* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With triethylamine In dichloromethane at 0 - 20℃; for 12 h;
enαto-8-Azabicyclo[3.2.1]octan-3-ol (3.6g, 28.3mmol) was dissolved in DCM (50ml) and cooled to O0C. Triethylamine (7.8ml, 56.7mmol) was added followed by addition of butyl dicarbonate (7.4g, 33.9mmol). The reaction mixture was warmed to ambient temperature and stirred for 12h. The reaction mixture was diluted with water. The organic layer was separated and washed with saturated citric acid (aq), water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to afford 3-enαto-hydroxy- 8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester as a white solid (6.45g, 28.4mmol, 100percent). M.S. (ESI) (m/z): 228 [M+H]+
97%
at 20℃;
Step 1: 3-endo-3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester To a stirred suspension of nortropine (1.272 g, 1 eq.) in tetrahydrofuran (25 mL) was added di-tert-butyl-dicarbonate (2.292 g, 1.05 eq.). The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue purified by column chromatography on silica gel eluding with a 1:0 to 4:1 gradient of dichloromethane/ethyl acetate, to yield 2.207 g (97percent) of the title compound as colourless solid. MS (m/e) 227.2 (M+)
97%
With triethylamine In dichloromethane at 20℃; for 16 h;
To a solution of (3-exo)-8-azabicyclo[3.2.1]octan-3-ol (0.95 g, 7.5 mmol) and triethylamine (1.7 mL, 12.2 mmol) in DCM (10 mL) was added di-tert-butyl dicarbonate (3.27 g, 15.0 mmol) portionwise and the resulting reaction mixture stirred at RT for 16 h. The reaction mixture was diluted with water then the organic layer was separated and washed with saturated citric acid (aq), water andbrine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford 1 .65 g (97percent yield) of the title compound as an off whitesolid.1H NMR (250 MHz, Chloroform-d): 6 [ppm] 4.41 - 3.95 (m, 3H), 2.00 - 1 .53 (m, 9H),1.45 (5, 9H).
93%
With sodium hydroxide In tetrahydrofuran at 20℃;
Compound 1 (10 g, 0.079 mol) was taken up in tetrahydrofuran (200 mL) followed by the addition of BOC-anhydride (17.2 g, 0.079 mol) in one portion. The solution was stirred at room temperature for overnight and then concentrated in vacuo to a brown solid. The crude product was taken up in 95percent dichloromethane/5percent) methanol and added to a pad of silica gel (elution with 95percent dichloromethane/5percent methanol). Fractions containing compound 2 were combined and concentrated to a white solid. Yield: 16.6 g (93percent); MS [M+H]+ 171.8 (M-56), 127.8 (M-100); 1HNMR (DMSO-d6) 54.59 (s, 1H), 3.98-3.91 (m, 3H), 2.11 (bs, 2H), 1.85 (m, 4H), 1.64 (m, 2H), 1.47 (s, 9H) ppm.
80%
at 20℃; for 1 h;
4j: (lS,3R,5R)-3-Hvdroxy-8-aza-bicvclo[3.2.1]octane-8-carboxylic acid tert-butyl ester O Nortropine (78 mmol) was dissolved in dry THF (250 mL), and di-tert-butyl-dicarbonate (82 mmol) was added. Stirred at ambient temperature for Ih. The solvent was removed by evaporation and the resisue recrystallized from ethyl acetate/heptane. The product was collected and dried in vacuo. Yield = 80percent 1H NMR (D6-DMSO): 1.38 (s, 9H); 1.61 (m, 2H); 1.70-1.93 (4H); 2.12 (m, 2H); 3.91 (br; IH); 3.99 (br, 2H); 4.58 (s, IH).
9 g
With triethylamine In ethanol at 25℃;
To a solution of (1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-ol (5.0 g) in ethanol (100 mL) was added TEA (11.0 mL) and Boc2O (10.0 mL). The resulting mixture was stirred at 25°C overnight, and then concentrated under reduced pressure to afford (1 R,3r,5S)-tert-butyl 3- hydroxy-8-azabicyclo[3.2.1 ]octane-8-carboxylate (9.0 g).
Reference：
[1] Patent: WO2007/63071, 2007, A1, . Location in patent: Page/Page column 15
[2] Patent: US2007/123525, 2007, A1, . Location in patent: Page/Page column 20
[3] Patent: WO2016/91776, 2016, A1, . Location in patent: Page/Page column 210; 211
[4] Patent: WO2014/152144, 2014, A1, . Location in patent: Paragraph 0190
[5] Patent: WO2009/106534, 2009, A1, . Location in patent: Page/Page column 73
[6] Organic and Biomolecular Chemistry, 2004, vol. 2, # 19, p. 2861 - 2869
[7] Patent: WO2006/18279, 2006, A2, . Location in patent: Page/Page column 63-64
[8] Patent: WO2007/93366, 2007, A1, . Location in patent: Page/Page column 104
[9] Patent: WO2013/16197, 2013, A1, . Location in patent: Page/Page column 90
[10] Patent: WO2015/181186, 2015, A1, . Location in patent: Page/Page column 156
[11] Patent: US9522906, 2016, B2, . Location in patent: Page/Page column 104
[12] Journal of the American Chemical Society, 2018, vol. 140, # 4, p. 1207 - 1210
3
[ 936701-56-3 ]
[ 143557-91-9 ]
Yield
Reaction Conditions
Operation in experiment
80%
at 20℃; for 72 h;
A mixture of endo-3-benzoyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (55.0 g, 166 mmol), potassium hydroxide (11.2 g 199 mmol) and ethanol (99percent, 400 ml) was stirred for 3 days at room temperature. Potassium benzoate was separated by filtration and the filtrate was evaporated. Diethylether (200 ml) was added and remaining potassium benzoate was separated by filtration and the filtrate was evaporated. The product was triturated with petroleum. Yield 30.0 g (80percent). Mp 139.5-140.8° C.
80%
at 20℃; for 72 h;
30 enc/o-3-Hvdroxy-8-aza-bicvclo[3.2.11octane-8-carboxylic acid fe/f-butyl esterA mixture of enc/o-3-benzoyloxy-8-aza-bicyclo[3.2.1 ]octane-8-carboxylic acid terf-butyl ester (55.0 g, 166 mmol), potassium hydroxide (1 1 .2 g 199 mmol) and ethanol (99percent, 400 ml) was stirred for 3 days at room temperature. Potassium benzoate was separated by filtration and the filtrate was evaporated. Diethylether (200 ml) was added and remaining potassium benzoate was separated by filtration and the filtrate was evaporated. The product was triturated with petroleum. Yield 30.0 g (80percent). Mp 139.5-140.8°C.
