PROCESS FOR PREPARING HETEROCYCLIC COMPOUNDS

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

Description: Title PROCESS FOR PREPARING HETEROCYCLIC COMPOUNDS Field of the Invention The present invention relates to a process for preparing azabicyclic compounds useful for modulating a muscarinic receptor. Background of the Invention 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. Summary of the Invention It is an obj ect of the invention to provide a new process for preparing compounds having muscarinic cholinergic receptor activity 1:1 endo/exo Mostly eκo (9:1) (40% from HAA) R is selected from the group consisting of halo, C.-C 9 4 8 5 6 7 alkyl, R O, R S, R NR R , aryl, and substituted aryl; z is a leaving group; 1 R is C 1 -C 6 alkyl or hydrogen.. Detailed Description 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-Cβ alkyl groups include methyl, ethyl, n-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, C -Cζ alkyl, NO 2 , halogen, halogen(Cι-C6) alkyl, halogen (C 2 -C6. alkenyl , C2-C6 alkenyl , CO 2 R 20 , (C1-C6 alkyl) a ino, -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-i5-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=CH2), 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 -C 6 . 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-1-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 , trichloro ethyl, 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 -C1 0 alkanoyl" represents a group of the formula C(O) (C 1 -C 9 ) alkyl. Typical C 2 -C 10 alkanoyl groups include acetyl, propanoyl , butanoyl, and the like. The term " (Cι-C 6 alkyl) amino" refers to a monoalkylamino group. Examples of such groups are methylamino, ethylamino, iso-propylamino, π-propylamino, ( n- propyl) amino, ( iso-propyl ) amino, n-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 (Cs-Cn 1 ) 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, C1-C 6 alkyl, NO 2 , halogen, halogen (Ci-C δ ) alkyl, halogen (C 2 -C 6 ) alkenyl , C 2 -C 6 alkenyl, C0 2 R 20 , (Ci-Cβ alkyl) amino, -SR 20 , and OR 20 ; wherein R 20 is selected from the group consisting of Cι_i 5 -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 C3-C8 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, C 1 -C. 6 alkyl, NO 2 , halogen, halogen (Ci-Cβ) alkyl, halogen (C 2 -C 6 ) alkenyl , C 2 -C 6 alkenyl, COR 20 , C2-C10 alkanoyl, C 7 -C 16 arylalkyl, CO 2 R 20 , (Ci-Cβ 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 C5-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-6 -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, O, . 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 C1-C 6 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, Cι-15-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:: W i s O or S As used m the above-illustrated scheme R is selected from . 8 5 6 7 the group consisting of halo, C j -C j alkyl, R 0, RS, 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; E) R 2 is R 8 S; F) R is C χ -C 6 alkyl; G) R is C χ -C 6 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. Preparation of (3 ' R) -ethyl-2- (piperidin-3-yl) acetate (C76- 2ZT-104A, 306684) : Ethyl-3 -pyridylacetate (100 g, 0.606 mol) was dissolved in EtOH (2B, 1.8 L), treated with 5 %- Rh/Al 2 0 3 (100 g) and hydrogenated at 60 °C and 60 psi H 2 overnight (ref. 518-4ZU-181) . Catalyst was removed by filtration and solvent evaporated to give a brown liquid (101.4 g, 98 %). The brown liquid was dissolved in EtOAc (600 mL) and treated with L- (+) -mandelic acid in warn EtOAc (600 mL) . After cooling in the refrigerator for 4 h (ca 7 °C) , the solid was collected and the crystallization fluid reserved for processing to the other enantiomer, designated 104B. The solid (designated 104A) was again recrystallized from EtOAc (1.15-1.2 L, over night at ambient) . The material was recrystallized twice more from EtOAc (1.55-1.6 L, over night ambient) to give 306684 as white needles, 81.6 g, 41 % yield, O.R.