PROCESS FOR PREPARING HETEROCYCLIC COMPOUNDS

Abstract: The present invention provides a process for preparing thiadiazole azabicyclic compounds.

Description: PROCESS FOR PREPARING HETEROCYCLIC COMPOUNDS The present invention relates to a process for preparing azabicyclic compounds useful for modulating a muscarinic receptor. Compounds having muscarinic receptor activity can be particularly desired for use in treating conditions such as, but not limited to, Alzheimers' disease, glaucoma, and for the treatment of pain. Certain known aza-bicyclic thiadiazole containing compounds have demonstrated such muscarinic receptor activity; however, the known preparation methods require a linear synthesis. Further, it can be particularly desired to isolate the diastereomers and enantiomers of the compounds. The known preparation methods provide for resolution of the diastereomers and enantiomers in the final step of the reaction sequence. Resolution of the diastereomers and enantiomers at an early stage of the synthesis could improve the yield and cost of production for such resolved compounds . The presently claimed process fulfills this need for a convergent synthesis useful for the preparation of azabicyclic thiadiazole compounds. It is an object of the invention to provide a new process for preparing compounds having muscarinic cholinergic receptor activity. A process for preparing a compound of the formula 9: comprising contacting a compound of the formula 8 with lithium diisopropylamide (LDA) ; wherein n is 0,1,2,3; m is 1,2,3; 2 R is selected from the group consisting of halo, C.-C 8 4 8 5 6 7 alkyl, R 0, R S, R NR R , aryl, and substituted aryl; z is a leaving group; 3 <3 R is selected from the group consisting of C0 2 R and CN; R 4 is C.-C, alkyl; s R is C.-C- alkyl; 6 R is hydrogen or ^-C 8 alkyl; 7 R .is hydrogen or ^-C 8 alkyl; R is C α -C 8 alkyl; 9 R is hydrogen or C 1 -C 3 alkyl . A further embodiment of the present invention is a process for preparing a compound of the formula 10: 10 comprising hydrolysing a compound of the formula 9: 9 R is selected from the group consisting of halo, C.-C 8 4 8 5 6 7 alkyl, R 0, R S, R NR R , aryl, and substituted aryl; 3 9 R is selected from the group consisting of -C0 2 R and -CN. It may be preferred that z is a sulfone. As used herein, the term "halogen" means Cl, Br, F, and I. Especially preferred halogens include Cl, Br, and I. The terms "Cι-C n' alkyl" wherein n ' can be from 2 through 15, as used herein, represent a branched or linear alkyl group having from one to the specified number of carbon atoms. Typical Ci-C δ alkyl groups include methyl, ethyl, π-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl , hexyl and the like. The term " substituted (C 5 -C n" ) alkyl" refers to an alkyl group as described supra wherein the alkyl group may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, aryl, substituted aryl, Ci-C δ alkyl, NO 2 , halogen, halogen (Ci-C δ ) alkyl , halogen (C 2 -C 6 ) alkenyl , C 2 -C 6 alkenyl, CO 2 R 20 , (Ci-C δ alkyl) amino, -SR 20 , and OR 20 ; wherein R 20 is selected from the group consisting of Cι- 15 -alkyl, C2-15- alkenyl, aryl, substituted aryl, and C2-l5-alkynyl . The terms "C 2 -C n' alkenyl" wherein n' can be from 3 through 10, as used herein, represents an olefinically unsaturated branched or linear group having from 2 to the specified number of carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, 1-propenyl, 2-propenyl (-CH 2 - CH=CH 2 ), 1,3-butadienyl, ( -CH=CHCH=CH 2 ) , 1-butenyl (- CH=CHCH 2 CH 3 ) , hexenyl , pentenyl, and the like. The term "C 2 -C 5 alkynyl " refers to an unsaturated branched or linear group having from 2 to 5 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, and the like. The terms "halogen (C 1 -C6) alkyl " and "halogen (C 2 - Cβ ) alkenyl" refer to alkyl or alkenyl substituents having one or more independently selected halogen atoms attached at one or more available carbon atoms. These terms include, but are not limited to, chloromethyl, 1-bromoethyl, 2- bromoethyl, 1 , 1 , 1-trifluoroethyl, 1, 1 , 2-trifluoroethyl, 1 , 2 , 2-trifluoroethyl , 2 , 2 , 2-trifluoroethyl , trifluoromethyl , trifluoroethylenyl, 3-bromopropyl, 3-bromo-l-propenyl , 2- bromopropyl, 2-bromo-l-propenyl, 3-chlorobutyl, 3-chloro-2- butenyl, 2 , 3-dichlorobutyl , 1-chloroethylenyl , 2- chloroethylenyl, 5-fluoro-3 -pentenyl , 3-chloro-2-bromo-5- hexenyl, 3-chloro-2-bromobutyl, trichloromethyl, 1,1- dichloroethyl, 1 , 2-dichloroethyl , 2 , 2-dichloroethyl , 1,4- dichlorobutyl, 3-bromopentyl , 1 , 3-dichlorobutyl , 1,1- dichloropropyl , and the like. The term "C 2 -C 10 alkanoyl" represents a group of the formula C(0)(Cι-Cg) alkyl. Typical C2-C 10 alkanoyl groups include acetyl, propanoyl, butanoyl, and the like. The term " (C 1 -C 6 alkyl) amino" refers to a monoalkylamino group. Examples of such groups are methylamino, ethylamino, iso-propylamino, ι--propylamino, ( n- propyl) amino, ( iso-propyl ) amino, -α-propylamino, t- butylamino, and the like. The term "C 3 -C n cycloalkyl" wherein n=4-8, represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl . The term " substituted (C5-C n' ) cycloalkyl" refers to a cycloalkyl group as described supra wherein the cycloalkyl group may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, C 3. -C6 alkyl, NO 2 , halogen, halogen (Ci-C δ ) alkyl, halogen (C 2 -C 6 ) alkenyl, C 2 -C6 alkenyl, CO 2 R 20 , (C 1 -C6 alkyl) amino, -SR 20 , and OR 20 ; wherein R 20 is selected from the group consisting of Ci- 15 -alkyl , C2-15- alkenyl, and C2-i5-alkynyl . The term "C 3 -C 8 cycloalkyl- (C 1 -C 3 ) alkyl" represents an alkyl group substituted at a terminal carbon with a C 3 -C 8 cycloalkyl group. Typical cycloalkylalkyl groups include cyclohexylethyl , cyclohexylmethyl, 3- cyclopentylpropyl, and the like. The term "C 5 -C 8 cycloalkenyl" represents an olefinically unsaturated ring having five to eight carbon atoms. Such groups include, but are not limited to, cyclohexyl-1 , 3-dienyl , cyclohexenyl, cyclopentenyl , cycloheptenyl , cyclooctenyl , cyclohexyl-1 , 4-dienyl , cycloheptyl-1, 4-dienyl, cyclooctyl-1 , 3 , 5-trienyl and the like. The term "substituted (C 5 -C 8 . cycloalkenyl" refers to a cycloalkenyl group as described supra , wherein the cycloalkenyl group may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, C1-C 6 alkyl, NO 2 , halogen, halogen (Cχ-C 6 ) alkyl , halogen (C 2 -C 6 ) alkenyl , C 2 -C 6 alkenyl, COR 20 , C2-C 10 alkanoyl, C7-C 16 arylalkyl, C0 R 2 °, (Cι-C 6 alkyl) amino, -SR 20 , and -OR 20 . Wherein R 20 is selected from the group consisting of Ci- 15 -alkyl, C2-l5-alkenyl , C2-15- alkynyl . The term "C 5 -C 8 cycloalkenyl- (C 1 -C 3 ) alkyl" represents a C 1 -C 3 alkyl group substituted at a terminal carbon with a C 5 -C 8 cycloalkenyl group. As used herein, the phrase "heterocycle " means a group containing from one to four N, 0 or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with Ci-β-alkyl, -CF3 , phenyl, benzyl or thienyl, or a carbon atom in the heterocyclic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused with a phenyl group. The phrase "heterocycle" includes, but is not limited to, 5-membered heterocycles having one hetero atom (e.g. thiophenes, pyrroles, furans); 5-membered heterocycles having two heteroatoms in 1,2 or 1,3 positions (e.g. oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heterocycles having three heteroatoms (e.g. triazoles, thiadiazoles ) ; 5-membered heterocycles having 3- heteroatoms ; 6-membered heterocycles with one heteroatom (e.g. pyridine, quinoline, isoquinoline, phenanthrine, 5 , 6-cycloheptenopyridine) ; 6-membered heterocycles with two heteroatoms (e.g. pyridazines, cinnolines, phthalazines , pyrazines, pyrimidines, quinazolines ) ; 6- membered heterocycles with three heteroatoms (e.g. 1,3,5- triazine) ; and 6-member heterocycles with four heteroatoms. Particularly preferred are thiophenes, pyridines, and furans. The term "Ci-C δ alkylheterocycle" means an alkyl group attached to the nucleus molecule (for example, but not limited to, at the W substituent) and a heterocycle attached at the distal end of the alkyl group. One example is W-CH 2 -thiophene; however, the term is in no way limited to this single embodiment. The term "heteroaryl" refers to a group which is a 5 or 6 membered heterocycle containing one to four N, 0, or S atoms or a combination thereof. As used herein the term "carboxy" refers to a substituent having the common meaning understood by the skilled artisan, wherein the point of attachment may be through the carbon or oxygen atom of the group. As used herein the term "aryl" means an organic radical derived from an aromatic hydrocarbon by the removal of one atom; e.g., phenyl or naphthyl . Most preferably, aryl refers to Cg-Cio aryl, wherein the aryl ring system, including any alkyl substitutions, comprises from 6 to 10 carbon atoms; e.g., phenyl, 3,3- dimethylphenyl, naphthyl , and the like. The aryl radical may be substituted by one or two Ci-Cβ straight or branched alkyl. The term "aryl (C 1 -C 3 ) alkyl " refers to any aryl group which is attached to the parent moiety via the alkyl group . "Substituted aryl" refers to an aryl group which may be substituted with from one to three substituents selected from the group consisting of halogen(s), -CF 3 , -CN, Ci-is-alkyl, C2-5-alkenyl , C2-5- alkynyl, and Cι- 10 -alkoxy . Oxone For example, the process of this invention can be further illustrated by the following:: is 0 or S As used in the above-illustrated scheme R is selected from 4 8 5 6 7 the group consisting of halo, C j -C 8 alkyl, R 0, R S, R NR R , aryl, and substituted aryl; The starting materials for the illustrated process are commercially available or may be prepared using methods known to the skilled artisan. The process of the present invention provide compounds having useful muscarinic receptor activity. Certain compounds and conditions within the scope of this invention are preferred. The following conditions, invention embodiments, and compound characteristics listed in tabular form may be independently combined to produce a variety of preferred compounds and process conditions. The following list of embodiments of this invention is not intended to limit the scope of this invention in any way. Some prefered characteristics of compounds of formula I include, but are not limited to the following: A) n is 2 ; B) m is 1; C) the bicyclic ring is saturated; \ D) R 2 is R 4 0; E) R 2 is R 8 S; F) R is C.-C 8 alkyl; G) R is C j^ -C 8 alkyl. The invention will now be described in further detail with reference to the following examples. The examples are provided for illustrative purposes, and are not to be construed as limiting the scope of the invention in any way. Cyanogen butyloxyimide (1) (Ref CA 60, 2796e (1964); A solution of 1-butanol (92 mL, 1 mol) and triethylamine (3 mL) was cooled to -8 °C and cyanogen (58 g, 1.12 mol) was slowly bubbled through the solution while maintaining the temperature below 2 °C . The reaction mixture was then distilled at 7 mm Hg to give a clear liquid (119.4 g) b.p. 43-49 °C. 3-Chloro-4-butyloxy-l,2.5-thiadiazole (2) ; A solution of DMF (400 mL) and sulfur monochloride (230 L) was cooled to 5 °C and 1(119.4 g, 0.95 mol) was added dropwise such that the temperature did not exceed 10 °C. Cooling was removed and the reaction was stirred over night . The reaction was cooled in an ice-water bath and the excess sulfur monochloride destroyed by dropwise addition of H2O such that the temperature did not exceed 30 °C . The liquid was decanted from the semi-solid sulfur precipitant and the sulfur residue triturated with hexane. The aqueous fraction was extracted with hexane (3 X) and the combined extracts and triturants were washed with H2O, agueous NaHC03 , brine, dried, and the solvent evaporated. The yellow liquid residue was distilled at 14 mm Hg to give a clear liquid (153 g) , b.p. 120-125 °C . 3-Methylthio-4-butyloxy-l, 2, 5-thiadiazole (3) : A solution of 2 (6 g, 0.031 mol) in DMF (75 mL) was rapidly stirred as ground flaked Na2S-9 H 2 0 (8 g, 0.034 mol) was added. After 1 h, CH3I (3 ml, 0.048 mol) was added and the reaction stirred 30 min . Ice-water (150 mL) was added to the reaction and the mixture extracted with hexane (3 X) . The extracts were washed with H2O (2 X), dried and the solvent evaporated to give a clear liquid (6.04 g) . 3-Methylsulfonyl-4-butyloxy-l.2, 5-thiadiazole (4) ; To a solution of Oxone (18.4 g, 0.03 mol) in H 2 0 (100 L) was added dropwise 3 (3 g, 0.0147 mol) in THF (45 mL) . After stirring overnight, the organics were evaporated and the residue extracted with ether (3 X) . The extracts were washed with H 2 0 (2 X) , dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with 50 % EtOAc-hexane to give a clear colorless liquid (2.93 g) that solidified on standing, m.p. 39-40 °C. . 3-Methylthio-4-hexyloxy-l.2, 5-thiadiazole (5) ; A solution of 3-chloro-4-hexyloxy-l, 2, 5-thiadiazole ( Ref : 954-7JN-57, CA 60, 2796e, 1964) ( 1.1 g, 0.005 mol) in DMF (30 mL) was rapidly stirred as ground flaked Na2S-9 H2O (1.5 g, 0.00625 mol) was added. After stirring overnight, CH3I (2 ml ) was added and the reaction stirred 30 min. Ice-water (150 mL) was added to the reaction and the mixture extracted with ether (2 X) . The extracts were washed with H2O (2 X) , dried and the solvent evaporated to give a clear liquid (1.025 g) . 3-Methylsulfonyl-4-hβxyloxy-l.2.5-thiadiazole (6) : To a solution of Oxone (18.4 g, 0.03 mol) in H 2 0 (100 mL) was added dropwise 5 (3.4 g, 0.0147 mol) in THF (50 mL) . After stirring for three days, the organics were evaporated and the residue extracted with ether (3 X) . The extracts were washed with H2O (2 X) , dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with 50 % EtOAc-hexane to give a clear colorless liquid (3.58 g) . Cyanogen propyloxyimide (7); A solution of 1-propanol (40 mL, 0.536 mol) and triethylamine (1.5 mL) was cooled to -8 °C and cyanogen (36 g, 0.69 mol) was slowly bubbled through the solution while maintaining the temperature below 2 °C . The reaction mixture was then distilled at 20 mm Hg to give a clear liquid ( 59 g) b.p. 63-64 °C . 