Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 6530-09-2 | MDL No. : | MFCD00137395 |
Formula : | C7H16Cl2N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | STZHBULOYDCZET-UHFFFAOYSA-N |
M.W : | 199.12 | Pubchem ID : | 197853 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 54.98 |
TPSA : | 29.26 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.44 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.51 |
Log Po/w (WLOGP) : | 1.26 |
Log Po/w (MLOGP) : | 1.22 |
Log Po/w (SILICOS-IT) : | 0.38 |
Consensus Log Po/w : | 0.87 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.03 |
Solubility : | 1.88 mg/ml ; 0.00942 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.73 |
Solubility : | 3.69 mg/ml ; 0.0185 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.29 |
Solubility : | 101.0 mg/ml ; 0.508 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.93 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate; In dimethyl sulfoxide; at 100℃; for 2h; | A mixture of [()-3-AMINOQUINUCLIDINE] dihydrochloride (3.0 g 15.1 [MMOL)] 1- [FLUORO-2-NITROBENZENE] (1.6 [ML,] 15.1 [MMOL),] cecium carbonate (9.84 g, 30.2 [MMOL)] and dimethylsulfoxide (5.0 ml) was stirred at [100C] for 2 hours. Aqueous sodium hydroxide (50 [ML,] 1 M) was added followed by extraction with [DICHLOROMETHANE] (2 x 50 ml). The combined organic phases were purified by chromatography on silica gel with [DICHLOROMETHANE,] methanol and conc. ammonia (89: 10: 1) gave the title compound as an oil. Yield 2.99 g (80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | A mixture of of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (2.0 g, 10.0 [MMOL),] NEt3 (1. 3 mL) and 3-chlorobenzaldehyde (1.5 g, 11.0 [MMOL)] in THF [(50,] [ML) WAS] stirred at room temperature. To this was added Na (OAc) 3BH (3.2 g, 15 [MMOL)] and the reaction was stirred overnight. The reaction mixture was diluted with 3N [NAOH] and water and extracted with EtOAc. The organic extracts were combined, washed with water and then brine and dried over K2CO3. The solution was filtered and the solvent was evaporated in vacuo to give an oil which was chromatographed on silica (94/6 [CHCI3/0.] 5 M NH3 in [MEOH).] The appropriate fractions were combined and the solvent was evaporated in vacuo to [GIVE N- [ (3-CHLOROPHENYL) METHYL]-1-AZABICYCLO] [2.2. 2] [OCTAN-3-AMINE] (0. 75g, 30 %) as an intermediate, a light yellow semi-solid. MH+ = 251,253. [THE 1H] NMR was consistent with the assigned structure. Using the same procedure as described above for Compound 1 and N- [ (3-chlorophenyl) methyl]-1-azabicyclo [2.2. 2] octan-3-amine) in place of [N-PHENYL-1-AZABICYCLO] [2.2. 2] [OCTAN-3-AMINE,] a crude product was obtained and chromatographed on silica [(96/4 CHCI3/0.] 5 M [NH3] in [MEOH).] The appropriate fractions were combined and the solvent was evaporated in vacuo. The residue was combined with 1 eq of fumaric acid in 2PrOH and the solvent was evaporated n vacuo and the residue was recrystallized from acetone to give Compound 17 (0.14 g, 9%) as an off-white solid mp 193-196 [C.] [MU+ =] 426, [428.'H] NMR (DMSO d6) 1.1 (t, [6H),] 1.55 (m, [1H),] 1.85 (m, [3H),] 2.2 (m, [1H),] 3.0 (m, [4H),] 3.3 (m, 7H), 4.15 (m, [1H),] 4.7 (dd, [2H),] 6.5 (s, 2H), 6.85 (d, 2H), 7.3 [(M,] 6H). Anal. [CALCD] for [C25H32CIN3OC4H404] : C, 64.26 ; [H,] 6.69 ; [N,] 7.75. Found C, 64.30 ; H, 6.54 ; N, 7.78. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; acetonitrile;Heating / reflux; | To 101 (3.056 g, 10.0 mmol) dissolved in anhydrous acetonitrile (30 mL) at about 0 C. was added a solution of 2-(aminomethyl)-1-ethylpyrrolidine (1.5 mL, 10.0 mmol) in anhydrous acetonitrile (5 mL) followed by addition of a DIEA (1.9 mL, 11.0 mmol). The reaction mixture was allowed to warm to room temperature and was stirred at room temperature overnight under nitrogen. Then DIEA (1.9 mL, 11 mmol) was added which was followed by addition of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (1.962 g, 10.0 mmol) in 1,4-dioxane (5 mL). The reaction mixture was allowed to stir at reflux overnight under nitrogen. The reaction mixture was extracted 2 times with dichloromethane and 1 time with ethyl acetate. The combined organic layers were washed one time with brine and dried over anhydrous potassium carbonate. The organic layer was with 20% HCl (aq). The aqueous layer was neutralized with 2.5 N NaOH (aq) and then extracted 3 times with ethyl acetate. The combined organic layers were washed 1 time with brine, dried over potassium carbonate, concentrated on a rotary evaporator and allowed to dry overnight under vacuum. Column chromatography (silica gel, 85:14:1 dichloromethane:methanol:conc. ammonium hydroxide) yielded a pale white solid 148 (100 mg, 2%), mp 83 C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 8.1 min, 71.2% purity); MS (ESI): m/z 488 (M+H, 18.7), 280 (100), 245 ([M+2H]++, 37.4), 236 (23.5). |
2% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; acetonitrile;Heating / reflux; | To 101 (3.056 g, 10.0 mmol) dissolved in anhydrous acetonitrile (30 mL) at about 0 C. was added a solution of 2-(aminomethyl)-1-ethylpyrrolidine (1.5 mL, 10.0 mmol) in anhydrous acetonitrile (5 mL) followed by addition of a DIEA (1.9 mL, 11.0 mmol). The reaction mixture was allowed to warm to room temperature and was stirred at room temperature overnight under nitrogen. Then DIEA (1.9 mL, 11 mmol) was added which was followed by addition of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (1.962 g, 10.0 mmol) in 1,4-dioxane (5 mL). The reaction mixture was allowed to stir at reflux overnight under nitrogen. The reaction mixture was extracted 2 times with dichloromethane and 1 time with ethyl acetate. The combined organic layers were washed one time with brine and dried over anhydrous potassium carbonate. The organic layer was with 20% HCl (aq). The aqueous layer was neutralized with 2.5 N NaOH (aq) and then extracted 3 times with ethyl acetate. The combined organic layers were washed 1 time with brine, dried over potassium carbonate, concentrated on a rotary evaporator and allowed to dry overnight under vacuum. Column chromatography (silica gel, 85:14:1 dichloromethane:methanol:conc. ammonium hydroxide) yielded a pale white solid 148 (100 mg, 2%), mp 83 C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 8.1 min, 71.2% purity); MS (ESI): m/z 488 (M+H, 18.7), 280 (100), 245 ([M+2H]++, 37.4), 236 (23.5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | To a solution of the carboxylic acid (4.77 mmol) in N, N-dimethylformamide (14 mL) was added N, N diisopropylethylamine (19 mmol) and <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (4. 29 mmol). The reaction mixture was maintained at room temperature for 30 min under nitrogen and then HATU (4.76 mol) was added. After 18 h, the reaction mixture was filtered through Celite (methanol rinse) and was divided equally amongst 3 SCX columns. The columns were washed with methanol (100 mL each) and the basic components were eluted with 2 M ammonia in methanol (100 mL each) and concentrated. The residue was purified by chromatography- [1/1 to 0/1 ethyl acetate/ (70/30/1 ethyl acetate/methanol/ammonium hydroxide) ] or by preparative HPLC, thus providing the product in 15%-50% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | Step B:; A mixture of 2-(4-nitrophenyl)benzoxazole-4-carboxylic acid from Step A (311 mg, 1.09 mmol), <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (261 mg, 1.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg, 2.19 mmol) and 1-hydroxybenzotriazole (296 mg, 2.19 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then DIPEA (0.72 mL, 4.38 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-nitrophenyl)benzoxazole-4-carboxamide (31 mg, 7%) as a yellow solid: 1H NMR (500 MHz, CDCl3) delta 9.35 (d, J=7.0 Hz, 1H), 8.47-8.40 (m, 4H), 8.24 (dd, J=7.5, 1.0 Hz, 1H), 7.79 (dd, J=8.0, 0.5 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 4.34-4.30 (m, 1H), 3.56-3.51 (m, 1H), 3.12-2.86 (m, 4H), 2.85-2.77 (m, 1H), 2.19-2.14 (m, 1H), 1.82-1.74 (m, 2H), 1.71-1.58 (m, 2H); MS (ESI+) m/z 393 (M+H); HPLC >99% (AUC), tR=12.18 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Step C:; A solution of 2-(4-fluorophenyl)benzoxazole-7-carboxylic acid (0.100 g, 0.39 mmol) in acetonitrile (10 mL) was treated with DCC (0.089 g, 0.43 mmol) and the mixture stirred at room temperature for 1 h. After this time a thick granular precipitate had formed. 3-Aminoquinuclidine dihydrochloride (0.086 g, 0.43 mmol) and DMAP (0.010 g, 0.08 mmol) were then added to the reaction followed by the dropwise addition of triethylamine (0.101 g, 1.00 mmol) over 15 min. The reaction was then stirred at room temperature overnight. Subsequent concentration of the reaction mixture and purification of the resulting solid residue by column chromatography afforded 0.100 g (70% yield) of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-fluorophenyl)benzoxazole-7-carboxamide as a white solid: mp 185-187 C.; 1H NMR (500 MHz, DMSO-d6) delta 8.46 (d, J=6.7 Hz, 1H), 8.24 (m, 2H), 7.95 (m, 1H), 7.70 (m, 1H), 7.51 (m, 3H), 4.06 (m, 1H), 3.21 (m, 1H), 2.92 (m, 1H), 2.74 (m, 4H), 1.96 (m, 2H), 1.64 (m, 2H), 1.44 (m, 1H); MS (ESI) m/z 366 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Step B:; A mixture of 2-(2-methoxyphenyl)benzoxazole-4-carboxylic acid from Step A (59 mg, 0.22 mmol), <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (51 mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (84 mg, 0.44 mmol) and 1-hydroxybenzotriazole (59 mg, 0.44 mmol) in DMF (10 mL) was stirred for 10 min at room temperature, then DIPEA (0.14 mL, 0.88 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(3-methoxyphenyl)benzoxazole-4-carboxamide (38 mg, 46%) as a white solid: 1H NMR (500 MHz, CDCl3) delta 9.60 (d, J=7.5 Hz, 1H), 8.20 (dd, J=7.5, 1.0 Hz, 1H), 7.86-7.82 (m, 1H), 7.78-7.75 (m, 1H), 7.72 (dd, J=8.0, 1.0 Hz, 2H), 7.48 (t, J=16.0 Hz, 2H), 7.15 (dd, J=8.5, 2.5 Hz, 1H), 4.36-4.28 (m, 1H), 3.56-3.48 (m, 1H), 3.10 (s, 3H), 3.15-2.98 (m, 2H), 2.96-2.87 (m, 2H), 2.86-2.79 (m, 1H), 2.20-2.05 (m, 2H), 1.80-1.60 (m, 2H); MS (ESI+) m/z 378 (M+H); HPLC >99% (AUC), tR=12.48 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Step B:; A mixture of 2-p-tolylbenzoxazole-4-carboxylic acid from Step A (62 mg, 0.24 mmol), <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (58 mg, 0.29 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94 mg, 0.49 mmol) and 1-hydroxybenzotriazole (66 mg, 0.49 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then DIPEA (0.16 mL, 0.98 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-p-tolylbenzoxazole-4-carboxamide (57 mg, 66%) as a white solid: 1H NMR (500 MHz, CDCl3) delta 9.61 (d, J=7.0 Hz, 1H), 8.18 (dd, J=8.0, 1.0 Hz, 1H), 8.13 (d, J=8.0 Hz, 2H), 7.70 (dd, J=8.5, 1.0 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 4.35-4.30 (m, 1H), 3.55-3.50 (m, 1H), 3.15-2.99 (m, 2H), 2.95-2.89 (m, 2H), 2.88-2.81 (m, 1H), 2.48 (s, 3H), 2.19-2.15 (m, 1H), 2.13-2.05 (m, 1H), 1.81-1.75 (m, 2H) 1.68-1.60 (m, 1H); MS (ESI+) m/z 362 (M+H); HPLC 98.4% (AUC), tR=12.90 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Step B:; A mixture of 2-(4-dimethylaminophenyl)benzoxazole-4-carboxylic acid from Step A (47 mg, 0.12 mmol), (+/-)-<strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (40 mg, 0.20 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (45 mg, 0.23 mmol) and 1-hydroxybenzotriazole (63 mg, 0.47 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then DIPEA (0.14 mL, 0.83 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and recrystallized from acetonitrile and ethyl acetate to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-dimethylaminophenyl)benzoxazole-4-carboxamide (40 mg, 60%) as an off-white solid: 1H NMR (500 MHz, CDCl3) delta 9.74 (d, J=6.5 Hz, 1H), 8.13-8.04 (m, 3H), 7.63 (d, J=8.