(EtOH) @589 n = 44.9 °, @365 ran =173.73 °, m.p. 118-119 °C . The chiral hplc analysis of this material is described below. Resolution of (3 ' S) -ethyl-2- (piperidin-3-γl) acetate (C76- 2ZT-104B, 306685) : The crystallization fluid from the initial crystallization of 104A was evaporated to give a dark oil (100.3 g) . This was dissolved in a cold solution of K 2 C0 3 (52 g, 0.377 mol) in H 2 0 (250 mL) and extracted with EtOAc (5 X 150 mL) . The extracts were combined, dried (MgS0 4 ), and the solvent evaporated to give a dark liquid (40.25 g) . The dark liquid was treated with a warm solution of D- (-) -mandelic acid (36 g) in EtOAc (650 mL) and cooled at ambient over night. The crystals were recrystallized twice more from EtOAc (1.2 L and 1.1 L, respectively) to give 306685 as white needles, 48.7 g, 24.9 % yield, O.R. (EtOH) ©589 nm = -43.14 °, (2365 nm = -164.31 °, m.p. 115.5- 117 °C. Chiral analytical method; Cold aqueous K 2 C0 3 (0.15 g K 2 C0 3 , 10 mL H 2 0) was treated with 0.3 g of the mandelic acid salt and the mixture extracted with EtOAc (3 X 5 mL) . The combined extracts were dried (MgSO^ and the solvent evaporated. The residue was dissolved in ether (10 mL) and treated with S- ( -) -a-methylbenzyl isocyanate (0.12 mL, Aldrich) . After 2.5 h, the reaction was treated with 1 N HC1 (2 mL) . The ether was separated, washed with brine, saturated aqueous NaHC0 3 , brine, dried (MgSO^, and the solvent evaporated. The residue was analyzed on a CHIRACEL OJ hplc column (4.6 X 250) eluting with 5 % EtOH/hexane at a flow rate of 2.5 mL/min. The slower component comes from the L- (+) -mandelic acid salt and the faster from the D-(-)- mandelic acid salt. HPLC analysis of final crystallization products of both enantiomers show less than 3 % of the opposite enantiomer. It could be much better, but present HPLC analysis does not provide good enough resolution to determine much below this limit . Preparation of ( 3 ' R) -ethyl-2- TN- ( -butoxycarbonyl)piperidin- 3-yllacetate (C76-2ZT-106) : 306684 (10.9 g, 0.034 mol) was dissolved in aqueous 12 % K 2 C0 3 (50 mL) and the mixture extracted with CHC1 . The extracts were dried and the solvent evaporated. The residue was suspended in ether, filtered, and evaporated to give the free base (5.36 g) . The liquid was dissolved in ether (50 mL) and treated dropwise with di-t-butyl-dicarbonate (7.9 g) in ether (10 mL) . After stirring over night, the solution was cooled in an ice-water bath and treated with dropwise with saturated aqueous citric acid (25 mL) . The organics were separated and the the aqueous extracted with ether. The combined extracts were washed with H 2 0, aqueous NaHC0 3 , brine, dried, and the solvent evaporated to give C76-2ZT-106 (9.1 g) as a clear liquid that had the appropriate nmr data for the desired material. Preparation of (3 ' S) -ethyl-2- [N- ( t-butoxycarbonyl)piperidin- 3-yl]acetate (C76-2ZT-118) : 306685 (48.6 g, 0.15 mol) was treated with a solution of K 2 C0 3 (30 g, 0.217 mol) in H 2 0 (220 mL) and the resulting solution extracted with CHC1 (3 X 100 mL) . The extracts were dried (Na 2 S0 4 ) and the solvent evaporated. The residue was mixed with ether (200 mL) and filtered to remove some suspended solids . Evaporation of the ether gave a brownish liquid (25 g, Theory = 25.7 g) . The residue was dissolved in ether (200 mL) , cooled in an ice-water bath, and a solution of di-t-butyl-dicarbonate (31.8 g, 0.146 mol) in ether (25 mL) was added dropwise with stirring. Cooling was removed and the reaction was stirred over night. The solution was again cooled in ice-water and a solution of saturated aqueous citric acid (100 mL) was added dropwise. The organics were separated and the aqueous washed with ether (40 mL) . The combined organics were washed with brine, saturated aqueous NaHC0 3 , brine, dried (Na 2 S0 4 ), and the solvent evaporated to give C76-2ZT-118 as a clear liquid (38.6 g, theory = 39.6 g) . The nmr was consistent with the desired material. Preparation of (2S, 3'S) and (2R,3'S) ethyl-2- (4-butylthio- 1,2, 5-thiadiazo-4-yl) -2- TN- ( -butoxycarbonyl)piperidin-3- yllacetate (C76-2ZT-119A) : A solution of 1 M LiN(TMΞ) 2 (44 L, 0.44 mol) in THF was cooled to -25 °C and a mixture of the (3'S) -ethyl-2- [N- ( t-butoxycarbonyl ) piperidin-3- yl]acetate (5.4 g, 