3-Chloro-4-propyloxy-l, 2, 5-thiadiazole (8) ; A solution of DMF (180 mL) and sulfur monochloride (120 mL, 1.5 mol) was cooled to 5 °C and 7 (59 g, 0.527 mol) was added dropwise such that the temperature did not exceed 10 °C . Cooling was removed and the reaction was stirred over night. The reaction was cooled in an ice-water bath and the excess sulfur monochloride destroyed by dropwise addition of H2O such that the temperature did not exceed 30 °C . The liquid was decanted from the semi-solid sulfur precipitant and the sulfur residue triturated with hexane. The aqueous fraction was extracted with hexane (3 X) and the combined extracts and triturants were washed with H2O, aqueous NaHCθ3 , brine, dried, and the solvent evaporated. The yellow liquid residue was distilled at 15 mm Hg to give a clear liquid (79.9 g) , b.p. 103-106 °C 3-Methylthio-4-propyloxy-l.2.5-thiadiazole (9) ; A solution of 8 (11.1 g, 0.062 mol) in DMF (150 mL) was rapidly stirred as ground flaked Na 2 S-9 H 2 0 (16.4 g, 0.068 mol) was added. After 1 h, CH3I (6 ml, 0.096 mol) was added and the reaction stirred 30 min. Ice-water (300 mL) was added to the reaction and the mixture extracted with hexane (3 X) . The extracts were washed with H2O (2 X) , dried and the solvent evaporated to give a clear liquid (11.02 g) . 3-Methylβul£onyl-4-propyloxy-l.2, 5-thiadiazole (10) ; To a solution of Oxone (20 g, 0.0325 mol) in H 2 0 (100 mL) was added dropwise 9 (3 g, 0.0158 mol) in THF (50 mL) . After stirring overnight, the organics were evaporated and the residue extracted with ether (3 X) . The extracts were washed with H2O (2 X) , dried, and the solvent evaporated to give a colorless oil. The residue was purified by radial chromatography eluting with 40 % EtOAc-hexane to give a clear colorless liquid (3.09 g) that solidified on standing. Recrystallization from hexane gave a white solid, m.p. 30-31 °C Cyanogen methoxyimide (11) ; A solution of methanol (25 mL, 0.618 mol) and triethylamine (1.5 mL) was cooled to -8 °C and cyanogen (38 g, 0.73 mol) was slowly bubbled through the solution while maintaining the temperature below 2 °C . The reaction mixture was then distilled at 45 mm Hg to give a clear liquid ( 51 g) b.p. 48-53 °C . 3-Chloro-4-methoxy-l, 2.5-thiadiazole (12) ; A solution of DMF (180 mL) and sulfur monochloride (120 mL, 1.5 mol) was cooled to 5 °C and 11 (51 g, 0.607 mol) was added dropwise such that the temperature did not exceed 15 °C . Cooling was removed and the reaction was stirred over night. The reaction was cooled in an ice-water bath and the excess sulfur monochloride destroyed by dropwise addition of H2O such that the temperature did not exceed 30 °C . The solution was further diluted with H2O (350 mL) and steam distilled until almost all of the distillate was homogeneous. The distillate was extracted with hexane (3 X) and the combined extracts washed with H2O, aqueous NaHC03 , brine, dried, and the solvent distilled off until the volume was 200 mL. The hot mixture was filtered and cooled to give white crystals (53 g) . 3-Methylthio-4-methoxy-1,2, 5-thiadiazole (13) ; A solution of 12 (9.4 g, 0.0623 mol) in DMF (150 mL) was rapidly stirred as ground flaked Na 2 S-9 H 2 0 (16.4 g, 0.068 mol) was added. After 1 h, CH I (6 ml, 0.096 mol) was added and the reaction stirred 30 in. Ice-water (300 mL) was added to the reaction and the mixture extracted with hexane (3 X) . The extracts were washed with H2O (2 X) , dried and the solvent carefully evaporated to give a clear liquid (4.4 g) . 3-Methylsulfonyl-4-methoxy-l, 2, 5-thiadiazole (14) : To a solution of Oxone (34 g, 0.0552 mol) in H 2 0 (170 mL) was added dropwise 13 (4.4 g, 0.027 mol) in THF (80 mL) . After stirring 5 h, the organics were evaporated and the residue extracted with ether (3 X) . The extracts were washed with H2O (2 X), dried, and the solvent evaporated to give a floculant white solid. Recrystallization from ether gave a white solid (2.76 g) , m.p. 110.5-111.5 °C . 3-Chloro-4-pentyloxy-l, 2, 5-thiadiazole (15) ; A solution of 1-pentanol (60 mL, 0.55 mol) and triethylamine (1.5 mL) was cooled to -8 °C and cyanogen (36 g, 0.69 mol) was slowly bubbled through the solution while maintaining the temperature below 2 °C . The reaction was then stirred another hour at -5 °C then added dropwise to a solution of DMF (180 mL) and sulfur monochloride (120 mL, 1.5 mol) that was cooled to 5 °C while maintaining the temperature of the DMF solution below 10 °C . Cooling was removed and the reaction was stirred over night. The reaction was cooled in an ice-water bath and the excess sulfur monochloride destroyed by dropwise addition of H2O such that the temperature did not exceed 30 °C . The liquid was decanted from the semi-solid sulfur precipitant and the sulfur residue triturated with hexane. The aqueous fraction was extracted with hexane (3 X) and the combined extracts and triturants were washed with H2O, aqueous NaHC03 , brine, dried, and the solvent evaporated. The yellow liquid residue was distilled at 9 mm Hg to give a clear liquid (92.7 g) , b.p. 129-135 °C . 3-Methylthio-4-pentyloxy-l, 2, 5-thiadiazole (16) ; A solution of 15 (12.8 g, 0.06 mol) in DMF (150 mL) was rapidly stirred as ground flaked Na 2 S-9 H 2 0 (16.4 g, 0.068 mol) was added. After 1 h, CH3I (6 ml, 0.096 mol) was added and the reaction stirred 30 min. Ice-water (300 mL) was added to the reaction and the mixture extracted with hexane (3 X) . The extracts were washed with H2O (2 X) , dried and the solvent evaporated to give a clear liquid (12.6 g) . 3-Methylsulfonyl-4-pentlvoxy-l, 2, 5-thiadiazole (17) ; To a solution of Oxone (72 g, 0.117 mol) in H 0 (350 mL) was added dropwise 16 (12.4 g, 0.0569 mol) in THF (180 mL) . After stirring overnight, the organics were evaporated and the residue extracted with ether (3 X) . The extracts were washed with H2O (2 X) , dried, and the solvent evaporated to give a colorless oil. The residue was purified by flash chromatography eluting with 40 % EtOAc-hexane to give a clear colorless liquid (13 g) . 3-Chloro-4-ethoxy-l, 2, 5-thiadiazole (18) ; A solution of ethanol (60 mL, 1.02 mol) and triethylamine (1.5 mL) was cooled to -8 °C and cyanogen (59 g, 1.13 mol) was slowly bubbled through the solution while maintaining the temperature below 2 °C. The reaction was then added dropwise to a solution of DMF (275 mL) and sulfur monochloride (225 L, 2.81 mol) that was cooled to 5 °C while maintaining the temperature of the DMF solution below 10 °C . Cooling was removed and the reaction was stirred over night. The reaction was cooled in an ice-water bath and the excess sulfur monochloride destroyed by dropwise addition of H2O such that the temperature did not exceed 30 °C. Additional H2O (400 mL) was added and the reaction internally steam distilled until the distillate was almost homogeneous. The distillate was extracted with hexane (3 X) and the combined extracts washed with H2O, aqueous NaHCU3 , brine, dried, and the solvent carefully evaporated. The liquid residue was distilled at 21 mm Hg to give a clear liquid (154.3 g) , b.p. 88-93 °C 3-Methylthio-4-ethoxy-l, 2, 5-thiadiazole (19) ; A solution of 18 (16.5 g, 0.1 mol) in DMF (250 mL) was rapidly stirred as ground flaked Na 2 S-9 H 2 0 (27 g, 0.113 mol) was added. After 1 h, CH3I (9.5 ml, 0.153 mol) was added and the reaction stirred 1 h. Ice-water (400 mL) was added to the reaction and the mixture extracted with hexane (3 X) . The extracts were washed with H2O (2 X), dried and the solvent evaporated to give a clear liquid (12.5 g) . 