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 6.79 (d, J=9.0 Hz, 2H), 4.35-4.27 (m, 1H), 3.51 (t, J=12.0 Hz, 1H), 3.11 (s, 6H), 2.96-2.82 (m, 3H), 2.22-2.11 (m, 2H), 1.80-1.50 (m, 5H); MS (ESI+) m/z 391 (M+H); HPLC >99% (AUC), tR=14.65 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | Step B:; A mixture of 2-(4-cyanophenyl)benzoxazole-4-carboxylic acid from Step A (289 mg, 1.09 mmol), <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (261 mg, 1.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (418 mg, 2.19 mmol) and 1-hydroxybenzotriazole (296 mg, 2.19 mmol) in DMF (15 mL) was stirred for 10 min at room temperature, then DIPEA (0.90 mL, 5.47 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate. The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-cyanophenyl)benzoxazole-4-carboxamide (7 mg, 2%) as a white solid: 1H NMR (500 MHz, CDCl3) delta 9.35 (d, J=7.5 Hz, 1H), 8.35 (d, J=8.5 Hz, 2H), 8.25 (d, J=7.5, Hz, 1H), 7.88 (d, J=8.5, Hz, 2H), 7.77 (d, J=7.5 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H), 4.36-4.26 (m, 1H), 3.58-3.47 (m, 1H), 3.12-3.00 (m, 2H), 2.97-2.89 (m, 2H), 2.86-2.79 (m, 1H), 2.30-2.00 (m, 2H), 1.82-1.75 (m, 3H); MS (ESI+) m/z 373 (M+H); HPLC 94.3% (AUC), tR=12.18 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | Step E:; A mixture of 6-chloro-2-p-tolylbenzoxazole-4-carboxylic acid from Step D (45 mg, 0.16 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg, 0.31 mmol), 1-hydroxybenzotriazole (43 mg, 0.31 mmol) and <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (37 mg, 0.19 mmol) in DMF (5 mL) was stirred 10 min at room temperature, then triethylamine (0.07 mL, 0.63 mmol) was added to the reaction mixture. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×25 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-p-tolylbenzoxazole-4-carboxamide (18 mg, 29%) as a white solid: 1H NMR (500 MHz, CDCl3) delta 9.48 (d, J=7.3 Hz, 1H), 8.16 (d, J=1.9 Hz, 1H), 8.10 (d, J=8.2 Hz, 2H), 7.69 (d, J=1.9 Hz, 1H), 7.37 (d, J=8.0 Hz, 2H), 4.32-4.25 (m, 1H), 3.55-3.45 (m, 1H), 3.12-3.00 (m, 2H), 2.95-2.85 (m, 2H), 2.82 (dd, J=14.3, 3.8 Hz, 1H), 2.48 (s, 3H), 2.20-2.00 (m, 2H), 1.80-1.70 (m, 3H); MS (ESI+) m/z 396 (M+H); HPLC >99% (AUC), tR=13.30 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Step B:; A mixture of 6-chloro-2-(4-methoxyphenyl)-benzoxazole-4-carboxylic acid from Step A (42 mg, 0.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol) and <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (33 mg, 0.17 mmol) in DMF (4 mL) was stirred for 10 min at room temperature, then triethylamine (0.08 mL, 0.55 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(4-methoxyphenyl)benzoxazole-4-carboxamide (14 mg, 25%) as a white solid: 1H NMR (500 MHz, CDCl3) delta 9.48 (d, J=7.3 Hz, 1H), 8.18-8.10 (m, 3H), 7.68 (d, J=1.9 Hz, 1H), 7.07 (d, J=8.9 Hz, 2H), 4.40-4.32 (m, 1H), 3.93 (s, 3H), 3.60-3.50 (m, 1H), 3.20-3.05 (m, 2H), 3.00-2.95 (m, 2H), 2.87 (dd, J=14.1, 3.5 Hz, 1H), 2.20 (q, J=3.1 Hz, 1H), 215-2.00 (m, 1H), 1.85-1.80 (m, 2H), 1.74-1.57(m, 1H); MS (ESI+) m/z 412 (M+H); HPLC >99% (AUC), tR=13.09 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Step D:; A mixture of 6-bromo-2-phenylbenzoxazole-4-carboxylic acid from Step C (82 mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (99 mg, 0.52 mmol), 1-hydroxybenzotriazole (70 mg, 0.52 mmol) and <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (62 mg, 0.31 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then triethylamine (0.10 mL, 1.03 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (50 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-phenylbenzoxazole-4-carboxamide (61 mg, 55%) as a white solid: 1H NMR (500 MHz, CDCl3) delta 9.45 (d, J=7.3 Hz, 1H), 8.32 (d, J=1.9 Hz, 1H), 8.25-8.15 (m, 2H), 7.89 (d, J=1.8 Hz, 1H), 7.65-7.52 (m, 3H), 4.40-4.25 (m, 1H), 3.60-3.45 (m, 1H), 3.18-3.12 (m, 2H), 2.90-2.80 (m, 2H), 2.83 (dd, J=14.3, 3.9 Hz, 1H), 2.22-2.15 (m, 1H), 2.10-2.00 (m, 2H), 1.85-1.60 (m, 2H); MS (ESI+) m/z 426 (M+H); HPLC 98.1% (AUC), tR=12.98 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Step B:; A mixture of 6-bromo-2-p-tolylbenzoxazole-4-carboxylic acid (85 mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg, 0.31 mmol), 1-hydroxybenzotriazole (60 mg, 0.31 mmol) and <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (61 mg, 0.31 mmol) in DMF (5 mL) was stirred 10 min at room temperature, then triethylamine (0.12 mL, 1.02 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×25 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-p-tolylbenzoxazole-4-carboxamide (60 mg, 54%) as a white solid: 1H NMR (500 MHz, CDCl3) delta 9.48 (d, J=7.3 Hz, 1H), 8.30 (d, J=1.8 Hz, 1H), 8.10 (d, J=8.3 Hz, 2H), 7.85 (d, J=1.8 Hz, 1H), 7.37 (d, J=8.0 Hz, 2H), 4.35-4.25 (m, 1H), 3.60-3.45 (m, 1H), 3.15-3.00 (m, 2H), 2.95-2.82 (m, 2H), 2.80 (dd, J=14.2, 4.1 Hz, 1H), 2.48 (s, 3H), 2.14 (q, J=3.1 Hz, 1H), 2.10-2.00 (m, 1H), 1.80-1.60 (m, 3H); MS (ESI+) m/z 440 (M+H); HPLC 98.6% (AUC), tR=13.51 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Step B:; A mixture of 6-bromo-2-(4-methoxyphenyl)benzoxazole-4-carboxylic acid from Step A (86 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94 mg, 0.49 mmol), 1-hydroxybenzotriazole (67 mg, 0.49 mmol) and (+/-)-<strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (59 mg, 0.30 mmol) in DMF (5 mL) was stirred 10 min at room temperature, then triethylamine (0.10 mL, 0.99 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-2-(4-methoxyphenyl)benzoxazole-4-carboxamide (56 mg, 50%) as a white solid: 1H NMR (500 MHz, CDCl3) delta 9.47 (d, J=7.0 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H), 8.20-8.10 (m, 2H), 7.83 (d, J=1.7 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 4.45-4.35 (m, 1H), 3.93 (s, 3H), 3.55-3.45 (m, 1H), 3.15-3.00 (m, 2H), 2.95-2.90 (m, 2H), 2.85-2.75 (m, 1H), 2.20-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.80-1.75 (m, 2H), 1.70-1.55 (m, 1H); MS (ESI+) m/z 456 (M+H); HPLC 96.9% (AUC), tR=14.64 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | Step E:; A mixture of phenylbenzoxazole carboxylic acid from Step D (180 mg, 0.56 mmol), (+/-)-<strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (134 mg, 0.67 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (215 mg, 1.12 mmol) and 1-hydroxybenzotriazole (151 mg, 1.12 mmol) in DMF (2.5 mL) was stirred for 5 min at room temperature, then triethylamine (0.31 mL, 2.24 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) followed by recrystallization from ethyl acetate to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-5-bromo-2-phenylbenzoxazole-4-carboxamide (20 mg, 8%) as an off-white solid: 1H NMR (500 MHz, CDCl3) delta 8.25 (d, J=5.5 Hz, 1H), 8.24-8.21 (m, 2H), 7.68 (d, J=8.5 Hz, 1H), 7.62-7.54 (m, 3H), 7.52 (d, J=8.5 Hz, 1H), 4.38-4.28 (m, 1H), 3.53 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.10-2.85 (m, 4H), 2.80 (dd, J=14.0, 4.5 Hz, 1H), 2.21 (dt, J=6.0, 3.0 Hz, 1H), 2.10-2.02 (m, 1H), 1.79-1.74 (m, 2H), 1.64-1.61 (m, 1H); MS (ESI+) m/z 426 (M+H); HPLC 98.4% (AUC), tR=11.29 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | Example 92; Preparation of N-(1-Azabicyclo[2.2.2]oct-3-yl)-7-bromo-2-phenylbenzoxazole-4-carboxamide; A mixture of 7-bromo-2-phenylbenzo[d]oxazole-4-carboxylic acid (200 mg, 0.62 mmol), (+/-)-<strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (148 mg, 0.74 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (237 mg, 1.24 mmol) and 1-hydroxybenzotriazole (167 mg, 1.24 mmol) in DMF (2.5 mL) was stirred 5 min at room temperature, then triethylamine (0.34 mL, 2.48 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) followed by semi-preparative HPLC to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-7-bromo-2-phenylbenzoxazole-4-carboxamide (34 mg, 13%) as a white solid: 1H NMR (500 MHz, CDCl3) delta 9.41 (d, J=7.0 Hz, 1H), 8.29-8.26 (m, 2H), 8.09 (d, J=8.5 Hz, 1H), 7.66-7.57 (m, 4H), 4.31-4.27 (m, 1H), 3.51 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.15-2.85 (m, 4H), 2.81 (dd, J=14.0, 4.0 Hz, 1H), 2.17-2.14 (m, 1H), 2.07-2.02 (m, 1H), 1.79-1.61 (m, 3H); MS (ESI+) m/z 426 (M+H); HPLC >99% (AUC), tR=13.09 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Step D:; A mixture of 6-iodo-2-phenylbenzoxazole-4-carboxylic acid from Step C (75 mg, 0.