80%
at 20℃; for 72 h;
encto-3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid terf-butyl ester; A mixture of enc/o-3-benzoyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (55.0 g, 166 mmol), potassium hydroxide (1 1.2 g 199 mmol) and ethanol (99percent, 15 400 ml) was stirred for 3 days at room temperature. Potassium benzoate was separated by filtration and the filtrate was evaporated. Diethylether (200 ml) was added and remaining potassium benzoate was separated by filtration and the filtrate was evaporated. The product was triturated with petroleum. Yield 30.0 g (80percent). Mp 139.5- 140.80C.
80%
With potassium hydroxide In ethanol at 20℃; for 72 h;
A mixture of enc/o-3-benzoyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid te/t-butyl ester (55.0 g, 166 mmol), potassium hydroxide (11.2 g 199 mmol) and ethanol (99percent, 400 ml) was stirred for 3 days at room temperature. Potassium benzoate was separated by filtration and the filtrate was evaporated. Diethylether (200 ml) was added and remaining potassium benzoate was separated by filtration and the filtrate was evaporated. The product was triturated with petroleum. Yield 30.0 g (80percent). Mp 139.5-140.8°C.
To a solution of 8- (4-fluoro-benzyl)-8-aza-bicyclo [3.2. 1] octanol (5.02 grams, 21.4 [MMOL)] in ethanol (150 ml) in a Par bottle was added carbonic acid di- ter-butyl ester (5.5 grams, 25.2 [MMOL)] and palladium hydroxide on carbon (0.3 grams, 20percent on carbon). The reaction mixture was subject to 50 psi hydrogen gas for 3 days. The reaction mixture was then filtered through a 0. [54, UM FILTER.] Concentration of the filtrate in vacuo followed by chromatography on silica gel gave the title compounds, (cis) (1.8 grams, 37percent yield) and (trans) (2.3 grams, 47percent yield)
Stage (i): (1 R,3R,5S)-tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate Boc-nortropinone (2,5 g, 11 ,097 mmol) was dissolved in methanol (20 ml) and cooled with an ice bath. Sodium boron hydride (1.26 g, 33.291 mmol) was added slowly under protective gas. After stirring for 4 h at RT the mixture was hydrolysed with saturated sodium hydrogen carbonate solution (30 ml), the methanol was removed under vacuum and the aqueous phase extracted with ethyl acetate (3 x 50 ml). The combined organic phases were dried over magnesium sulfate and concentrated to small volume under vacuum. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/dichloromethane/ ammonia (25percent eq.) (400:40:40:1). The isomers were separated in this process and they were assigned by NMR analysis. Yield: endo 53percent [reacted further in stage (N)], exo 25percent
25%
at 20℃; Cooling; Inert atmosphere
Stage (i): (1R,3R,5S)-tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and (1R,3s,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylateBoc-nortropinone (2.5 g, 11.097 mmol) was dissolved in methanol (20 ml) and the solution was cooled with an ice bath. Sodium borohydride (1.26 g, 33.291 mmol) was added slowly under an inert gas. After stirring at room temperature for 4 h, hydrolysis was carried out with saturated sodium bicarbonate solution (30 ml), methanol was removed in vacuo and the aqueous phase was extracted with ethyl acetate (3.x.50 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/methylene chloride/ammonia (25 aq) (400:40:40:1). The isomers were separated by this procedure; this was assigned by NMR analysis. Yield: endo 50percent [reacted further in stage (ii)], exo 25percent
47.3%
at 0 - 20℃; for 16 h;
Step 2. Preparation of (1R,3R,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of (1R,5S)-tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxy late (3.14 g, 13.9 mmol) in MeOH (25 mL) was added sodium borohydride (0.791 g, 20.9 mmol) portion wise at 0° C. The ice bath was removed and the stirring continued for 16 hours at room temperature. The mixture was diluted with DCM and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=3:1) to give the (1R,3R,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate, endo product (1.50 g, 47.3percent) and (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate, exo product (1.18 g, 37.2percent) as a white solid each.Endo isomer; (1R,3R,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate1H-NMR (400 MHz, CDCl3) δ 1.46 (9H, s), 1.69 (2H, d), 1.94-2.16 (6H, m), 4.14-4.22 (3H, m).Exo isomer; (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate1H-NMR (400 MHz, CDCl3) δ 1.47 (9H, s). 1.56-1.62 (4H, m), 1.95 (4H, m), 4.11-4.28 (3H, m).
19.7%
at 20℃; for 24 h; Inert atmosphere
Synthesis of bicyclic amine intermediates Bicyclic amine 1 : 3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl esterTo a solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.03 g, 4.57 mmol) in EtOH (20 mL) was added NaBH4 dropwise. The mixture was stirred for 4.5 hours at room temperature under nitrogen, followed by a second addition of NaBH4 (0.36 g, 9.60 mmol). The reaction was stirred at room temperature for 17.5 hours and a last addition of NaBH4 (0.36 g, 9.60 mmol) was performed. The solution was stirred at room temperature for 2 hours, then a saturated solution of ammonium chloride was added and the aqueous phase was extracted with EtOAc. The combined organic fractions were dried over Na2S04, filtered and concentrated. The crude was purified by flash chromatography on silica gel using cyclohexane/EtOAc as eluent to yield, after evaporation, to the axial and equatorial isomers (186 mg, 17.9percent) and (205 mg, 19.7percent) as white solids. 1 H NMR (600 MHz, CDCI3): 4.57 (d, 1 H), 4.02 (m, 2H), 3.89 (d, 1 Hax), 1.89 - 1.71 (m, 5H), 1.65 - 1 .54 (m, 1 H), 1.47 - 1.28 (m, 1 1 H) and 4.60 (d, 1 H) 3.99 (m, 2H), 3.91 (m, 1 Heq), 2.18 - 2.03 (m, 2H), 1 .92 - 1 .72 (m, 4H), 1.67 - 1.56 (m, 2H), 1 .39 (s, 9H)
Example 5 Preparation of Intermediate Compounds 5 A and 5B; iV-BOC-nortropinone (1.38 g, 6.13mmol) was dissolved in methanol (21 niL) and the resulting solution was cooled to 0 0C. Sodium borohydride (0.59 g, 15.68 mmol) was slowly added to the cooled solution and the resulting reaction was allowed to stir for 1 hour at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted 2 times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide a residue which was purified using flash column chromatography on silica gel (hexane/ ethyl acetate (60/40)) to provide endo-product 5A (0.63 g, 46percent) and exo-product alcohol 5B (0.64 g, 46percent).