0.02 mol) and 3-chloro-4-.n-butylth.io- 1, 2, 5-thiadiazole (4.6 g, 0.022 mol) in THF (10 mL) was added dropwise at such a rate that the reaction temperature did not exceed -15 °C . The temperature was maintained at - 15 to -20 °C for 45 min then allowed to warm to -5°C. The reaction was then cooled to -15 °C, hexane (10 mL) was added, followed by dropwise addition of 2 N HC1 (25 mL) at such a rate that temperature did not exceed 2 °C . The organics were separated, washed with 2 N HC1 (12 mL) , brine, the solvent dried and evaporated to give a mixture of (2S, 3'S) and (2R,3'S) ethyl-2- ( 4-butylthio-l , 2 , 5-thiadiazo-4- yl) -2- [N- ( t-butoxycarbonyl ) piperidin-3-yl] acetate as a yellow oil (10.1 g) . Preparation of (2S, 3'S) and (2R, 3 ' S ) -2- (4-butylthio-l, 2 , 5- thiadiazo-4-yl) -2- TN- ( fc-butoxycarbonyl)piperidin-3- yllacetate (C76-2ZT-119B) : The oil from C76-2ZT-119A (10.1 g) was dissolved in EtOH (40 mL) , 1 N NaOH (30 mL) added, and the mixture stirred at 42-44 °C for 4 h. The EtOH was evaporated, the residue suspended in H 2 0, and the mixture extracted 2 X with ether. The aqueous solution was cooled in an ice-water bath and acidified with 1 N HC1 (30 mL) The mixture was extracted with ether, the extracts washed with brine, dried, and the solvent evaporated to give the carboxylic acid C76-2ZT-119B as yellow glass (6.79 g, theory = 8.32 g) . Preparation of (2S, 3'S) and (2R, 3 ' S) -2- (4-butylthio-l, 2 , 5- thiadiazo-4-yl) -2- TN- ( t-butoxycarbonyl )piperidin-3- yllethanol: The glass from C76-2ZT-119B (6.79 g) was dissolved in dry THF (35 mL) and cooled to -22 °C . To the cold solution was added 1 M BH 3 (33 mL, 0.033 mol, i.e. 2 mol-equivalents) in THF dropwise at such a rate that temperature did not exceed -15 °C. Cooling was removed and when the reaction temperature rose to -5 °C the reaction was cooled in an ice-water bath for 45 min. The cooling was removed and after 1.5 h, the reaction cooled to -5 °C and the excess BH 3 destroyed by careful dropwise addition of H 2 0 (25 mL) . Cooling was removed and after 30 min, the THF was evaporated and the residue extracted with EtOAc (3 X 50 mL) . The extracts were washed with brine, dried, and the solvent evaporated to give a yellow oil (6.8 g) . The oil was purified by hplc using an 8 L gradient going from hexane to 50 % EtOAc to give C76-2ZT-122A as an oil (4.03 g, theory = 6.55 g, 63 %) that is a mixture of the expected diastereomeric alcohols by nmr. Preparation of (2S. 3'S) and (2R, 3 'S) -2- (4-butylthio-l, 2 , 5- thiadiazo-4-yl, -2- _N- ( t-butoxycarbonyl )piperidin-3- yllethanol mesylate) ; The diastereomeric alcohols, C76-2ZT- 122A (4.03 g) , were dissolved in EtOAc (35 mL) , the solution cooled to -22 °C, and triethylamine (4.3 mL) was added. To the reaction was added a solution of methanesulfonyl chloride (1.2 mL, 0.0154 mol) in EtOAc (4 mL) , at such a rate that the temperature did not exceed -15 °C. After another 45 min, 1 N HC1 (27 mL) was added at such a rate that temperature did not exceed 0 °C . The organics were separated and the aqueous solution washed with EtOAc. The combined organics were washed with 1 N HC1 (13 mL) , brine, the solvent dried and evaporated to give the mesylates as a yellow oil ( 5 g) . (5S, 6R) -endo-6- (3-Butylthio-l, 2, 5-thiadiazo-4-yl) -1- azabicyclo [3.2.11 octane, 320819 and (5S, 6S) -exo-6- (3- butylthio-1,2, 5-thiadiazo-4-yl) -1-azabicyclo [3.2.1] octane, 320351: The mesylates C76-2ZT-122B (5 g) were dissolved in EtOAc (40 mL) and the solution cooled to 10-15 °C when dry HC1 was bubbled into the solution for approximately 5 min while maintaining the temperture below 22 °C . After another 5 min., the reaction was cooled to 15 °C and H 2 0 (20 mL) was added dropwise while maintaining the temperture below 25 °C. When the mixture was again at 15 °C, a 1:1 weight : volume mixture of K 2 C0 3 -H 2 0 (30 mL) was added dropwise to give a mixture with pH > 9. Cooling was removed and after 1 h, organics were separated. The pH of the aqueous solution was adjusted to >11 and extracted with EtOAc. The combined organics were dried and the solvent evaporated to give a 1:1 