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78 mg, 0.41 mmol), 1-hydroxybenzotriazole (55 mg, 0.41 mmol) and (+/-)-<strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (50 mg, 0.25 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then triethylamine (0.08 mL, 0.82 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (50 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (3×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 methylene chloride/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-6-iodo-2-phenylbenzoxazole-4-carboxamide (52 mg, 53%) as an off-white solid: 1H NMR (500 MHz, CDCl3) delta 9.44 (d, J=7.1 Hz, 1H), 8.49 (d, J=1.5 Hz, 1H), 8.25-8.15 (m, 2H), 8.08 (d, J=1.6 Hz, 1H), 7.65-7.52 (m, 3H), 4.35-4.30 (m, 1H), 3.60-3.50 (m, 1H), 3.16-3.05 (m, 2H), 3.00-2.90 (m, 2H), 2.85 (dd, J=14.2, 3.5 Hz, 1H), 2.22-2.17 (m, 1H), 2.12-2.05 (m, 1H), 1.85-1.78 (m, 2H), 1.75-1.63 (m, 1H); MS (ESI+) m/z 474 (M+H); HPLC >99% (AUC), tR=13.41 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3.08333h; | Step C:; A 25 mL round bottomed flask equipped with a reflux condenser was purged with nitrogen and charged with 2-(4-chlorophenyl)benzoxazole-4-carboxylic acid (0.050 g, 0.18 mmol) followed by thionyl chloride (5 mL). The resulting suspension was heated to reflux for 1 hr, after which time a light yellow solution was obtained. The reaction was then cooled and the thionyl chloride removed under reduced pressure affording an off-white solid. This solid was dissolved in methylene chloride (10 mL) and quinuclidine dihydrochloride (0.056 g, 0.27 mmol) added followed by the drop-wise addition of diisopropylethylamine (0.371 g, 2.87 mmol) over 5 min. After stirring at room temperature for 3 hrs the reaction was quenched by the addition of water (10 mL) and the organic layer separated. Subsequent washing of the organic layer with water (10 mL) followed by brine (10 mL), drying over MgSO4, filtration and concentration afforded a tan solid. This solid was purified by preparative HPLC to afford 0.012 g (17% yield) of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-chlorophenyl)benzoxazole-4-carboxamide as an white solid: mp 194-196 C.; 1H NMR (500 MHz, DMSO-d6) delta 9.13 (m, 1H), 8.23 (dd, J=6.7, 1.9 Hz, 2H), 8.03 (dd, J=8.2, 0.9 Hz, 1H), 7.97 (dd, J=7.7, 0.9 Hz, 1H), 7.78 (dd, J=6.7, 1.9 Hz, 2H), 7.58 (t, J=8.0 Hz, 1H), 4.09 (m, 1H), 3.28 (m, 1H), 2.85 (m, 2H), 2.75 (m, 2H), 2.63 (m, 1H), 2.08 (m, 1H), 1.99 (m, 1H), 1.65 (m, 2H), 1.57 (m, 1H); MS (ESI) m/z 382 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Step C:; A mixture of the carboxylic acid from Step B (190 mg, 0.52 mmol), (+/-)-<strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (124 mg, 0.624 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (199 mg, 1.04 mmol) and 1-hydroxybenzotriazole (140 mg, 1.04 mmol) in DMF (10 mL) was stirred under nitrogen at room temperature for 10 min, and then triethylamine (0.29 mL, 2.08 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight, and then was quenched with a saturated solution of sodium bicarbonate, extracted with methylene chloride. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:10:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide (150 mg, 61%) as a white solid: 1H NMR (500 MHz, CDCl3) delta 9.47 (d, J=7.0 Hz, 1H), 8.20 (dd, J=8.0, 1.0 Hz, 1H), 7.94 (s, 4H), 7.72 (dd, J=8.0, 1.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 4.36-4.29 (m, 1H), 3.53 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.12-2.82 (m, 5H), 2.18-2.02 (m, 2H), 1.80-1.65 (m, 3H); MS (ESI+) m/z 474 (M+H); HPLC >99% (AUC), tR=13.35 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Step B:; A mixture of the carboxylic acid from Step A (76 mg, 0.27 mmol), (+/-)-<strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (65 mg, 0.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg, 0.54 mmol) and 1-hydroxybenzotriazole (73 mg, 0.54 mmol) in DMF (5 mL) was stirred under nitrogen at room temperature for 10 min, and then triethylamine (0.15 mL, 1.08 mmol) was added. The resulting reaction mixture was stirred at room temperature for 15 h, and then was quenched with a saturated solution of sodium bicarbonate, extracted with methylene chloride. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:10:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzofuran-5-ylbenzoxazole-4-carboxamide (77 mg, 73%) as a white solid: 1H NMR (300 MHz, CDCl3) delta 9.62 (d, J=7.2 Hz, 1H), 8.51 (d, J=1.5 Hz, 1H), 8.21 (dd, J=8.4, 1.5 Hz, 1H), 8.19 (dd, J=7.8, 1.2 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.73 (dd, J=8.4, 1.2 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.46 (t, J=8.1 Hz, 1H), 6.93 (dd, J=2.4, 1.2 Hz, 1H), 4.38-4.32 (m, 1H), 3.55 (ddd, J=14.1, 9.3, 2.1 Hz, 1H), 3.21-2.86 (m, 5H), 2.25-2.09 (m, 2H), 1.83-1.67 (m, 3H); MS (ESI+) m/z 388 (M+H); HPLC >99% (AUC), tR=12.89 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(B) (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-bromothiophene-2-carboxamide) Prepared by a method analogous to that described for the preparation of Intermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and <strong>[16694-18-1]4-bromothiophene-2-carboxylic acid</strong>. The residue from evaporation of the reaction mixture was partitioned between aqueous hydrochloric acid and chloroform. The aqueous layer was then basified with aqueous sodium hydroxide and extracted with chloroform. The organic extracts were dried (MgSO4), filtered, and evaporated and resulting solid was recrystallized from ethyl acetate/hexane to give the title compound as a colourless solid; MS (ES+) 315, 317 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; N-methyl-acetamide; water; | EXAMPLE 2 (1-Aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid benzyl ester 3-Aminoquinuclidine dihydrochloride 996 mg (5.0 mmol) is added slowly to a stirred suspension of 676 mg (15.5 mmol) sodium hydride (dispersion 55%) in dimethylformamide (15 ml). Thereafter the suspension is stirred for another 90 minutes at room temperature and then carbobenzoxy chloride 0.72 ml (5.1 mmol) is added slowly. After another two hours at room temperature, the suspension is quenched by carefully adding water. The solvent is then evaporated at 70 C./16 mbar. The residue is taken up in water and ethyl acetate. The organic phase is separated and the water phase two-times re-extracted with ethyl acetate. The combined organic phase is dried and evaporated to give the crude oily product which is taken up in dioxane and 0.72 ml of a 4M hydrochloric acid is added. The precipitating product is recrystallized from dioxane/ether to give the hydrochloride of the title product. Mp=192-193 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
634 mg (71%) | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In acetonitrile; | EXAMPLE 1 N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-2,3-dihydro-1,4-benzodioxine-6-carboxamide fumarate To a stirred solution of 0.59 g (3.3 mmol) of 1,4-benzodioxane-6-carboxylic acid in CH3CN (30 mL) in a -10 C. methanol-ice bath is added sequentially DIEA (1.65 mL, 9.5 mmol), 3(R)-aminoquinuclidine dihydrochloride (0.62 g, 3.11 mmol) and HATU (1.18 g, 3.11 mmol). The mixture is stirred at -10 C. for 1 h, followed by warming to rt and stirring overnight. The mixture is concentrated in vacuo to a yellow residue. The crude product is purified by flash chromatography on SiO2. Elution with CHCl3-MeOH-NH4OH (90:9:1) gave 634 mg (71%) of a light yellow solid. MS(ESI) m/e 289 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; acetone; | EXAMPLE 5 N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzothiazole-6-carboxamide.fumarate To a stirred solution of 1,3-benzothiazole-6-carboxylic acid (500 mg, 2.8 mmol) and 3-(R)-aminoquinuclidine dihydrochloride (530 mg, 2.7 mmol) in DMF (27 mL) is added DIEA (1.5 mL, 8.4 mmol). The solution is stirred for 10 min, followed by cooling with an ice bath. HATU (1.0 g, 2.7 mmol) is added and the mixture is allowed to warm to rt and stir 16 h. The solvent is removed in vacuo and the remaining residue is partitioned between saturated aqueous potassium carbonate solution and 9:1 CHCl3-MeOH. The aqueous layer is extracted with 9:1 CHCl3-MeOH, and the combined organic layers are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a clear residue. The residue is taken up in acetone (3.0 mL) and a hot solution of fumaric acid (320 mg, 2.8 mmol) in isopropyl alcohol is added. The mixture is warmed in a water bath at 45 C. for 15 min, and then the reaction is concentrated in vacuo. The residue is triturated in acetone (3.0 mL) to afford Example 5 as a white solid (850 mg, 79%): 1H NMR (CD3OD) delta 9.4, 8.6, 8.2, 8.1, 6.7, 4.5, 3.9, 3.5-3.3, 2.4, 2.3, 2.1, 2.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethanolamine; diphenylphosphoranyl azide; p-toluenesulfonic acid monohydrate; In methanol; dichloromethane; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 7 N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzodioxole-5-carboxamide 4-methylbenzenesulfonate To a stirred suspension of 1,3-benzodioxole-5-carboxylic acid (380 mg, 2.3 mmol) in dry CH2Cl2 (5.0 mL) is added TEA (320 muL, 2.3 mmol), followed by diphenylphosphoryl azide (405 muL, 2.0 mmol). In a separate flask, to a stirred suspension of 3-(R)-aminoquinuclidine dihydrochloride (300 mg, 1.5 mmol) in CH2Cl2 (5.0 mL) is added TEA (530 muL, 3.8 mmol). After 10 min, the aminoquinuclidine solution is rapidly added to the benzodioxole solution. DMF (1.0 mL) is added, and the combined mixture is stirred for 24 h at rt. The reaction mixture is partitioned between saturated aqueous potassium carbonate solution and CH2Cl2. The aqueous layer is extracted with CH2Cl2, and the combined organic layers are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a clear residue. The crude product is purified by flash chromatography on silica gel. Elution with CHCl3-MeOH-ammonium hydroxide (90:9:1) gives 130 mg (31%) of a white foam. The foam (125 mg, 0.46 mmol) is dissolved in EtOAc (1.0 mL) and a solution of p-toluenesulfonic acid monohydrate (90 mg, 0.48 mmol) in MeOH (0.5 mL) is added. The solution is allowed to stand overnight. The solid that forms is filtered and dried in vacuo at 50 C. for 48 h to afford the title compound (160 mg, 76%): 1H NMR (CD3OD) delta 7.7, 7.5, 7.4, 7.3, 6.9, 6.1, 4.4, 3.8, 3.5-3.2, 2.4, 2.3, 2.2, 2.1, 1.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