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 14, p. 4111 - 4114
[2] Patent: WO2010/9195, 2010, A1, . Location in patent: Page/Page column 82
[3] Patent: WO2008/101914, 2008, A2, . Location in patent: Page/Page column 68
7
[ 185099-67-6 ]
[ 143557-91-9 ]
Yield
Reaction Conditions
Operation in experiment
45%
at 20℃; Cooling with ice
A stirred solution of Boc-nortropinone (930 mg, 4.1 mmol) in MeOH (40 mL) was cooled in an ice bath and a NaBH4 caplet (1 g, 26.7 mmol) was added. The ice bath was allowed to melt and stirring was continued overnight at rt. The mixture was concentrated to leave a white solid which was partitioned between EtOAc (100 mL), brine (10 mL) and water (10 mL). The organic layer was separated, dried over Na2SO4 and concentrated to leave an oil (966 mg). Chromatography on a 40-g silica gel cartridge eluted with a 0-100percent EtOAc in hexanes gradient afforded two isomeric alcohols. The less polar alcohol, (1R,3r,5S)-tert-butyl 3-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate, was isolated (462 mg, 45percent).
With triethylamine; In dichloromethane; at 0 - 20℃; for 12h;
enalphato-8-Azabicyclo[3.2.1]octan-3-ol (3.6g, 28.3mmol) was dissolved in DCM (50ml) and cooled to O0C. Triethylamine (7.8ml, 56.7mmol) was added followed by addition of butyl dicarbonate (7.4g, 33.9mmol). The reaction mixture was warmed to ambient temperature and stirred for 12h. The reaction mixture was diluted with water. The organic layer was separated and washed with saturated citric acid (aq), water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to afford 3-enalphato-hydroxy- 8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester as a white solid (6.45g, 28.4mmol, 100%). M.S. (ESI) (m/z): 228 [M+H]+
97%
In tetrahydrofuran; at 20℃;
Step 1: 3-endo-3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester To a stirred suspension of <strong>[538-09-0]nortropine</strong> (1.272 g, 1 eq.) in tetrahydrofuran (25 mL) was added di-tert-butyl-dicarbonate (2.292 g, 1.05 eq.). The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue purified by column chromatography on silica gel eluding with a 1:0 to 4:1 gradient of dichloromethane/ethyl acetate, to yield 2.207 g (97%) of the title compound as colourless solid. MS (m/e) 227.2 (M+)
97%
With triethylamine; In dichloromethane; at 20℃; for 16h;
To a solution of <strong>[538-09-0](3-exo)-8-azabicyclo[3.2.1]octan-3-ol</strong> (0.95 g, 7.5 mmol) and triethylamine (1.7 mL, 12.2 mmol) in DCM (10 mL) was added di-tert-butyl dicarbonate (3.27 g, 15.0 mmol) portionwise and the resulting reaction mixture stirred at RT for 16 h. The reaction mixture was diluted with water then the organic layer was separated and washed with saturated citric acid (aq), water andbrine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford 1 .65 g (97% yield) of the title compound as an off whitesolid.1H NMR (250 MHz, Chloroform-d): 6 [ppm] 4.41 - 3.95 (m, 3H), 2.00 - 1 .53 (m, 9H),1.45 (5, 9H).
93%
With sodium hydroxide; In tetrahydrofuran; at 20℃;
Compound 1 (10 g, 0.079 mol) was taken up in tetrahydrofuran (200 mL) followed by the addition of BOC-anhydride (17.2 g, 0.079 mol) in one portion. The solution was stirred at room temperature for overnight and then concentrated in vacuo to a brown solid. The crude product was taken up in 95% dichloromethane/5%) methanol and added to a pad of silica gel (elution with 95% dichloromethane/5% methanol). Fractions containing compound 2 were combined and concentrated to a white solid. Yield: 16.6 g (93%); MS [M+H]+ 171.8 (M-56), 127.8 (M-100); 1HNMR (DMSO-d6) 54.59 (s, 1H), 3.98-3.91 (m, 3H), 2.11 (bs, 2H), 1.85 (m, 4H), 1.64 (m, 2H), 1.47 (s, 9H) ppm.
86%
With triethylamine; In dichloromethane; at 20℃; for 18h;Cooling with ice;
A stirred solution of <strong>[538-09-0]nortropine</strong> (12.72 g. 100 mmol) in DCM (150 mL) was treated with triethylamine (27.9 mL, 20.24 g, 200 mmol) and cooled to in ice. Solid di-ierf-butyl dicarbonate (32.74 g, 150.0 mmol) was then added over 10 min and the addition vessel washed DCM (50 mL). A vigorous gas evolution was observed, and the resulting mixture stirred for 2 H while warming to RT and then at RT for 16 H. The resulting mixture was diluted DCM (100 mL), washed 10% citric acid (aq) so In, brine (50 mL) and the layers separated. The combined organic fractions were dried (Na2S04), filtered and cone, in vacuo to give a cream solid. The solid residue was triturated with diethyl ether (30 mL) and sonicated to give a free flowing solid collected by filtration, 19.67g (86%). NMR (400 MHz, CDC13) delta 4.29-4.06 (3H, m), 2.26-1.87 (6H, m), 1.75-1.65 (2H, m), 1 .55 (1 I I. d, J 1 .5 Hz), 1.45 (9H, s). I . MS (ESI) [ I I I f not observed R, 1 .21 min.
80%
In tetrahydrofuran; at 20℃; for 1h;
4j: (lS,3R,5R)-3-Hvdroxy-8-aza-bicvclo[3.2.1]octane-8-carboxylic acid tert-butyl ester O Nortropine (78 mmol) was dissolved in dry THF (250 mL), and di-tert-butyl-dicarbonate (82 mmol) was added. Stirred at ambient temperature for Ih. The solvent was removed by evaporation and the resisue recrystallized from ethyl acetate/heptane. The product was collected and dried in vacuo. Yield = 80% 1H NMR (D6-DMSO): 1.38 (s, 9H); 1.61 (m, 2H); 1.70-1.93 (4H); 2.12 (m, 2H); 3.91 (br; IH); 3.99 (br, 2H); 4.58 (s, IH).
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 2h;
(l S,3R,5R)-3-Hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester; A solution of (l S,3R,5R)-8-azabicyclo[3.2.1]octan-3-ol (10 g) in THF (100 mL) was added to a solution of sodium hydroxide (3.15 g) in water (50 mL). Di-tert-butyl dicarbonate (17.2 g) was then added, and the reaction mixture was stirred at room temperature for 2 h. The THF was removed in vacuo and the residue was mixed with water and ethyl acetate. The aqueous phase was extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed in vacuo. The product with the molecular weight of 227.30 (C12H21NO3) was obtained in this way; MS (ESI): 228 (M+H+).
In tetrahydrofuran; at 20℃;
Example 10(3-^«A solution of <strong>[538-09-0]nortropine</strong> (5 g, 39.3 mmol) and Boc20 (9.44g, 43.2 mmol) in THF (100 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was triturated with heptanes to provide crude (3-e«i o)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8- carboxylate as a off white solid. MS (ESI+) m/z 228.0 (M+H)+.