3-Methylsulfonyl-4-ethoxy-l, 2, 5-thiadiazole (20) ; To a solution of Oxone (90 g, 0.146 mol) in H 0 (435 mL) was added dropwise 19 (12.5 g, 0.071 mol) in THF (220 mL) . After stirring overnight, the organics were evaporated and the residue extracted with ether (3 X) . The extracts were washed with H2O (2 X) , dried, and the solvent evaporated to give a white solid. Recrystallization from ether gave a white solid (9.9 g) , m.p. 94-95 °C 3-Chloro-4-(4- ethylpentyloxy) -1,2, 5-thiadiazole (21) ; A solution of 4-methylpentan-l-ol (25 mL, 0.245 mol) and triethylamine (1. mL) was cooled to -8 °C and cyanogen (14 g, 0.27 mol) was slowly bubbled through the solution while maintaining the temperature below 2 °C . The reaction was then stirred another hour at -5 °C then added dropwise to a solution of DMF (75 mL) and sulfur monochloride (49 mL) that was cooled to 5 °C while maintaining the temperature of the DMF solution below 10 °C . Cooling was removed and the reaction was stirred over night. The reaction was cooled in an ice-water bach and the excess sulfur monochloride destroyed by dropwise addition of H2O such that the temperature did not exceed 35 °C . The liquid was decanted from the semi-solid sulfur precipitant and the sulfur residue triturated with hexane. The aqueous fraction was extracted with hexane (3 X) and the combined extracts and triturants were washed with H2O, aqueous NaHC03 , brine, dried, and the solvent evaporated. The yellow liquid residue was distilled at 4.5 mm Hg to give a clear liquid (40.45 g) , b.p. 120-124 °C . 3-Methylthio-4-(4-methylpentyloxy) -1,2, 5-thiadiazole (22) : A solution of 21 (22 g, 0.1 mol) in DMF (250 L) was rapidly stirred as ground flaked Na2S-9 H2O (27 g, 0..113 mol) was added. After 1 h, CH3I (9.5 ml, 0.153 mol) was added and the reaction stirred 30 min. Ice-water (300 mL) was added to the reaction and the mixture extracted with hexane (3 X) . The extracts were washed with H2O (2 X) , dried and the solvent evaporated to give a clear liquid (21.6 g) . 3-Methylsulfonyl-4- (4- ethylpentyloxy) -1,2, 5-thiadiazole (23) ; To a solution of Oxone (119 g, 0.193 mol) in H 2 0 (600 mL) was added dropwise 22 (21.6 g, 0.093 mol) in THF (300 mL) . After stirring overnight, the organics were evaporated and the residue extracted with ether (3 X) . The extracts were washed with H2O (2 X) , dried, and the solvent evaporated to give a colorless oil . The residue was purified by HPLC (8 L gradient, hexane to 40 % EtOAc-hexane) to give a clear colorless liquid (19.7 g Cyanogen butylthioimide (24): Ref: U.S. Patent 3,462,471. Cyanogen (57 g, 1.096 g) was bubbled through CH 2 C1 2 (150 mL) maintained at -5 °C . To the solution was added Et2NH (3 mL, 0.029 mol) . The solution was then cooled to -8 °C and butanethiol (70 mL, 0.65 mol) was added dropwise over 15 min. Reaction was stirred at 0 °C for 30 min then at ambient for 2.5 h. The amine was neutralized with glacial acetic acid (1.65 mL) and most of the CH2CI2 distilled from the reaction. The residue was distilled at 3-4 mm Hg to give a dark liquid (27.5 g) , b.p. 75-93 °C, that solidified on cooling in the refrigerator. 3-Chloro-4-butylthio-l, 2, 5-thiadiazole (25) ; A solution of DMF (50 mL) and sulfur monochloride (55 mL, 0.688 mol) was cooled to 5 °C as a solution of 24 (35.8 g, 0.25 mol) in DMF (40 mL) was added at such a rate that the temperature did not exceed 16 °C. Cooling was removed and reaction was stirred over night. The reaction was cooled in an ice-water bath and excess sulfur monochloride destroyed by careful addition of H2O while maintaining the temperature below 40 °C . The liquid was decanted from the semi-solid sulfur precipitant and the sulfur residue triturated with hexane. The aqueous fraction was extracted with hexane (3 X) and the combined extracts and triturants were washed with H2O, aqueous NaHC03 , brine, dried, and the solvent evaporated. The residue was distilled at 2 mm Hg to give a yellow liquid (24.6 g) , b.p. 105-110 °C 3-Chloro-4-ethylthio-l, 2 , 5-thiadiazole (26) : Cyanogen ( 36 g, 0.69 mol) was bubbled into ether (250 mL) maintained at - 10 °C . To the solution was added dropwise diethylamine (3 mL) followed by dropwise addition of ethanethiol (47 mL, 0.64 mol) at such a rate that the temperature did not exceed -5 °C. The reaction was maintained below 0 °C for 5 h then stirred at ambient over night. Ether was distilled from the reaction until the pot temperature reached 50 °C . The reaction was cooled to ambient and then added dropwise to a solution of sulfur monochloride (125 mL, 1.56 mol) in DMF (150 mL) that was cooled to 5 °C . Cooling was removed and the reaction was stirred over night . The reaction was cooled in an EtOH-ice bath as the excess sulfur monochloride was destroyed by dropwise addition of water while maintaining the temperature below 35 °C. The liquid was decanted from the semi-solid sulfur precipitant and the sulfur residue triturated with hexane. The aqueous fraction was extracted with hexane (3 X) and the combined extracts and triturants were washed with H2O, aqueous NaHCθ3 , brine, dried, and the solvent evaporated. The brown liquid residue was distilled at 3 mm Hg to give a yellow liquid (80.2 g) , b.p. 91-96 °C. (+, -) endo-3-(3-Pentyloxy-l, 2, 5-thiadiazo-4-yl) -1- azabicvclo [2.2.1] heptane (27); A solution of endo-3- ethoxycarbonyl-1-azabicyclo [2.2.1] heptane (2.6 g, 0.0154 mol, Ref: J. Che . Soc . Perkin I 1991, 1091) in THF (30 mL) was cooled in a dry ice-acetone bath with efficient stirring. A solution of 2 M LDA in THF (9 mL, 0.018 mol) was added dropwise followed by stirring for 1 h. To the reaction was added a solution of 17 (4.5 g, 0.018 mol) in THF (30 mL) dropwise. Cooling was removed and the reaction stirred 3.5 h. The solvent was evaporated, the residue suspended in cold H2O, treated with 5 N HCl (10 mL) , and extracted with ether (2 X) . The aqueous fraction was made basic and extracted with EtOAc (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography (5 % EtOH-0.5 % NH 4 0H-CHC1 3 ) to give a reddish brown liquid (2.45 g) . (C76-2ZT-53) A mixture of this liquid (2.4 g, 0.0071 mol) and concentrated HCl (90 mL) was heated to reflux over night. The solvent was evaporated, residue suspended in H2O, and the mixture extracted with ether (2 X) . The aqueous fraction was made basic and extracted with CHCI3 (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography (10 % EtOH-1 % NH 4 0H-CHC1 3 ) to give a two component mixture of endo and exo isomers (0.43 g) followed by a pure fraction of the slower endo isomer 27 (0.367 g) . The pure 27 was converted to the fumarate salt and recrystallized from EtOAc to give a white solid, m.p. 100-101 °C. (+, -) exo-3- (3-Pentyloxy-l,2, 5-thiadiazo-4-yl) -1- azabicyclo [2.2.llheptane (28): A mixture of the endo and exo isomers