mixture as a yellow oil (2.75 g) . A portion of the mixture (1.5 g) was purified by radial chromatography (10 % EtOH-1 % NH 4 0H-CHC1 3 ) to first elute 320351 that was converted to an oxalate salt (298452) and recrystallized from EtOAc (0.75 g) , OR (EtOH) @ 589 nM = 23.68 °, @ 365 nM = 21.32 °. Further elution (20 % EtOH-2 % H4OH-CHCI3) gave 320819 that was converted to an HC1 salt (306869) and recrystallized from EtOAc (0.29 g) , OR (EtOH) @ 589 nM = -82.35 °, @ 365 nM = -201.18 °, m.p. 198-199 °C . Epimerization of the 1:1: A solution of a 1:1 mixture of 320819 and 320351 (2.75 g) in EtOH (5-10 mL) was added to a solution of sodium ethoxide (2.2 g Na, 70 mL EtOH) and the mixture heated to reflux for two days . The solvent was evaporated, the residue treated with cold water, and the mixture extracted with CHC1 3 (3 X 50 mL) . The extracts were dried and the solvent evaporated to give a yellow liquid (2.45 g) . The oxalate salt crystallized from EtOAc, OR in EtOH589 nM = 23.68 °, (2365 nM = 21.32 °. Preparation of (2S, 3'R) and (2R,3'R) ethyl-2- (4-butylthio- 1,2, 5-thiadiazo-4-yl) -2- [N- ( t-butoxycarbonyl . piperidin-3- yll acetate: A solution of 1 M LiN(TMS) (44 L, 0.44 mol) in THF was cooled to -25 °C and a mixture of the ( ' R) - ethyl-2- [N- ( t-butoxycarbonyl) piperidin-3-yl] acetate (5.4 g, 0.02 mol) and 3-chloro-4-r_-butylthio-l , 2 , 5-thiadiazole (4.6 g, 0.022 mol) in THF (10 mL) was added dropwise at such a rate that the reaction temperature did not exceed -15 °C . The temperature was maintained at -15 to -20 °C for 45 min then allowed to warm to -10°C. The reaction was then cooled to -15 °C, hexane (10 mL) was added, followed by dropwise addition of 2 N HCl (26 mL) at such a rate that temperature did not exceed 2 °C . The organics were separated, washed with 2 N HC1 (13 mL), brine, the solvent dried and evaporated to give a mixture of (2S, 3'R) and (2R,3'R) ethyl-2- ( 4-butylthio-l, 2 , 5-thiadiazo-4-yl ) -2- [N- ( t- butoxycarbonyl) piperidin-3-yl] acetate as a yellow oil (10 g) . Preparation of (2S, 3'R) and (2R, 3 'R) -2- (4-butylthio-l, 2, 5- thiadiazo-4-yl) -2- TN- ( fc-butoxycarbonyl)piperidin-3- ylT acetate: The oil from C76-2ZT-108A (10 g) was dissolved in EtOH (40 mL) , 1 N NaOH (30 mL) added, and the mixture stirred at 40 °C for 5 h. The EtOH was evaporated, the residue suspended in H 2 0, and the mixture extracted 2 X with ether. The aqueous solution was cooled in an ice-water bath and acidified with 1 N HC1 (30 mL) The mixture was extracted with ether, the extracts washed with brine, dried, and the solvent evaporated to give the carboxylic acid C76- 2ZT-108B as yellow glass (6.55 g, theory = 8.32 g) . Preparation of (2S, 3'R) and (2R, 3 'R) -2- (4-butylthio-l, 2, 5- thiadiazo-4-yl) -2- [N- ( t-butoxycarbonyl )piperidin-3- yllethanol: The glass from C76-2ZT-108B (6.55 g) was dissolved in dry THF (30 mL) and cooled to -28 °C . To the cold solution was added 1 M BH (39 mL, 0.039 mol, i.e. 2.5 mol-equivalents) in THF dropwise at such a rate that temperature did not exceed -25 °C . The temperature was then allowed to rise to 0 °C over 1 h. The cooling was removed and after 2.5 h, the reaction cooled to -5 °C and the excess BH 3 destroyed by careful dropwise addition of H 0 (30 mL) . Cooling was removed and after 1 h, the THF was evaporated and the residue extracted with EtOAc (3 X 50 mL) . The extracts were washed with brine, dried, and the solvent evaporated to give a yellow oil (6.1 g) . The oil was purified by hplc using an 8 L gradient going from hexane to 50 % EtOAc to give C76-2ZT-110A as an oil (3.5 g) that is a mixture of the expected diastereomeric alcohols by nmr. Preparation of (2S, 3'R) and (2R, 3 'R) -2- (4-butylthio-l, 2, 5- thiadiazo-4-yl) -2- [N- ( t-butoxycarbonyl )piperidin-3- yllethanol mesylate : The diastereomeric alcohols, C76-2ZT- 110A (3.5 g) , were dissolved in EtOAc (35 mL) , the solution cooled to -22 °C, and triethylamine (3.7 mL) was added. To the reaction was added a solution of methanesulfonyl chloride (1.0 mL) in EtOAc (4 mL) , at such a rate that the temperature did not exceed -15 °C . After another 45 min, 1 N HCl (23.5 mL) was added at such a rate that temperature did not exceed 0 °C . The organics were separated and the aqueous solution washed with EtOAc. The combined organics were washed with 1 N HCl (12 mL) , brine, the solvent dried and evaporated to give the mesylates C76-2ZT-110B as a yellow oil (4.6 g) . (5R, 6S) -endo-6- (3-Butylthio-l, 2, 5-thiadiazo-4-yl) -1- azabicyclor3.2.1] octane, 320818 and (5R, 6R) -exo-6- (3- butylthio-1, 2, 5-thiadiazo-4-yl) -1-azabicyclo [3.2.1] octane: The mesylates C76-2ZT-110B (4.6 g) were dissolved in EtOAc (40 mL) and the solution cooled to 10-15 °C when dry HCl was bubbled into the solution for approximately 5 min while maintaining the temperture below 22 °C . After another 5 min., the reaction was cooled to 5 °C and H 0 (20 mL) was added dropwise while maintaining the temperture below 20 °C. When the mixture was again at 15 °C, a 1:1 weight : volume mixture of K 2 C0 3 -H 2 0 (30 mL) was added dropwise to give a mixture with pH > 9. Cooling was removed and after 1 h, organics were separated. The pH of the aqueous solution was adjusted to >11 and extracted with EtOAc. The combined organics were dried and the solvent evaporated to give a 1:1 mixture of 320818 and the free base of 298828 as a yellow oil (2.4 g) . The diastereomers were separated by radial chromatography (10 % EtOH-1 % NH 4 0H-CHC1 3 ) to first elute (5R, 6R) -exo-6- ( 3-butylthio-l , 2, 5-thiadiazo-4-yl ) -1- azabicyclo [3.2.1] octane that was converted to an oxalate salt (298828) and recrystallized from EtOAc (1.12 g) , OR (EtOH) (2589 nM = -26.86, (2365 nM = -24.90. Further elution gave 320818 that was converted to an HCl salt (306868) and recrystallized from EtOAc (0.49 g) , OR (EtOH) (2589 nM = 83.68, (2365 nM = 205.86, m.p. 198-199 °C . Preparation of (2S, 3'R) and (2R,3'R) ethyl-2- (4-n-butoxy- 1,2, 5-thiadiazo-4-yl) -2- „N- ( -butoxycarbonyl .piperidin-3- yll acetate: A solution of 1 M LiN(TMS) 2 (27 mL, 0.27 mol) in THF was cooled to -27 °C and a mixture of the ( 3 ' R) - ethyl-2- [N- ( t-butoxycarbonyl ) piperidin-3-yl] acetate (3.4 g, 0.0126 mol) and 3 -chloro-4-n-butoxy-l , 2 , 5-thiadiazole (2.66 g, 0.0138 mol) in THF (5 mL) was added dropwise at such a rate that the reaction temperature did not exceed -15 °C. The temperature was maintained at -15 to -20 °C for 45 min then allowed to warm to -10°C. The reaction was then cooled to -15 °C, hexane (10 mL) was added, followed by dropwise addition of 2 N HCl (16 mL) at such a rate that temperature did not exceed 2 °C . The organics were separated, washed with 2 N HCl (8 mL) , brine, the solvent dried and evaporated to give a mixture of (2S, 3'R) and (2R,3'R) ethyl-2- (4-n- butoxy-l,2,5-thiadiazo-4-yl) -2-[N-(t- butoxycarbonyl)piperidin-3-yl] acetate as a yellow oil (6.13 g ) • Preparation of (2S, 3'R) and (2R, 3 'R) -2- (4-rt-butoxy-l, 2 , 5- thiadiazo-4-yl) -2- [N- ( t-butoxycarbonyl )piperidin-3- yll acetate: The oil from C76-2ZT-247A (6.13 g) was dissolved in EtOH (25 mL) , I N NaOH (19 mL) added, and the mixture stirred at 35-40 °C for 4 h. The EtOH was evaporated, the residue suspended in H 2 0, and the mixture extracted 2 X with ether. The aqueous solution was cooled in an ice-water bath and acidified with 1 N HCl (20 mL) The mixture was extracted with ether, the extracts washed with brine, dried, and the solvent evaporated to give the carboxylic acid as yellow glass (3.6 g) . Preparation of (2S, 3'R) and (2R, 3 'R) -2- (4-n-butoxy-l, 2 , 5- thiadiazo-4-yl) -2- [N- ( -butoxycarbonyl)piperidin-3- yllethanol: The glass from C76-2ZT-247B (3.6 g) was dissolved in dry THF (25 L) and cooled to -22 °C . To the cold solution was added 1 M BH 3 (18 mL, 0.018 mol) in THF dropwise at such a rate that temperature did not exceed -14 °C . The temperature was then allowed to rise to 0 °C over 1 h. The cooling was removed and after 1.5 h, the reaction cooled to -5 °C and the excess BH 3 destroyed by careful dropwise addition of H 2 0 (15 mL) . Cooling was removed and after 1 h, the THF was evaporated and the residue extracted with ether. The extracts were washed with aqueous NaHC0 3 , brine, dried, and the solvent evaporated