9 g
With triethylamine; In ethanol; at 25℃;
To a solution of <strong>[538-09-0](1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-ol</strong> (5.0 g) in ethanol (100 mL) was added TEA (11.0 mL) and Boc2O (10.0 mL). The resulting mixture was stirred at 25C overnight, and then concentrated under reduced pressure to afford (1 R,3r,5S)-tert-butyl 3- hydroxy-8-azabicyclo[3.2.1 ]octane-8-carboxylate (9.0 g).
With sodium hydroxide; In acetonitrile; at 20℃; for 20h;
A reaction flask was charged with 8-azabicyclo[3.2.1]octan-3alpha-ol (42.3 g, 0.33 mol) and di-t-butyldicarbonate (80 g, 0.37 mol) in MeCN (500 mL) and 1 M NaOH (150 mL). The reaction was stirred at rt for 20 h. Then water was added and the product extracted into EtOAc. The combined organic phases were washed with 5% aqueous citric acid and brine, then dried over Na2SO4, filtered, and concentrated. The solid material was washed with n-heptane and dried to give the crude title compound (76.19 g).
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 1 - 12h;Product distribution / selectivity;
A solution of <strong>[538-09-0]nortropine</strong> (10 g) in THF (100 mL) was added to a stirred solution of sodium hydroxide (3.15 g) in water (50 mL), and di-tert-butyl carbonate (17.2 g) was added. After 12 hours, the reaction mixture was partitioned between water and ethyl acetate. The organic 0 phase was dried and concentrated. The product with the molecular weight of 227.31 (C12H21NO3) was obtained in this way; MS (ESI): 228 (M+H+).; 3-Hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl esterA solution of <strong>[538-09-0]nortropine</strong> (2.5 g) in THF (25.0 mL) was added dropwise to a solution of sodium hydroxide (786.4 mg) in water (12.5 ml) and stirred at room temperature for 1 h. The reaction <n="102"/>mixture was then diluted with water and extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed in vacuo. The product with the molecular weight of 227.30 (C12H21NO3) was obtained in this way; MS (ESI): 228 (M+H+).
With hydrogen;20% Pd(OH)2 on carbon; In ethanol; under 2585.81 Torr; for 72h;
To a solution of 8- (4-fluoro-benzyl)-8-aza-bicyclo [3.2. 1] octanol (5.02 grams, 21.4 [MMOL)] in ethanol (150 ml) in a Par bottle was added carbonic acid di- ter-butyl ester (5.5 grams, 25.2 [MMOL)] and palladium hydroxide on carbon (0.3 grams, 20% on carbon). The reaction mixture was subject to 50 psi hydrogen gas for 3 days. The reaction mixture was then filtered through a 0. [54, UM FILTER.] Concentration of the filtrate in vacuo followed by chromatography on silica gel gave the title compounds, (cis) (1.8 grams, 37% yield) and (trans) (2.3 grams, 47% yield)
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;
tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.22 g, 1.0 eq., 9.74 mmol) was dissolved in 5 MeOH (25 mL) and the resulting solution was cooled to 0 C. 6 Sodium borohydride (0.9 g, 2.5 eq., 24.35 mmol) was slowly added and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with a saturated solution of 7 NH4Cl (15 mL) and extracted with DCM (2×15 mL). The organic extracts were dried over Na2SO4 and concentrated in vacuo to furnish the crude product, which was purified by flash chromatography eluting with cyclohexane/EtOAc (0 to 60%) to give the 8 endo product (0.12 g, 56%) and exo product (0.66 g, 30%) as white solids. UPLC-MS: Rt. 1.95 min (TIC), ionization ES+ 228 [M+H]+ endo product; Rt. 1.84 min (TIC), ionization ES+ 228 [M+H]+ exo product. Endo: 1H NMR (400 MHz, DMSO-d6): delta 4.60 (d, J=2.4 Hz, 1H), 4.03-3.95 (m, 2H), 3.94-3.87 (m, 1H), 2.20-2.07 (m, 2H), 1.93-1.70 (m, 4H), 1.69-1.57 (m, 2H), 1.39 (s, 9H). Exo: 1H NMR (400 MHz, DMSO-d6): delta 4.60 (d, J=5.5 Hz, 1H), 4.09-3.97 (m, 2H), 3.95-3.83 (m, 1H), 1.79 (d, J=16.8 Hz, 4H), 1.65-1.53 (m, 2H), 1.41 (s, 9H), 1.38-1.29 (m, 2H).
25%; 53%
With methanol; sodium tetrahydroborate; at 20℃;Inert atmosphere;
Stage (i): (1 R,3R,5S)-tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate Boc-nortropinone (2,5 g, 11 ,097 mmol) was dissolved in methanol (20 ml) and cooled with an ice bath. Sodium boron hydride (1.26 g, 33.291 mmol) was added slowly under protective gas. After stirring for 4 h at RT the mixture was hydrolysed with saturated sodium hydrogen carbonate solution (30 ml), the methanol was removed under vacuum and the aqueous phase extracted with ethyl acetate (3 x 50 ml). The combined organic phases were dried over magnesium sulfate and concentrated to small volume under vacuum. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/dichloromethane/ ammonia (25% eq.) (400:40:40:1). The isomers were separated in this process and they were assigned by NMR analysis. Yield: endo 53% [reacted further in stage (N)], exo 25%
50%; 25%
With methanol; sodium tetrahydroborate; at 20℃;Cooling; Inert atmosphere;
Stage (i): (1R,3R,5S)-tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and (1R,3s,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylateBoc-nortropinone (2.5 g, 11.097 mmol) was dissolved in methanol (20 ml) and the solution was cooled with an ice bath. Sodium borohydride (1.26 g, 33.291 mmol) was added slowly under an inert gas. After stirring at room temperature for 4 h, hydrolysis was carried out with saturated sodium bicarbonate solution (30 ml), methanol was removed in vacuo and the aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/methylene chloride/ammonia (25 aq) (400:40:40:1). The isomers were separated by this procedure; this was assigned by NMR analysis. Yield: endo 50% [reacted further in stage (ii)], exo 25%
37.2%; 47.3%
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 16h;
Step 2. Preparation of (1R,3R,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of (1R,5S)-tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxy late (3.14 g, 13.9 mmol) in MeOH (25 mL) was added sodium borohydride (0.791 g, 20.9 mmol) portion wise at 0 C. The ice bath was removed and the stirring continued for 16 hours at room temperature. The mixture was diluted with DCM and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=3:1) to give the (1R,3R,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate, endo product (1.50 g, 47.3%) and (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate, exo product (1.18 g, 37.2%) as a white solid each.Endo isomer; (1R,3R,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate1H-NMR (400 MHz, CDCl3) delta 1.46 (9H, s), 1.69 (2H, d), 1.94-2.16 (6H, m), 4.14-4.22 (3H, m).Exo isomer; (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate1H-NMR (400 MHz, CDCl3) delta 1.47 (9H, s). 1.56-1.62 (4H, m), 1.95 (4H, m), 4.11-4.28 (3H, m).