obtained in the preparation of 27 (0.78 g, 0.0029 mol) was added to a sodium pentoxide solution (0.7 g Na, 20 mL 1-pentanol) and heated to 110 ° C over night. The reaction was cooled, acidified, and the pentanol evaporated. The residue was suspended in H2O and extracted with ether (2 X) . The aqueous phase was made basic, extracted with CHCI3 (3 X), the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography (10 % EtOH-1 % NH4OH-CHCI3) to give pure exo isomer 28 (0.35 g). The oxalate salt crystallized from EtOAc to give floculant tan crystals, m.p. 142-143 °C (+, -) endo-3- (3-Butyloxy-l,2, 5-thiadiazo-4-yl) -1- azabicyclo [2.2.llheptane (29); A solution of endo-3- ethoxycarbonyl-1-azabicyclo [2.2.1] heptane (3.1 g, 0.0183 mol, Ref: J. Chem. Soc . Perkin I 1991, 1091) in THF (35 L) was cooled in a dry ice-acetone bath with efficient stirring. A solution of 2 M LDA in THF (11 mL, 0.022 mol) was added dropwise followed by stirring for 1 h. To the reaction was added a solution of 4 (4.7 g, 0.02 mol) in THF (30 mL) dropwise. Cooling was removed and the reaction stirred over night. The solvent was evaporated, the residue suspended in cold H 2 0, treated with 5 N HCl (10 L) , and extracted with ether (2 X) . The aqueous fraction was made basic and extracted with EtOAc (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography (5 % EtOH-0.5 % NH 4 0H-CHC1 3 ) to give a reddish brown liquid (3.5 g) . (C76-2ZT-54) A mixture of this liquid (3.5 g, 0.0108 mol) and concentrated HCl (140 mL) was heated to reflux over night. The solvent was evaporated, residue suspended in H2O, and the mixture extracted with ether (2 X) . The aqueous fraction was made basic and extracted with CHCI3 (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography (10 % EtOH-1 % NH4OH-CHCI3) to give a two component mixture of endo and exo isomers (0.76 g) followed by a pure fraction of the slower endo isomer 29 (0.37 g) . The pure 29 was converted to the fumarate salt and recrystallized from EtOAc to give a white solid, m.p. 103-104 °C. (+, -) exo-3-(3-Butyloxy-l,2,5-thiadiazo-4-yl)-l- azabicvclo [2.2.llheptane (30); A mixture of the endo and exo isomers obtained in the preparation of 29 (1.21 g, 0.0048 mol) was added to a sodium butyloxide solution (0.7 g Na, 20 mL 1-butanol) and heated to 110 ° C over night. The reaction was cooled, acidified, and the butanol evaporated. The residue was suspended in H2O and extracted with ether (2 X) . The aqueous phase was made basic, extracted with CHCI3 (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography (10 % EtOH-1 % NH 4 0H-CHC1 ) to give pure exo isomer 30 (0.74 g). The oxalate salt crystallized from EtOAc to give floculant white crystals, m.p. 164-165 °C (+, -) endo-3-(3-Hexyloxy-l,2,5-thiadiazo-4-yl) -1- azabicvclo [2.2. llheptane (31): A solution of endo-3- ethoxycarbonyl-1-azabicyclo [2. 2 .1] heptane (2.85 g, 0.0168 mol, Ref: J. Che . Soc . Perkin I 1991, 1091) in THF (20 mL) was cooled in a dry ice-acetone bath with efficient stirring. A solution of 2 M LDA in THF (9.26 mL, 0.0185 mol) was added dropwise followed by stirring for 1 h. To the reaction was added a solution of 6 (4.9 g, 0.0185 mol) in THF (30 mL) dropwise. Cooling was removed and the reaction stirred 1 h at ambient and then at 30-40 °C for 2 h. The solvent was evaporated, the residue suspended in cold H2O, treated with 5 N HCl (10 mL) , and extracted with ether (2 X) . The aqueous fraction was made basic and extracted with EtOAc (3 X) , the extracts dried, and the solvent evaporated to give 4.54 g crude product. ( 909-ZA1-258) A mixture of this liquid and 9 N HCl (182 mL) was heated to reflux over night. The solvent was evaporated, residue suspended in H 2 0, and the mixture extracted with ether (2 X) . The aqueous fraction was made basic and extracted with EtOAc (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography (10 % EtOH-1 % NH4OH-CHCI3) to give a two component mixture of endo and exo isomers (1.22 g) followed by a pure fraction of the slower endo isomer 31 (0.24 g) . The pure 31 was converted to the fumarate salt and recrystallized from MeOH-EtOAc to give a white solid, m.p. 141-143 °C. (+, -) exo-3- (3-Hexyloxy-l,2, 5-thiadiazo-4-yl) -1- azabicvclo [2.2.llheptane (32): A mixture of the endo and exo isomers obtained in the preparation of 30 (1.22 g, 0.0043 mol) was added to a sodium hexyloxide solution (1.1 g Na, 35 L 1-hexanol) and heated to 128 ° C over night. The reaction was cooled, acidified, and the hexanol evaporated. The residue was suspended in H2O and extracted with ether (2 X) . The aqueous phase was made basic, extracted with ether (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography (10 % EtOH-1 % NH4OH-CHCI3) to give pure exo isomer 32 (0.6 g). The oxalate salt crystallized from MeOH-ether to give a white solid, m.p. 99-101 °C (+, -)3-(3-Heχyloxy-l,2,5-thiadiazo-4-yl)-l- azabicvclo[2.2.2]octane (33): A solution of 3- methoxycarbonyl-1-azabicyclo [2.2.2 ] octane (Ref: J. Med. Chem. 1991, 34 , 2726-2735, loc ci t . ) (0.67 g, 0.004 mol) in THF (15 mL) was cooled in a dry ice-acetone bath with efficient stirring. A solution of 2 M LDA in THF (1.99 mL, 0.004 mol) was added dropwise followed by stirring for 2 h. To the reaction was added a solution of 6 (1.0 g, 0.0038 mol) in THF (5 mL) dropwise. After 1 h, cooling was removed and the reaction stirred over night. The solvent was evaporated, the residue suspended in cold H2O, and extracted with CH2CI2 (3 X) . The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography (5 % EtOH-0.5 % NH4OH-CHCI3) to give a yellow oil (1.05 g) . (909-ZA1-227) A mixture of this liquid and 4 N HCl (20 mL) was heated to reflux over night. The concentration of HCl was increased to 6 N and heating was continued another day. The solvent was evaporated, residue suspended in H2O, made basic, and extracted with CH2CI2 (3 X) . The extracts dried, the solvent evaporated, and the residue purified by radial chromatography (20 % EtOH-2 % NH4OH-CHCI3) to give a yellow oil (0.63 g) . The oil was converted to the fumarate salt and recrystallized from EtOAc to give a white solid, m.p. 110-111 °C . This material was identical by NMR to that previously described in earlier patents . (+, -)3-(3-Methoxy-l,2,5-thiadiazo-4-yl) -1- azabicycloC2.2.21octane (33): A solution of 3- methoxycarbonyl-1-azabicyclo [2.2.2 ] octane (0.68 g, 0.004 mol) in THF (15 mL) was cooled in a dry ice-acetone bath with efficient stirring. A solution of 2 M LDA in THF (2.1 mL, 0.0042 mol) was added dropwise followed by stirring for 1 h. To the reaction was added a solution of 14 (0.85 g, 0.0044 mol) in THF (10 mL) dropwise. After 1 h, cooling was removed and the reaction stirred 2 h. The solvent was evaporated, the residue suspended in cold H2O, and extracted with CH2CI2 (3 X) . The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography (10 % EtOH-1 % NH4OH-CHCI3) to give a yellow oil (0.94 g) . (C76-OJT-262 ) A mixture of this liquid and 9 N HCl (20 mL) was heated to reflux 5 h. The solvent was evaporated, residue suspended in H2O, made basic, and extracted with CH2CI2 (3 X) . The extracts dried, the