to give a yellow oil (3 g) . The oil was purified by hplc eluting with 20 % EtOAc-heptane to give C76-2ZT-249A as an oil (1.46 g) that is a mixture of the expected diastereomeric alcohols by nmr. Preparation of (2S, 3'R) and (2R, 3 'R) -2- (4-n-butoxy-l, 2, 5- thiadiazo-4-yl) -2- _N- ( -butoxycarbonyl)piperidin-3- yl] ethanol mesylate : The diastereomeric alcohols, C76-2ZT- 249A (1.46 g) , were dissolved in EtOAc (15 mL) , the solution cooled to -22 °C, and triethylamine (1.5 mL) was added. To the reaction was added a solution of methanesulfonyl chloride (0.44 mL) in EtOAc (2 mL) , at such a rate that the temperature did not exceed -15 °C . After another 45 min, 1 N HCl (10 mL) was added at such a rate that temperature did not exceed 0 °C . The organics were separated and the aqueous solution washed with EtOAc. The combined organics were washed with 1 N HCl (5 mL) , brine, the solvent dried and evaporated to give the mesylates as a yellow oil (1.9 g ) • Preparation of (5R, 6R) -exo-6- ( 3-n-butoxy-l, 2, 5-thiadiazo-4- yl) -l-azabicyclo[3.2.11 octane: The mesylates C76-2ZT-249B (1.9 g) were dissolved in EtOAc (20 mL) and the solution cooled to 10-15 °C when dry HCl was bubbled into the solution for approximately 5 min while maintaining the temperture below 25 G C . After another 5 min., the reaction was cooled to 15 °C and H 2 0 (8 mL) was added dropwise while maintaining the temperture below 25 °C . When the mixture was again at 15 °C, a 1:1 weight : volume mixture of K 2 C0 3 -H 2 0 (15 mL) was added dropwise to give a mixture with pH > 9. Cooling was removed and after 1 h, organics were separated. The pH of the aqueous solution was adjusted to >11 and extracted with EtOAc. The combined organics were dried and the solvent evaporated to give a mixture of diastereomers as a yellow oil (0.95 g) . The oil was dissolved in 1-butanol (5 mL) and added to a solution of sodium-1-butoxide (0.6 g Na, 15 mL 1-butanol) and the reaction heated to 95-105 °C for 5.5 h. The reaction was cooled, treated with 5 N HCl (6 mL) and the solvent evaporated. The residue was suspended in H 2 0, the solution made basic, and the mixture extracted with EtOAc. The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography (10 % EtOH-1 % NH 4 0H-CHC1 3 ) to give a clear oil that was converted to an HCl salt and recrystallized from acetone (0.6 g) , OR (EtOH) (2589 nM = -23.31, (2365 nM = -48.78, m.p. 185-186 C. Preparation of (2S, 3'S) and (2R,3'S) ethyl-2- (4-n-butoxy- 1,2, 5-thiadiazo-4-yl) -2- TN- ( t-butoxycarbonyl)piperidin-3- yl] acetate: A solution of 1 M LiN(TMS) (44 mL, 0.044 mol) in THF was cooled to -25 °C and a mixture of the (3 ' S) - ethyl-2- [N- ( t-butoxycarbonyl) piperidin-3-yl] acetate (5.4 g, 0.02 mol) and 3-chloro-4-n-butoxy-l , 2 , 5-thiadiazole (4.25 g, 0.022 mol) in THF (5 mL) was added dropwise at such a rate that the reaction temperature did not exceed -14 °C . The temperature was maintained at -15 to -20 °C for 45 min then allowed to warm to -5°C over 1 h. The reaction was then cooled to -15 °C, hexane (10 mL) was added, followed by dropwise addition of 2 N HCl (25 mL) at such a rate that temperature did not exceed 2 °C . The organics were separated, washed with 2 N HCl (12 mL) , brine, the solvent dried and evaporated to give a mixture of (2S, 3'S) and (2R,3'S) ethyl-2- (4-n-butoxy-l , 2 , 5-thiadiazo-4-yl) -2-[N-(t- butoxycarbonyl)piperidin-3-yl] acetate as a yellow oil (9.1 g ) • Preparation of (2S, 3'S) and (2R, 3 'S) -2- (4-n-butoxy-l, 2 , 5- thiadiazo-4-yl) -2- [N- ( -butoxycarbonyl)piperidin-3- yll acetate: The oil from C76-2ZT-274A (9.1 g) was dissolved in EtOH (40 mL) , 1 N NaOH (30 mL) added, and the mixture stirred at 40-45 °C for 3.5 h. The EtOH was evaporated, the residue suspended in H 2 0, and the mixture extracted 2 X with ether. The aqueous solution was cooled in an ice-water bath and acidified with 1 N HCl (32 L) The mixture was extracted with ether, the extracts washed with brine, dried, and the solvent evaporated to give the carboxylic acid as yellow glass (6.4 g) . Preparation of (2S, 3'S) and (2R.3 ' S) -2- (4-n-butoxy-l, 2 , 