19.7%; 17.9%
With sodium tetrahydroborate; ethanol; at 20℃; for 24h;Inert atmosphere;
Synthesis of bicyclic amine intermediates Bicyclic amine 1 : 3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl esterTo a solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.03 g, 4.57 mmol) in EtOH (20 mL) was added NaBH4 dropwise. The mixture was stirred for 4.5 hours at room temperature under nitrogen, followed by a second addition of NaBH4 (0.36 g, 9.60 mmol). The reaction was stirred at room temperature for 17.5 hours and a last addition of NaBH4 (0.36 g, 9.60 mmol) was performed. The solution was stirred at room temperature for 2 hours, then a saturated solution of ammonium chloride was added and the aqueous phase was extracted with EtOAc. The combined organic fractions were dried over Na2S04, filtered and concentrated. The crude was purified by flash chromatography on silica gel using cyclohexane/EtOAc as eluent to yield, after evaporation, to the axial and equatorial isomers (186 mg, 17.9%) and (205 mg, 19.7%) as white solids. 1 H NMR (600 MHz, CDCI3): 4.57 (d, 1 H), 4.02 (m, 2H), 3.89 (d, 1 Hax), 1.89 - 1.71 (m, 5H), 1.65 - 1 .54 (m, 1 H), 1.47 - 1.28 (m, 1 1 H) and 4.60 (d, 1 H) 3.99 (m, 2H), 3.91 (m, 1 Heq), 2.18 - 2.03 (m, 2H), 1 .92 - 1 .72 (m, 4H), 1.67 - 1.56 (m, 2H), 1 .39 (s, 9H)
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 3h;
To a solution of N-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane (20 g, 93 mmol) in EtOAc (220 mL) were added t-BOC anhydride (24.2 g, 112 mmol) and 20% Pd(OH)2/C (4 g). The mixture was hydrogenolyzed at 38.5 psi. After the reaction was complete, catalyst was filtered and filtrate was evaporated to give a solid crude product (21 g). The crude material (19 g, 84 mmol) was dissolved in CH3OH (100 mL) and NaBH4 (4.8 g, 127 mmol) was added portion wise at 0 C. The reaction was stirred at 0 C and gradually warmed to RT. After 3 h, the reaction was quenched with acetic acid (8 mL) and CH3OH was evaporated. The residue was redissolved in CH2Cl2 (300 mL) and washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and evaporated to give a solid. The crude material was purified by flash chromatography (400 g silica gel), eluting with 25% EtOAc/ hexane to give exo compound 3 (9.8 g, 43.1 mmol, 51.4%) and endo compound 4 (5 g, 22 mmol, 26.2%) as white solids.
An ice-cold mixture of Compound II (3.0 g), calcium chloride (1.78 g) and methanol (66 mL) was stirred for 30 minutes, and thereto was added portionwise sodium borohydride. The mixture was stirred for one hour, and water was added to the reaction mixture, and concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=80/20 to 40/60) to give the title compound III (840 mg) and the title compound IV (2.0 g).Compound III1H NMR (CDCl3) delta1.43 (s, 9H), 1.53 (m, 1H), 1.66-1.69 (m, 2H), 1.89-2.15 (m, 6H), 4.01-4.18 (m, 3H)Compound IV1H NMR (CDCl3) delta1.45 (s, 9H), 1.52-1.61 (m, 5H), 1.91-2.1.96 (m, 4H), 4.04-4.12 (m, 1H), 4.21 (m, 2H)
With sodium tetrahydroborate;Pd(OH)2; In methanol; dichloromethane; ethyl acetate;
EXAMPLE 52 1,1-Dimethylethyl 3-exo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (3) and 1,1-dimethylethyl 3-endo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (4) STR209 To a solution of N-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane (20 g, 93 mmol) in EtOAc (220 mL) were added t-BOC anhydride (24.2 g, 112 mmol) and 20% Pd(OH)2 /C (4 g). The mixture was hydrogenolyzed at 38.5 psi. After the reaction was complete, catalyst was filtered and filtrate was evaporated to give a solid crude product (21 g). The crude material (19 g, 84 mmol) was dissolved in CH3 OH (100 mL) and NaBH4 (4.8 g, 127 mmol) was added portion wise at 0 C. The reaction was stirred at 0 C. and gradually warmed to RT. After 3 h, the reaction was quenched with acetic acid (8 mL) and CH3 OH was evaporated. The residue was redissolved in CH2 Cl2 (300 mL) and washed with saturated NaHCO3 solution, dried (Na2 SO4), filtered and evaporated to give a solid.
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃;
7.2 3-endo-[5-(8-Isopropyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone
Step 2: 3-exo-3-(4-Nitro-benzoyloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester To a solution of 3-endo-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (227 mg, 1.0 eq.), triphenylphosphine (393 mg, 1.5 eq.) and 4-nitrobenzoic acid (250 mg, 1.5 eq.) in tetrahydrofuran (4 mL) was added diethylazodicarboxylate (0.23 mL, 1.5 eq.) dropwise. The mixture was stirred overnight at room temperature. The mixture was poured into water (20 mL) and the organics extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to afford an oil that was purified by column chromatography on silica gel eluding with 4:1 heptane/ethyl acetate to yield 340 mg (90%) of the title product as white solid. MS (m/e) 377.4 (M+H)+.