150 mg (35%) | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; N,N-dimethyl-formamide; acetone; | Method B. Preparation of N-(1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-6-carboxamide.fumarate. To a stirred solution of Acid C1 (194 mg, 1.19 mmol) in anhydrous THF/DMF (5:1, 12 mL) are added DIEA (600 muL, 3.44 mmol) and 3-(R)-aminoquinuclidine dihydrochloride (225 mg, 1.13 mmol). The mixture is cooled to -10 C. and HATU (430 mg, 1.13 mmol) is added in one portion. The reaction mixture is allowed to warm to rt and stirred overnight. The solvents are removed in vacuo and the residue is partitioned between saturated aqueous potassium carbonate solution and 95:5 CHCl3-MeOH. The aqueous layer is extracted with 95:5 CHCl3-MeOH (2*), and the combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography on silica gel. Elution with CHCl3-MeOH-ammonium hydroxide (90:9:1) gives an orange solid. The solid is dissolved in acetone (5 mL) and a hot solution of fumaric acid (66 mg, 0.58 mmol) in isopropyl alcohol (2 mL) is added. The mixture is stirred for 30 min in a 50 C. water bath. The solvents are removed in vacuo and the remaining residue is dissolved in acetone (5 mL). The mixture is stirred overnight at rt. The solid precipitate is collected by filtration and washed with acetone. The solid is dried in vacuo overnight to give 150 mg (35%) of the title compound as a light yellow solid: 1H NMR (CD3OD) delta 8.6, 8.2, 8.0, 7.9, 6.7, 4.9, 4.5-4.4, 3.9-3.8, 3.5-3.3, 2.4, 2.3-2.2, 2.1, 2.0-1.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In methanol; water; N,N-dimethyl-formamide; acetone; | To a stirred solution of 2,3-dihydro-1,4-dioxino[2,3-c]pyridine-7-carboxylic acid (130 mg, 0.72 mmol) in anhydrous DMF (10 mL) in an ice bath is added sequentially DIEA (381 muL, 2.19 mmol), 3(R)-aminoquinuclidine dihydrochloride (143 mg, 0.72 mmol) and HATU (273 mg, 0.72 mmol). The mixture is stirred at 0 C. for 30 min, followed by warming to rt and stirring overnight. The mixture is concentrated in vacuo to a yellow residue. The residue is partitioned between CHCl3-MeOH (90:10) and half saturated aqueous K2CO3 solution. The aqueous layer is extracted with CHCl3-MeOH (90:10), and the combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product is purified by flash chromatography on SiO2. Elution with CHCl3-MeOH-NH4OH (90:9:1) gives 130 mg (62%) of a white foam. To a stirred solution of the above amide (128 mg, 0.44 mmol) in MeOH (10 mL) is added fumaric acid (51 mg, 0.44 mmol). The mixture is warmed on a water bath to 40 C. for 30 min, followed by removal of the solvent in vacuo. Acetone and two drops of water are added to the residue, which produces a white precipitate. The solid precipitate is filtered, washed with acetone and dried in vacuo to afford 116 mg (65%) of Example 13 as a white solid: 1H NMR (400 MHz, MeOH-d,) delta8.17, 7.59, 6.70, 4.41-4.40, 3.78, 3.47-3.29, 2.33, 2.20, 2.11-2.07, 1.93. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In ethanol; ethyl acetate; | EXAMPLE 34 5-[(1-Azabicyclo[2.2.2]oct-3-ylamino)methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide Prepared according to the method described in Example 31b from 2-chloro-5-formyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.30 g, Example 31a), 1-azabicyclo[2.2.2]octan-3-amine dihydrochloride salt (0.18 g), sodium triacetoxyborohydride (0.135 g) and 1,2-dichloroethane (10 ml). The residue was purified by chromatography over silica gel eluding with ethyl acetate: iso-hexane (1:1) followed by ethyl acetate: ethanol (95:5). Repurification by chromatography over silica gel eluding with dichloromethane: methanol (95:5) then (9:1) gave the title compound as a white gum (0.013 g). MS (APCI+ve) 442 (M+H)+ 1H NMR (CDCl3) delta 7.68 (1H, d); 7.39 (1H, d); 7.31 (1H, dd); 6.41 (1H, t); 3.75 (2H, s); 3.42-3.31 (2H, m); 3.25-3.09 (6H, m); 2.94 (1H, d); 2.38-2.23 (2H, m); 2.22-2.14 (1H, m); 2.01 (3H, s); 1.92-1.83 (2H, m); 1.69 (6H, q); 1.59 (6H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; N,N-dimethyl-formamide; | Example 99 Preparation of N-boc-L-aspartate-(beta-3-(S)-amino quinuclidinyl)-alpha benzyl ester STR117 To a solution of N-Boc-L-aspartamic acid-alpha benzyl ester (3.3 g, 10 mmole) in N,N-dimethyl formamide (50 mL) is added 3-(S)-aminoquinuclidine dihydrochloride (3.0 g, 15 mmole), 1-hydroxy-7-azabenzotriazole (2.0 g, 15 mmole), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (3.8 g, 10 mmole) and N,N-diisopropylethyl amine (10.5 mL, 60 mmole) and the reaction stirred at room temperature for 18 hours. The reaction mixture is diluted in ethyl acetate (500 mL) and washed successively with saturated aqueous sodium bicarbonate (100 mL) and brine (2*100 mL). The organic phase is dried over MgSO4, filtered and the solvent removed in vacuo to provide the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium; In ethanol; | a N-(1-azabicyclo[2,2,2]-oct-3-yl)-beta-alanine ethyl ester 0.92 g (20 mmol) of sodium were dissolved in 100 ml of ethanol. 4.0 g (20 mmol) of 3-amino-quinuclidine dihydrochloride were added and the mixture was stirred for 5 minutes. 2 g (20 mmol) of ethyl acrylate were added, the mixture was boiled for 20 hours, and evaporated in vacuo. The residue was shaken with little water and methylene chloride. The organic layer was separated and evaporated in vacuo, giving 3.1. g of the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In chloroform; water; | (R-N-(quinuclidinyl-3-yl)-2,4-dimethoxybenzamide hydrochloride [1:1] A mixture of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong>, 6.95 g, (0.0349), 2,4-dimethoxybenzoyl chloride, 700 g, (0.0349 mole), anhydrous sodium carbonate, 36.99 g, (0.349 mile), 175 ml water, and 175 ml chloroform was stirred rapidly to achieve good mixing of the 2 layers for 20 hrs. The chloroform layer was then separated, washed with water, dried over anhydrous magnesium sulphate, and concentrated to an impure oil. The oil was triturated twice with 20 ml portions of petroleum ether to remove some impurities. The oil was then dissolved in ether and filtered to remove a small amount of insoluble material. The filtrate was treated with ethereal hydrogen chloride and the resulting salt collected to yield 2.70 g (23.7% yield) white solid. The salt was recrystallized from ethanol-isopropyl ether. Further recrystallization from methanol-ethyl ether yielded a white solid, m.p. 211-212 C. The NMR analysis was satisfactory. Analysis: Calculated for C16 H23 N2 O3 Cl: C,58.80; H,7.09; N,8.57. Found: C,58.38; H,7.13; N,8.44. | |
With sodium carbonate; In chloroform; water; | (S-N-(quinuclidinyl-3-yl)-2,4-dimethoxybenzamide hydrochloride [1:1] A mixture of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong>, 6.95 g, (0.0349), 2,4-dimethoxybenzoyl chloride, 700 g, (0.0349 mole), anhydrous sodium carbonate, 36.99 g, (0.349 mile), 175 ml water, and 175 ml chloroform was stirred rapidly to achieve good mixing of the 2 layers for 20 hrs. The chloroform layer was then separated, washed with water, dried over anhydrous magnesium sulphate, and concentrated to an impure oil. The oil was triturated twice with 20 ml portions of petroleum ether to remove some impurities. The oil was then dissolved in ether and filtered to remove a small amount of insoluble material. The filtrate was treated with ethereal hydrogen chloride and the resulting salt collected to yield 2.70 g (23.7% yield) white solid. The salt was recrystallized from ethanol-isopropyl ether. Further recrystallization from methanol-ethyl ether yielded a white solid, m.p. 211-212 C. The NMR analysis was satisfactory. Analysis: Calculated for C16 H23 N2 O3 Cl: C,58.80; H,7.09; N,8.57 Found: C,58.38; H,7.13; N,8.44. | |
With sodium carbonate; In chloroform; water; | EXAMPLE 6 N-(1-Azabicyclo[2.2.2]oct-3-yl)-2,4-dimethoxybenzamide hydrochloride [1:1] A mixture of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong>, 6.95 g, (0.0349), 2,4-dimethoxybenzoyl chloride, 700 g, (0.0349 mole). anhydrous sodium carbonate, 36.99 g, (0.349 mole), 175 ml water, and 175 ml chloroform was stirred rapidly to achieve good mixing of the 2 layers for 20 hrs. The chloroform layer was then separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated to an impure oil. The oil was triturated twice with 20 ml portions of petroleum ether to remove some impurities. The oil was then dissolved in ether and filtered to remove a small amount of insoluble material. The filtrate was treated with ethereal hydrogen chloride and the resulting salt collected to yield 2.70 g (23.7% yield) white solid. The salt was recrystallized from ethanol-isopropyl ether. Further recrystallization from methanol-ethyl ether yielded a white solid, m.p. 211-212 C. The NMR analysis was satisfactory. Analysis: Calculated for C16 H23 N2 O3 Cl: C,58.80; H,7.09; N,8.57. Found: C,58.38; H,7.13; N,8.44. |
With sodium carbonate; In chloroform; water; | EXAMPLE 6 N-(1-Azabicyclo[2.2.2]oct-3-yl)-2,4-dimethoxybenzamide hydrochloride [1:1] A mixture of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong>, 6.95 g, (0.0349), 2,4-dimethoxybenzoyl chloride, 700 g, (0.0349 mole), anhydrous sodium carbonate, 36.99 g, (0.349 mole), 175 ml water, and 175 ml chloroform was stirred rapidly to achieve good mixing of the 2 layers for 20 hrs. The chloroform layer was then separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated to an impure oil. The oil was triturated twice with 20 ml portions of petroleum ether to remove some impurities. The oil was then dissolved in ether and filtered to remove a small amount of insoluble material. The filtrate was treated with ethereal hydrogen chloride and the resulting salt collected to yield 2.70 g (23.7% yield) white solid. The salt was recrystallized from ethanol-isopropyl ether. Further recrystallization from methanol-ethyl ether yielded a white solid, m.p. 211-212 C. The NMR analysis was satisfactory. Analysis: Calculated for C16 H23 N2 O3 Cl: C, 58.80; H, 7.09; N, 8.57. Found: C, 58.38; H, 7.13; N, 8.44. | |
With sodium carbonate; In chloroform; water; | Preparation 6 N-(1-Azabicyclo[2.2.2]oct-3-yl)-2,4-dimethoxybenzamide, hydrochloride [1:1] A mixture of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong>, 6.95 g, (0.0349), 2,4-dimethoxybenzoyl chloride, 700 g, (0.0349 mole), anhydrous sodium carbonate, 36.99 g, (0.349 mole), 175 ml water, and 175 ml chloroform was stirred rapidly to achieve good mixing of the 2 layers for 20 hrs. The chloroform layer was then separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated to an impure oil. The oil was triturated twice with 20 ml portions of petroleum ether to remove some impurities. The oil was then dissolved in ether and filtered to remove a small amount of insoluble material. The filtrate was treated with ethereal hydrogen chloride and the resulting salt collected to yield 2.70 g (23.7% yield) white solid. The salt was recrystallized from ethanol-isopropyl ether. Further recrystallization from methanol-ethyl ether yielded a white solid, m.p. 211-212 C. The NMR analysis was satisfactory. Analysis: Calculated for C16 H23 N2 O3 Cl: C, 58.80; H, 7.09; N, 8.57. Found: C, 58.38; H, 7.13; N, 8.44. | |
With sodium carbonate; In diethyl ether; chloroform; water; | PREPARATION 6 N-(1-Azabicyclo[2.2.2]oct-3-yl)-2,4-dimethoxybenzamide, hydrochloride [1:1] A mixture of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong>, 6.95 g, (0.349), 2,4-dimethoxybenzoyl chloride, 700 g, (0.0349 mole), anhydrous sodium carbonate, 36.99 g, (0.349 mole), 175 ml water, and 175 ml chloroform was stirred rapidly to achieve good mixing of the 2 layers for 20 hrs. The chloroform layer was then separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated to an impure oil. The oil was triturated twice with 20 ml portions of petroleum ether to remove some impurities. The oil was then dissolved in diethyl ether and filtered to remove a small amount of insoluble material. The filtrate was treated with ethereal hydrogen chloride and the resulting salt collected to yield 2.70 g (23.7% yield) white solid. The salt was recrystallized from ethanol-isopropyl ether. Further recrystallization from methanol-ethyl ether yielded a white solid, m.p. 211-212 C. The NMR analysis was satisfactory. Analysis: Calculated for C16 H23 N2 O3 Cl: C,58.80; H,7.09; N,8.57. Found: C,58.38; H,7.13; N,8.44. | |