solvent evaporated, and the residue purified by radial chromatography (20 % EtOH-2 % NH4OH-CHCI3) to give a yellow oil (0.356 g) . The oil was converted to the oxalate salt and recrystallized from 2-propanol to give a white solid, m.p. 158-159 °C . (+, -)3-(3-Butylthio-l,2,5-thiadiazo-4-yl)-l- azabicyclo [2.2.2] octane (34): A solution of 3- methoxycarbonyl-1-azabicyclo [2.2.2 ] octane (0.85 g, 0.005 mol) in THF (25 mL) was cooled in a dry ice-acetone bath with efficient stirring. A solution of 2 M LDA in THF (3 mL, 0.006 mol) was added dropwise followed by stirring for 1 h. To the reaction was added a solution of 25 (1.25 g, 0.006 mol) in THF (15 mL) dropwise. After 1 h, cooling was removed and the reaction stirred over night. The solvent was evaporated, the residue suspended in cold H2O, and extracted with CHCI3 (3 X) . The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography (10 % EtOH-1 % NH4OH-CHCI3 ) to give a brown oil (0.9 g) . The oxalate salt crystallized from EtOAc to give a tan solid, m.p. 93.5-95 °C . A mixture of the oxalate salt (0.5 g, 0.0012 mol) and concentrated HCl (20 mL) was heated to reflux 6 h. The solvent was evaporated, residue suspended in DMF (15 mL) , and heated to 150 °C for 30 min. The solvent was evaporated, residue suspended ^0, made basic, and extracted with CHCI3 (3 X) . The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography (20 % EtOH-2 % NH4OH-CHCI3) to give a yellow oil (0.137 g) . The oil was converted to the fumarate salt and recrystallized from EtOAc to give a white solid that was identical by NMR with the material previously reported in other patents. (+,-)3-(3-Ethoxy-l,2,5-thiadiazo-4-yl)-l- azabicyclo T2.2.2] octane (35): A solution of 3- methoxycarbonyl-1-azabicyclo [2.2.2 ] octane (1.01 g, 0.006 mol) in THF (25 mL) was cooled in a dry ice-acetone bath with efficient stirring. A solution of 2 M LDA in THF (3.3 mL, 0.0066 mol) was added dropwise followed by stirring for 1 h. To the reaction was added a solution of 20 (1.35 g, 0.0065 mol) in THF (15 L) dropwise. After 1 h, cooling was removed and the reaction stirred 2 h. The solvent was evaporated, the residue suspended in cold H2O, and extracted with CHCI3 (3 X) . The extracts were dried, and the solvent evaporated to give a yellow oil. A mixture of this liquid and 9 N HCl (40 mL) was heated to reflux 5 h. The solvent was evaporated, residue suspended in H2O, made basic, and extracted with CHCI3 (3 X) . The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography (20 % EtOH-2 % NH4OH-CHCI3) to give a brown oil (0.54 g) . The oil was converted to the fumarate salt and recrystallized from EtOAc to give a white solid identical to the material reported in a previous patent. (+, -) 3-Methoxycarbonyl-3- (3-Hexyloxy-l,2, 5-thiadiazo-4-yl) - l-azabicvclo[2.2.21octane (36): A solution of 3- methoxycarbonyl-1-azabicyclo [2.2.2 ] octane (0.85 g, 0.005 mol) in THF (30 mL) was cooled in a dry ice-acetone bath with efficient stirring. A solution of 2 M LDA in THF (3 L, 0.006 mol) was added dropwise followed by stirring for 1 h. To the reaction was added a solution of 3-chloro-4- hexyloxy-1, 2, 5-thiadiazole (1.4 g, 0.0063 mol) in THF (10 mL) dropwise. Cooling was removed and the reaction stirred 2 h. The solvent was evaporated, the residue suspended in cold H2O, and extracted with CHCI3 (3 X) . The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography (5 % EtOH-0.5 % NH4OH-CHCI3) to give a yellow oil (1.4 g) . The oil was converted to the fumarate salt and recrystallized from EtOAc to give a white solid, m.p. 132-133 °C . The free base of this material was identical to that produced as an intermediate in the synthesis of 33 (+, -) -endo-6- (3-propyloxy-l, 2, 5-thiadiazo-4-yl) -1- azabicvclo[3.2.11octane (37): A solution of 6- methoxycarbonyl-1-azabicyclo [3.2.1] octane (Ref: J. Med. Che . 1991, 34 , 2726-2735, loc ci t . ) (2.73 g, 0.016 mol) in THF (20 mL) was cooled in a dry ice-acetone bath with stirrring. A solution of 2 M LDA in THF (7.5 mL, 0.015 mol) was added dropwise and stirring continued for 1 h. To the - reaction was added dropwise a solution of 10 (3.06 g, 0.0138 mol) in THF (10 L) . After 20 min, cooling was removed, the reaction stirred 2 h, and the reaction quenched by the addition of H2O. The solvents were evaporated, the residue suspended in EtOAc, and the mixture washed with H2O. The organics were dried, the solvent evaporated and the residue purified by radial chromatography (10 % EtOH-1 % NH4OH- CHCI3) to give 3 g of an oil. ( 909-ZA1-245 ) The oil was dissolved in 9 N HCl (60 mL) and heated to reflux for 2 days. The solvent was evaporated, the residue dissolved in H2O (20 mL) , and the solution extracted with ether. The aqueous solution was made basic, extracted with EtOAc (3 X), the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with (10 % EtOH-1 % NH4OH-CHCI3) to initially elute an exo-endo mixture (0.485 g) followed by the pure endo isomer 37 (0.37 g) that was converted to an oxalate salt and recrystallized from EtOAc, m.p. 97-102 °C . (+, -) -exo-6-(3-propyloxy-l,2, 5-thiadiazo-4-yl) -1- azabicvclo-3.2.lloctane (38); A mixture of the endo and exo isomers from the preparation of 37 (0.6 g) was treated with sodium propoxide (1.22 g Na, 25 mL 1-propanol) and heated to reflux for 3 days . The solution was cooled, treated with H2O, and the solvents evaporated. The residue was suspended in H2O, acidified and washed with ether. The aqueous solution was made basic, extracted with EtOAc (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography (10 % EtOH-1 % NH4OH- CHCI3 ) to give the pure exo isomer 38 (0.32 g) that was converted to the oxalate salt and recrystallized from EtOAc- ether to give a white solid, m.p. 162-163 °C . (+, -) -endo-6-(3-butyloxy-l,2, 5-thiadiazo-4-yl) -1- azabicvclo [3.2.lloctane (49): A solution of 6-cyano-l- azabicyclo [3.2.1] octane (Ref: J. Med. Chem. 1991, 34 , 2726- 2735, loc ci t . ) (1.3 g, 0.0095 mol) in THF (20 mL) was cooled in a dry ice-acetone bath with stirrring. A solution of 2 M LDA in THF (4.77 mL, 0.0095 mol) was added dropwise and stirring continued for 2 h. To the reaction was added dropwise a solution of 4 (2.26 g, 0.0095 mol) in THF (10 L) . After 30 min, cooling was removed, the reaction stirred 30 min, and the reaction quenched by the addition of H2O. The solvents were evaporated, the residue suspended in EtOAc, and the mixture washed with H2O. The organics were dried, the solvent evaporated, and the residue purified by radial chromatography (5 % EtOH-0.5 % NH4OH-CHCI3 ) to give- an oil (1.16 g) . ( 909-ZA1-230 ) The oil (0.64 g) was dissolved in cone HCl (10 mL) and heated to reflux for 1 day. The solvent was evaporated, the residue dissolved in H2O (20 mL) , and the solution extracted with EtOAc. The aqueous solution was made basic, extracted with EtOAc (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with (10 % EtOH-1 % NH4OH-CHCI3) to give endo isomer 49 that was converted to an oxalate salt and recrystallized from EtOAc to give a white solid (0.056 g) , m.p. 118-120 °C. (+, -) -endo-6-(3-butyloxy-l,2, 5-thiadiazo-4-yl) -1- azabicvclo [3.2. lloctane (49) and (+, -) -exo-6- (3-butyloxy- 1,2, 5-thiadiazo-4-yl) -1-azabicvclo [3.2.lloctane (50) : A solution of 6-carbomethoxy-l-azabicyclo [3.2.1] octane (2.36 g, 0.014 mol) in THF (20 mL) was cooled in a dry ice-acetone bath with stirrring. A solution of 2 M LDA in THF (7 mL, 0.014 mol) was added dropwise and stirring continued for 1 h. A solution of 4 (3 g, 0.0127 mol) in THF (10 mL) was added to the reaction dropwise. After 1 h, cooling was removed, the reaction warmed at ambient temperature for 30 min, and the reaction quenched by the addition of H2O. The solvents were evaporated, the residue suspended in EtOAc, and the mixture washed with H2O. The organics were dried, the solvent evaporated, and the residue purified by radial chromatography (10 % EtOH-1 % NH4OH-CHCI3) to give an oil (3.45 g) . (909-ZA1-242) The oil (2.95 g) was dissolved in 9 N HCl (60 L) and heated to reflux for 1.5 days. The solvent was evaporated, the residue dissolved in H2O (20 mL) , and the solution extracted with ether. The aqueous solution was made basic, extracted with EtOAc (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with (10 % EtOH-1 % NH4OH-CHCI3) to give endo isomer 49 (0.55 g) that was identical to the previously prepared material. Further elution gave a mixture of the exo and endo isomers (0.6 g) . ( 909-ZA1-243 ) The endo-exo mixture (0.6 g) was treated with sodium ethoxide (0.52 g Na, 25 mL EtOH) and heated to reflux for 3.5 days. The solution was cooled, treated with H2O, and the solvents evaporated. The residue was suspended in H2O, acidified and washed with ether. The aqueous solution was made basic, extracted with EtOAc (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography (10 % EtOH-1 % NH4OH-CHCI3) to give the pure exo isomer 50 (0.30 g) that was converted to the oxalate salt and recrystallized from 2-propanol-ether to give a white solid, m.p. 135-136 °C . (+, -) -endo-6- (3-Methoxy-l,2, 5-thiadiazo-4-yl) -1- azabicvclo[3.2.11octane (39) and (+, -) -exo-6- (3-Methoxy- l.2, 5-thiadiazo-4-yl) -1-azabicvclo [3.2. lloctane (40) A solution of 6-methoxycarbonyl-l-azabicyclo [3.2.1] octane (1.81 g, 0.0104 mol) in THF (20 mL) was cooled in a dry ice- acetone bath with stirrring. A solution of 2 M LDA in THF (5.88 mL, 0.0116 mol) was added dropwise and stirring continued for 2 h. To the reaction was added dropwise a solution of 14 (1.88 g, 0.0097 mol) in THF (30 mL) . After 2 h, cooling was removed and the reaction heated at 30-45 °C for 1.5 h. After adding H2O to the reaction, the solvents were evaporated, the residue suspended in EtOAc, and the mixture washed with H2O. The organics were dried and the solvent evaporated to give a crystalline solid (2.65 g) . (909-ZA1-251) The solid was dissolved in 9 N HCl (106 mL) and heated to reflux 24 h. The solvent was evaporated, the residue dissolved in H2O, and the solution extracted with ether. The aqueous solution was made basic, extracted with EtOAc (2 X) , the extracts dried, and the solvent evaporated. The residue was treated with sodium methoxide (0.4 g Na, 25 mL MeOH) and heated to reflux for 4 days. The solvent was evaporated, the residue suspended in water, and the solution extracted with EtOAc (3 X) . The extracts were dried, solvent evaporated and the residue purified by radial chromatography (10 % EtOH-1 % NH4OH-CHCI3 ) to elute first 40 (0.2 g) followed by 39 (0.05 g) . The oxalate salt of 40 crystallized from MeOH-ether to give a white solid, m.p. 143-145 °C. The hydrochloride salt of 39 crystallized from ether, m.p. 192-194 °C . (+, -) -endo-6- (3-Hexyloxy-l, 2, 5-thiadiazo-4-yl) -1- azabicvclor3.2.11octane (41): A solution of 6- methoxycarbonyl-1-azabicyclo [3.2.1] octane (2.61 g, 0.0154 mol) in THF (20 mL) was cooled in a dry ice-acetone bath with stirrring. A solution of 2 M LDA in THF (8.47 mL, 0.017 mol) was added dropwise and stirring continued for 1 h. To the reaction was added dropwise a solution of 6 (3.7 g, 0.014 mol) in THF (10 mL) . After 2 h, cooling was removed, the reaction stirred 2 h, and the reaction quenched by the addition of H2O. The solvents were evaporated, the residue suspended in EtOAc, and the mixture washed with H2O. The organics were dried, the solvent evaporated and the residue purified by radial chromatography (10 % EtOH-1 % NH4OH-CHCI3) to give 4.3 g of an oil. ( 909-ZA1-249 ) The oil was dissolved in 9 N HCl (172 mL) and heated to reflux for 1.5 days. The solvent was evaporated, the residue dissolved in H2O (20 mL) , and the solution extracted with ether. The aqueous solution was made basic, extracted with EtOAc (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with (10 % EtOH-1 % NH4OH-CHCI3 ) to initially elute an exo- endo mixture (1.17 g) followed by the pure endo isomer 41 (0.49 g) . The hydrochloride salt of 41 crystallized from EtOAc to give colorless crystals, m.p. 148-149 °C . (+, -) -exo-6- (3-Hexyloxy-1.2, 5-thiadiazo-4-yl) -1- azabicvclo [3.2.lloctane (42): A mixture of the endo and exo isomers from the preparation of 41 (1.46 g) was treated with sodium hexyloxide (1.0 g Na, 25 mL 1-hexanol) and heated to 90-120 °C for 3 days. The solution was cooled, treated with H2O, and the solvents evaporated. The residue was suspended in H2O, acidified, and washed with ether. The aqueous solution was made basic, extracted with EtOAc (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography (10 % EtOH-1 % NH4OH- CHCI3) to give the pure exo isomer 42 (1.0 g) that was converted to the oxalate salt and recrystallized from ether to give a white solid, m.p. 109-111 °C. (+, -)-endo-6-(3-Pentyloxy-l,2, 5-thiadiazo-4-yl) -1- azabicvclo [3.2. lloctane (43): A solution of 6- methoxycarbonyl-1-azabicyclo [3.2.1] octane (2.34 g, 0.0138 mol) in THF (20 mL) was cooled in a dry ice-acetone bath with stirrring. A solution of 2 M LDA in THF (7.6 mL, 0.0152 mol) was added dropwise and stirring continued for 1 h. To the reaction was added dropwise a solution of 17 (3.15 g, 0.0126 mol) in THF (10 mL) . After 2 h, cooling was removed, the reaction stirred 2 h, and the reaction quenched by the addition of H 2 0. The solvents were evaporated, the residue suspended in EtOAc, and the mixture washed with H2O. The organics were dried, the solvent evaporated to give an orange liquid (4.61 g) . ( 909-ZA1-255) The oil was dissolved in 9 N HCl (185 mL) and heated to reflux for 1 day. The solvent was evaporated, the residue dissolved in H2O (20 mL) , and the solution extracted with EtOAc. The aqueous solution was made basic, extracted with EtOAc (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with (10 % EtOH-1 % NH4OH-CHCI3) to initially elute an exo-endo mixture (0.9 g) followed by the pure endo isomer 43 (0.25 g) . The hydrochloride salt of 43 crystallized from EtOAc to give colorless crystals, m.p. 146-147 °C . (+, -) -exo-6- (3-Pentyloxy-l,2, 5-thiadiazo-4-yl) -1- azabicvclo [3.2. lloctane (44): A mixture of the endo and exo isomers from the preparation of 43 (0.9 g) was treated with sodium pentyloxide (1.0 g Na, 35 L 1-pentanol) and heated to 110 °C for 1 day. The solution was cooled, treated with H2θ, and the solvents evaporated. The residue was suspended in H2O, acidified, and washed with ether. The aqueous solution was made basic, extracted with EtOAc (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography (10 % EtOH-1 % NH4OH- CHCI3) to give the pure exo isomer 44 (0.72 g) that was converted to the oxalate salt and recrystallized from EtOAc to give a white solid, m.p. 109-110 °C . (+, -) -endo-6- [3- (4- ethylpentyloxy) -1,2, 5-thiadiazo-4-yll -1- azabicvcloC3.2. lloctane (45) and (+, -) -exo-6- [3- (4- methylpentyloxy) -1,2, 5-thiadiazo-4-yll -1- azabicvclo-3.2. lloctane (46): A solution of 6- methoxycarbonyl-1-azabicyclo [3.2.1] octane (1.58 g, 0.0093 mol) in THF (20 mL) was cooled in a dry ice-acetone bath with stirrring. A solution of 2 M LDA in THF (5.14 mL, 0.0103 mol) was added dropwise and stirring continued for 1 h. A solution of 23 (2.72 g, 0.0103 mol) in THF (20 mL) was added to the reaction dropwise. After 2 h, cooling was removed, the reaction warmed to 45 °C for 2 h, and the reaction quenched by the addition of H2O. The solvents were evaporated, the residue suspended in 1 N HCl, and the mixture extracted with ether. The aqueous phase was made basic, extracted with EtOAc (3X) , the extracts dried, and the solvent evaporated to give an orange oil (2.4 g) . (909- ZA1-272) The oil was dissolved in 9 N HCl (136 L) and heated to reflux for 2.5 days. The solvent was evaporated, the residue dissolved in H2O (20 mL) , and the solution extracted with ether. The aqueous solution was made basic, extracted with ether (3 X) , the extracts dried, and the solvent evaporated to give an orange oil (0.4 g) . The aqueous fraction was acidified and the solvent evaporated. The residue was dissolved in DMF (30 mL) and heated at 140- 150 °C for 1 h. The solvent was evaporated, the residue dissolved in H2O, the solution made basic and extracted with ether. The extracts were dried and evaporated to give an oil (0.3 g) that was combined with the previously obtained orange oil. The orange oil (0.7 g) was treated with sodium 4-methylpentyloxide (1.0 g Na, 25 L 4-methylpentan-l-ol ) and heated to 110-125 °C for 3 h. The solution was cooled, treated with H2O, and the solvents evaporated. The residue was suspended in H2O, acidified, and washed with ether. The aqueous solution was made basic, extracted with ether (3 X) , the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography (5 % EtOH-0.5 % NH4OH- CHCI3) to give the pure endo isomer 45 (0.08 g) that was converted to the hydrochloride salt and recrystallized from EtOAc-ether, m.p. 140-142 °C . ( 909-ZA1-274, analytical, 306635) Further elution gave exo isomer 46 (0.4 g) that was converted to the oxalate salt and recrystallized from EtOAc- MeOH to give a white solid, m.p. 94-96 °C (+, -)-endo-6-(3-Butylthio-l,2,5-thiadiazo-4-yl)-l- azabicvclo [3.2. lloctane (47) and (+,-) -exo-6- (3-butylthio- l,2,5-thiadiazo-4-yl) -1-azabicvclo [3.2. lloctane (48) : A solution of 6-methoxycarbonyl-l-azabicyclo [3.2.1] octane (1.58 g, 0.0093 mol) in THF (20 mL) was cooled in a dry ice- acetone bath with stirrring. A solution of 2 M LDA in THF (5.14 mL, 0.0103 mol) was added dropwise and stirring continued for 1 h. A solution of 25 (2.15 g, 0.0103 mol) in THF (20 mL) was added to the reaction dropwise. After 35 min, cooling was removed, the reaction warmed to 45 °C for 1.5 h, and the reaction quenched by the addition of H2O. The solvents were evaporated, the residue suspended in 1 N HCl, and the mixture extracted with ether. The aqueous phase was made basic, extracted with ether (3X) , the extracts dried, and the solvent evaporated to give an orange oil (2.85 g) . ( 909-ZA1-275 ) The oil (1.82 g) was dissolved in 9 N HCl (110 mL) and heated to reflux for 3 days. The solvent was evaporated, the residue dissolved in H2O (20 mL) , and the solution extracted with ether. The aqueous solution was made basic, extracted with ether (3 X), the extracts dried, and the solvent evaporated to give an oil (0.85 g) . Purification by radial chromatography (5 % EtOH- 0.5 % NH4OH-CHCI3) gave the pure endo isomer 47 (0.58 g) followed by a mixture of the the endo and exo isomer (47 + 48) that were identical by NMR to the previously prepared materials obtained by the patented method. (+, -)-7-(3-Butyloxy-l,2,5-thiadiazo-4-yl)-l- azabicvclo[4.3.01 onane (49): A solution of 6- ethoxycarbonyl-1-azabicyclo [4.3.1] nonane (1.8 g, 0.009 mol) (Ref J. Org. Chem. 1977. 42, 909-910) in THF (50 mL) was cooled in a dry ice-acetone bath with stirrring. A solution of 2 M LDA in THF (5.9 mL, 0.0118 mol) was added dropwise and stirring continued for 1 h. A solution of 4 (2.4 g, 0.0103 mol) in THF (20 mL) was added to the reaction dropwise. After 15 min, cooling was removed, the reaction stirred for 1 h, and the reaction quenched by the addition of H2O. The solvents were evaporated, the residue suspended in 1 N HCl, and the mixture extracted with ether. The aqueous phase was made basic, extracted with EtOAc (3X) , the extracts dried, and the solvent evaporated. The residue was purified by raidial chromatography (40 % EtOAc-hexane) to give a mixture of the endo and exo esters as an oil (0.95 g) . (C76-2ZT-37) The oil (0.5 g) was dissolved in cone HCl (25 mL) and heated to reflux for 6 h. The solvent was evaporated and residue dried in vacuo over night. The residue was dissolved in DMF (10 mL) and heated to 140-150 °C for 45 min. The solvent was evaporated, the residue treated with ice-water, the solution made basic, and the mixture extracted with CHCI3 (3 X) . The extracts were dried, the solvent evaporated, and the residue purification by radial chromatography (2.5 % EtOH-0.25 % NH4OH-CHCI3 ) to give 49 (0.1 g). The oxalate salt crystallized from EtOAc to give a white solid, m.p. 98-99.5 °C

Claims: We Claim: 1. A process for preparing a compound of the formula 9 : comprising contacting a compound of the formula 8 with lithium diisopropylamide (LDA) ; wherein n is 0,1,2,3; m is 1,2,3; 2 R is selected from the group consisting of halo, C.-C 8 A 8 5 6 7 alkyl, R 0, RS, R NR R , aryl, and substituted aryl; z is a leaving group; 3 . 9 R is selected from the group consisting of C0 2 R and CN; R is C- ^ -C 8 alkyl; R is C- ^ -C 8 alkyl; 6 R is hydrogen or C^C g alkyl; 7 R .is hydrogen or C- ^ -C 8 alkyl; 8 R is C j^ -C 8 alkyl; 9 R is hydrogen or C 1 -C 3 alkyl . 2. A process for preparing a compound of the formula 10 : comprising hydrolysing a compound of the formula 9 2 R is selected from the group consisting of halo, C.-C 8 4 8 5 6 7 alkyl, R 0, RS, R NR R , aryl, and substituted aryl; 3 9 R is selected from the group consisting of -C0 2 R and -CN. 3. A process as claimed by Claim 1 wherein z is a sulfone. 4. A process as claimed by Claim 1 wherein z is chloro . 2 5. A process as claimed by Claim 3 wherein R is 8 R S. 2 , 6. A process as claimed by Claim 3 wherein R is 4 R 0.

Inventors: MERRITT LEANDER, WARD JOHN STANLEY, MERRITT, LEANDER, WARD, JOHN, STANLEY
Applicants: LILLY CO ELI, MERRITT LEANDER, WARD JOHN STANLEY, ELI LILLY AND COMPANY, MERRITT, LEANDER, WARD, JOHN, STANLEY
Application year: 1998
Main classification: C07D221
IPC codes: C07D453, C07D471, C07D487