illustrates the preparation of ex-3-(2,6-chloopyrid-yl)- d-3-cyano-8methyl-8-azabicyclo[3.2. lI]octane.

xo-3-Cyano-8-methyl-8-azabicyclo[3.2.lI]octane (0.5g) in tetrahydrofuran (3rn) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (l.6m1d of a 2.5M solution in hexane) to diisopropylarnine (0.4g) in tetrahydrofuran (3m1)] 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 The combined extracts were washed with brine and water, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiO 2 dichloromethane:mnethanol (95:5) to (90: 10)] gave exo-3-(2,6-dichloropyrimid-4-yl)endo-3-cyano-8-methyl-8-azabjcyclo[3.2. I ]octane (0.087g) m.p. 95-97*C.

EXAMPLE 24 This example illustrates the preparation of exo-3-(2-chloropyrid-4-yl)-e~ndgo-3-cyano-8methyl-8-azabicyclo[3 .2.1 Ijoctane.

exo- 3 -Cyano-8-methyl-8-azabicyclo[3.2. I octane (0.5g) in tetrahydrofuran (3ml) was adde -d to a solution. of lithium diisopropylaxnide [made,-by adding nLButi (1.6m1 of a 2.5M solution in hexane) to -diisopropylaniine (0.4g) in tetrahydrofuan (3m1)] 'at -25*C under nitrogen.

After 30 minutes the mixture'was cooled to -78 0 C and a solution of 2,4,6-trichloropyridinie (0.724g) in tetrahydrofuran (5ml) was added. After I hour the mixture was allowed to warm to- room temperature and allowed to stand overnight. Water was added and the mixture ~25 extracted with ethyl acetate The combined extracts were dried (MgSQ 4 and evaporated under reduced pressure. Chromatography [SiO 2 dichloromethane:methanol gave a solid product which' was recrystallised (ethyl acetate/hexane) to give 'ex-3-(2,6dichloropyrid-4-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2. 1 ]octane (0.3 89g) m.p. 165- 166 0

C.

gy,-- 3 -(2,6-Dichloropyrid-4-yl)- endo-3-cyano-8-methyl-8-azabicyclo[3.2.1 octane (0.50g) and hydrazine hydrate- 106m1) Were refluxed in isoprop'yL alcohol (5mI) for 5 hours and then left to'stand overnight Hydrazine hydrate 106m1) was added and the mixture refluxed -32for 8 hou rs. More hydrazine hydrate (O.106m1) was added and the mixture refluxed for a further 8 hours. After cooling to room temperature the mixture was evaporated under reduced pressure and the residue extracted with dichioromethane. The extracts washed with water dried (MgSO 4 -evaporated under reduced pressure and triturated with hexane and ether .to give ex-3-(2-chloro-6-hydrazinopyrid-4-yl)-ndo-3-cyano-8-methyl-8azAbicyclo[3.2. 1 ]octane (0.205g) m.p. 215-21 6 0

C.

Copper(ll) sulphate octahydrate (0.36g) was added to a solution of ex-3-(2-chloro-6hydrazinopyrid-4-yl)-endo-3-cyano-8-methyl-8-azabicyclo(3 1 ]octane (0.1 70g) in water (3m1) and the mixture refluxed for 7 hours. After cooling to room temperature ammronium.

hydroxide solution (density=-0.88) was added and the mixture extracted with ethyl acetate The combined extracts were washed with brine and water, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiO 2 dichloromethane:methaol (90:10)] gave ex-3-(2-chloropyrid-4-yl)-td-3-cyano-8-methyl-8-azabicyclo[3.2. 1 ]octane (0.052g) m.p. 104-105*C.

EXAMPLE This example illustrates the preparation of exo..3-(pyrid-4-yl)-endo-3-cyano-8-methyl-8azabicyclo (3.2.1 I octane.

exo-3-(2,6-Dichloropyrid-4-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3 1 ]octane (0.35g), crushed potassium hydroxide (0.133g) and palladium on charcoal (0.20g) were stirred in methanol (10rrl) 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 ethylacetate. :'.The resulting solution was washed with aqueous sodium hydroxide and water, dried (MgS 04) and evaporated under reduced pressure to give a solid product which was washed with hexane and ether to give exo-3-(pyrid-4-yl)-ndo-3-cyano-8-methyl-8azabicyclo[3.2.1I]octane (0.072g) mn.p. 74.5-76*C.

EXAMPLE 26 This example illustrates the preparation of ex-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(3,3difluoroprop-2-en- I -yl)-8-azabicyclo[3.2. 1 ]octane.

exo-3-(5-Chloropyrid-3-yl)-gnd-3-cyano-8-azabicyclo[3 .2.1I ]octane (0.248g), 1 -bromo- 1,1 difluoroprop-2-ene (0.3 14g) and potassium carbonate (0.345g) were stirred in ethanol (2m1) 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 -33- (x0) and the combined extracts were washed with brine, dried (MgSO 4 and evaporated under reduced pressure. Filtration [Si0 2 dlichloromethane:methanol gave chloropyrid-3-yl)-en-do-3-cyano-8-(3,3-difluoroprop-2-en- 1 -yl)-8-azabicyclo[3 1 ]octane (0.287g).

EXAMPLE 27 This example illustrates the preparation of e~xo-3-(5-chloropyrid-3-y)-endo-3-cyano-8-(3oxo-4,4,4-trifluorobut-l1-en-I yl)-8-azabicyclo[3.2. 1 ]octane.

exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3 1 ]octane (0.30g), 4-ethoxy- 1,1,1 trifluorobut-3-en-2-one (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 (x0) and the combined extracts were washed with brine (x2) and water, dried (MgSO 4 and evaporated under reduced pressure.

Chromatography [SiO 2 dichloromethane:methanol gave 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 (0.1 62g) mp.

144-145 0

C.

EXAMPLE 28 This example illustrates the preparation of ex-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-acetyl- 8-azabicyclo [3 1 ]octane.

N.N-Diisopropylethylanmune (0.43m1i) and acetyl chloride (0.18m1) were added to chloropyrid-3-y1)-tndo-3-cyano-8-azabicyclo(3.2. I]octane (0.50g) in. dichloromethane (IlOmi) at room temperature. After 10 minutes the mixture was evaporated under reduced pressure and ethyl acetate (5Orn}) added. The resulting mixture was washed wit h potassium carbonate solution, dried (MgSO 4 and evaporated under reduced pressure. The resulting product was triturated with hot hexane and evaporated under reduced -pressure to give chloropyrid-3-yl)-endo-3-cyano-8-acetyl-8-azabicyclo[3.2.l1joctane (0.43g) m.p. 1215C EXAMPLE 29 This example illustrates -the preparation of exo-3-(5-chloropyrid-3-yl)-en4 o-3-cyano-8azabicyclo[3.2.l1joctane hydroperchlorate.

Perchioric acid 19m1) was added dropwise to a stirred suspension of 3 -yl)--end---3-cyano-8-azabicyclo[3.2.1I]octane (5.0g) in diethyl ether (lO0ml) at- room temperature. After 5 hours the mixture was filtered and- the precipitate washed with diethyl 34 ether to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2. 1l)octane hydroperchiorate (5.3 6g).

EXAMPLE This example illustrates the preparation of ex-3-(5-chloropyrid-3-yl)-e-nd--3-cyano-8-(tertbutyl)-8-azabicyclo[3.2. 1i]octane.

Acetone (O.42rn1) was added to a stirred solution of exo-3-(5-chloropyrid-3-yl)-endo-3cyano-8-azabicyclo[3.2.l]octanhe hydroperchiorate (1.0g) in ethanol (2mld) at room temperature under nitrogen. After 30 minutes the mixture was heated to 50*C. After I 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 (lniW) was added followed by methylmagnesium bromide (4.3m1 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 amnmonium chloride solution was then added and the mixture extracted with dichioromethane The combined extracts were washed with brine, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [Si0 2 dichloromethane:methanol gave ex-3-(5-chloropyrid-3-yl)-e-nd-o-3-cyano-8-(ertbutyl)-8-azabicyclo 1 ]octane (0.21 8g) m.p. 127- 129*C.

EXAMPLE 31 This example illustrates the preparation of ex-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2phenY173-oxo-prop-2-yl)-8-azabicyclo[3.2. 1 ]octane; 2-Phenyipropanal (1 .08g) was added to a mixture of exo-3-(5-chloropyrid-3-yl)-endo-3cyano-87gzabicyclo[3.2.1 ]octane (2.0g) and p-toluenesulphonic acid (0.15g) in toluene (30m1d) 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 chloropyrid-3-yl)-egndo-3-cyano-8-(2-phenylprop- 1 -en- I -yl)-8-azabicyclo[3.2. 1 ]octane which was used without further purification.

Sodium N-chloro-L)-toluenesulphonamide (2.3g) was added to the ex-3-(5-chloropyrid-3-yl)- *endo-3-cyano-8-(2-phenylprop- 1-en-1I-yl)-8-azabicyclo[3.2. 1]octane from the above reaction in dichloromethane (30m1) 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 dichioromethane. The combined filtrates were washed with sodium hypochiorite (x2) and brine, dried (MgS 04) and evaporated under reduced pressure. Chromatography [SiC) 2 dichloromethane:methanol followed by chromatography [SiO 2 dichloromethane:methanol gave exo-3-(5-chloropyrid-3-yl)-nd-3-cyano-8-(2phenyl-3-oxo-prop-2-yl)-8-azabicyclol3.2. 1 ]octane (0.43g) m.p. 124-1 26*C.

EXAMPLE 32 This example illustrates the preparation of exo-3-(5-chloropyrid-3-y1)-endo-3-cyano-8-.(2phenylbut-3-en-2-yl)-8-azabicyclo[3 1 ]octane.

Sodium methoxide (0.085g) was added in two portions to a stirred solution of, methylti-iphenyiphosphonium bromide (0.56g) in dimethyl suiphoxide (30m1J) at room temperature under nitrogen. The mixture was warmed to 70*C and after 2 hours chloropyrid-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 suiphoxide 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 The combined extracts were washed with brine dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiC) 2 ;'ethyl acetate:hexane (90:10)] gave chloropyrid-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-8-(2phenyl-3-hydroxyprop-2-yl)-8-azabicyclo[3.2- 1 ]octane.

Sodium borohydride (0.094g) was added to a stirred solution of exo-3-(5-chloropynid-3-yl)t-nd--3-cyano-8-(2-phenyl-3-oxo-prop-2-yl)-8-azabicyclo3.2. 1 ]octane (0.90g) in ethanol 9 9- 9 (15ra1) under nitrogen. After 2 hours the mixture was poured into brine and the resulting mixture extracted with ethyl acetate The combined extracts were dried (MgSO4), **25 evaporated under reduced pressure and chromnatographed[(SiC) 2 ethyl acetate:hexane (50:50)1 to give exo-3-(5-chloropyrid-3-yl)-etn4o-3-cyano-8-(2-phenyl-3-hydroxyprop-2-yl)-8azabicyclo[3.2. 1 ]octane (0.777g) m.p. 124- 126*C.

