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INTERMEDIATE PRODUCTION EXAMPLE 27 (endo)-8-Azabicyclo[3.2.1]octan-3-ol Hydrochloride The title compound was obtained after acetylation from (endo)-8-methyl-8-azabicyclo[3.2.1]octan-3-ol in the same manner as in Intermediate Production Example 22.
Example 20 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid (endo-8-azabicyclo [3.2.1]oct-3-yl) ester (Compound 38) A suspension of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carbonyl chloride (1.3 g) and endo-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (1.0 g) in o-dichlorobenzene (5 ml) was heated at 180C for 1 hour under stirring. The reaction mixture was then allowed to cool and the solvent was removed by filtration. The crude product so obtained was washed with a little ethanol and crystallized from ethanol. 1.1 g of the desired product was obtained. M.p.>260C. MS (C.I.): 288 m/e [M + H]+
In 1,2-dichloro-benzene;
EXAMPLE 15 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid (endo-8-azabicyclo[3.2.1]oct-3-yl) ester (Compound 38) A suspension of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carbonyl chloride (1.3 g) and endo-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (1.0 g) in o-dichloro-benzene (5 ml) was heated at 180 C. for 1 hour under stirring. The reaction mixture was then allowed to cool and the solvent was removed by filtration. The crude product so obtained was washed with a little ethanol and crystallized from ethanol. 1.1 g of the desired product was obtained. M.p.>260 C.
endo-8-(N-Cyanoguanyl)-8-azabicyclo[3.2.1]octan-3-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In butan-1-ol;
Example 3 endo-8-(N-Cyanoguanyl)-8-azabicyclo[3.2.1]octan-3-ol A suspension of endo-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (2.0 g) and sodium dicyanamide (1.2 g) in n-butanol (6.25 ml) was heated at 140C for 2.5 hours. The reaction mixture was concentrated to dryness, the solid residue was taken up with water and the insoluble solid was collected by filtration. After washing accurately with water and after drying under vacuum 1.25 g of the desired product sufficiently pure were obtained. M.p. 197-200C.
endo-8-guanyl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 6 endo-8-guanyl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride A mixture of endo-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (10.0 g) and cyanamide (5.14 g) was heated with stirring for 3 hours at 120C and then allowed to cool. It was taken up with 30 ml of warm absolute ethanol, acidified with alcoholic HCl and the insoluble solid was collected by filtration. The desired product was crystallized from absolute ethanol. M.p. > 270C.
A mixture of the above nortropinol hydrochloride (from Step B) (325 mg, 2.00 mmol), the product from Intermediate 8 (200 mg, 0.5 mmol), molecular sieves (4 , 200 mg), DIEA (390 mg, 3.0 mmol) and sodium triacetoxyboride (0.64 g, 3.0 mmol) in dichloromethane (5 mL) was stirred overnight. The reaction was mixed with aq. Sat. sodium carbonate (20 mL), heated at 60 C. for 30 min, extracted with dichloromethane (2×20 mL). The dichloromethane solution was dried over sodium sulfate, filtered and evaporated. The residue was loaded on preparative TLC (1000 micron), developed with 10% [1/9 aq. NH4OH/MeOH]/DCM. The desired product was obtained as a white solid (120 mg). LC-MS: 507. Calc. C25H32F6N2O2: 506.
With triethylamine; In acetonitrile; at 20.0℃; for 16.0h;
Step 4: tert-butyl (3S)-3-([(3-endo)-3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl]carbonyl}amino)piperidine-1-carboxylate To a mixture of tert-butyl (3S)-3-[(4-nitrophenoxy)carbonyl]amino}piperidine-1-carboxylate (4.91 g, 0.0134 mol) and (3-endo)-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (2.00 g, 0.0122 mol) in acetonitrile (100.0 mL, 1.915 mol) was added triethylamine (5.11 mL, 0.0367 mol). After stirring at rt for 16 h, the reaction mixture was diluted with methylene chloride, washed with 1 N NaOH, brine, dried, and concentrated in-vacuo. The residue was purified on silica gel, eluding with 0 to 100% EtOAc in hexane, then 0 to 10% MeOH in methylene chloride, to give the desired product. LCMS (M+H)+=354.3.
With hydrogenchloride; In 1,4-dioxane; at 20.0℃; for 16.0h;
Step 2: (3-endo)-8-Azabicyclo[3.2.1]octan-3-ol hydrochloride tert-Butyl (3-endo)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (195 mg, 0.000858 mol) was treated with 10 mL of 4 M HCl in dioxane at rt for 16 h. After removal of the volatiles in-vacuo, the desired HCl salt was isolated and used directly in the next step. LCMS (M+H)+=128.2.
With hydrogenchloride; In 1,4-dioxane; acetonitrile; at 70.0℃; for 1.0h;
General procedure: Bicyclic amine 2: 8-Aza-bic clo[3.2.1]octan-3-olA solution of HCI (4N in dioxane, 0.82 mL, 3.27 mmol) was added to a suspension of 3- hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in acetonitrile. The mixture was stirred at 70C for 1 hour, cooled down and concentrated. The product (138 mg, 93%) was isolated as a hydrochloric acid salt.1 H NMR (600 MHz, CDCI3): 9.07 - 8.49 (m, 1 H), 3.94 (m, 2H), 3.85 (m, 1 H), 1 .97 - 1.74 (m, 6H), 1 .60 (t, 2H)
13
[ 124-63-0 ]
[ 14383-51-8 ]
[ 1361531-80-7 ]
Yield
Reaction Conditions
Operation in experiment
74.5%
With sodium hydroxide; In water; at 20.0℃;
Step 2. Preparation of (1R,3R,5S)-8-(methylsulfonyl)-8-azabicyclo[3.2.1]octan-3-ol To stirred solution of (1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (560 mg, 4.4 mmol) in 2M NaOH (22.0 mL, 44.0 mmol) was added methanesulfonyl chloride (0.55 mL, 7.04 mmol) over 10 minutes. The solution was stirred at room temperature for a further 15 hours. The reaction mixture was poured into EtOAc and the organic phase separated. The aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hexanes/EtOAc=2:1) to give the desired product (673 mg, 74.5%) as a white solid. 1H-NMR (400 MHz, CDCl3) delta 1.86 (2H, m), 2.01 (2H, m), 2.18 (2H, m), 2.29 (2H, m), 2.88 (3H, s), 4.14 (1H, m), 4.22 (2H, m).
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