With sodium carbonate; In chloroform; water; | (N-(quinuclidinyl-3-yl)-2,4-dimethoxybenzamide hydrochloride [1:1]. A mixture of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong>, 6.95g, (0.0349), 2,4-dimethoxybenzoyl chloride, 700g, (0.0349 mole), anhydrous sodium carbonate, 36.99g, (0.349 mile), 175ml water, and 175ml chloroform was stirred rapidly to achieve good mixing of the 2 layers for 20 hrs. The chloroform layer was then separated, washed with water, dried over anhydrous magnesium sulphate, and concentrated to an impure oil. The oil was triturated twice with 20ml portions of petroleum ether to remove some impurities. The oil was then dissolved in ether and filtered to remove a small amount of insoluble material. The filtrate was treated with ethereal hydrogen chloride and the resulting salt collected to yield 2.70g (23.7% yield) white solid. The salt was recrystallized from ethanol-isopropyl ether. Further recrystallization from methanol-ethyl ether yielded a white solid, m.p. 211-212C. The NMR analysis was satisfactory. Analysis: Calculated for C16H23N2O3Cl: C,58.80; H,7.09; N,8.57 Found: C,58.38; H,7.13; N,8.44 | |
With sodium carbonate; In chloroform; water; | Example 6 N-(1-Azabicyclo[2.2.2]oct-3-yl)-2,4-dimethoxybenzamide hydrochloride [1:1]. A mixture of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong>, 6.95 g, (0.0349), 2,4-dimethoxybenzoyl chloride, 700 g, (0.0349 mole), anhydrous sodium carbonate, 36.99 g, (0.349 mole), 175 ml water, and 175 ml chloroform was stirred rapidly to achieve good mixing of the 2 layers for 20 hrs. The chloroform layer was then separated, washed with water, dried over anhydrous magnesium sulphate, and concentrated to an impure oil. The oil was triturated twice with 20 ml portions of petroleum ether to remove some impurities. The oil was then dissolved in ether and filtered to remove a small amount of insoluble material. The filtrate was treated with ethereal hydrogen chloride and the resulting salt collected to yield 2.70 g (23.7% yield) white solid. The salt was recrystallized from ethanol-isopropyl ether. Further recrystallization from methanol-ethyl ether yielded a white solid, m.p. 211-212C. The NMR analysis was satisfactory. Analysis: Calculated for C16H23N2O3Cl: C,58.80; H,7.09; N,8.57 Found: C,58.38; H,7.13; N,8.44 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In N-methyl-acetamide; dichloromethane; toluene; | Method A (RS)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2,3-dimethylbenzamide The following is the preparation of a compound of Formula II via Scheme I, Step 1 in which the optional bond is present; X is methyl in the 3-position; Y is hydrogen; R1 is hydrogen; and R2 is (RS)-1-azabicyclo[2.2.2]oct-3-yl. 2,3-dimethylbenzoic acid (5.0 g; 33.3 mmol), oxalyl chloride (40.0 mmol, 3.5 mL) and dimethylformamide (0.1 mL) were dissolved in methylene chloride (100 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. A solution of the concentrate in toluene (100 mL) was added dropwise to a stirred solution of <strong>[6530-09-2](RS)-3-amino-1-azabicyclo[2.2.2]octane dihydrochloride</strong> (7.0 g; 35 mmol)in toluene (50 mL) and NaOH (2.0N, 50 mL) at 0 C. The reaction mixture was maintained at 0 C. and stirred for 30 minutes. The aqueous layer was extracted with of toluene (2*50 mL) and the combined organic layers dried over magnesium sulfate. Removal of the solvent under reduced pressure gave (RS)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2,3-dimethylbenzamide as a white solid (5.5 g, 25.4 mmol), m.p. 160-161 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In pyridine; | EXAMPLE 15 N-[[[1-azabicyclo[2.2.2]octan-3-yl]amino]carbonyl]-4-methoxybenzamide The above compound was prepared, following the procedure of Example 14b, from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (1.0 g, 5 mmol), 4-methoxybenzoylurea (0.97 g, 5 mmol) and di-isopropylethylamine (1.29 g, 10 mmol) in pyridine (20 ml). The product (1.12 g) was converted to 1:1 maleate half hydrate, mp 166-168 C. | |
In pyridine; | EXAMPLE 5 N-[[[1-azabicyclo[2.2.2]octan-3-yl] amino]carbonyl]-4-methoxybenzamide The above compound was prepared, following the procedure of Example 4b, from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (1.0 g, 5 mmol), 4-methoxybenzoylurea (0.97 g, 5 mmol) and di-isopropylethylamine (1.29 g, 10 mmol) in pyridine (20 ml). The product (1.12 g) was converted to 1: 1 maleate half hydrate, mp 166-168C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In pyridine; | (b) N-[[[1-Azabicyclo[2.2.2]octan-3-yl]amino]carbonyl]naphthalene-2-carboxamid The above compound was prepared, following the procedure of Example 14b, from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (1.0 g, 5 mmol), 2-naphthoylurea (1.07 g, 5 mmol) and di-isopropylethylamine (1.29 g, 5 mmol) in pyridine (20 ml). The title compound was isolated as hydrochloride half hydrate (1.39 g), mp 271-273 C. (dec). | |
In pyridine; | (b) N-[[[1-Azabicyclo[2.2.2]octan-3-yl]amino] carbonyl]naphthalene-2-carboxamide The above compound was prepared, following the procedure of Example 4b, from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (1.0 g, 5 mmol), 2-naphthoylurea (1.07 g, 5 mmol) and di-isopropylethylamine (1.29 g, 5 mmol) in pyridine (20 ml). The title compound was isolated as hydrochloride half hydrate (1.39 g), mp 271-273C (dec). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In pyridine; | (b) N-[[[1-Azabicyclo[2.2.2]-3yl]amino] carbonyl]-2-pyridinecarboxamide The above compound was prepared, following the procedure of Example 14b, from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong>(1.0 g, 5 mmol), 2-pyridoylurea (0.82 g, 5 mmol) and di-isopropylethylamine (1.3 g, 10 mmol) in pyridine (20 ml) by refluxing for 4 days. The pyridine was evaporated and the residue partitioned between ether and 10% aqueous w/v citric acid. The mixture was filtered, the aqueous phase washed with ether, then basified with potassium carbonate to precipitate the title compound (0.60 g) which was converted to the 1:1 fumarate, mp 202-203 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In pyridine; | (b) N-[[[1-azabicyclo[2.2.2]octan-3-yl]amino]carbonyl]-3-trifluoromethylbenzamide The above compound was prepared from 3-amino quinuclidine dihydrochloride (1.0 g, 5 mmol), 3-trifluoromethylbenzoylurea (1.16 g, 5 mmol) and diisopropylethylamine (1.29 g, 10 mmol) in pyridine (20 ml), by refluxing under nitrogen overnight. The solvent was evaporated and the residue worked-up as in Example 1. The product (1.18 g) was converted to oxalate salt, mp 197-200 C. | |
With N-ethyl-N,N-diisopropylamine; In pyridine; | (b) N-[[[1-azabicyclo[2.2.2]octan-3-yl] amino]carbonyl]-3-trifluoromethylbenzamide The above compound was prepared from 3-amino quinuclidine dihydrochloride (1.0 g, 5 mmol), 3-trifluoromethylbenzoylurea (1.16 g, 5 mmol) and diisopropylethylamine (1.29 g, 10 mmol) in pyridine (20 ml), by refluxing under nitrogen overnight. The solvent was evaporated and the residue, worked-up as in Reference Example A. The product (1.18 g) was converted to oxalate salt, mp 197-200C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; triethylamine; In chloroform; water; | EXAMPLE 6 N-(Azabicyclo[2.2.2]octan-3-yl)-N'-(3,5-dichlorophenyl)thiourea Thiophosgene (1.0 ml, 1.51 g, 13.13 mmol) was suspended in water (10 ml) and stirred vigorously while 3,5-dichloroaniline (1.62 g, 10 mmol) in chloroform (8 ml) was added over 1 min. Triethylamine (1.4 g, 13.86 mmol) was added and stirring was continued for 30 min. The aqueous phase was discarded and the chloroform retained. 3-Aminoquinuclidine dihydrochloride (1.99 g, 10 mmol) was dissolved in water (2 ml) and treated with sodium hydroxide pellets until the pH was 9. This solution was then added to the above chloroform solution and the two stirred together overnight. The aqueous phase was extracted 3 times with chloroform. The combined organic phases were washed once with water. An insoluble oil was separated. The chloroform solution was dried (Na2 SO4) and evaporated, and the residue combined with the insoluble oil. This material was triturated with dichloromethane for 3 h to give the title product, 2.09 g, mp 137-140 C., as hydrochloride containing 0.5 mole of dichloromethane not removable by drying. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; triethylamine; In chloroform; benzene; | EXAMPLE 29 A mixture of 3.5 g of 6-chloro-3,4-dihydro-2,2,4-trimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid and 5 ml of thionyl chloride is refluxed under heating for 1.5 hours. After completion of the reaction, the excess thionyl chloride is distilled off under reduced pressure, and further 50 ml of benzene is added thereto followed by complete removal of thionyl chloride by distillation under reduced pressure. A solution of the residue in 50 ml of chloroform is added dropwise to a solution of 2.6 g of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> and 4.7 g of triethylamine under cooling and stirring. The resultant solution is stirred at room temperature for 2 hours, and then washed with water and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is recrystallized from ethanol-isopropyl ether followed by treating with ethanolic acid to give 6-chloro-3,4-dihydro-2,2,4-trimethyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide hydrochloride, melting at 260-261 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In pyridine; | (b) N-[[[1-Azabicyclo[2.2.2]octan-3-yl]amino]carbonyl]-2,6-dimethylbenzamide The above compound was prepared, following the procedure of Example 14b, from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (1.0 g, 5 mmol), 2,6-dimethylbenzoylurea (0.96 g, 5 mmol) and diisopropylethylamine (1.3 g, 10 mmol) in pyridine (20 ml) by refluxing for 4 days. The product was recrystallized from acetonitrile to give the title compound quarter hydrate (0.54 g), mp 230-231 C. | |