75%
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 18h;
Diethylazodicarboxylate (1.74ml_, 1 1 mmol) was added dropwise to a solution of 3-endo- hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.09g, 9.2mmol), triphenylphosphine (2.89g, 11 mmol) and 4-nitrobenzoic acid (1.69g, lOmmol) in THF (25mL). The reaction mixture was stirred under a nitrogen atmosphere for 18h at ambient temperature. Volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel. Elution with DCM afforded the ester as a pale yellow solid (2.6g, 6.9mmol, 75%). 4N sodium hydroxide (aq) (3.6ml_, 14mmol) was added to a solution of the ester in THF (25ml_) and the reaction mixture stirred at ambient temperature for 3 days. Diethyl ether (35ml_) and water (1OmL) were added to the reaction mixture. 2N sodium hydroxide (aq) solution was added to the organic layer which was removed, dried over NaaSCu and the solvent evaporated in vacuo. The crude material was purified by chromatography on silica gel. Elution with DCM with a gradient to 5:95 methanokDCM afforded 3-exo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert- butyl ester (1.4g, 6.2mmol, 89%) M.S. (ESI) (m/z): 228[M+H]+
75%
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 18h;
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 45℃;
104
tert-butyl 3β-hydroxy-8-azabicyclof3.2.1]octane-8-carboxylate[0340] A reaction flask was charged with 3α-hydroxy-8-azabicyclo[3.2.1]octane- 8-carboxylic acid tert-butyl ester (3.94 g, 17.3 mmol), 4-nitrobenzoic acid (1 1.3 g, 67.8 mmol), PPh3 (18.8 g, 68.6 mmol) in dry THF (140 mL) and cooled to 0 0C. Diisopropylazodicarboxylate (13.8 mL, 70.1 mmol) was added drop wise over 15 min. After 1 h cooling was removed and the mixture stirred at rt overnight. The mixture was then stirred at 45 0C for 5 h followed by cooling to rt and the mixture was diluted with diethylether and washed with several portions of saturated aqueous NaHCO3. The combined aqueous layers were extracted with diethyl ether and the combined organic layers dried over Na2SO4 and evaporated to dryness. The resulting gum was stirred with diethyl ether (80 mL) while n- heptane (40 mL) was added slowly to cause crystallization. The mixture was filtered and the filter cake extracted with diethyl ethern-heptane 1 :1 (300 mL). The filtrate was adsorbed onto celite and purified by flash column chromatography (SiO2; n-heptane → n-heptane/ethyl acetate 7:3) to give the intermediate benzoic acid ester. The ester was dissolved in THF (40 mL) and LiOH-H2O (0.60 g, 14.3 mmol) in water (7 mL) was added. After stirring at rt for 5 h saturated aqueous NaHCO3 was added and the mixture extracted with diethyl ether. The combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and evaporated to dryness to give the title compound as colorless crystals (3.33 g, 82%).
With triphenylphosphine; diethylazodicarboxylate
1.05 g
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 20℃; Cooling with ice;
30.1 [Step 1] Preparation of tert-butyl (1R,3s,5S)-3-[(4-nitrobenzoyl)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate
To a solution of tert-butyl (1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (0.790 g) in THF (10mL) were added 4-nitrobenzoic acid (0.871 g) and PPh3 (1.37 g), and DEAD (40% in toluene, 2.05 mL) was further added dropwise under ice-cooling. The reaction mixture was stirred at room temperature overnight. Then the reactionmixture was diluted with ethyl acetate, washed with saturated aq. sodium bicarbonate and saturated saline sequentially,and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reducedpressure, and the residue was purified by silica gel column chromatography to afford the title compound (1.05 g).
N-Boc-nortropinol (Step A) (0.6 g) was treated with 5 mL of 4 N HCl/dioxane for 1 h, evaporated, dried to give a white solid which was used for further reaction without purification.
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 triphenylphosphine; diethylazodicarboxylate In 1,4-dioxane at 8 - 20℃; for 15.25h;
1
exo-7-(8-tert-Butoxycarbonyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-chromen-2-one; Thphenylphosphine (7.5 g, 28.6 mmol) was solved in dioxane (70 ml) and cooled to 80C. Diethylazodicarboxylate (5.0 g, 28.6 mmol) was added to the mixture below 150C, 25 followed by stirring for 15 minutes. encfo-3-Hydroxy-8-aza-bicyclo[3.2.1 ] octane-8- carboxylic acid tert-butyl ester (5.0 g, 22.0 mmol) and 7-hydroxycoumarine (4.3 g, 26.4 mmol) was added to the mixture. The temperature raised due to an exothermic reaction. The mixture was allowed to stir for 15 h at room temperature. Water (200 ml) was added followed by extraction with diethylether (2 x 100 ml). The mixture was dried and evaporated. Chromatography on silica gel with dichloromethane and 5% methanol as solvent. The crude product was solved in diethylether (200 ml) and washed with aqueous sodium hydroxide (3 x 200 ml, 1 M). The product was dried and evaporated. Yield 5.32 g (65%).
65%
With triphenylphosphine; diethylazodicarboxylate In 1,4-dioxane at 8 - 20℃; for 15.25h;
1.A
exo-7-(8-tert-Butoxycarbonyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-chromen-2-one; Triphenylphosphine (7.5 g, 28.6 mmol) was solved in dioxane (70 ml) and cooled to 80C. Diethylazodicarboxylate (5.0 g, 28.6 mmol) was added to the mixture below 150C, followed by stirring for 15 minutes. enc/o-3-Hydroxy-8-aza-bicyclo[3.2.1 ] octane-8- carboxylic acid tert-butyl ester (5.0 g, 22.0 mmol) and 7-hydroxycoumarine (4.3 g, 26.4 mmol) was added to the mixture. The temperature raised due to an exothermic reaction. The mixture was allowed to stir for 15 h at room temperature. Water (200 ml) was added followed by extraction with diethylether (2 x 100 ml). The mixture was dried and evaporated. Chromatography on silica gel with dichloromethane and 5% methanol as solvent. The crude product was solved in diethylether (200 ml) and washed with aqueous sodium hydroxide (3 x 200 ml, 1 M). The product was dried and evaporated. Yield 5.32 g (65%).
With triphenylphosphine; diethylazodicarboxylate In 1,4-dioxane at 8 - 20℃; for 15.25h;
1
Method 1 exo-7-(8-fert-Butoxycarbonyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-chromen-2-one; Thphenylphosphine (7.5 g, 28.6 mmol) was solved in dioxane (70 ml) and cooled to 80C. Diethylazodicarboxylate (5.0 g, 28.6 mmol) was added to the mixture below 150C, followed by stirring for 15 minutes. enc/o-3-Hydroxy-8-aza-bicyclo[3.2.1 ] octane-8- carboxylic acid tert-butyl ester (5.0 g, 22.0 mmol) and 7-hydroxycoumahne (4.3 g, 26.4 mmol) was added to the mixture. The temperature raised due to an exothermic reaction. The mixture was allowed to stir for 15 h at room temperature. Water (200 ml) was added followed by extraction with diethylether (2 x 100 ml). The mixture was dried and evaporated. Chromatography on silica gel with dichloromethane and 5% methanol as solvent. The crude product was solved in diethylether (200 ml) and washed with aqueous sodium hydroxide (3 x 200 ml, 1 M). The product was dried and evaporated. Yield 5.32 g (65%).
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;
tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate. tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.22 g, 1 eq., 9.74 mmol) was dissolved in MeOH (25 mL) and the resulting solution was cooled to 0C. Sodium borohydride (0.9 g, 2.5 eq., 24.35 mmol) was slowly added and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with a saturated solution NH4Cl (15 mL) and extracted with DCM (215 mL). The organic extracts were dried over Na2SO4 and concentrated in vacuo to furnish the crude product, which was purified by flash chromatography eluting with cyclohexane/EtOAc (0 to 60%) to give the endo product (0.12 g, 56%) and exo product (0.66 g, 30%) as white solids. UPLC-MS (method A): Rt. 1.95 min (TIC), ionization ES+228 [M+H]+ endo product; Rt. 1.84 min (TIC), ionization ES+228 [M+H]+ exo product. Endo: 1H NMR (400 MHz, DMSO-d6): delta 4.60 (d, J=2.4 Hz, 1H), 4.03-3.95 (m, 2H), 3.94-3.87 (m, 1H), 2.20-2.07 (m, 2H), 1.93-1.70 (m, 4H), 1.69-1.57 (m, 2H), 1.39 (s, 9H). Exo: 1H NMR (400 MHz, DMSO-d6): delta 4.60 (d, J=5.5 Hz, 1H), 4.09-3.97 (m, 2H), 3.95-3.83 (m, 1H), 1.79 (d, J=16.8 Hz, 4H), 1.65-1.53 (m, 2H), 1.41 (s, 9H), 1.38-1.29 (m, 2H).