5- thiadiazo-4-yl) -2- [N- ( -butoxycarbonyl)piperidin-3- yllethanol : The glass from C76-2ZT-274B (6.4 g) was dissolved in dry THF (35 mL) and cooled to -22 °C . To the cold solution was added 1 M BH 3 (33 mL, 0.033 mol) in THF dropwise at such a rate that temperature did not exceed -15 °C . The temperature was then allowed to rise to 0 °C over 1 h. The cooling was removed and after 16 h, the reaction cooled to -5 °C and the excess BH 3 destroyed by careful dropwise addition of H 2 0 (25 mL) . Cooling was removed and after 1.5 h, the THF was evaporated and the residue extracted with ether. The extracts were washed with aqueous NaHC0 3 , brine, dried, and the solvent evaporated to give a yellow oil (5.6 g) . The oil was purified by hplc eluting with 20 % EtOAc-heptane to give C76-2ZT-275A as an oil (3.92 g) that is a mixture of the expected diastereomeric alcohols by nmr. Preparation of (2S, 3'S) and (2R, 3 'S) -2- (4-n-butoxy-l, 2, 5- thiadiazo-4-yl) -2- [N- ( -butoxycarbonyl)piperidin-3- yl]ethanol mesylate : The diastereomeric alcohols, C76-2ZT- 275A (3.92 g) , were dissolved in EtOAc (50 mL) , the solution cooled to -22 °C, and triethylamine (4 mL) was added. To the reaction was added a solution of methanesulfonyl chloride (1.2 mL) in EtOAc (6 mL) , at such a rate that the temperature did not exceed -15 °C. After another 45 min, 1 N HCl (25 mL) was added at such a rate that temperature did not exceed 0 °C . The organics were separated and the aqueous solution washed with EtOAc. The combined organics were washed with 1 N HCl (12 mL) , brine, the solvent dried and evaporated to give the mesylates C76-2ZT-275B as a yellow oil (5 g) . Preparation of ( 5S, 6S) -exo-6- ( 3-n-butoχy-l, 2, 5-thiadiazo-4- yl) -l-azabicycloπ .2.1] octane: The mesylates C76-2ZT-275B (5 g) were dissolved in EtOAc (40 mL) and the solution cooled to 10-15 °C when dry HCl was bubbled into the solution for approximately 5 min while maintaining the temperture below 22 °C . After another 5 min., the reaction was cooled to 15 °C and H 2 0 (20 mL) was added dropwise while maintaining the temperture below 25 °C . When the mixture was again at 15 °C, a 1:1 weight : volume mixture of K 2 C0 ~H 2 0 (30 mL) was added dropwise to give a mixture with pH > 9. Cooling was removed and after 1 h, organics were separated. The pH of the aqueous solution was adjusted to >10 and extracted with EtOAc. The combined organics were dried and the solvent evaporated to give a mixture of diastereomers as a yellow oil (2.7 g) . The oil was dissolved in 1-butanol (10 mL) and added to a solution of sodium-1-butoxide (1.5 g Na, 40 mL 1-butanol) and the reaction heated to 95-100 °C for 6 h. The reaction was cooled, treated with 5 N HCl (15 mL) and the solvent evaporated. The residue was suspended in H 2 0, the solution made basic, and the mixture extracted with EtOAc. The extracts were dried and the solvent evaporated to give an oil (2.45 g) . The exo and endo isomers were separated by radial chromatography (10 % EtOH-l % NH 4 0H-CHC1 3 ) to give the exo isomer as a clear oil that was converted to an HCl salt and recrystallized from acetone (0.6 g) , OR (EtOH) (2589 nM = -23.31, (2365 nM = -48.78, m.p. 185-186 C. Preparation of (2S, 3'S) and (2R,3'S) βthyl-2- (4-n- pentyloxy-1,2, 5-thiadiazo-4-yl) -2- TN- ( t- butoxycarbony1)piperidin-3-yl] acetate : A solution of 1 M LiN(TMS) 2 (33 mL, 0.033 mol) in THF was cooled to -25 °C and a mixture of the (3 ' S) -ethyl-2- [N- ( t- butoxycarbonyl) piperidin-3-yl] acetate (4.05 g, 0.015 mol) and 3-chloro-4-n-pentyloxy-l, 2 , 5-thiadiazole (3.42 g, 0.0165 mol) in THF (5 mL) was added dropwise at such a rate that the reaction temperature did not exceed -15 °C . The temperature was maintained at -15 to -20 °C for 45 min then allowed to warm to -5°C over 1 h. The reaction was then cooled to -15 °C, hexane (10 mL) was added, followed by dropwise addition of 2 N HCl (18 mL) at such a rate that temperature did not exceed 2 °C. The organics were separated, washed with 2 N HCl (10 mL) , brine, the solvent dried and evaporated to give a mixture of (2S, 3'S) and (2R, 3'S) ethyl-2- (4-n-pentyloxy-l, 2, 