With N-ethyl-N,N-diisopropylamine; In pyridine; | (b) N-[[[1-Azabicyclo[2.2.2]octan-3-yl] amino]carbonyl]-2,6-dimethylbenzamide The above compound was prepared, following the procedure of Example 4b, from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (1.0 g, 5 mmol), 2,6-dimethylbenzoylurea (0.96 g, 5 mmol) and diisopropylethylamine (1.3 g, 10 mmol) in pyridine (20 ml) by refluxing for 4 days. The product was recrystallized from acetonitrile to give the title compound quarter hydrate (0.54 g), mp 230-231C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In pyridine; | EXAMPLE 19 N-[[[1-Azabicyclo[2.2.2]octan-3-yl]amino]carbonyl]-2-thiophenecarboxamide The above compound was prepared, following the procedure of Example 14b, from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (1.0 g, 5 mmol), 2-thienoylurea (0.85 g, 5 mmol) and diisopropylethylamine (1.3 g, 10 mmol) in pyridine (20 ml). The product (0.79 g) was converted to hydrochloride half hydrate, mp 232-233 C. | |
With N-ethyl-N,N-diisopropylamine; In pyridine; | EXAMPLE 9 N-[[[1-Azabicyclo[2.2.2]octan-3-yl]amino] carbonyl]-2-thiophenecarboxamide The above compound was prepared, following the procedure of Example 4b, from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (1.0 g, 5 mmol), 2-thienoylurea (0.85 g, 5 mmol) and diisopropylethylamine (1.3 g, 10 mmol) in pyridine (20 ml). The product (0.79 g) was converted to hydrochloride half hydrate, mp 232-233C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In pyridine; | EXAMPLE 17 N-[[[1-Azabicyclo[2.2.2]octan-3-yl]amino]carbonyl]-2-furancarboxamide The above compound was prepared, following the procedure of Example 14b, from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (1.0 g, 5 mmol), 2-furoylurea (0.77 g, 5 mmol), and diisopropylethylamine (1.3 g, 10 mmol) in pyridine (20 ml). The product (0.58 g) was converted to the 1:1 succinate mp 156-159 C. | |
With N-ethyl-N,N-diisopropylamine; In pyridine; | EXAMPLE 7 N-[[[1-Azabicyclo[2.2.2]octan-3-yl]amino] carbonyl]-2-furancarboxamide The above compound was prepared, following the procedure of Example 4b, from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (1.0 g, 5 mmol), 2-furoylurea (0.77 g, 5 mmol), and diisopropylethylamine (1.3 g, 10 mmol) in pyridine (20 ml). The product (0.58 g) was converted to the 1: 1 succinate mp 156-159C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; methanol; water; benzene; | EXAMPLE 12 N-(1-Azabicyclo[2.2.2]oct-3-yl)-4-nitrobenzamide hydrochloride hydrate [1:1:0.75] A solution of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (5.0 g, 0.0246 mole) in ca. 15 ml methanol/5 ml water was treated with barium hydroxide octahydrate (9.0 g, 0.0286 mole), warmed over steam for ca. 10 min, then taken to dryness on the rotary evaporator at 40-45 C./35 mm. The resultant dry powder was repeatedly extracted with ca. 6*50 ml dry tetrahydrofuran. The tetrahydrofuran solution was concentrated by boiling until an 80-90 ml volume remained. This clear solution was added dropwise with stirring to a hot solution of 4-nitrobenzoyl chloride (4.36 g., 0.235 mole) in benzene. The solid produced was recrystallized from anhydrous methanol several times to yield 5.13 g of solid, melting at 277-279 C. Microanalysis and NMR showed 0.75 mole of water present. Mass spec. and IR were satisfactory, yield of title compound was 0.186 mole (79.4%). Analysis: Calculated for C56 H78 Cl4 N12 O15: C, 51.70; H, 6.04; N, 12.92. Found: C, 51.48; H, 5.93; N, 12.91. | |
In methanol; water; benzene; | EXAMPLE 12 N-(1-Azabicyclo[2.2.2]oct-3-yl)-4-nitrobenzamide hydrochloride hydrate [1:1:0.75]. A solution of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (5.0 g, 0.0246 mole) in ca. 15 ml methanol/5 ml water was treated with barium hydroxide octahydrate (9.0 g, 0.0286 mole), warmed over steam for ca 10 min, then taken to dryness on the rotary evaporator at 40-45 C./35 mm. The resultant dry powder was repeatedly extracted with ca 6*50 ml dry tetrahydrofuran. The tetrahydrofuran solution was concentrated by boiling until an 80-90 ml volume remained. This clear solution was added dropwise with stirring to a hot solution of 4-nitrobenzoyl chloride (4.36 g, 0.235 mole) in benzene. The solid produced was recrystallized from anhydrous methanol several times to yield 5.13 g of solid, melting at 277-279 C. Microanalysis and NMR showed 0.75 mole of water present. Mass spec. and IR were satisfactory, yield of title compound was 0.186 mole (79.4%). Analysis: Calculated for C56 H78 C14 N12 O15: C, 51.70; H, 6.04; N, 12.92 Found: C, 51.48; H, 5.93; N, 12.91 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.3 g (97%) | With potassium hydroxide; In tetrahydrofuran; ethanol; water; | EXAMPLE 14 5-Aminosulfonyl-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-methoxybenzamide Hydrochloride Hydrate [1:1:0.25] A solution of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (2.5 g, 0.0126 mole) in 25 ml of water was treated with approximately 5 g of KOH and the resultant slurry/solution taken to complete dryness on the rotary evaporator at 50/35 mm. The dry residue was carefully extracted by repeated triturations with warm tetrahydrofuran until a total volume of 130 ml had been collected and dried over magnesium sulfate. This solution of 3-aminoquinuclidine base was treated with a solution of 2-methoxy-5-sulfamylbenzoyl chloride (2.92 g, 0.0117 mole) in 50 ml of dry tetrahydrofuran by dropwise addition under nitrogen. The resultant very turbid solution was refluxed gently for about 30 min, then freed of tetrahydrofuran by allowing it to evaporate. The residue was taken up in 90% ethanol containing a few drops of ethereal hydrogen chloride, filtered and chilled. The solid produced was then recrystallized again to yield 4.3 g (97%), m.p. 233-234 C. NMR, MS, and IR were in support of the structure proposed. Analysis: Calculated for C60 H90 Cl4 N12 O17 S4: C, 47.37; H, 5.96; N, 11.05. Found: C, 47.28; H, 5.93; N, 10.87. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With barium dihydroxide; In tetrahydrofuran; ethanol; | EXAMPLE 15 2-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide Dihydrochloride The free base was liberated from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (4.0 gm, 0.020 mole) using barium hydroxide and keeping the process under dry nitrogen. The base thus obtained (0.018 mole) was dissolved in dry tetrahydrofuran, treated with isatoic anhydride (2.04 gm, 0.018 mole) and brought to reflux. The clear, dark brown solution within five minutes became tan-turbid. Reflux was continued for 1 hr, the excess tetrahydrofuran distilled off, and the residue added to boiling ethanol. A small amount of insoluble solid was filtered off. Chilling produced 3.8 g (68%) crystalline amine base, m.p. 241-243 C. The base was converted to the hydrochloride salt by reacting with ethereal hydrogen chloride and recrystallized from either hot water-isopropanol or methanol-methylethylketone (1:1) to yield a crystalline solid melting 280.5-283.5 C. NMR, MS, and IR were satisfactory. MW 318.249. Analysis: Calculated for Cl2 N3 OC14 H21: C, 52.84; H, 6.65; N, 13.20. Found: C, 52.90; H, 6.54; N, 13.24. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With barium dihydroxide; In tetrahydrofuran; ethanol; | EXAMPLE 14 2-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide dihydrochloride. The free base was liberated from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (4.0 gm, 0.020 mole) using barium hydroxide and keeping the process under dry nitrogen. The base thus obtained (0.018 mole) was dissolved in dry tetrahydrofuran, treated with isatoic anhydride (2.04 gm, 0.018 mole) and brought to reflux. The clear, dark brown solution within five minutes became tan-turbid. Reflux was contined for 1 hr, the excess tetrahydrofuran distilled off, and the residue added to boiling ethanol. A small amount of insoluble solid was filtered off. Chilling produced 3.8 g (68%) crystalline amine base, m.p. 241-243 C. The base was converted to the hydrochloride salt by reacting wiht etheralhydrogen chloride and recrystallized from either hot water-isopropanol or methanol-methylethylketone (1:1) to yield a crystalline solid melting 280.5-283.5 C. NMR, MS, and IR were satisfactory. MW 318.249. Analysis: Calculated for C12 N3 OC14 H21: C, 52.84; H, 6.65; N, 13.20 Found: C, 52.90; H, 6.54; N, 13.24 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In pyridine; | (b) N-[[[1-Azabicyclo[2.2.2]-3-yl]amino] carbonyl]-2-pyridinecarboxamide The above compound was prepared, following the procedure of Example 4b, from <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (1.0 g, 5 mmol), 2-pyridoylurea (0.82 g, 5 mmol) and di-isopropylethylamine (1.3 g, 10 mmol) in pyridine (20 ml) by refluxing for 4 days. The pyridine was evaporated and the residue partitioned between ether and 10% aqueous w/v citric acid. The mixture was filtered, the aqueous phase washed with ether, then basified with potassium carbonate to precipitate the title compound (0.60 g) which was converted to the 1: 1 fumarate, mp 202-203C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dimethyl sulfoxide; at 120℃; for 0.0833333h;Microwave; | A solution of 2-chloromethyl-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg, 0.06 mmol), <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (22.9 mg, 0.12 mmol) and triethylamine (18.2 mg, 0.18 mmol) in dimethylsulfoxide(500 muL) was heated in the Creator microwave at 120 C. for 5 minutes. The mixture was filtered and purified by preparative HPLC to afford 2-[(1-aza-bicyclo[2.2.2]oct-3-ylamino)-methyl]-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (14.8 mg) 1H NMR (MeOD) delta 8.34-8.27 (m, 3H) 7.29 (d, 2H) 4.95 (s, 2H) 4.29-4.21 (m, 3H) 4.00 (m, 1H) 3.86-3.69 (m 5H) 2.46 (m, 1H) 2.27-2.10 (m, 4H) 1.45 (t, 3H). MS m/z 471.8 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Step (a) 3-amino-N-l-azabicyclo[2.2.2]oct-3-ylbenzamide acetate salt(+/-)-3-Aminoquinculidine dihydrochloride (10 g, 0.067 moles) was dissolved in water (20 mL) and cooled to 00C and sodium hydroxide (8 g, 0.22 mmoles) was added slowly. A solution of 3-nitrobenzoyl chloride (11 g, 0.07 moles) in dry acetonitrile (20 mL) was then <n="110"/>added in 1 mL aliquots over a period over 10 min. The mixture was left to stir for 20 min. and then diluted with water (50 mL) and extracted into chloroform (3 x 25 mL). The organic layer was then washed with sodium carbonate solution (pH 10.5) and concentrated to give the crude material, which was then triturated in ether (100 mL) to give N-I- azabicyclo[2.2.2]oct-3-yl-3-nitrobenzamide as a colourless crystalline solid (11.2 g, 74%). This was used in the next step without further purification.3-amino-N-l-azabicyclo[2.2.2]oct-3-ylbenzamide acetate salt (11 g, 0.45 moles) was dissolved in ethanol (150 mL) and hydrogenated at room temperature and 5 bar hydrogen pressure. After 8 h glacial acetic acid was added to the suspension that had formed and the mixture re-hydrogenated at 