46%; 46%
With methanol; sodium tetrahydroborate; at 0 - 20℃;
Example 5 Preparation of Intermediate Compounds 5 A and 5B; iV-BOC-nortropinone (1.38 g, 6.13mmol) was dissolved in methanol (21 niL) and the resulting solution was cooled to 0 0C. Sodium borohydride (0.59 g, 15.68 mmol) was slowly added to the cooled solution and the resulting reaction was allowed to stir for 1 hour at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted 2 times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide a residue which was purified using flash column chromatography on silica gel (hexane/ ethyl acetate (60/40)) to provide endo-product 5A (0.63 g, 46%) and exo-product alcohol 5B (0.64 g, 46%).
With sodium tetrahydroborate; In ethanol; at 0 - 20℃;
NaBH4 (8.8 g, 0.23 mol) was added to a 0 0C solution of 3-oxo-8-azabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (35 g, 0.16 mol) in ethanol (200 ml). The reaction mixture was stirred for 45 min at 00C, whereupon it was allowed to reach 20 0C. After stirring overnigth the suspension was evaporated to dryness. EtOAc (350 ml) was added, and the precipitate was filtered off. Water (200 ml) was added to the filtrate, and the layers were separated. The aqueous layer was extracted with EtOAc (100 ml), and the combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford 29.5 g of an oil, which crystallised on standing. The two isomers were separated by flash chromatography (EtOAc/heptane 1 :5 D 1 : 1), affording 5 g of the title compound. LC-MS (m/z) : 250 (M+ 23 (Na)).
With di-isopropyl azodicarboxylate; triphenylphosphine; In toluene; at 20℃;
To a solution of Compound I (517 mg), <strong>[2613-23-2]3-chloro-4-fluorophenol</strong> (500 mg) and triphenylphosphine (894 mg) in toluene (7.6 mL) was added diisopropyl azodicarboxylate (676 muL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to give Compound II (739 mg).
With sodium hydride In N,N-dimethyl-formamide; mineral oil
60.iii
To a solution of Compound III (470 mg) and Compound IV (423 mg) in DMF (10 mL) was added sodium hydride (180 mg), and the mixture was stirred overnight. The reaction mixture was diluted with aqueous ammonium chloride solution, extracted with ethyl acetate, dehydrated with sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=6/1) to give the title compound V (448 mg).1H-NMR (CDCl3) δ 1.46 (s, 9H), 1.95-2.04 (m, 8H), 3.69-3.72 (m, 1H), 4.13-4.19 (m, 2H), 4.45 (s, 2H), 7.00 (s, 2H), 7.07 (s, 1H)
Stage #1: (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.25h;
Stage #2: 2-fluorobenzonitrile In tetrahydrofuran at 20℃; for 2h;
Step 1 : (1S.3R.5R)-3-(2-cvano-phenoxy)-8-aza-bicvclor3.2.11octane-8-carboxylic acid tert-butyl ester
tBuOK (1.43 g; 12.7 mmol; 2.2 eq.) was added to a solution of tert-butyl 3-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate (2.63 g; 11.6 mmol; 2 eq.) in THF (10 mL) and the reaction mixture was stirred at room temperature for 15 minutes whereupon a solution of 2-fIuorobenzonitrile (627 μΙ5.78 mmol; 1 eq.) in THF (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours then diluted with water and extracted with EA (2x). The combined organics were dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (10% to 25% ΕΞΑ in heptane) afforded the title compound (2 g, 97%) as a white solid. HPLC (max plot) 99.3%; Rt 4.91 min. 1H NMR (300 MHz, DMSO-d6) δ 7.74 (dd, J = 7.7, 1.7 Hz, 1 H), 7.64 (ddd, J = 8.6, 7.5, 1.7 Hz, 1 H), 7.16 (d, J = 8.7 Hz, 1 H), 7.07 (td, J = 7.5, 0.8 Hz, 1 H), 4.93 (t, J = 4.5 Hz, 1 H), 4.08 (s, 2H), 2.22-2.00 (m, 4H), 2.00-1.70 (m, 4H), 1.42 (s, 9H).
To a solution of (1R,5S)-8-Boc-3-hydroxy-8-azabicyclo[3.2.1]octane (Compound 44-30) (1.14 g, 5 mmol, TCI America) in DMF (4 mL) was added NaH (60% in mineral oil, 0.24 g, 6 mmol) at 0C, and the mixture was stirred at RT for 30 min. The mixture was then cooled to 0C and a solution of <strong>[68322-84-9]2-bromo-1-fluoro-4-(trifluoromethyl)benzene</strong> (Compound 44-29) (1.22 g, 5 mmol) in DMF (2 mL) was added rapidly. The mixture was stirred at 80C for 1 h, quenched by the addition of water and extracted with EtOAc. The EtOAc was removed under reduced pressure to give Compound 44-31 which was used in the next step without further purification.
(1R,3R,5S)-tert-butyl 3-(3,5-dichlorophenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With copper(l) iodide; 3,4,7,8-Tetramethyl-o-phenanthrolin; caesium carbonate; In toluene; at 80℃; for 120h;Inert atmosphere; Sealed tube; Molecular sieve;
To a mixture of (1R, 3r, 5S) -tert-butyl 3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate (5.00 g, 22.00 mmol) in toluene (50 mL) was added 3, 5-dichloroiodobenzene (6.00 g, 22.00 mmol) , cesium carbonate (21.50 g, 66.00 mmol) , copper (I) iodide (0.63 g, 3.30 mmol) , 3, 4, 7, 8-tetramethyl-1, 10-phenantroline (1.60 g, 6.60 mmol) and molecular sieves (4A, 5.00 g) . The reaction mixture was degassed by passing a stream of argon through it and then heated at 80 in a sealed vial for 120 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (150 mL) and filtered over diatomaceous earth. Concentration of the filtrate in vacuo gave a residue which was purified by flash chromatography (0 to 20ethyl acetate in hexanes) to afford the title compound as a yellowish oil (3.80 g, 46) :1H NMR (300 MHz, CDCl3) delta 6.93-6.90 (m, 1H) , 6.71-6.69 (m, 2H) , 4.59-4.53 (m, 1H) , 4.28-4.09 (m, 2H) , 2.24-1.85 (m, 8H) , 1.45 (s, 9H) MS (ES+) m/z 316.1, 318.1 (M -55) .