9 EXAMPLE 34 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2- 30 fluoro-2-phenylprop. 1-yl)-8-azabicyclo[3.2. 1 ]octane.

.Diethylaminosulphur trifluoride -(0.4m1) and.- g-3-(5-chloropyrid-3-y)-endo-3-cyano-8-(2phenyl-3-hydroxyprop-2-yl)-8-azabicyclo[3.2. I]octane (0.10g) were stirred .in -36dichioromethane (O.2m1) 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 (MgSO 4 and evaporated under reduced pressure. Chromatography [SiO 2 ethyl -acetate~hexane (17:83)] gave ex'o-3- (5-chloropyrid-3-yl)-endo-3-cyano-8-(2-fluoo-2-phelylprop- 1 -yl)-8-azabicyclo[3.2. 1 ]octane (0.075g).

EXAMPLE This example illustrates the preparation of exo-3-(5-chloropynid-3-yl)-endo-3-cyano-8-(2phenyl-3-acetoxyprop-2-yl)-8-azabicyclo[3.2. 1 ]octane.

Triethylanine (0.06m1) and acetyl chloride (0.029m1) were added to a stirred solution of exo- 3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2-phenyl-3-hydroxyprop- 2 -yl)- 8 azabicyclo[3.2. 1]octane (0.15g) in dichloromethane (5m1) at room temperature under nitrogen. -After 1.5 hours dichloromethane was added and the mixture washed with water (x2) and brine, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiO 2 ethyl acetate:hexane (20:80)] gave ex-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2phenyl-3-acetoxyprop-2-yl)-8-azabicyclo[3 .2.1 I octane 14g) rnmp. 130-13 1 *C.

EXAMPLE 36 This example. illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8formyl-8&azabicyclo[3.2. 1 ]octane.

exo-3-(5-Chloropyrid-3-yl)-ndo-3-cyano-8-azabicyclo[3 .2.1 I octane (3.0g) and formnic acid 14m1) were heated at reflux for 4 hours. The mixture was then heated at 1 10 0 C overnight and formic acid (1 .Om-l) 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 water and brine, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiO 2 ethyl acetate:methanol gave chloropyrid-3-yl)-endo-3-cyano-8-formyl-8-azabicyclo[3 I1]octane (1 .675g) imp. 141- 142 0

C.

*30 EXAMPLE 37 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endQ-3-cyano-8- (diisopropylcarbamnyl)-8-azabicyclo[3.2. 1 ]octane.

3*7 Triethylamine (O.27m1) followed by dilsopropylcarbamyl chloride (0.3 17g) was added to a stirred solution of o-3-(5-chloropyrid-3-yl)-ndo-3-cyano-8-azabicyclo[3.2. Ij]octane (0.40g) in dichioromethane at room temperature. After 2 hours the mixture was allowed to stand at room temperature for 4 days. Dichioromethane was then added and the mixture washed with water (x2) and brine, dried (MgSO 4 and evaporated under reduced pressure. Filtration [SiO 2 ethyl acetate] gave ex-3-(5-chlorpyrid-3-yl) .ndo-3-cyano-8- (diisopropylcarbamyl)-8-azabicyclo[3.2. 1 ]octane 12g) m.p. 118-121' 0

C.

EXAMPLE 38 This example illustrates the preparation of ex-3-(5-chloropyrid-3-yl)-nd-3-cyano-8-(tertbutylcarbaxnyl)-8-azabicyclo(3.2. 1 ]octane.

Triethylainine (0.27m1) followed by tert-butylisocyanate (0.22m1) was added to a stirred solution of exo-3-(5-chloropyrid-3-yl)-e-nd-3-cyano-8-azabicyclo [3 1 ]octane (0.40g) in dichioromethane (4ml) at room temperature. After 3 hours the mixture was allowed to stand at room temperature overnight and dichlorometbane then added. The mixture was then washed with water (x2) and brine, dried (MgSQ 4 and evaporated under reduced pressure.

Chromatography [Si0 2 diethyl ether] gave exo-3-(5-chloropyrid-3-yl)- endo-3-cyano-8-(tertbutylcarbamyl)-8-azabicyclo[3.2. 1 ]octane (0.40g) mp. 62-65*C.

EXAMPLE 39 This example illustrates the preparation of (R)-Lx -3-(5-chloopyrid-3-yl)-ndo-3-cyano-8-( 1phenylethyl)-8-azabicyclo[3.2. 1 ]octane.

Three drops -of SM hydrochloric acid were added to a mixture of dimethoxytetrahydrofuran (16.5g) and water- (70m1). A cooled mixture of methylbenzylarnine (15. 125g) and 5M hydrochloric acid (30m1) was then added followed by 1.3-acetonedicarboxylic acid (18.26g) sodium acetate (10g) and water (lO0ml). After 5 days the mixture was basified with aqueous sodium carbonate solution and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSQ 4 and evaporated under reduced pressure. Chromatography [SiO 2 ethyl acetate:hexane (10:90) to (20:80)] gave phenylethyl)-8-azabicyclo[3.2. I1]octan-3-one.

Potassium t-butoxide (13.4g) was added portionwise to a stirred mixture of gave phenylethyl)-8-azabicyclo[3.2.1]octan-3-one (1 1.45g) and tosyirrthyl isocyanide (12.7g) in *dinieth2oxyetbane (200m1) and ethanol (6ml) at -5 0 C at such a rate to maintain the -temperature below After stirring overnight the mixture was filtered (celite) and the filtrate. evaporated -38 under reduced pressure. The residue was then dissolved in ethyl acetate, washed with water, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiO 2 ethyl acetate:hexane (50:50)] gave (g)-ex-3-cyano-8-( 1 -phenylethyl)-8-azabicyclo[3.2. 1 ]octane (3 .5g) mrp. 138- 139.5 0

C.

Lithium bis(trimethylsilyl)amide (4.8ml. of a 1 OM solution in tetrahydrofuran) was added to a.

stirred solution of (R)-gx-3-cyano-8 (l -phenylethyl)-8* azabicyclo[3.2. 1 ]octane (1 .0g) and (0.674g)"in tetrahydrofuran (20mrn) at 0 0 T under nitrogen. The mixture was allowed to warm to room temperature and stand for 24 hours. Water (20m1) 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 (MgSO 4 and evaporated under reduced pressure. Chromatography [SiO 2 ethyl ac-etate:hexane (50:50)], preparative thin layer chromatography [SiO 2 ethyl acetate:hexane (25:75)] and recrystalisation from hexane gave (B,)-exo-3-(5-chloropyrid-3-yl)- endo-3-cyano-8-( 1phenylethyl)-8-azabicyclo[3.2.l ]octane (0.46g) m.p. 1 13-1 EXAMPLE This example illustrates the. preparation of exo-3-(5-aminopyrid-3-yl)- endo-3-cyano-8methyl-8-azabicyclo[3 .2.1 IJoctane.

Ammonia solution was added to exo-3-(5-bromopyrid-3-yl)-tn4d--3-cyano-8-methyl-8azabicyclo[3.2. I]octane (0.106g) and copper(ll) sulphate hydrate (0.001lg) and the tube sealed. The mixture was heated at 100 0 C for 20 hours and then 150TC 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 dichioromethane were added followed by ammonia solution and the resulting mixture was extracted with dichloromethane. The combined extracts were washed 'with brine, dried (MgSQ 4 and evaporated under reduced pressure to .give anminopyrid-3-yl}--endo-3-cyano-8-methyl-8-azabicyclo(3.2. 1 ]octane (0.045g) m.p. 188- 190 0

C.

EXAMvPLE 41 This example illustrates the preparation of exQ-3-(5-acetylamidopyrid-3-yl)-end-3-cyano-8- 30 methyl-8-azabicyclo[3.2. 1 ]octane.

Acetic anhydride (1 .Oml) was added to ex--5aioyi--l-e----yn--ehl8 azabicyclo[3.2.1 ]octane (0.10g). After 3 days dilute sodium bicarbonate solution and ethyl 39 acetate were added followed by sodium bicarbonate and potassium carbonate to basify the mixture. The mixture was extracted with ethylI acetate and the extracts dried (MgSO 4 and evaporated under reduced pressure to give ex--5aeyaioyid3y) do3caog methyl-8-azabicyclo[3.2. 1 ]octane 107g).

EXAMPLE 42 This example illustrates the preparation of exo-3-(5-oropyrid-3-y)-nd43-cyao8-(acyanobenzyl)-8-aiabicyclo[3.2. I ]octane.

exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2. 1 ]octane (2.0g) and benzaldehyde (0.89m1) were added to lM hydrochloric acid (20m1) and the mixture stim~d for 20 minutes.

Sodium cyanide (0.549g) in water (6m1) was then added. After 18 hours ethanol (20m1) was added to give one phase. After. 6 days the reaction mixture was partitioned between ethyl acetate and water and the organic layer was washed with water and brine, dried (MgSO 4 and evaporated under reduced pressure. Chromatography (SiC) 2 dichloromethane-methanol:iriethylaxnine (99.4:0.5:0.1)1 gave exo-3-(5-chloropyrid-3-yl)end-3-cyano-8-(a-cyanobenzyl)-8-azabicyclo[3.2-; 1 ]octane 104g) mp. 141- 142*C.

EXAMPLE 43 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-no-3-cyano-8-(acarbamylbenzyl)-8-azabicyclo [3 1 ]octane.

Concentrated sulphuric acid (10mi) was added to tx-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- (a-cyanobenzyl)-8-6azabicyclo[3.2.1I]octane (0.5 ig) and -the mixture stirred for 1t hour. Ice (100g) was added and the mixture basified with sodium bicarbonate solution. A precipitate formed which was collected by filtration, dissolved in ethyl acetate, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiC) 2 dichloromethane:methanol (99:1) -to gave ex-3-(5-choroyrid-3-yl)-ei~d-3-cyano-8-(a-carb.miylbenzyl)-8- 25 azabicyclo[3.2.1I]octane (0.181g) m.p. 193-195*C.

This example illustrates the preparation of exo-3-(5-iodopyrid-3-yl)-gnd-3-cyano-8-methylo 8-azabicyclo[3.2. I]octane.

OVC

Nickel(ll) bromide (1 .55m1 of a 0. 16M solution in N,N-dixnethylformamide) was added to a 30 stirred solution of tri(n-butyl)phosphine 124m1) in &N.-dimrethylformaride (5mi) under *0C.0.