3 bar hydrogen pressure for 18 h. The mixture was filtered and the filtrate concentrated in vacuo to give an oil as crude product. This was then triturated with 2:1 isohexane/ether, then with ether and then with isohexane alone for 18 h. The subtitle compound was isolated as a colourless solid (11.3 g, 99%).1HNMR (250 MHz, DMSO-d) 8.09 (IH, d), 7.10 - 6.94 (3H, m), 6.67 (IH, ddd), 5.39 - 5.03 (2H, m), 3.93 (IH. d), 3.93 (IH, d), 3.15 - 3.04 (IH, m), 2.96 - 2.84 (IH, m), 1.95 - 1.73 (5H, m), 1.72 - 1.50 (3H, m), 1.43 - 1.21 (IH, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With polymer-bound trimethyl ammonium cyanoborohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 24 - 36h;Combinatorial reaction / High throughput screening (HTS); | All sixty diamines were separated in four groups based on their steric and electronic characteristics, Figures 1-4. Each diamine was measured in the amount of 0.05 g (approximately 0.3 mmol) and pooled together with the others in the group. Obtained diamine mixtures were dissolved in 5 ml of 1,2-dichloroethane and used for the syntheses. Each well of the 96-well filterplates was loaded with 0.2 ml of 1: 10 mixture of acetic acid: DCE, 0.03 ml of the diamine mixture in DCE (group 1, group 2, group 3, or group 4) to assure 0.04 mmol of the diamines per well, and shaken for 5 min at room temperature. Appropriate carbonyl compounds from the master plate (0.1 ml of 1.2 M solution) were added into corresponding wells of the reaction plates followed by the addition of (polystyrylmethyl) trimethylammonium cyanoborohydride, (0.020 g, 0.08 mmol per well). The reaction plates were sealed and placed on a shaker. The reaction was allowed to proceed 24-36 hours at room temperature. At the end, the reaction mixtures were filtered using a filtration manifold, and products were collected into four (one per group) collection plates. Solvents were evaporated in SpeedVac and formed residues were analyzed by mass spectrometry prior to biological screening. Mono and double alkylated products were observed in 1: 0.5 to 1: 2 ratios by mass spectral analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | Example 53 Synthesis of N-(1-Aza-bicyclo[2.2.2]oct-3-yl)-N'-(3-chloro-4-methoxy-phenyl)-N"-)1-ethyl-pyrrolidin-2-ylmethyl)-[1,3,5]triazine-2,4,6-triamine (148) To 101 (3.056 g, 10.0 mmol) dissolved in anhydrous acetonitrile (30 mL) at about 0 C. was added a solution of 2-(aminomethyl)-1-ethylpyrrolidine (1.5 mL, 10.0 mmol) in anhydrous acetonitrile (5 mL) followed by addition of a DIEA (1.9 mL, 11.0 mmol). The reaction mixture was allowed to warm to room temperature and was stirred at room temperature overnight under nitrogen. Then DIEA (1.9 mL, 11 mmol) was added which was followed by addition of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (1.962 g, 10.0 mmol) in 1,4-dioxane (5 mL). The reaction mixture was allowed to stir at reflux overnight under nitrogen. The reaction mixture was extracted 2 times with dichloromethane and 1 time with ethyl acetate. The combined organic layers were washed one time with brine and dried over anhydrous potassium carbonate. The organic layer was with 20% HCl (aq). The aqueous layer was neutralized with 2.5 N NaOH (aq) and then extracted 3 times with ethyl acetate. The combined organic layers were washed 1 time with brine, dried over potassium carbonate, concentrated on a rotary evaporator and allowed to dry overnight under vacuum. Column chromatography (silica gel, 85:14:1 dichloromethane:methanol:conc. ammonium hydroxide) yielded a pale white solid 148 (100 mg, 2%), mp 83 C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 8.1 min, 71.2% purity); MS (ESI): m/z 488 (M+H, 18.7), 280 (100), 245 ([M+2H]++, 37.4), 236 (23.5). | |
To 101 (3.056 g, 10.0 mmol) dissolved in anhydrous acetonitrile (30 mL) at about 0 C was added a solutionof 2- (aminomethyl)-l-ethylpyrrolidine (1.5 mL, 10.0 mmol) in anhydrous acetonitrile (5mL) followed by addition of a DIEA (1.9 mL, 11.0mmol). The reaction mixture was allowed to warm to room <Desc/Clms Page number 334>temperature and was stirred at room temperature overnight under nitrogen. Then DIEA (1.9 mL, 11 mmol) was added which was followed by addition of 3- aminoquinuclidine dihydrochloride (1.962 g, 10.0 mmol) in 1,4-dioxane (5 mL). The reaction mixture was allowed to stir at reflux overnight under nitrogen. The reaction mixture was extracted 2 times with dichloromethane and1 time with ethyl acetate. The combined organic layers were washed one time with brine and dried over anhydrous potassium carbonate. The organic layer was with 20%HC1(aq). The aqueous layer was neutralized with 2.5 N NaOH(aq) and then extracted 3 times with ethyl acetate. The combined organic layers were washed1 time with brine, dried over potassium carbonate, concentrated on a rotary evaporator and allowed to dry overnight under vacuum. Column chromatography (silica gel, 85 : 14: 1 dichloromethane: methanol :conc. ammonium hydroxide) yielded a pale white solid 148 (100 mg,2%), mp83 C ; HPLC: Inertsil ODS-3V C18, 40: 30: 30[KH2P04(O. 01M, pH 3.2) : CH30H:CH3CN], 264nm, Rt 8.1 min, 71.2% purity); MS(ESI) :nilz 488 (M+H, 18.7),280 (100), 245( [M+2H] ++, 37.4), 236 (23.5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | To a solution of the 1H-indazole-3-carboxylic acid (16.1 mmol) in N,N-dimethylformamide (65 ml) was added HBTU (16.1 mmol), catalytic amount of dimethylaminopyridine, N, N- diisopropylethylamine (96.6 mmol) and 4 A activated molecular sieves (2.6 g). The reaction mixture was maintained at room temperature for 2 h under nitrogen and then 3- aminoquinuclidine dihydrochloride (16.1 mmol) was added. After 18 h, the solvent was removed under reduced pressure. The oily residue was partitioned between saturated, aqueous sodium bicarbonate (25 ml) and dichloromethane (100 mL). The aqueous layer was further extracted with 9/1 dichloromethane/methanol (5 x 100 ml) and the combined organic layers were concentrated. The residue was purified by chromatography using either a mixture of 90/10/1 dichloromethane/methanol/ammonium hydroxide or 70/30/1 ethyl acetate/methanol/ammonium hydroxide as the eluent to provide the product in 30%- 70% yield. Alternatively, the products were purified by preparative HPLC using an 8 min gradient of 95/5 to 20/80 water (0. 1% formic acid)/acetonitrile (0. 1% formic acid). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Compound [194]: (+/-)-4-(9-Cyclopentyl-5, 7, 7-trimethyl-6-oxo-6, 7,8,9-tetrahydroSH- pyrimido[4>5-b][l,4]diazepin-2-ylomeganino)-3-inethoxy-N-(quinuclidin-3-yl)benzamide; 4-(9-Cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5- b][l,4]diazepin-2-ylamino)-3-methoxybenzoic acid (Intermediate 6) (20 rng, 0.046 mmol, 1 eq), DPEA (16 mul, 0.091 mmol, 2 eq) and TBTU (16 mg, 0.05 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 5 min before the addition of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (11 mg, 0.055 mmol, 1.1 eq). The RM <n="95"/>was then stirred at rt for 16 hours before purifying by preparative RP-HPLC-MS (Preparative_l) to provide (+/-)-4-(9-cyclopentyl-5, 7, 7-tmethyl-6-oxo-6, 7,8,9- tetrahydro-5H-pyrimido[4,5-b][l,4]diazepin-2-ylamino)-3-methoxy-N~(quinuclidin-3- yljbenzamide (8 mg, 32%).Rt = 3.28 min (Analytical_l); MS(+ve): 548.5; IH NMR (DMSO-d) delta ppm: 8.37 (IH, d, J 8 Hz), 8.07 (IH, d, J 6.5 Hz), 7.98 (IH, s), 7.69 (IH, s), 7.47 - 7.50 (2H3 m), 5.19 (IH, quint, J 8 Hz), 3.95 (4H, m), 3.37 (2H, s), 3.18 (3H, s), 3.11 (IH, m), 2.89 (IH, m), 2.65 - 2.72 (4H, m), 1.88 (2H, m), 1.73 - 1.87 (4H5 m), 1.57 - 1.61 (6H, m), 1.31 (IH, m), 1.09 (6H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compound [186]: (+/-)-4-(9 '-Cyclopentyl-5 '-methyl-6'-oxo-5 6 89'- tetrahydrospiro [cyclopropane- 1, 7'-pyrimido[4, 5-b][l, 4]diazepine]-2 '-ylamino)-3- methoxy-N-(quinuclidin-3-yl)benzamide; 4-(9'-Cyclopentyl-5'-methyl-6'-oxo-5',6l,8',9'-tetrahydrospiro[cyclopropane-l,7'- pyrimido[4,5-b][l,4]diazepine]-2'-ylamino)-3-methoxybenzoic acid (Intermediate 5) (25 mg, 0.057 mmol, 1 eq), DIPEA (20 muL, 0.11 mmol, 2 eq) and TBTU (20 mg, 0.063 mmol, 1.1 eq) were added to 0.5 xL DMF and the resulting solution stirred at rt for 15 min before the addition of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (11 mg, 0.055 mmol, 1.1 eq) and DIPEA (40 muL). The RM was then stirred at rt for 16 hours before purifying by preparative RP-HPLC-MS (Preparative_l) to provide (+/-)-4-(9'-cyclopentyl-5'- methyl-6'-oxo-5 ' 6', 8', 9'-tetrahydrospiro[cyclopropane-l, 7'-pyrimido[4, 5- b][l,4]diazepine]-2'-ylamino)-3-methoxy-N-(quinuclidin-3-y)benzamide. <n="96"/>Rt = 3.02 min (Analytical^); MS(+ve): 546.4; IH NMR (DMSO-d6) delta ppm: 8.40 (IH, d, J 8 Hz), 8.08 (IH, d, J 7 Hz)5 7.98 (IH, s), 7.69 (IH, s), 7.47 - 7.50 (2H5 m)5 4.87 (IH, quint, J 9 Hz), 4.10 (IH5 q, J 5.5 Hz), 3.95 (4H, m), 3.47 (2H, s), 3.27 (3H, s), 3.07 (IH, m), 2.08 (IH, m), 2.63 - 2.86 (4H, m), 1.88 (3H, m), 1.78 (IH, m), 1.68 (2H, m), 1.50 - 1.62 (5H5 m), 1.32 (IH, m), 0.90 (2H5 m), 0.66 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compound [218]: (+/-)-4-(9'-Cyclopentyl-5'-methyl-6'-oxo-5',6',8',9r- tetrahydrospiro[cyclobutane~l, 7'-pyrimido[4, 5-67/7, 4JdiazepineJ-2 '-ylamino)-3- methoxy-N-(quinuclidin-3-yl)benzamide; 4-(9'-Cyclopentyl-5'-methyl-6'-oxo-5',6l58'59'-tetrahydrospiro[cyclobutane-l57'- pyrimido[455-b][l54]diazepine]-2'-ylamino)-3-methoxybenzoic acid (Intermediate 7) (15 mg, 0.033 mmol), DIPEA (12 mul, 0.066 mmol, 2 eq) and TBTU (12 mg5 0.036 mmol5 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 5 min before the addition of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (8 mg, 0.04 mmol, 1.2 eq) and DIPEA (13 muL). The RM was then stirred at rt for 3 hours before purifying by preparative RP-HPLC-MS (Preparative_2) to provide (+/-)-4-(9'-cyclopentyl-5'-methyl- &-OXO-5 ',6', 8 ',9 '-tetrahydrospirofcyclobutane-l , 7'-pyrimido[4, 5-b][l, 4]diazepine]-2 '- ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide.Rt = 3.26 min (AnalyticalJ); MS(+ve): 560.4; IH NMR (DMSO-d6) delta ppm: 8.37 (d, J = 8.3 Hz, IH)5 8.08 (d, J = 6.8 Hz5 IH), 8.05 (s, IH)5 7.73 (s, IH)5 7.45 - 7.53 (m5 2H)5 4.82 (quin, J = 8.3 Hz5 IH), 3.84 - 4.01 (m, 4H), 3.64 (s, 2H), 3.18 (s, 3H)5 3.04 - 3.14 (m, IH)5 2.88 (t, J = 9.8 Hz5 IH), 2.58 - 2.75 (m, 4H)5 2.21 - 2.33 (m, 2H)5 2.07 (s, 2H), 1.97 (br. s., 2H)5 1.87 (br. s, 2H)5 1.76 (d, J = 4.9 Hz5 2H), 1.56 - 1.70 (m, 8H), 1.30 (br. s., IH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 10; To a solution of 5-phenyl-1,3-thiazole-4-carboxylic acid (300 mg) in toluene (6 mL) were added dropwise TEA (672 muL) and DPPA (409 muL) at room temperature, followed by