2-(((1R,3R,5S)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)isonicotinic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of encio-8-Boc-3-hydroxy-8-azabicycio[3.2.1]octane (0.500 g, 2.20 mmol, 1.2 equiv) in anhydrous DMF (5 mL) was added to a stirring suspension of sodium hydride (60% dispersion in mineral oil, 0.293 g, 7.33 mmol, 4 equiv) in anhydrous DMF (5 mL) under an atmosphere of nitrogen. The mixture was stirred at room temperature for 10 minutes before a solution of <strong>[402-65-3]2-fluoroisonicotinic acid</strong> (0.259 g, 1.83 mmol, 1 equiv) in DMF (5 mL) was added. The mixture was then stirred for a further 16 hours at room temperature. H2O (-20 mL) was carefully added and the pH of the aqueous mixture was adjusted to ~ 3 with a 0.5 M solution of aqueous citric acid. The aqueous layer was extracted with EtOAc (3 * 30 mL), the organic layers were combined, washed with brine, dried a2S04) and the solvent removed in vacuo. The resulting residue was purified by column chromatography (Biotage Isolera, 40 g Si02 cartridge, 0-100% EtOAc in petroleum benzine 40-60 C) to give the title compound (328 mg, contaminated with starting material encfo-8- Boc-3-hyd roxy-8- azabicyclo[3.2.1]octane) as a white solid. The impure material was carried through to the next step without further purification and analysis
tert-butyl (1R,3r,5S)-3-[(5-methyl-2-pyridyl)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
With potassium <i>tert</i>-butylate In tetrahydrofuran for 16h; Reflux;
tert-Butyl (1R,3r,5S)-3-[(5-methyl-2-pyridyl)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate
General procedure: . Following GP2, t-BuOK (0.1 g, 1 eq., 0.88 mmol) was added to a solution of tert-butyl (1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (0.2 g, 1 eq., 0.88 mmol), and 2-chloro-5-methylpyridine (0.1 mL, 1 eq., 0.88 mmol) in dry THF (7 mL). The reaction mixture was refluxed for 16 h. Then, the mixture was quenched with water (15 mL) and extracted with DCM (210 mL). The organic extracts were washed with brine (15 mL), dried over Na2SO4 and concentrated in vacuo to furnish the crude product, which was purified by flash chromatography eluting with cyclohexane/EtOAc (0 to 60%) to give the pure title compound as colourless oil (0.02 g, 7%). UPLC-MS (method A): Rt. 3.15 min (TIC); ionization ES+319 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 7.99-7.90 (m, 1H), 7.54 (dd, J=8.4, 2.5 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 5.25 (t, J=5.0 Hz, 1H), 4.17-3.97 (m, 2H), 2.20 (s, 3H), 2.11-1.98 (m, 4H), 1.93-1.76 (m, 4H), 1.42 (s, 9H).
tert-butyl (1R,3r,5S)-3-(5-methylpyrazin-2-yl)oxy-8-azabicyclo[3.2.1]octane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With potassium tert-butylate; In tetrahydrofuran; for 16h;Reflux;
General procedure: . Following GP2, t-BuOK (0.1 g, 1 eq., 0.88 mmol) was added to a solution of tert-butyl (1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (0.2 g, 1 eq., 0.88 mmol), and <strong>[59303-10-5]2-chloro-5-methylpyrazine</strong> (0.11 g, 1 eq., 0.88 mmol) in dry THF (7 mL). The reaction mixture was refluxed for 16 h. Then, the mixture was quenched with water (15 mL) and extracted with DCM (210 mL). The organic extracts were washed with brine (15 mL), dried over Na2SO4 and concentrated in vacuo to furnish the crude product, which was purified by flash chromatography eluting with cyclohexane/EtOAc (0 to 80%) to give the pure title compound as colourless oil (0.07 g, 25%). UPLC-MS (method A): Rt. 2.58 min (TIC); ionization ES+320 [M+H]+. 1H NMR (400 MHz, DMSO-d6): delta 8.17 (d, J=1.3 Hz, 1H), 8.06 (s, 1H), 5.26 (t, J=5.0 Hz, 1H), 4.18-4.03 (m, 2H), 2.39 (s, 3H), 2.17-1.97 (m, 4H), 1.96-1.77 (m, 4H), 1.42 (s, 9H).
tert-butyl (1R,3r,5S)-3-pyridazin-3-yloxy-8-N-azabicyclo[3.2.1]octane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
With potassium tert-butylate; In tetrahydrofuran; for 16h;Reflux;
General procedure: . Following GP2, t-BuOK (0.1 g, 1 eq., 0.88 mmol) was added to a solution of tert-butyl (1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (0.2 g, 1 eq., 0.88 mmol), and <strong>[1120-95-2]3-<strong>[1120-95-2]chloropyridazine</strong></strong> (0.1 g, 1 eq., 0.88 mmol) in dry THF (7 mL). The reaction mixture was refluxed for 16 h. Then, the mixture was quenched with water (15 mL) and extracted with DCM (210 mL). The organic extracts were washed with brine (15 mL), dried over Na2SO4 and concentrated in vacuo to furnish the crude product, which was purified by flash chromatography eluting with cyclohexane/EtOAc (0 to 70percent) to give the pure title compound as colourless oil (0.06 g, 21percent). UPLC-MS (method A): Rt. 2.26 min (TIC); ionization ES+306 [M+H]+. 1H NMR (400 MHz, DMSO-d6): delta 8.87 (dd, J=4.4, 1.3 Hz, 1H), 7.62 (dd, J=8.9, 4.4 Hz, 1H), 7.20 (dd, J=9.0, 1.3 Hz, 1H), 5.52 (t, J=5.0 Hz, 1H), 4.18-3.99 (m, 2H), 2.19-2.00 (m, 4H), 1.99-1.84 (m, 4H), 1.43 (s, 9H).
tert-butyl (1R,5S)-3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.4g
With potassium carbonate; In N,N-dimethyl-formamide; at 65℃;
At room temperature, compound (T1-a) (1.0 g, 3.33 mmol) was dissolved in DMF (20 mL), after complete dissolution, potassium carbonate (0.919 g, 6.66 mmol) and tert-butyl (1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (0.756 g, 3.33 mmol) were added under stirring, and the reaction was stirred at 65C overnight after the addition. A large number of white solids were precipitated in the reaction solution, and filtered. The filtrate was sequentially washed with water (50 mL) and a saturated brine solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent, and the residue was purified by column chromatography on silica gel to afford the title compound of this step (1.4 g). MS m/z (ESI): 494.4 [M+H]+.
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