.*.nitrogen. Potassium iodide (3.96g) was then added followed by gx-3-(5_bromopyrid-3-yl)ond--3-cyano-8-methyl-8-azabicyclo[3.2. I]octane (1.522g) and the mixture heated under 40 reflux for 48 hours. The mixture was then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried (MgSO 4 evaporated under reduced pressure and chromatographed [SiO 2 dichloromethane:methanol to give ex- 3-(5-iodopyrid-3-yl)-gndo-3-cyano-8-methyl-8-azabicyclo[3 .2.1I ]octane (0.399g) m.p. 144- 145 0

C.

EXAMPLE This example illustrates the preparation of ex--3-(5-trifluoromethylpyrid-3-yl)-end-3-cyano- 8-methyl-8-azabicyclo[3.2. 1l]octane.

exo-3-(5-Iodopyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclol3 .2.1I ]octane (0.50g) followed by copper(I) iodide were added to a stirred solution of sodium trifluoroacetate (2.6g) in tNmethylpyrrolidinone (5ml) and the mixture heated to 180*C. After 3 hours the mixture was cooled to room temperature, watei added and extracted with dichioromethane. The organic layer was filtered and the filtrate dried (MgSO 4 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 1iM hydrochloric acid and the aqueous fraction basified with potassium carbonate and extracted with diethyl ether. Thie -extracts were dried (MgSO 4 and evaporated under reduced pressure. Preparative thin layer chromatography [A1 2 0 3 diethyl ether] gave ex-3-(5-trifluoromethylpyrid-3-yl)-endo-3cyano-8-methyl-8-azabicyclo[3.2.1]octane (0.027g) m.p. 118.2-1 18.5*C.

EXAMPLE 46 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)- endo-3-cyano-8so (mercaptothiocarbonyl)-8-azabicyclo[3.2. 1 ]octane.

Carbon disulphide (O.12m1) was added to a stirred solution of ex-3-(-choropyrid-3-yl)endo-3-cyano-8-azabicyclo[3.2. 1]octane (0.50g) in ethanol (5m1) 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 ex-3-(5-chloropyrid-3-yl)-endo-3cyano-8-(mercaptothiocarbonyl)-8-azabicyclo[3.2. 1 ]octane (0.509g) mp. 224 0

C

(decomposed).

EXAMPLE 47 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-gndo-3-cyano-8- (fluorocarbonyl)-8-azabicyclo 13.2.1 I octane.

41 Iodomethane (0.08m1) was added to a stirred mixture of exo-3-(5-chloropyrid-3-yl)-en~-3cyano-8-(mercaptothiocarbonyl)-8-azabicyclo[3.2. 1]octane (0.40g) 'in dimethyl suiphoxide (3m1) at room temperature. After 3 hours water was added and the mixture extracted with dichioromethane The combined extracts were washed with water (x2) and brine, dried (MgSO 4 and evaporated under reduced pressure. Dichioromethane was added and the mixture washed with brine dried (MgSQ 4 and evaporated under reduced pressure to give ex-3-(5-chropyrid-3-yl)-n -3-cyano-8-(methylmercaptothiocarbonyl)-8azabicyclo[3.2. I1]octane (0.1 87g).

Tetra(n-butyl)axnmonium dihydrogentrifluoride (0.48g) was added to a solution of chloropyrid-3-yl)-end-3-cyano-8-(methylmercaptothiocarbony)-8-azabicyclo[3.2. 1 ]octane (0.180g) in dichloromethane at 0 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 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 bisuiphite solutions added.

The mixture was extracted with dichioromethane and the ext racts dried (MgSO 4 and evaporated under reduced pressure. Ethyl acetate was added and the mixture washed with water (x2) and brine, dried (MgSO 4 and evaporated under reduced pressure.

00 ~Chromatography [SiQ 2 diethyl etherhexane- (80:20)] gave tx-3-(5-chloropyrid-3-y)-endo- ~20 3-cyano-8-(fluorocarbonyl)-8-azabicyclo(3.2. 1]octane (0.l10g) m.p. 165-167*C.

EXAMPLE 48 This example illustrates the preparation of ex-3-(5-choropyrid-3-y1)-g~nd-3-cyano-8-(2,2o difluoroethyl)-8-azabicyclo[3.2. 1]octane.

2.2-Difluoroethyl bromide (1.08g), potassium carbonate (1.38g), potassium iodide (0.30g) and ex-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2. 1 )octane (1 .238g) were stirred at 50*C in ethanol (l0ml). 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 30 (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 dichioromethane (x2) and the combined extracts washed with brine, dried (MgSO 4 and 42 evaporated under reduced pressure. Chromatography [SiC) 2 dichloromethane:methanol gave exo-3-(5-chloropyrid-3-yl)- ado-3-cyano-8-(2,2-difluoroethyl)-8azabicyclo[3.2.l1]octane (0.278g) m.p. 10l-104*C.

EXAMPLE 49 This example illustrates the preparation of exo.3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2phenylethyl)-8-azabicyclol3.2. 1)]octane.

2-Phenylethyl bromide (0.112g), potassium carbonate (0.345g) and ex-3-(5-chloropyrid-3yl)-endo-3-cyano-8-azabicyclo[3.2. 1 ]octane (0.248g) were heated under reflux in ethanol (2m1) for 9 hours. 2-Phenylethyl bromide (0.1g) was added and the mixture refluxed for 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 (MgSO 4 and -evaporated under reduced pressure. Chromatography [SiC) 2 dichloromethane:methanol gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2phenylethyl)-8-azabicyclo[3.2. 1 ]octane (0.08g).

EXAMPLE This example illustrates the preparation of exo-3-(5-hydroxypyrid-3-yl)-endo-3-cyano-8methyl-8-azabicyclo[13 1 ]octane.

Pyridinium. hydrochloride (1 .0g) and eio -3-(5-rnethoxypyrid-3-yl)-endo3-cyano-8-methyl-8- 20azabicyclo[3.2.lI]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 The aqueous fraction was neutralised with dilute hydrochloric acid and extracted with ethyl acetate The combined organic extracts were washed with water, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiC) 2 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-3cyano-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)-Lndo-3-cyano-8benzyl-8-azabicyclo[3.2. 1 ]octane.

~30 exo-3-Cyano-8-methyl-8-azabicyclo[3.2. I]octane (0.5g) in tetrahydrofuran (3m1) was added to a solution of lithium diisopropylamide [made by adding n-BuLi (1.6m1d of a 2.5M solution in hexane) to diisopropylamine (0.4g) in tetrahydrofuran (3m1)] at -25*C under nitrogen.

43 After 15 minutes at the mixture was cooled to -78*C and 3,5-dichioropyridine (0.588g) in tetrahydrofuran (3m1) 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 The combined extracts were washed with brine and water, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [Si0 2 dichloromethane:nethanol (90: 10)] gave exo-3-(5-chloropy'd-3-yl)-tndo-3-cyano-8-methyl-8azabicyclo[3.2. lioctane (0.240g).

Vinyl chioroformate (2.6m1) in tetrahydrofuran (5mi) was added to a stirred solution of exo- 3-(5-chloropyrid-3-yl)-en-do-3-cyano-8-methyl-8-azabicyclo[3.2. 1 ]octane (2.6g) in tetrahydrofuran (25m1) at 0 0 2C. 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 g~-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2. 1 ]octane cQ-3-(5-Chloropyrid-3-yl)-end-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2. 1 ]octane (2.6g) was dissolved in methanol (50mi) 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)--ead-3-cyano-8azabicyclo[3.2.1I]octane (1.2g).

exo-3-(5-Chloropyrid-3-yl)-erido-3-cyano-8-azabicyclo[3.2. lloctane 104g) in ethanol *(5m1) 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 a 'cetate. The organic layer was separated and evaporated under reduced pressure. Preparative thin layer chromatography [SiO 2 dichloronethane:nmthano1 gave exo-3-(5-chloropyrid-3-yl)endo-3-cyano-8-benzyl-8-azabicyclo[3.2.1I]octane (0.077g).

30 7 1.EXAMPLE-52 This example illustrates -the preparation- -of p-3-(5-chloopyrid-3-yl)-enqd-3-cyano-8- (pentafluorophenylmethyl)-8-azabicyclo[3.2. lioctane.

-44- Chloropyrid-3-yl)--end-3-cyano-8-azabicyclo[3.

2 1 ]octane (0.248g), 2,3,4,5,6pentafluorobenzyl bromide (0.3 13g), potassium carbonate (0.345g) and ethanol (2m1) were stirred under reflux. for 3 hours. The mixture was then evaporated under reduced pressure and water added. The mixture was then extracted with dichioromethane (x3) and the combined extracts were washed with brine, dried (MgSO 4 and evaporated under reduced pressure to give an oil which crystallised on standing. The crystals were washed with a small volume of ether to gie exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8- (pentafluorophenylmethyl)-8-azabicyclo[3 lloctane (0.258g) m.p. 143- 144*C.

EXAMPLE 53 This example illustrates the preparation of potassium exo-3-(5-chloropyrid-3-yl)-endo-3cyano-8:-(4-carboxylatobenzyl)-8-azabicyclo[3.2. 1 ]octane.

exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicycloi3.2. 1 )octane (0.2-48g) 4bromomethylbenzoic acid (0.258g), potassium carbonate (0.345g) and ethanol (2m1) 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 ex-3-(5-chloropyid-3-yl)endo-3-cyano-8-(4-carboxylatobenzyl)-8-azabicyclo[3.2.l ]octane (0.292g).

EXAMPLE 54 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-etndo-3-cyano-8-(3chloro-4-fluorobenzyl)-8-azabicyclo[3 .2.1 I octane.

exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2. 1 ]octane (0.495g), 3-chloro-4fluorobenzaldehyde (0.3 17g) and formic acid 0.230g) were heated under reflux. hours:",---.he mixture was then cooled to room temperature, basified with dilute sodium *hydroxide and extracted with dichloromethane The combined extracts were washed with brine, dried (MgSQ4), and evaporated under reduced pressure. Chromatography [SiO 2 :25 dichlorornethane:nethanol (100:0) to gave exo-3-(5-chloropyrid-3-y)-eno-3-cyano-8-- (3-chloro-4-fluorobenzyl)-8-azabicyclol3.2.1]octane (0.290g) rnp. 95-97*C.

EXAMPLE This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)- endo-3-cyano-8-(pyrid- 2-ylmethyl)-8-azabicyclo[3.2. 1]octane.

:30 2-Picolyl chloride hydrochloride (0.361g), potassium carbonate (0.828g) and chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2. I]octane (0.495g) were heated under reflux in ethanol (4m1) for 2 hours. The mixture was then cooled to room temperature and water added. The mixture was extracted with dichioromethane (x2) and the combined extracts washed with brine, dried (MgS 04) and evaporated under reduced pressure. Chromatography [SiO 2 dichloromethane:methanol (100:0) to gave ex-3-(5-chloropyrid-3-yl)-endo-3- -cyano-8-(pyrid-2-ylmethyl)-8-azabicyclo[3.2.1]loctane (0.447g) rn.p. 123-125 0

C.

EXAMPLE 56 This example illustrates the preparation of ex-3-(5-chlorpyrid-3-yl)-nd-3-cyan6-8-((2methylthiazol-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 (2m1) 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 (MgSO 4 and evaporated under reduced pressure. Chromatography [SiO 2 dichloromnethane:methanol (99:1) to gave exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-((2-methylthiazol-4yl)methyl)-8-azabicyclo[3.2. 1 ]octane (0.269g) mp. 8 1-83*C.

EXAMPLE 57 This example ilustrates the preparation of ex-3-(5-chloropyrid-3-yl)- endo-3-cyano-8-((3,5dimethylisoxazol-4-yl)methyl)-8-azabicyclo[3.2. lioctane.

4-Chloromethyl-3,5-dimethylisoxazolc 160g),. potassium- -carbonate (0.345g), potassium iodide .(0.02g) and exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2. I]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 dichioromethane -(x2) and the combined extracts washed with brine, dried (MgSO 4 and evaporated under reduced pressure. -Filtration'[SiO 2 dichlorometbane:methanol gave exo-3-(5-chloropyrid-3-yl)endo- 3 -cyano-8-((3,5-dimethylisoxazol-4.yl)methyl)--azabicyclo[3.2. 1 ]octane (0.25 8g) mp.

95-99 0

C.

EXAMPLE 58 :::*This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(5- :30 chlorothiophen-2-yl)-8-azabicyclo[3.2.ljoctane.

-(0.367g), ,potassium carbonate (0.690g) and chloropyrid-3-yl)-tud-3-cyano-8-azabicyclo[3.2. 1 ]octane (0.495g) were heated under reflux -46in ethanol (2m1) 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 dichioromethane (x2) and the combined extracts washed with -brine, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiO 2 dichloromethane:methanol (100:0) to gave ex-3-(5-chloropyrid-3-yl)-endo-3-cyano- 8-(5-chlorothiophen-2-yl)-8-azabicyclo[3.2. 1 ]octane (0.37g) m.p. 119-12 1 0

C.

EXAMPLE 59 This example illustrates the preparation of ex-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-((5chloro- 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 exo- 3-(5-chloropyrid-3-yl)-Lndo-3-cyano-8-azabicyclo[3 .2.1 I octane (0.248g.) were heated under reflux in ethanol (2m1) for 4 hours. The mixture was then cooled to room temperature and water added. The mixture was extracted with dichioromethane (x2) and the combined extracts washed with brine, dried (MgSO 4 and evaporated under reduced pressure.

Chromatography [SiO 2 dichloromethane:methanol (100:0) to gave chloropyrid-3-yl)-endo-3-cyano-8-((5-chloro- 1 ,2,3-thiadiazol-4-yl)methyl)-8azabicyclo[3 .2.1 I octane (0.1 48g).

EXAMPLE This example illustrates the preparation of exo-3-(5-fluoropyrid-3-yl)-endo-3-cyano-8- 20 methyl-8-azabicyclo[3.2. 1]octane.

exo-3-(5-Amninopyrid-3-yl)-endo-3-cyano-8-methyl--azabicyclo[3 .2.1 ]octane (0.40g) in dichioromethane (150m1) was added to boron trifluoride etherate (1.5m1) at -10 to -15 0

C.

After a few minutes I-butyl nitrite (2m1) was added and the mixture allowed to warm to room temperature and stand overnight. The solid precipitate was collected and heated to cause :25 decomposition. The residue was dissolved in 2M hydrochloric acid, washed with ethyl acetate, basified and extracted with ethyl acetate. The extracts were dried (MgSQ 4 evaporated under reduced pressure and chromnatographed [SiO 2 dichloromethane:methanol 10)] to give exo-3-(5-fluoropyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2. 1 ]octane (0.089g).

:30 EXAMAPLE 61 This example illustrates the preparation of ex-3-(5-(pyrrol-1-yl)pyrid-3-y)-tnd-3-cyano-8methyl-8-azabicyclo [3.2.1I ]octane.

-47- (O.53m1) was added to a mnixture of ex-3-(5-aminopyrid-3yl)-tndo-3-cyano-8-methyl-8-azabicyclo[3.2. 1]octane and acetic acid (13m1). 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 mnixture extracted with 2M hydrochloric acid and water. The combined extracts were basified with potassium carbonate and-extracted with ethyl acetate. The extracts were dried (MgSO 4 and evaporated under reduced pressu re tO give ex-3-(5-(pyrrol- 1-yl)pyrid-3-yl)-end-3-cyano-8-methyl-8-azabicyclo[3 1 ]octane 105g).

EXAMPLE 62 This example illustrates the preparation of Il-ethoxyvinyl)pyrid-3-yl)-endo-3-cyano- 8-methyl-8-azabicyclo[3 .2.1 I octane.

(l-Ethoxyvinyl)tri-n-butyltm ((0.82n-f) was added to a stirrd mixture of 3-yl)-tn4do-3-cyano-8-methyl-8-azabicyclo[3.2. 1 ]octane (0.81 7g) and N 1

,N-

dimnethylformamide (30m1) at room temperature under nitrogen.

Bis(triphenylphosphine)palladium(fl) chloride (0.65g) was then added and the mixture heated at 130*C for 3 hours. The mixture was then allowed to cool to roam temperature, water added and the mixture extracted with dichloromethane The combined extracts were washed with brine, dried (MgSQ 4 and evaporated under reduced pres sure. Chromatography [SiO,; dichloromethane:methanol followed by chromatography ([SiO 2 :dichloromethane:methanol (98:2) to (92:8] gave ex-3 -ethoxyvinyl)pyrid-3-yl)-endo-3cyano-8-methyl-8-azabicyclo[3.2. 1 ]octane EXAMPLE 63 This example illustrates the preparation of exo-3-(5-acetylpyrid-3-yl)-t.nd--3-cyano-8-methyl- :25 8-azabicyclo[3.2. lI]octane.

2M Hydrochloric acid (Img) was added to a stirred mixture of ex-3-(5-(1-ethoxyvinyl)pyrid- 3-yl}--end4--3-cyano-8-methyl-8-azabicyclo[3.2. I octane (0.18g) in acetone (2m1). 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).

30 The combined extracts were dried (MgSO4), evaporated under reduced pressure and chromatographed [Si0 2 dichloromethane:methanol to give ao-3-(5-acetylpyrid-3yl)--eid--3-cyano-8-methyl-8-azabicyclo[3.2. I]octane 13g).

-48- EXAMPLE 64 This example illustrates the preparation of exo-3-(5-ethynylpyrid-3-yl)-endo-3-cyano-8methyl-8-azabicyclo[3 .2.1 I octane.

exo-3-(5-Iodopyrid-3-yl)-e.ndo-3-cyano-8-methyl--azabicyclo[3.2. 1 ]octane (0.50g) in tetrahydrofuran (imi) was added dropwise to a stirred mixture of trimethylsilylacetylene (O.22m1), diethylamine 13m1), copper(I) iodide (0.O1g) 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 (1 OmI) was added followed by tetrabutylainmonium fluoride (1.7m1 of a IM solution in tetrahydrofuran) and the mixture stirred at room temperature for 1.5 hours. Water was added and the mixture extracted with dichloromethane The combined extracts were washed with brine, dried (MgSO4), evaporated under reduced pressure and chromatographed [SiO 2 dichloromethane:methanol (95:5) to (90:10)] to give a crude product. Chromatography [SiO 2 dichloromethane:methanol followed by dissolving the product in dichloromethane, washing with water (x2) and brine, drying (MgSO 4 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 0 This example illustrates the preparation of gx~-3-(5-coropyrid-3-y)-endo-3-cyano-8- (1 'hydroxy-l1-cyano-2-phenylprop-2-yl)-8-azabicyclol3 Il]octane.

Sodium cyanoborohydride (0.033g) was added to a stirred solution of isopropylamine 0 (0.045m1) and exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2-phenyl-3-oxo-prop- 2 -yl)- 8 azabicyclo[3.2. I]octane (0.20g) in methanol (2m1d). Methanolic hydrogen chloride was then added-to give pH5. After 2 hours the mixture was allowed to stand at room temperature for 2 days and isopropylanine (0.045m1l) 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 The combined extracts were washed with brine, dried (MgSO 4 evaporated under reduced pressure and chromatographed [SiO 2 ::dichloromethane:methanol (100:0) to (90:10)] to give ex-3-(5-chloropyrid-3-yl)-ndo-3- S. 30 cyano-8-(1-hydroxy-lI-cyano-2-phenylprop-2-yl)-8-azabicyclo[3.

2 .]octalne (0.75g) nmp. 172- 175 0

C.

49- EXAMPLE 66 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2- (isopropylaniino)-2-phenylprop- 1-yl)-8-azabicyclo[3.2. 1 loctane.

Triethylamine (O.lml) and methanesuiphonyl chloride (O.053m1) were added to. a stirred solution of exo-3-(5-chloropyrid-3-yl)-tndo-3-cyano-8-(2-phenyl-3-hydroxyprop-2-yl)-8azabicycloll3.2. 1]octane (0.25g) in dichloromethane (5m1) at room temperature. After 2 hours isopropylaniine (O.65ni1) Was added. After 2 hours the mixture was allowed to stand at room temperature overnight and dichioromethane then added. The mixture was washed with water (x2) and brine, dried (MgSO 4 evaporated under reduced pressure and -chromatographed [SiO 2 dic hloromethane:methanol (98:2) to (95:5)]to give chloropyrid-3-yl)-endo-3-cyano-8-(2-(isopropylamino)-2-phenylprop- 1-yl)-8azabicyclo[3.2. lI]octane (0.24g).

EXAMPLE 67 This example illustrates -the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8cyanomethyl-8-azabicyclo[3.2. I ]octane.

Bromoacetonitrile (0.85m1) was added to a mixture of xo-3-(5-chloropyrid-3-yl)-endo-3cyano-8-azabicyclo[3.2.1I]octane (2.0g) and potassium carbonate (2.23g) in ethanol (l0ml) 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, chromnatographed [SiO 2 dichloromethane:methanol and recrystallised (ethyl acetate/hexane) to give ex-3-(5-chloropyrid-3-yl)-endo-3cyano-8-cyanomethyl-8-azabicyclo[3.2. I]octane (1.36g). m.p. 149-151'C.

EXAMPLE 68 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-en-d-3-cyano-8-( 1- (ethoxycarbonyl)ethyl)-8-azabicyclo[3.2. I1]octane.

Ethyl 2-bromopropionate (O.29m1) was added to a mixture of exo-3-(5-chloropyrid-3-yl)endo-3-cyano-8-azabicyclo(3.2.1]or-tane (0.5g) and potassium carbonate (0.42g) in tetrahydrofuran (8m1) 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 30 filtrates were evaporated under reduced pressure and. chromatographed [SiQ 2 dichloromethane:methanol (100:0 to to give LxQ-3-(5-chloropyrid-3-yl)--eldo-3cyano-8-( 1 -(ethoxycarbonyl)ethyl)-8-azabicyclo[3.2. 1 ]octane (0.49g).

EXAMPLE 69 Ths example illustrates the preparation of ex-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(6fluoropyrid-2-yl)-8-azabicyclo[3.2. 1 ]octane.

2,6-Difluoropyridine (0.37m1), potassium carbonate 12g) and -ex-3-(5-chloropyrid-3-yl)endo-3-cyano-8-azabicyclo[3.2.1]loctane (1.0g) were heated at 140TC in N methylpyrrolidinone (l0mi) 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 (MgSO4), evaporated under reduced pressure and chromatographed [SiO 2 hexane:ethyl acetate (90:10)] to give chloropyrd-3-yl)-endo-3-cyano-8-(6-fluoropyrid-2-yl)-8-azabicyclo [3 .2.1I ]octane (0.796g) m.p. 131.5-132.5*C.

EXAMPLE This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(5chlorothiazol-2-yl)-8-azabicyclo[3.2. 1 ]octane.

potassium carbonate (1.67g) and ex-3-(5-chloropyrid-3yl)-endo-3-cyano-8-azabicyclo[3.2. 1]octane (1.0g) were heated at 140*C in Nmiethylpyrrolidinone (l0mI) 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 (x0).

The combined extracts were washed with brine, dried (MgSO4). evaporated -under -reduced pressure and chromatographed [SiO 2 hexane:ethyl acetate Recrystailisation (hexane) gave exo-3-(5-chloropyrid-3-yl)-end-3-cyano-8-(5-chlorothiazol-2-yl)-8azabicyclo[3.2.1I]octane 17g) m.p. 111- 1 12*C.

EXAMPLE 71 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8pentafiuorophenyl-8-azabicyclo[3.2. 1 ]octane.

Hexafluorobenzene (0.93m1), potassium carbonate (1.12g) and exo-3-(5-chloropyrid-3-yl)endo-3-cyano-8-azabicyclo[3.2. 1]octane (1.0g) were heated at 150*C in Nmethylpyrrolidinone (l0mi) for 5 hours. Hexafluorobenzene (0.93m1) and potassium 30 carbonate -(l.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 The combined extracts were washed with brine, dried (MgSQ 4 -51evaporated under reduced pressure and chromatographed [SiO 2 hexane:ethyl acetate (90: to give exo-3-(5-chloropyrid-3-yi)-gn-d-3-cyano-8-pentafluorophenyl-8azabicyclo[3.2. lloctane (0.55 g).

EXAMPLE 72 This example illustrates the preparation of ex-3-(5-choropyid-3-yl)-ndo-3-cyano-8-cyano- 8-azabicyclol3.2. 1 ]octane.

Tosy cynide(0.8m1)wasadded dropwise to a stirred mnxture of exo-3-(5-chloropyrid-3yl)-endo-3-cyano-8-azabicyclo[3.2. 1 ]octane (1 .0g) and N,N-diisopropylethylaxniine (0.85m1) in tetrahydrofuran (5m1) 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 (MgSO 4 evaporated under reduced pressure and chromatographed [SiO 2 hexane:ethyl acetate (90:10)].

Recrystallisation (hexane/ethyl acetate) gave ex-3-(5-chloropyrid-3-yl)-ndo-3-cyano-8cyano-8-azabicyclo[3.2. 1 ]octane (0.20g) m.p. 168-1 EXAMPLE 73 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-ndo-3-cyano-8methoxy-8-azabicyclo 1 ]octane.

Nii_-Diisopropylethylamine (14.5m1) was added dropwise to a stirred suspension of 0methyihydroxylamine hydrochloride (2.32g) -in isopropyl alcohol (25m1). After 30 minutes :600 20 cyclohepta-2,6-dienone (3.0g) in isopropyl alcohol (5iul) was, added dropwise. After 24.

hours N,N-diisopropylethylamiune (4.9m1) was added. After 6 hours the mixture was allowed to stand at r oom temperature overnight. The mixture was evaporated under reduced pressure, diethyl ether added and the resulting mixture extracted with 2M hydrochloric acid The combined aqueous fractions were washed with diethyl ether neutralised with ::25 sodium hydroxide and extracted with diethyl ether The combined extracts 'were washed with brine, dried (MgSO 4 and evaporated under reduced pressure. Kugelrohr distillation gave 8-methoxy-8-azabicyclo[3.2. 1]octan-3-one (0.86g).

Tosylmethyl isocyanide (2.5 2g) was added to a stirred suspension of potassium 1-butoxide (2.17g) in 1.2-dimethoxyethane (l0mi) at such a rate to keep the temperature below; l00C.

After 45 minutes 8-methoxy-8-azabicyclo[3.2.1]octan-3-one (1.0g) in 1,2-dimethoxyethae (l0mi) 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 52 and water was then added. The resulting mixture was extracted with ethyl acetate (x0) and the combined extracts washed with brine, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiO 2 hexane:ethyl acetate (90:10)] gave exo-3-cyano-8methoxy-8-azabicyclo[3 .2.1I ]octane (0.40g).

Lithium bis(triniethylsilyl)amide (2.42m1 of a iM solution in tetrahydrofuran) was added dropwise to a stirred solution of ex-3-yano-8-methoxy-8-azabicyclo[3.2.lI]octane (0.40g) and 3,5-dichioropyridine (0.358g) in tetrahydrofuan (5mI) at 0 0 C. After 1 hour the mixture was allowed to warm to room temperature. After 5 hours water was added and the mixture extracted with ethyl acetate The combined extracts were washed with brine, dried (MgSO 4 and evaporated under reduced pressure. Preparative thin layer chromatography [SiO 2 ethyl -acetate] gave exo-3-(5-chloropyrid-3-yl)-endo~-3-cyano-8-methoxy-8azabicyclo[3.2. 1 ]octane 192g) iii 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 1 ]octane.

Sodium hydride (0.095g of an 80% dispersion in oil) was added to exo-3-(5-chloropyrid-3yl)-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 The combined .:20 extracts were washed with brine, dried (MgSO 4 and evaporated under reduced pressure.

Chromatography [SiO 2 chloroform:methanol followed by chromatography -[SiO 2 ethyl acetate:dichloromethane (80:20)] gave exo-3-(5-chloropyrid-3-yl)-efldo-3-cyano-8-(2 (ethoxycarbonyl)ethyl)-8-azabicyclo[3.2. 1 ]octane.

EXAMPLE :25 This example illustrates the preparation of x--5clrprd3y)ed--yn--2 carboxyethyl)-8-azabicyclo[3 1 ]octane.

3M Sodium hydroxide (4m1) was added to a stirred solution of exo-3-(5-chloropyrid-3-yl)eno3cao8(-ehxcronlehl--zbcco32 1 ]octane (0.41 g) in ethanol (8m1) 0.0 at room temperature. After 24 hours th e mixture was basified to pH9 and evaporated under reduced pressure. The product was azeotroped with methanol/toluene and chromatographed [SiO 2 dichloromethane:methanol (75:25)] to give ex-3-(5-chloropyrid-3-y)-tnd4Q-3-cyano- 8-(2-carboxyethyl)-8-azabicyclo lloctane (0.21 g) mp. 180-18 1 *C.

-53. EXAMPLE 76 This example illustrates the preparation of ex-3-(5-chloropyrid-3-yl)-_nd-3-cyano-8-(Q,Qdiethylphosphonomethyl)-8-azabicyclo[3.2. 1 ]octane.

exo-3-(5-Chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3 1 ]octane (0.20g), 0,9diethylphosphonomethyl triflate (0.245g) and potassium carbonate 15g) were heated under reflux intetrahydrofuran (8m1). After'3 hours the mixture was cooled to room temperature, filtered and evaporated -under -reduced pressure. Chromatography [SiO 2 dichloromethane:methanol followed by high pressure liquid chromatography [SiO 2 dichloromethane:methanol gave ex-3-(5-chloropyrid-3-y)-endo-3-cyano-8-(Q,Qdiethylphosphonomethyl)-8-azabicyclo [3 1 ]octane m.p. 69-70*C.

EXAMPLE 77 This example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-en-do-3-cyano-8phosphonomethyl-8-azabicyclo[3.2. 1 ]octane.

Trimethylsilyl bromide (1.5m1) was added dropwise to a stirred solution -of chloropyrid-3-yl)-endo-3-cyano-8-(Q,-diethylphosphonomethyl)-8-azabicyclo[3.2. I ]octane (0.56g) in dichloromethane (30m1) at 0 0 C. After 30 mntes the mixture was allowed to warm to room temperature. After 7 hours trimethylsilyl bromide (0.8m1) was added, after 23 hours more trimethylsilyl bromnide (O.5m1) was added and after 18 hours further trimethylsilyl bromide (0.5ml) was added. After 24 hours the -mixture was evaporated under reducedpressure, water added and the mnixture filtered. After 10 minutes the filtrate was azeotroped with methanol./toluene to give Lx-3-(5-choropyrid-3-yl)-ndo-3-cyano-8-phosphonomethyl- 8-azabicyclo[3 .2.1 I octane (0.49g) mn.p. 242-245*C.

EXAMPLE 78 Ths example illustrates the preparation of exo-3-(5-chloropyrid-3-yl)-en-do-3-cyano-8-(2cyanoethyl)-8-azabicyclo[3.2. 1l]octane.

3-Bromopropionitrile (0.174m1) was added to exo-3-(5-chloropyrid-3-yl)-endo-3-.cyano-8azabicyclo[3.2.1I]octane (0.40g) and potassium carbonate (0.45g) in ethanol (l0mi) and the mixture heated under reflux for 16 hours. 3-Bromopropionitrile (O.13m1) was added. and the mixture refluxed for 3 hours and allowed tocool to room temperature. Water was added and the mixture extracted with dichioromethane The combined extracts were washed with brine, dried (MgSO 4 and: evaporated under. reduced -pressure. -Chromatography '[Si 2 54 dichloromethane:mnethanol (100:0) to (98:2].gave ex-3-(5-chloropyrid-3-yl)-nd-3-cyano- 8-(2-cyanoethyl)-8-azabicyclo[3 1 ]octane- (0.343g).

EXAMPLE 79 This example illustrates the preparation of ex--3-(5-choropyrid-3-yl)-endo-3-cyano-8-(1,1 dimethyl-2,2,2-trifluoroethyl)-8-azabicyclo 1 ]octane.

4A Molecular sieves (1 .0g) were added to a suspension of exo-3-(5-chloropyrid-3-yI)-endo-3cyano-8-azabicyclo[3.2.l1loctane hydroperchiorate (3.42g) in acetone (3Onil) and the mixture heated under reflux for 5 hours. The mixture was then allowed to cool to room temperature and filtered to give ex-3-(5-chloropyrd-3-yl)-nd-3-cyano-8-isopropylene-8azabicyclo[3.2. 1 )octanium perchiorate (0.279g).

Trixnethyl(trifluoromethyl)silane (5.2rnl of a 0.5M solution in tetrahydrofuran) was added to a suspension of ex-3-(5-chloropyrid-3-yl)-nd-3-cyano-8-isopropylene-8azabicyclo[3.2.1]octanium perchiorate (0.50g) in tetrahydrofuran (5m1). 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 The combined extracts were washed with brine, dried (MgS 04) and evaporated under reduced pressure. Chromatography [SiO 2 dichloromethane:methanol followed by preparative thin layer chromatography [SiO 2 'dichloromethane:methanol gave chloropyrid-3-yl)-endo-3-cyano-8-( 1, 1-dimethyl-2,2,2-trifluoroethyl)-8azabicyclo[3.2. I]octane (0.02g). EXML- 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. I ]octane.

Sodium (0.46g) was added portionwise to a solution of 2,22,-trifluoroethanol (2.3m1) in N- 25 methylpyrrolidinone (20m1) under nitrogen. Tetraphenylphosphomum 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 1 I0 0 C for 18 hours and 140 0 C for 5 hours. Sodium (0-6g) was added to a solution of 2,22,-trifluoroethanol (3m1) in N-methylpyrrolidinone (5m1) 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 (MgSQ 4 and evaporated under reduced pressure. The resulting mixture was filtered [SiO 2 55 dichloromethane:methanol and chromatographed [SiQ 2 dichloromethane:methanol to give exo-3-(5-(2,2,2-trifluoroethoxy)pyrid-3-yl)-tndo-3-Cyaflo-gmethylh8azabicyclo[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-(1cyanoethyl)-8-azabicyclo[l3.2. 1]octane.

exo-3-(5.Chloopyrid-3-yl)-nd-3-cyano-8-aabicyclo( 3 2 1 ]octane (0.50g), 2brornopropionitrile (2m1) and potassium carbonate (0.50g) were refluxed in ethanol (5m1).

After 24 hours the mixture was cooled to room temperature, water. added and the mixture extracted with dichloromethane The combined extracts were. washed -with brine, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiO 2 dichloromethane:methanol (100:0) to followed by chromatography (SiQ 2 ethyl acetate:hexane (80:20)] and -preparative thin layer chromatography (A1 2 0 3 ethyl acetate:hexane (40:60)] gave ex-3-(5-chloropyrd-3-yl)-endo-3-cyano-8-( I-cyanoethyl)-8azabicyclo[3.2. I]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 chioroformate (2.17m1l) was added a solution of exo-3-(5-iodopyrid-3-yl}--endo-3- 20 cyano-8-methyl-8-azabicyclo[3.2. Iloctane (3-0g) in tetrahydrofuran (2Onil) at 0 0 C. 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 dichioromethane -The combined extracts were washed with water and brine, dried (MgSQ 4 and evaporated under 'reduced pressure. Chromatography [SiQ 2 dichloromiethane:methanol gave iooyi--l-t--yn--vnyoyabnl -zbcco321 ]octane (3.64g).

2* Tetrakis(triphenylphosphine)paladium(O) (0.042g) was added to a stirred -solution of 6xo-3- (5idprd3y)gd--yn--viyoyabnl--zbcco32 1 ]octane (0.50g) in toluene (2m1). To this mixtur was added 2M sodium carbonate solution (1.22m1) and phenylboronic acid 16g) in ethanol (0.5m1) 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 The combined extracts were washed with brine, dried (MgSO 4 and evaporated under reduced pressure. Chromatography [SiO 2 ethyl acetate:hexane (45:55)] -56gave exo-3-(5-phenylpyrid-3-y)-ndo-3-cyao-8-(viflyloxycarbonyl)-8azabicyclo[3.2. 1]octane (0.33g).

EXAMPLE 83 -This example illustrates the preparation of exo-3-(5-phenylpyrid-3-yl)-endo-3-cyano-8azabicyclo 1]octane.

Concentrated hydrochloric acid (0.5m1l) was added to a solution of exo-3-(5-phenylpyri-3 yl)-tndo-3-cyano-8-(vinyloxcarbonyl)--azabicyclo[3.2. 1 ]octane (0.30g) in methanol (1 Oml) 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 dichioromethane The combined extracts were washed with brine and extracted with 2M hydrochloric acid The acidic extracts were basifled and re-extracted with dichloromethane The combined organic extracts were washed with brine, dried (MgSO 4 and evaporated under reduced pressure to give exo-3-(5-phenylpyrid-3-yl)-endo-3cyano-8-azabicyclo[3 .2.1 I 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.

Methyulithiumn (8.7m1 of a 1.4M solution in diethyl ether) was added dropwise to a stirred suspension of copper(I) iodide 16g) in diethyl ether (l0mi) at 0 0 C under nitrogen. After :minutes ex--5idprd3y)ed--yn--vnlxcroy)8 azabicyclo[3.2.lIloctane (0.50g) in diethyl ether (5mi) was added. After 5 days at room temperature water was added and the mixture extracted with ethyl acetate The combined extracts were washed with brine, dried (MgSO 4 and evaporated under reduced 25 pressure. Chromatography [SiO 2 ethyl acetate:hexane (60:40)] gave 3-yl)-en-do-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclol 3 2 1 ]octane (0.085g).

EXAMPLE This example illustrates the preparation of exo 3-(5-chloropyrid-3-yl)-endo-3-cyano-8-(2cyanoprop-2-yl)-8-azabicyclo[3.2. I ]octane.

Sodium cyanide (0.069g) was added to a stirred solution of ex-3-(5-chloropyrid-3-yl)-endo- 3-cyano-8-isopopylene-8-azabicycloII3.2.lI]octanium perchlorate (0.50g) in acetonitrile (5m1) at room temperature under nitrogen. After 4 hours the mixture was allowed to stand at room 57 temperature over the weekend, water added and the mixture extracted with dichioromethane The combined extracts were washed with brine, dried (MgSO 4 and evaporated under reduced pressure to give exo-3-(5-chloropyrid-3-yl)-endo-3-cyano-g-(2-cyanoprop-2-yl)-8azabicyclo[3 .2.1I ]octane (0.38g, 90% pure).

EXAMPLE 86 This example illustrates the preparation of exo-3-(5-(ethoxycarbonyl)pyrid-3-yl)-endo-3cyano-8-(vinyloxycarbonyl)8-azabicyclol3.2. 1 ]octane.

Potassium carbonate (0.205g) and bis(triphenylphosphine)pafladium(ll) chloride (0.026g) were added to a stirred solution of ex-3-(5-iodopyrid-3-yl)-nd-3-cyano-8-methyl-8azabicyclo[3.2.lIjoctane (0.50g) in ethanol (l1ini) under nitrogen. The reaction vessel was then flushed with carbon monoxide, uiethylaxnine (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 midxture extracted with ethyl acetate The combined extracts were dried (MgSO 4 evaporated under reduced pressure and chromatographed [SiO 2 ethyl acetate:hexane (35:65)] to give ex-3-(5-(ethoxycarbonyl)pyrid-3-yl)-endo-3-cyano-8- (vinyloxycarbonyl)-8-azabicyclo[3 .2.1 I octane (0.29g).

Confirmation of the structural identity of the compounds prepared in Examples 20 to 106 was obtained by proton magnetic resonance spectroscopy. The results are set outi in the following 20 table.

EXAMPLE 'H NMR (270MHz), in CDC1 3 unless otherwise stated- 1 8.81 (1 H, 8.56 (1 H, dd), 7.85 (1 H, dt), 7.30 (1 H, dd), 3.44 in). 2.45-2.15 mn) *and 2.33 3H, *2 8.80 (1 H, 8.55 (1 H, dd), 7.85 (1 H, in), 7.30 (1 H, in), 4.55 (2H, dt), 3.4 in), 2.7'0 (2H, dt) and 2.4-2.1 (8H, in).

3 7.09 (2H-1 in), 6.75 (1 H, in), 3.31 in), 2.4-2.1 in) and 2.35 (3H, s).

*4 8.80 (1 H, 8.54 (1 H, dd), 7.83 (1 H, dt), 7.29 (1 H, dd), 3.40 in), 2.4-2.0 (1 OH, in), 1.48 hex) and 0.91 (3H, s).

7.53 in), 7.4-7.2 (8H, in), 3.59 (2H, 3.36 (2H, in) and 2.5-2.15 (8H, in).

8.82 (1 H, 8.58 (1 H, dd), 7.86 (1 H, dt), 7.4-7.2 (6H, in), 3.59 (2H, 3.39 in) and 2.45-2.15 in).

7 8.80 (1 H, 8.56 (1 H, dd), 7.84 (1 H, dl), 7.31 (1 H, dd), 3.50 (2H, 3.48 (2H, in), 3.36 (3H, 2.61 (2H, t) and 2.4-2.05'(8H, in).

9 8.94 (1 H, 8.59 (1 H, 8.53 (1 H, 3.35 (2H, in), 2.65-2.55 (2H, in), 2.4-2.1 6H, in) and 2.36 (3H, in).

58 8.82 (1 H, 8.54 (1 H, 3.37 (2H, in), 2.54 (2H, cid), 2.4-2.1 (6H, mn) and 2.35 (3H, s).

11 7.78 (1 H, 7.55 (1 H, 3.40 (2H, mn), 2.70 (2H, mn), 2.5-2.1l (6H, m) and 2.37 (3H, s).

12 8.49 (1 H. 7.95 (1 H, 3.34 (2H, mn), 2.4-2.15 (8H, m) and 2.35 (3H, s).

13 8.81 (1 H, 8.56 (1 H dd), 7.84 (1 H, dt), 7.31 (1 H, dd), 3.72 (3H, 3.50 (2H, in), 3.22 (2H, 2.5-2.3 (6H, m) and 2.2-2.1 (2H, mn).- 14 8.89 (1 H, 8.60 (1 H, dd), 7.87 (1 H, dt), 7.35 (1IH, dd), 4.54 (2H, mn), 4.50 (2H, 3.22 (3H, s) and 2.6-2.25 (8H, in).

8.59 (1 H, 7.81 dd), 7.34 (1 H, 3.33 (2H, m) 2.4-2.15 (8H, m) and 2.35 (3H, s).

16 8.69 (1 H, 8.51 (1IH, 7.82 (1 H, 3.42 (2H, in), 2.4-2.0 (1 OH, in), 1.5-1.2 (8H, mn) and 0.89 (3H, in).

17 8.70 (1 H, 8.52 (1 H, 7.83 (1 H, 5.88 (1 H, in), 5.18 (2H, mn), 3.42 (2H. 3.02 (2H, m) and 2.4-2.05 (8H, mn).

18 8.70 (1 H, 8.55 (1 H, 7.80 (1 H, 3.50 (2H, mn), 2.90 (2H, 2.5-2.2 (6H, m) and 2.10 (2H, mn).

19 8.74 (1 H, 8.61 (1IHX), 8.00 (1 H, 3.35 (1 H, mn), 2.4-2.1.5 (8H. m) and 2.33 (3H, s).

9.03 (1 H, 8.82 (11-H, 8.15 (1 H, 3.36 (1 H, mn), 2.4-2.2 (8H. m) and 2.35 (3H, s).

21 8.40 (1H, 8.21 (1 H, 7.34 (1 H, 4.10 (2H, 3.31 (2H, mn), 2.4-2.15 (8H, in), 2.32 (3H, s) and 1.44 (3H, t).

22 8.70 (1 H, 8.50 (1 H, 7.80 (1 H, 3.70 (2H, in), 2.65 (1 H, in), 2.35 (2H, 2.25 (4H, in), 2.05 (2H, mn) and 1.05 (6H, d).

23 7.47 (2H, 3.32 (2H, mn), 2.35-2.15 (8H, m) and 2.32 (3H, s).

:24 8.39 (1 H, 7.51 (1 H, 7.40 (1 H, dd), 3.32 (2H, in), 2.4-2.1 (8H, m) and 2.32 (3H, s).

*.25 8.61 (2H, in), 7.49 (2H, in), 3.33 (2H, mn), 2.4-2.1 (8H, in) and 2.32-(3H, s).

.26 8.69 (1 H, 8.51 (1 H, 7.81 (1 H, 4.35 (1 H, ddt), 3.41 (2H, in), 3.00 (2H, dt) and 2.4- *2.1 (8H, in).I 27 8.59 (2H, in), 7.98 (1 H, 7.72 (1 H. 5.55 (1 H. 4.36 (1 H, in), 4.25 (1 H, in), 2.7-2.2 in).

*28 8.65 (1 H, 8.55 (1 H, 7.75 (1 H, 4.95 (1 H, in), 4.40 (1 H, in), 2.65-2.1 (8H, in) and 2.15 (3H, s).

29 (in DMSOJ 8.79 (1 H, brs), 8.70 (1 H, 8.64 (1 H, brs), 8.61 (1 H, 4.16 (2H, in), 2.7-2.6 (2H, in), 2.45-2.25 (4H, in), and 2.1 5-2.0 (2H, in).

8.67 (1 H, 8.49 (1 H, 7.80 (1 H, 3.79 (2H, in), 2.4-2.15 (6H, in), 2.0-1.9 (2H, in) and 1.09 (9H, s).

33 8.69 (1 H, 8.52 (1 H, 7.82 (1 H, 7.54 (2H, in), 7.4-7.25 (3H, in), 3.90 (1 H, in), 3.70 (1 H, 3.65 (1 H, 3.31 (1 H, in), 2.5-2.0 (8H, in) and 1.49 (3H, in).

34 8.60 (1H 8.50 (1 H, 7.71 (1 H, 7.4-7.25 (5H, in), 3.40 (1 H, in), 3.32 (1H, in), 2.82 (1 H, 2.66 (1 H, 2.3-1.95 (8H, in) and 1.74 (3H, d).

8.70 (1 H, 8.54 (1 H, 7.85 (1IH, 7.50 (2H, in), 7.4-7.25 (3Hr i, 4.31 (1 H, 4.19 (1 H, 3.85 (1 H, in), 2.34 (IH. in), 2.5-2.15 (8H, in), 2.00 (3H, s) and 1.56 (3H, s).

-59- 36 8.64 (1 H, 8.56 (1 H, 8.20 (1 H, 7.77 (1 H, 4.86 (1 H, in), 4.32 (1IH, m) and 2.6- 2.1 (8H, in).

37 8.69 (1IH, 8.52 (1 H, 7.85 (1 H, 4.11 (2H, in), 3.65 (2H, hept), 2.55-2.1 (8H, mn) and 1.30 (12H, d).

38 8.62 (1 H, 8.52 (1 H, 7.75 (1 H, 4.26 (2H, in), 2.5-2.15 (8H, m) and 1.40 (9H, s).

39 8.71 (1 H, 8.53 (1 H, 7.84 (1 H, 7.4-7.2 (5H, mn), 3.71 (1 H, in), 3.49 (1 H, 3.28 (I1H, mn), 2.4-2.05 (8H, mn) and 1.30 (3H, d)- 8.20 (1 H, 8.00 (1 H, 7.11 H, 1;76 (2H, brs), 3.32 (2H, in), 2.4-2.1 (8H, m) and- 2.32 (3H, s).

41 8.62 (1 H. 8.56 (1 H, 8.22 (1 H. 7.46 (1 H. brs), 3.35 (2H, mn), 2.4-2.2 (8H, in), 2.35 (3H, s) and 2.21 (3H, s).

42 8.69 (1 H, 8.54 (1 H, 7.81 (1 H, 7.55-7.35 (5H, in), 4.38 (1 H, 3.94 (1 H, mn), 3.29 (1 H, m) and 2.6-2.1 (8H. in).

43 8.69 (1 H, 8.55 (1 H, 7.81 (1 H, 7.45-7.3 (5H, in), 6.91 (1 H, in), 5.70 (1 H, mn), 3.96 (1 H, 3.60 (1 H, in), 3.35 (1 H, mn), 2.5-2.2 (6H, m) and 2.05-1.9 (2H, in).

44 8.77 (2H, in), 8.16 (1 H. 3.32 (2H, in), 2.4-2.1 (8H, m) and 2.32 (3H, s).

9.02 (1 H, 8.83 (1 H, in), 8.07 (1 H, in), 3.36 (2H, in) and 2.4-2.05 (11 H, in).

46 [in DMSO] 8.72 and 8.62 (1 H, in), 8.58 (1 H, in), 8.14 and 7.86 (1 H, in), 5.39 (1 H, in), 4.20 (I1H, in) 2.7-2.0 (8H, in).

47 8.65 (1 H, 8.58 (1 H, 7.78 (1 H, 4.51 (2H, in), 2.6-2.2 (8H, in).

48 8.69 H, 8.52 (1 H, 7.81 (1 H, 5.85 (1 H, tt), 3.45 (1 H, in), 2.71 (2H, dt) and (8H, in).

49 8.69 (1 H, 8.52 (1 H, 7.82 (1 H, 7.35-7.15 (5H, in), 3.45 (2H, in), 2.79 (2H, mn), 2.61 (2H, in) and 2.4-2.05 (8H, in).

8.39 (1 H, in), 8.05 (1 H, in), 7.59 (1 H, in), 3.43 (2H, in) 2.5-2.1 (8H, in) and 2.40 (3H, s).

51 8.70 (1 H. 8.52 (1 H, 7.83 (1 H, 7.4-7.2 (5H, in), 3.57 (2H, 3.40 (2H, in) an d 2.45-2.2 (8H, in).

52 8.63 (1 H, 8.50 (1 H, 7.77 (1 H, 3.60 (2H, in), 3.42 (2H, in) and 2.5-2.2 (8H, in).

*53 8.71 (1 H, 8.53 (1 H, 8.10 (1 H, t),'7.90 (2H, in), 7.39 2H, in), 3.45 (2H, in), 3.30 (2H, in) and 2.4-2.2 (8H,in).

54 8.69 (1 H. 8.53 (1 H, 7.83 (1 H, 7.42 (1 H, dd), 7.22 (1 H, in), 7.09 (1 H, 3.50 (2H, 3.36 (2H, in) and 2.45-2.15 (8H, in).

to. 55 8.71 (1 H, 8.52 (2H, in), 7.86 (1 H, 7.69 (1 H, dt), 7.54 (1 H, 7.19 (1 H, in), 3.73 3.43 (2H, in) and 2.5-2.2 (8H, in).

-56 8.70 (1 H, 8.52 (1 H, 7.85 (1 H, 7.00 (1 H, 3.66 (2H, 3.49 (2H, in), 2.70 (3H, and 2.45-2.15 (8H, in).

57 -8.61 (1 H, 8.52 (1 H, 7.78 (1 H, 3.33 (2H, in), 3.29 (2H, 2.5-2.1 (8H, in), 2.38 (3H, s) and 2.32 (3H, s).

58 8.70 (1 H, 8.52 (1 H, 7.83 (1 H, 6.74 (1 H, 6.65 (1 H, 3.65 (2H, 3.46 (2H, in) and 2.45-2.1 (8H, in).

59 8.65 (1 H, 8.50 (1 H, 7.80 (1 H, 3.94 (2H, 3.55 (2H, in) and 2.5-2.25 (8H, in).

8.65 (1 H, 8.41 (1 H. 7.60 (1 H, dt), 3.44 (2H, in), 2.4-2.15 (8H, in) and 2.35 (3H, s).

61 8.69 (2H, in), 7.84 (1IH. 7.10 (2H, in), 6.40 (2H, in), 3.34 (2H, 2.4-2.15 (8H, in) and 2.33 (3H, s).

62 8.79 (1 H, 8.75 (1 H, 8.05 (1 H, in), 4.74 (1 H, 4.31 (1 H, 3.94 (2H, 3.40 (2H, in), 2.5-2.2 (11 H, m) and 1.44 (3H, t).

63 9.09 (1 H, 8.99 (1 H, 8.39 (1 H, 3.37 (2H, mn), 2.69 (3H, 2.45-2.15 (8H, m) and 2.34 (3H, s).

64 8.76 (1 H, .8.62 (1 H, 7.94 (1 H, in), 3.34 (2H, in), 3.24 (1 H, 2.45-2.15 (8H, m) and 2.35 (3H, 8.80 and 8.70 (1 H, in), 8.29 (1 H, in), 7.95 (1 H, in), 7.71 (1lHm), 7.56 (1 H, in), 7.4-7.1 (3H, in), 5.65 and 5.29 (1 H, mn), 4,91 and 4.75 (1 H, in), 4.30 and 4.11 (1 H, in), 3.30 (1 H, mn), 2.8-2.0 (8H, m) and 1.73 and 1.62 (3H, in) 66 8.61 (1IH, 8.52 (1 H, 7.79 (1 H, 7.5-7.15 (5H, in), 3.01 (1 H, in), 2.91 (1 H, mn), 2.79 (1 H, in), 2.39 (2H, 2.3-1.6 (12H, in), 1.09 (3H, d) and 0.91 (3H, d).

67 8.69 (1 H, 8.52 (1IH, 7.81 (1 H, 3.55 (2H, in), 3.35 (2H, s) and 2.5-2.1 (8H, in).

68 8.69 (1 H, 8.52 (1 H, 7.81 (1 H, 4.20 (2H, in), 3.61 (1 H, mn), 3.49 (1 H, in), 3.23 (1 H, 2,45-2.0 (8H, mn), 1.31 (3H, d) and 1.29 (3H, t).

69 8.50 (1 H, 8.35 (1 H, 7.7-7.5 (2H, in), 6.40 (2H, dd), 6.25 (1 H, dd), 4.70 (2H, in), 2.6- (2H, m) 2.45-2.20 (6H, mn).

8.51 (1 H, 8.49 (1 H, d),l 7.70 (1 H, 4.45 (2H, in), 2.6-2.5 (4H,m) and 2.4-2.2 (4H, in).

71 8.70 (1 H, 8.55 (1 H, 7.85 (1 H, 4.25 (2H, m) and 2.6-2.2 (8H, mn).

72 8.29 (1 H, 8.10 (1 H, 7.90 (1 H, mn), 4.15 (2H, m) 2.6-2.25 (8H, in).

73 8.75, 8.65 and 8.50 (1 H, mn), 7.90 and 7.80 (1 H, in), 3.80 and 3.70 (2H, in), 3.6 and (3H, mn) and 2.7-1.8 (8H, in).

74 8.65 (1 H, 8.51 (1IH, 7.80 (1 H, 4.16 (2H, 3.41 (2H, in), 2.69 (2H, 2.48 (2H, 2.4-2.05 (8H, mn) and 1.27 (3H, t).

8.76 (1 H, mn), 8.52 (1 H, in), 7.98 (1H. in), 3.85 (2H, mn), 3.01 (2H, 2.8-2.2 (1 OH, in).

*76 8.64 (1 H, 8.51 (1 H, 7.80 (1 H, 4.18 (4H, mn), 3.60 (2H, in), 2.78 (2H, 2.45-2.05 (8H, mn) and 1.36 (6H, in).

*77 (in DMSO] 8.89 (1 H, 8.62 (1 H, 8.29 (1 H, 4.50 (2H, in), 3.48 (2H, d) and 2.85- 2.45 (8H, mn).

78 8.69 (1 H, 8.51 H, 7.80 (1 H, 3.46 (2H, mn), 2.64 (2H, in), 2.51 (2H, in) and 2.45- 79 9.65 (1 H, 8.51 (1 H, 7.79 (1 H, 3.91 (2H, nm), 2.45-2.2 (8H, in) and 1.28 (6H, s).

80 8.55 (1H, 8.3 (1 H,d) 7.45 (1H, 3.35 (2H, mn), 2.4-2.1 (8H, in) and 2.3 (3H, s).

81 8.69 (1 H, 8.52 (l1H, 7.81 (1 H, 3.85 (1 H, mn), 3.60 (1 H, in), 3.50 (1 H, 2.5-2.1 (8H, in) and 1.51 (3H, d).

*82 8.81 (1 H, 8.71 (1 H, 7.92 (1 H, 7.6-7.35 (5H, in), 7.25 (1 H, dd), 4.80 (1 H, dd), 4.61 (2H, in), 4.49 (1 H, dd) and 2.55-2.15 (8H, in).

83 8.79 (2H, in), 7.99 (1 H, 7.6-7.35 (5H, in), 3.75 (2H, in), 2.55-2.2 (6H, in) and 2.05-1.85 (2H, in).

.*84 8.55 (1 H, mn), 8.40 (1 H, in), 7.55 (1 H, in), 7.23 (1 H, dd), 4.80 (1 H, dd), 4.59 (1 H, in), 4.49 (1 H, dd), 2.6-2.1 (8H, in) and 2.39 (3H, s).

8.64 (1 H, 8.52 (1 H, 7.70 (1 H. 3.91 (1 H, in), 2.55-215 (8H, in) and 1.52 (6H, s).

86 9.19 (1 H, 8.90 (1 H, 8.31 (1 H, 7.24 (1 H, dd), 4.82 (1 H, dd), 4.63 (2H, in), 4.51 (1 H, dd), 4.44 (2H, 2.6-2.2 (8H, in) and 1.43 (3H, t).

61 a a a. a a a a 4 a 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. 1 25.5 SYNPERONIC NP13 Calcium dodecylbenzenenesulphonate AROMASOL H 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: Weight Compound No.5 50.0 SYNPERONIC NP13 Calcium dodecylbenzenesulphonate AROMASOL H 40.0 20 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 25 Compound No.9 SYNPERONIC OP10 Calcium dodecylbenzenesulphonate AROMASOLH 94.0 EXAMPLE 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: 62 Weight Compound No.13 25.0 Silica 25.0 Sodium lignosulphonate Sodium lauryl sulphate 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 Sodium lignosulphonate Sodium lauryl sulphate 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 S wettable power has the following composition: Weight Compound No.21 40.0 Silica 40.0 Calcium lignosulphonate 25 Sodium lauryl sulphate Kaolinite 13.0 EXAMPLE 93 This Example illustrates a dusting powder which may be applied directly to Splants or other surfaces and comprises 1% by weight of Compound No.25 and 99% by weight of talc.

63 EXAMPLE 94 This Example illustrates a concentrated liquid formulation suitable for application by ultra low volume techniques after mixing with paraffinic diluents.

Weight ComDound No.29 90.0 SOLVESSO 200 10.0 EXAMPLE 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 9 *98* 9* .9 9 9,.

9* 9* *9e9 9* *9 0 EXAMPLE 97 This Example illustrates a liquid formulation suitable for application (undiluted) by ultra low volume techniques.

Weight Compound No.41 Cotton seed oil SOLVESSO 200 *9 00 0 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.

Weight Compound No.45 10.0 64 Alkylbenzene solvent AROMASOL H) Toluene di-isocyanate Ethylenediamine Polyvinyl alcohol Bentonite Polysaccharide 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 Alkylbenzene solvent AROMASOL H) 10.0 Toluene di-isocyanate Ethylenediamine Polyvinyl alcohol Bentonite Polysaccharide KELTROL) 0.1 20 Water 80.4 EXAMPLE 100 A ready for use granular formulation: Weight Compound No.4 25 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: Weight 65 Compound No.8 Kaolinite 15.0 Sodium lignosulphonate nonylphenolethoxylate (eg Synperonic NP 8) propylene glycol 10.0 Bentonite 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 made from a concentrate Concentrate: Weight Compound No.12 Silica Magnesium Carbonate 20 Dust Example containing 1% active ingredient: Above concentrate Talc EXAMPLE 103 This Example illustrates a ready for use granule formulaton.

Weight Compound No.16 Synperonic NP8 2 Pumice granules (20/40 BS Mesh) 93 EXAMPLE 104 This Example illustrates a water dispersible granule formulation.

Weight 66 Compound No.20 Silica Sodium lignosuiphate Sodium dioctylsulphosuccinate Sodium acetate Montmorillonite powder EXAMPLE 105 This Example illustrates the insecticidal properties of the compounds of Formula 1. 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 HI.

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.

a.....Information regarding the pest species, the support medium or food, and the type and duration of the test is given in Table MI. The pest species is designated by a letter code.

67 TABLE ]a Comp'd Score No I1.

9 13 17 21 29 33 37 41 49 53 57 61 69 73 77 81 89 93 97 101 105 Comp'd No ,.2 6 10 14 18 22 26 30 34 38 42 46 50 54 58 62 66 70 74 78 82 86 90 94 98 102 106

A

C

A

B

A

C

A

C

A

C

A

3 7 15 19 23 27 35 39 43 47 51 55 59 63 67 71 75 79 83 87 91 95 99 103 107 Score Cornp'd Score No

A

C

A

C

A

C

A

C

A

36 44 48 52 56 64 68 72 76 84 88 92 96 100 104 108 Comp'd Score No 68 109 A 113 A 117 A 121 A 125 A 129 A 133 A 137 C 141 A 145 A 149 A 153 A 157 C 161 A 165 A 169 A 173 A 177 A 181 A 185 A 189 A 193 A 197 A 201 A 205 A 209 A 213 A 217 A 221 A 225 A 229 A 233 A 110 114 118 122 126 130 134 138 142 146 150 154 158 162 166 170 174 178 182 186 190 194 198 202 206 210 214 218 222 226 230 111 115 119 123 127 131 135 L 139 L 143 147 151 155 S159 163 k 167 3 171 A 175 A 179 A 183 A 187 191 A 195 A 199 A 203 A 207 A 211 A 215 A 219 C 223 227 A 231 A 235 112 116 120 124 128 132 136 140 144 148 152 156 160 164 168 172 176 180 184 188 192 196 200 204 208 212 216 220 224 228 232

B

A

C

A

B

A

*o *r *r A 236 A 69 237 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, 14, 18, 23, 66, 72, 95, 99, 102, 104,120, 131, 156, 169, 170, 227, 229, 231, S 5 234,236,243,260,262,270,274,312.

In tests against root knot nematodes (Meloidogyme incognita) the following compounds scored A orB.

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 (Bernesia 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.

Throughout the description and claims of the specification the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps.

The chemical formulae referred to in the preceding description are set out below.

a

*O

oe C:\WINORD\ANNANODEETE\SPECIE8\58988-98.DOC 71 R2 R cI

N

R ci

CH

3 R Cf (11) (111)

CH

3

I

N

(IV)

CH3

I

R2

(V)

N

CN

H

N

(IX)

(VII)

9 a. a a. a. a.

a a

(VIII)

(XI) Rl-CH 2

-CN

CH

3

(XII)

CH

3

N

OH

(XIII)

R

W

Claims

1. A process of preparing a compound of formula (VI): 2 N S(VI) CN which comprises reacting a compound of formula (VII): H N S(VII) CN with a compound of formula R L where L is a leaving group in the presence of a base.

2. A compound of formula (VI): R 2 CN CN wherein R 2 represents hydrogen or cyano or a group selected from alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkenyl, aralkenyl, alkynyl, alkoxycarbonyl, 15 alkanesulfonyl, arenesulfonyl, alkanyloxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, heterocyclylalkyl, carbamyl or dithiocarboxyl groups, said groups C:\WINWORD\ANNA\NODELETE\SPECIES\POV5698SDOC -73 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; with the proviso that R 2 is not methyl, 3-methylbutyl, n-hexyl, cyclohexylmethyl, benzyl, 4-chlorobenzyl,

4-methylbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, 3-trifluoromethylbenzyl, 2- phenethyl, 2-thienyl or trichloroethyl. 3. A compound of formula (VI) according to claim 2 when produced by a process according to claim 1. 4. A compound according to claim 2 substantially as hereinbefore described with reference to any of the examples. 5 DATED: 7 March 2000 PHILLIPS ORMONDE FITZPATRICK Attorneys for: ZENECA LIMITED oo•