5-thiadiazo-4-yl) -2- [N- ( t-butoxycarbonyl )piperidin-3-yl] acetate as a yellow oil (7.25 g) . Preparation of (2S, 3'S) and (2R, 3 'S) -2- (4-n-penty oxy- 1,2, 5-thiadiazo-4-yl) -2- TN- ( t-butoxycarbonyl )pjperidin-3- yll acetate; The oil from C76-2ZT-277A (7.25 g) was dissolved in EtOH (30 mL), I N NaOH (23 mL) added, and the mixture stirred at 38-45 °C for 6 h. The EtOH was evaporated, the residue suspended in H 0, and the mixture extracted 2 X with ether. The aqueous solution was cooled in an ice-water bath and acidified with 1 N HCl (24 mL) The mixture was extracted with ether, the extracts dried, and the solvent evaporated to give the carboxylic acid as yellow glass (4.6 g ) • Preparation of (2S, 3'S) and (2R, 3 ' S) -2- (4-n-pentyloxy- 1,2, 5-thiadiazo-4-yl) -2- TN- ( -butoxycarbonyl)piperidin-3- yl]ethanol; The glass from C76-2ZT-277B (4.6 g) was dissolved in dry THF (30 mL) and cooled to -22 °C. To the cold solution was added 1 M BH 3 (22 mL, 0.022 mol) in THF dropwise at such a rate that temperature did not exceed -15 °C. The temperature was then allowed to rise to ambient temperature over night. The cooling was removed and after 16 h, the reaction cooled to -5 °C and the excess BH 3 destroyed by careful dropwise addition of H 2 0 (25 mL) . Cooling was removed and after 1.5 h, the THF was evaporated and the residue extracted with ether. The extracts were washed with aqueous NaHC0 3 , brine, dried, and the solvent evaporated to give a yellow oil (4 g) . The oil was purified by hplc eluting with 20 % EtOAc-heptane to give the title compound as an oil (2.23 g) that is a mixture of the expected diastereomeric alcohols. Preparation of (2S, 3'S) and (2R, 3 'S) -2- (4-n-pentyloxy- 1,2, 5-thiadiazo-4-yl) -2- TN- ( -butoxycarbonyl)piperidin-3- yllethanol mesylate; The diastereomeric alcohols, C76-2ZT- 278A (2.23 g) , were dissolved in EtOAc (30 mL) , the solution cooled to -22 °C, and triethylamine (2.2 mL) was added. To the reaction was added a solution of methanesulfonyl chloride (0.66 mL) in EtOAc (4 mL) , at such a rate that the temperature did not exceed -15 °C . After another 45 min, 1 N HCl (14 mL) was added at such a rate that temperature did not exceed 0 °C . The organics were separated and the aqueous solution washed with EtOAc. The combined organics were washed with 1 N HCl (7 mL) , brine, the solvent dried and evaporated to give the mesylates C76-2ZT-278B as a yellow oil. Preparation of (5S, 6S) -exo-6- (3-n-butoxy-l, 2, 5-thiadiazo-4- yl) -l-azabicyclor3.2.11 octane: The mesylates C76-2ZT-275B (5 g) were dissolved in EtOAc (40 mL) and the solution cooled to 10-15 °C when dry HCl was bubbled into the solution for approximately 5 min while maintaining the temperture below 22 °C. After another 5 min., the reaction was cooled to 15 °C and H 0 (20 mL) was added dropwise while maintaining the temperture below 25 °C. When the mixture was again at 15 °C, a 1:1 weight :volume mixture of K 2 C0 3 -H 0 (30 mL) was added dropwise to give a mixture with pH > 9. Cooling was removed and after 1 h, organics were separated. The pH of the aqueous solution was adjusted to >10 and extracted with EtOAc. The combined organics were dried and the solvent evaporated to give a mixture of diastereomers as a yellow oil (2.7 g) . The oil was dissolved in 1-butanol (10 mL) and added to a solution of sodium-1-butoxide (1.5 g Na, 40 mL 1-butanol) and the reaction heated to 95-105 °C for 5.5 h. ****** The reaction was cooled, treated with 5 N HCl (6 mL) and the solvent evaporated. The residue was suspended in H 2 0, the solution made basic, and the mixture extracted with EtOAc. The extracts were dried, the solvent evaporated, and the residue purified by radial chro atography (10 % EtOH-1 % NH 0H-CHC1 3 ) to give a clear oil that was converted to an HCl salt and recrystallized from acetone (0.6 g) , OR (EtOH) (2589 nM = -23.31, (2365 nM = -48.78, m.p. 185-186 C.

Claims: We Claim: 1. A process for preparing a compound of the formula 9 comprising hydrolyzing a compound of the formula wherein R is a nitrogen protecting group.

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: C07D417
IPC codes: C07D471