stirring at the same temperature for 20 minutes. Next, after stirring at 90C for 5 minutes, a mixture of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (407 mg) and DMF (2 mL) was added thereto, followed by heating under reflux for 1 hour. To the reaction liquid was added water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (YAMAZEN YFLC WPrep2XY, eluent; CHCl3:MeOH:28% aqueous ammonia=80:10:1) to obtain an oily substance. This was dissolved in EtOH, followed by addition of 10% HCl/MeOH at room temperature and concentration under reduced pressure. The residue obtained was added with EtOH and EtOAc, and left to stand, and the solid precipitated was collected by filtration, and washed with EtOAc to obtain 1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(5-phenyl-1,3-thiazol-4-yl) urea hydrochloride (15 mg) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.1% | (+/-)-N-(1-Aza-bicyclor2.2.21oct-3-yl)-4-methoxy-2-nitro-benzamide (Intermediate compound)A mixture of (+/-)-3-aminoquinuclidine dihydrochlohde (4.38 g, 21.97 mmol), sodium-methoxide (2.61 g, 48.3 mmol) and methanol (40 ml) was stirred at reflux for 10 minutes. The solvent was evaporated. The mixture was suspended inTHF and 4-methoxy-2-nitro-benzoyl chloride was added (2.77 g, 21.97 mmol) followed by addition of isopropanol (5 ml). The mixture was stirred for 15 h.Aqueous sodium hydroxide (50 ml, 1 M) was added followed by extraction with dichloromethane (2 x 60 ml). The crude mixture was purified by silica gel chromatography, using a 9 : 1 + 1 % dichloromethane : methanol + aqueous ammonia mixture as eluent. Yield 540 mg (8.1 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | To a solution of <strong>[6530-09-2]3-aminoquinuclidine dihydrochloride</strong> (8.0 g, 40.0 [MMOL)] in EtOH (100 mL) was added excess [NA2CO3] and the mixture was stirred for 1 h and then filtered. To this solution was added [BENZALDEHYDE] (3.2 g, 30.0 [MMOL)] and the reaction was stirred at room temperature for 2 h and then NaBH4 (3 [PELLETS,'0.] 4 [G] ea. ) was added and the reaction was stirred overnight at room temperature. The solvent was evaporated in vacuo and the residue was partitioned between 10% [NA2CO3] and EtOAc. The organic layer was separated, dried over [K2CO3,] filtered and the solvent was evaporated in vacuo. The residue was chromatographed on silica (92/8 CHCl3/1. [0] M [NH3] in [MEOH)] to give [N-PHENYLMETHYL-1-AZABICYCLO] [2.2. 2] octan-3-amine (4.2 g, 76%) as an intermediate, a pale yellow oil. MH+ = 217.'H NMR (CDCl3) 1.4 (m, [3H),] 1.7 (m, [1 H),] 1.9 (m, [2H),] 2. 45 (2m, 1H), 2.8 (m, [5H),] 3.2 (m, [1 H),] 3.75 (d, 2H), 7.3 (m, 5H). Using the same procedure as described above for Compound 1 andt [N-PHENYLMETHYL-1-AZABICYCLO] [2.2. 2] [OCTAN-3-AMINE)] in place of [N-PHENYL-1-AZABICYCLO] [2.2. 2] [OCTAN-3-AMINE,] a crude product was obtained and chromatographed on silica (94/6 CHCl3/0. 5 M [NH3] in [MEOH).] The appropriate fractions were combined and the solvent was evaporated in vacuo. The residue was treated with 1 eq of fumaric acid and the residue was recrystallized from acetone to give Compound 16 (0.22 g, 9%) as a beige solid mp 107-110 [C.] MH+ = 392.'H NMR (DMSO d6) 1.15 (t, 6H), 1.6 [(M,] [1H),] 1.9 (m, 3H), 2.25 (m, [1H),] 3.05 [(M,] 4H), 3.3 (m, 5H), 3.55 (t, [1H),] 4.2 (t, [1H),] 4.5 (d, 1H), 4.85 (d, [1 H),] 6.5 (s, 2H), 6.8 (s, 2H), 7.35 (m, 7H). Anal. [CALCD] for [C25H33N3001.] 5 [C4H404H20] : C, 63.79 ; H, 7.08 ; N, 7.20. Found C, 63.94 ; H, 7.15 ; N, 7.09. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
529 mg of <strong>[6624-49-3]isoquinoline-3-carboxylic acid</strong> hydrate are dissolved in 18 mi of DMF, followed by addition of 508 mg of 1-hydroxy-benzotriazol and 1.81 G of dicyclohexyl-carbodiimide. After stirring for 1 h at r. t. , the precipitated dicylohexyl-urea is filtered off and 500 mg of 3 (S)- aminoquinuclidine dihydrochloride and 1.3 ml of ethyl-diisopropylamine is added to the filtrate. After stirring for 48 h at room temperature, a second portion of dicylohexyl-urea is filtered off and washed with MeOtBu/DMF (4: 1). Wash solution and filtrate are combined and crystallized by standing over night at 5° The crystalline precipitate is filtered off and washed with MeOtBu/DMF (4: 1), followed by MeOtBu to yield the title compound as monohydrochloride. NMR (1H, 400 MHz, AH d6-DMSO) : 1.75 (1H, t), 1.96 (2H, m), 2.12 (1H, q), 2.24 (1H, d), 3.24 (3H, m), 3.43 (2H, m), 3.65 (1'H, t), 4.49 (1H, q), 7. 86 (1H, t), 7.92 (1H, t), 8. 24 (1H, d), 8.30 (1H, d), 8. 61 (1H, s), 9.31 (1 H, d), 9. 46 (1H, s), 10.59 1H, br). MS (ES+) : 282 (MH)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | To a solution of the carboxylic acid (16.1 mmol) in N, N dimethylformamide (65 mL) was added HBTU (16. 1 mmol), catalytic amount of dimethylaminopyridine, N, N- diisopropylethylamine (96. 6 mmol) and 4 A activated molecular sieves (2.6 g). The reaction mixture was maintained at room temperature for 2 h under nitrogen and then 3- aminoquinuclidine dihydrochloride (16.1 mmol) was added. After 18 h, the solvent was removed under reduced pressure. The oily residue was partitioned between saturated, aqueous sodium bicarbonate (25 mL) and dichloromethane (100 mL). The aqueous layer was further extracted with 9/1 dichloromethane/methanol (5 x 100 mL) and the combined organic layers were concentrated. The residue was purified by chromatography [90/10/1 dichloromethane/methanol/ammonium hydroxide or 1/1 to 0/1 ethyl acetate/ (70/30/1 ethyl acetate/methanol/ammonium hydroxide)] or by preparative HPLC, thus providing the product in 30%-70% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | The suspension of lH-indazole-4-carboxaldehyde (100 mg), 3-aminoquinuclidine dihydrocloride salt (1.0 eq), and 4 A molecular sieves in dioxane (4 mL) was heated at reflux for 4 h. The reaction mixture was allowed to cool to rt and was treated with sodium triacetoxyborohydride (3 eq). The reaction mixture was maintained at rt for 2 h and was poured into water, extracted with 5% methanol in dichloromethane (2 x 30 mL), and the combined extracts were concentrated. The residue was purified by preparative HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chiral stationary phase including isopropyl-functionalized CF6; In methanol; triethylamine; acetonitrile; trifluoroacetic acid; at 20℃;Purification / work up; | In addition to the foregoing, numerous other chromatographic separations using a column bonded with a CSP including a derivatized cyclofructan residue were carried out. Tables 5-9 list some additional examples of chromatographic separations using a column bonded with a CSP of the present invention. AU examples of chromatographic separations using columns bonded with CSPs of the present invention were carried out using the following experimental conditions and procedures.|0132| The high performance liquid chromatography (HPLC) column packing system was composed of an air driven fluid pump (HASKEL, DSTV- 122), an air compressor, a pressure regulator, a low pressure gauge, two high-pressure gauges (10,000 and 6,000 psi), a slurry chamber, check valves, and tubings. The CSPs were slurry packed into a 25 cm x 0.46 cm (inner diameter, I. D.) stainless steel column.|0133| The HPLC system was an Agilent 1 100 system (Agilent Technologies, Palo Alto,CA), which consisted of a diode array detector, an autosampler, a binary pump, a temperature- controlled column chamber, and Chemstation software. All chiral analytes were dissolved in ethanol, methanol, or other appropriate mobile phases, as indicated. For the LC analysis, the injection volume and flow rate were 5 muL and 1 mL/min, respectively. Separations were carried out at room temperature (~20 0C) if not specified otherwise. The wavelengths of UV detection were 195, 200, 210, and 254 nm. The mobile phase was degassed by ultrasonication under vacuum for 5 min. Each sample was analyzed in duplicate. Three operation modes (the normal phase mode, polar organic mode, and reversed phase mode) were tested, unless indicated otherwise. In the normal phase mode, heptane with ethanol or isopropanol was used as the mobile phase. In some cases, trifluoroacetic acid (TFA) was used as an additive, as indicated. The mobile phase of the polar organic mode was composed of acetonitrile/methanol and small amounts of acetic acid and triethylamine. Water/acetonitrile or acetonitrile/acetate buffer (20 mM, pH = 4.1 ) was used as the mobile phase in the reversed-phase mode.|0134| Two different supercritical fluid chromatographic instruments were used. One was a Berger SFC unit with an FCM 1200 flow control module, a TCM 2100 thermal column module, a dual pump control module, and a column selection valve. The flow rate was 4 mL/min. The cosolvent was composed of methanol/ethanol/isopropanol = 1 : 1 : 1 and 0.2% diethylamine (DEA). The gradient mobile phase composition was 5% cosolvent hold during 0- 0.6 min, 5-60% during 0.6-4.3 min, 60% hold during 4.3-6.3 min, 60%-5% during 6.3-6.9 min, and 5% hold during 6.9-8.0 min. The other SFC system was a Jasco (MD, USA) system comprised of an autosampler unit (AS-2059-SF Plus), a dual pump module (PU-2086 Plus), a column thermostat module (CO-2060 Plus), a UV/Vis detector (UV-2075 Plus), and a back pressure regulator module (SCH-Vch-BP). Unless otherwise specified, the mobile phase was composed of CCVmethanol (0.1 % TFA or 0.1% diethylamine). The flow rate was 3 mL/min.|0135| For the calculations of chromatographic data, the "dead time" to was determined by the peak of the refractive index change due to the sample solvent or determined by injecting l ,3,5-tri-/e/-/-butylbenzene in the normal phase mode. |
Tags: 6530-09-2 synthesis path| 6530-09-2 SDS| 6530-09-2 COA| 6530-09-2 purity| 6530-09-2 application| 6530-09-2 NMR| 6530-09-2 COA| 6530-09-2 structure
[ 1157849-51-8 ]
(S)-1-Methylpiperidin-3-amine dihydrochloride
Similarity: 0.88
[ 1440799-70-1 ]
(1-Methylpiperidin-2-yl)methanamine dihydrochloride
Similarity: 0.85
[ 334618-07-4 ]
(S)-Piperidin-3-amine dihydrochloride
Similarity: 0.81
[ 1157849-51-8 ]
(S)-1-Methylpiperidin-3-amine dihydrochloride
Similarity: 0.88
[ 1440799-70-1 ]
(1-Methylpiperidin-2-yl)methanamine dihydrochloride
Similarity: 0.85
[ 334618-07-4 ]
(S)-Piperidin-3-amine dihydrochloride
Similarity: 0.81
[ 138060-07-8 ]
Piperidin-3-amine dihydrochloride
Similarity: 0.81
[ 67496-77-9 ]
Quinuclidin-4-ylmethanamine dihydrochloride
Similarity: 0.81
[ 18339-49-6 ]
1-Azabicyclo[2.2.2]octan-4-amine dihydrochloride
Similarity: 0.79
[ 40117-63-3 ]
Quinuclidine-4-carboxylic acid hydrochloride
Similarity: 0.51
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :