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. : | 283-38-5 | MDL No. : | MFCD14581694 |
Formula : | C7H14N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XJKNACDCUAFDHD-UHFFFAOYSA-N |
M.W : | 126.20 | Pubchem ID : | 398407 |
Synonyms : |
|
Num. heavy atoms : | 9 |
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 : | 45.06 |
TPSA : | 15.27 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.96 cm/s |
Log Po/w (iLOGP) : | 1.76 |
Log Po/w (XLOGP3) : | 0.16 |
Log Po/w (WLOGP) : | -0.71 |
Log Po/w (MLOGP) : | 0.57 |
Log Po/w (SILICOS-IT) : | 0.92 |
Consensus Log Po/w : | 0.54 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.72 |
Solubility : | 23.9 mg/ml ; 0.189 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.04 |
Solubility : | 116.0 mg/ml ; 0.916 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.94 |
Solubility : | 14.7 mg/ml ; 0.116 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.9 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
90% | With lithium aluminium tetrahydride In tetrahydrofuran; 1,4-dioxane for 6 h; Reflux | To a stirred solution of l,4-diazabicyclo[3.2.2]nonan-3-one (1.0 g, 7.2 mmol) in 1,4-dioxane (7.2 mL) at room temperature was added lithium aluminum hydride [2.0M/THF] (4.1 mL, 8.2 mmol). The reaction mixture was then heated at reflux for 6 hours before cooling to room temperature. The reaction was quenched by the stepwise addition of 200 μ, of H20, 200 μ, of 15percent aqueous NaOH, and 600 μ, of H20. The mixture was filtered through Celite which was subsequently washed with EtOAc. The combined filtrate was concentrated in vacuo to afford the product (0.82 g, 90percent) which was used without further purification. XH NMR (400 MHz, CDC13) δ 3.28-3.25 (m, IH), 2.99-2.95 (m, 8H), 1.86-1.80 (m, 3H), 1.69-1.64 (m, 2H) ppm. |
90% | With lithium aluminium tetrahydride In tetrahydrofuran; 1,4-dioxane for 6 h; Reflux | To a stirred solution of 1,4-diazabicyclo[3.2.2]nonan-3-one (1.0 g, 7.2 mmol) in 1,4-dioxane (7.2 mL) at room temperature was added lithium aluminum hydride [2.0M/THF] (4.1 mL, 8.2 mmol). The reaction mixture was then heated at reflux for 6 hours before cooling to room temperature. The reaction was quenched by the stepwise addition of 200 L of H2O, 200 L of 15percent aqueous NaOH, and 600 L of H2O. The mixture was filtered through Celite which was subsequently washed with EtOAc. The combined filtrate was concentrated in vacuo to afford the product (0.82 g, 90percent) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.28-3.25 (m, 1H), 2.99-2.95 (m, 8H), 1.86-1.80 (m, 3H), 1.69-1.64 (m, 2H) ppm. |
78% | With lithium aluminium tetrahydride In 1,4-dioxane at 20℃; for 6 h; Heating / reflux | To the solution of 1, 4-diazabicyclo [3.2. 2] nonan-3-one (15.8 g ; 113 mmol) in absolute dioxane (130 mi) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then tittered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1,4- diazabicyclo [3.2. 2] nonane (11.1 g; 78percent) as colourless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Heating / reflux Stage #2: With water In 1,4-dioxane at 20℃; for 0.5 h; |
To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78percent) as colourless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane at 20℃; for 6 h; Heating / reflux Stage #2: With water In 1,4-dioxane for 0.5 h; |
To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The <n="16"/>mixture was refluxed for 6 hours and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78percent) as colourless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Heating / reflux Stage #2: With water In 1,4-dioxane at 20℃; for 0.5 h; |
To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78percent) as colourless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Heating / reflux Stage #2: With water In 1,4-dioxane at 20℃; for 0.5 h; |
To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78percent) as colourless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Heating / reflux Stage #2: With water In 1,4-dioxane at 20℃; for 0.5 h; |
To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C <n="16"/>(0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (1 1 .1 g; 78percent) as colourless hygroscopic material. |
78% | With lithium aluminium tetrahydride; water In 1,4-dioxane at 20℃; for 6.5 h; Heating / reflux | To a solution of 1, 4-DIAZABICYCLO [3.2. 2] nonan-3-one (15.8 g, 113 MMOL) in absolute dioxane (130 ML), LiAIH4 (4.9 g, 130 MMOL) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperatre. To this reaction mixture, water (5 ml in 10 ml of dioxane) was added, by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using a Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1, 4-DIAZABICYCLO [3. 2.2] nonane (11.1 g, 78percent) as colourless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Heating / reflux Stage #2: With water In 1,4-dioxane for 0.5 h; |
1 ,4-Diazabicvclo[3.2.2]nonane (Intermediate compound) To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78percent) as colourless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Heating / reflux Stage #2: With water In 1,4-dioxane for 0.5 h; |
1 ,4-Diazabicvclo[3.2.2]nonane (Intermediate compound) To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78percent) as colourless hygroscopic material. |
78% | With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Inert atmosphere; Reflux | 1 ,4-Diazabicyclo[3.2.21nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78percent) as colourless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Inert atmosphere; Reflux Stage #2: With water In 1,4-dioxane at 20℃; |
1 ,4-Diazabicvclo[3.2.2]nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78percent) as colourless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Inert atmosphere; Reflux Stage #2: With water In 1,4-dioxane at 20℃; |
,4-Diazabicyclo[3.2.2]nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78percent) as colorless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Inert atmosphere; Reflux Stage #2: With water In 1,4-dioxane at 20℃; |
1 ,4-Diazabicvclo[3.2.2]nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78percent) as colourless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Inert atmosphere; Reflux Stage #2: With water In 1,4-dioxane at 20℃; |
1 ,4-Diazabicvclo[3.2.2]nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 1 13 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added20 by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (1 1 .1 g; 78percent) as colourless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Inert atmosphere; Reflux Stage #2: With water In 1,4-dioxane at 20℃; for 0.5 h; |
1 ,4-Diazabicvclo[3.2.2]nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78percent) as colorless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Inert atmosphere; Reflux Stage #2: With water In 1,4-dioxane at 20℃; for 0.5 h; |
1 ,4-Diazabicyclo[3.2.2]nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78percent) as colourless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Inert atmosphere; Reflux Stage #2: With water In 1,4-dioxane at 20℃; for 0.5 h; |
1 ,4-Diazabicvclo[3.2.2]nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78percent) as colorless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Inert atmosphere; Reflux Stage #2: With water In 1,4-dioxane for 0.5 h; |
1,4-Diazabicvclo[3.2.21nonane (Intermediate compound). To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 1 13 mmol) in absolute dioxane (130 ml) LiAIH (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (1 1 .1 g; 78percent) as colourless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Inert atmosphere; Reflux Stage #2: With water In 1,4-dioxane at 20℃; for 0.5 h; |
1 ,4-Diazabicvclo[3.2.21nonane (Intermediate compound)To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 1 13 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (1 1 .1 g; 78percent) as colourless hygroscopic material. |
78% | With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Heating / reflux | was prepared according to J. Med. Chem. 1993 36 2311-2320, and according to the following slightly modified method. To the solution of 1, [4-DIAZABICYCLO] [3.2. 2] nonan-3-one (15.8 g, 113 [MMOL)] in absolute dioxane (130 ml) LiAIH4 (4.9 g, 130 [MMOL)] was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperature. Water (5 ml in 10 ml of dioxane) was added by drops to the reaction mixture, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at [90°C] (0.1 mbar) to yield 1, 4-diazabicyclo [3.2. 2] nonane (11.1 g, 78percent) as colourless hygroscopic material. |
78% | With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Heating / reflux | 1,4-Diazabicyclo[3.2.2]nonane (Intermediate Compound) Was prepared according to J. Med. Chem. 1993 36 2311-2320 and the following slightly modified method. To a solution of 1,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g, 113 mmol) in absolute dioxane (130 ml), LiAlH4 (4.9 g, 130 mmol) was added under argon.The mixture was refluxed for 6 hours and then allowed to reach room temperatre.To this reaction mixture, water (5 ml in 10 ml of dioxane) was added, by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter.The solvent was evaporated and the residue was distilled using a Kugelrohr apparatus at 90° C. (0.1 mbar) to yield 1,4-diazabicyclo[3.2.2]nonane (11.1 g, 78percent) as colourless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Heating / reflux Stage #2: With water In 1,4-dioxane for 0.5 h; |
To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The 20 mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78percent) as colourless hygroscopic material. |
78% | Stage #1: With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Heating / reflux Stage #2: With water In 1,4-dioxane for 0.5 h; |
1 ,4-Diazabicyclor3.2.2lnonane (Intermediate compound)To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 1 13 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (1 1 .1 g; 78percent) as colourless hygroscopic material. |
78% | With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Heating / reflux | To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 1 13 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 9O0C (0.1 mbar) to yield 1 ,4- diazabicyclo[3.2.2]nonane (1 1 .1 g; 78percent) as colourless hygroscopic material. |
78% | With lithium aluminium tetrahydride In 1,4-dioxane for 6 h; Heating / reflux | To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 9O0C (0.1 mbar) to yield 1 ,4- diazabicyclo[3.2.2]nonane (1 1.1 g; 78percent) as colourless hygroscopic material. |
68% | With lithium aluminium tetrahydride In tetrahydrofuran for 36 h; Heating / reflux | 1, 4-DIAZABICYCLO [3.2. 2] NONAN-3-ONE (5.12 G ; 36 MMOL) was dissolved in tetrahydrofuran (50 ML), litium aluminium hydride 2.28 G (60 MMOL) was added to the solution and the reaction mixture was refluxed for 36 hours. After cooling the reaction mixture to room temperature, water (2.3 ml) was added dropwise and the mixture was filtered. The solvent was removed from the filtrate by rotavapor at reduced pressure. The formed substance was distilled with Kugelrohr (0.5 MBAR, 70 C). Yield of the title compound 3.11 G (68percent). |
68% | With lithium aluminium tetrahydride In tetrahydrofuran for 36 h; Heating / reflux | 1. 4-Diazabicyclor3. 2. 21nonane fJ. Med. Chem. 1993 36 2311-23201 (Intermediate compound); 1, 4-Diazabicyclo [3.2. 2] nonan-3-one (5.12 g ; 36 mmol) was dissolved in tetrahydrofuran (50 ml), litium aluminium hydride 2. 28 g (60 mmol) was added to the solution and the reaction mixture was refluxed for 36 hours. After cooling the reaction mixture to room temperature, water (2.3 ml) was added dropwise and the mixture was filtered. The solvent was removed from the filtrate by rotavapor at reduced pressure. The formed substance was distilled with Kugelrohr (0.5 mBar ; 70°C). Yield of the title compound 3.11 g (68percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With pyridine at 100℃; for 18h; | |
25% | In pyridine; water | 7 (Y=ethyl; R1 =H; A=CH; R2 =e; n=2) EXAMPLE 7 1-Ethyl-6-fluoro-1,4-dihydro-7-(1,4-diazabicyclo[3.2.2]non-4-yl)-4-oxo-3-quinolinecarboxylic acid (Y=ethyl; R1 =H; A=CH; R2 =e; n=2) A stirred suspension of 1-ethyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (76 mg, 0.302 mmol) and 1,4-diazabicyclo[3.2.2]nonane (95 mg, 0.754 mmol) in 3 ml of dry pyridine under N2 was heated to 90° C. for 18 hours. The mixture was cooled to room temperature and diluted with 50 ml of water. The aqueous solution was extracted two times with 50 ml of chloroform. The combined organic layers were then washed twice with water, dried over Na2 SO4, filtered and concentrated in vacuo. The solid was triturated several times with diethylether and filtered to give (27 mg, 25% yield) of a pale yellow solid, m.p. 223°-225° C. |
25% | In pyridine; water | 8 (Y=ethyl; R1 =H; A=CH; R2 =e; n=2) EXAMPLE 8 1-Ethyl-6-fluoro-1,4-dihydro-7-(1,4-diazabicyclo[3.2.2]non-4-yl)-4-oxo-3-quinolinecarboxylic acid (Y=ethyl; R1 =H; A=CH; R2 =e; n=2) A stirred suspension of 1-ethyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (76 mg, 0.302 mmol) and 1,4-diazabicyclo[3.2.2]nonane (95 mg, 0.754 mmol) in 3 ml of dry pyridine under N2 was heated to 90° C. for 18 hours. The mixture was cooled to room temperature and diluted with 50 ml of water. The aqueous solution was extracted two times with 50 ml of chloroform. The combined organic layers were then washed twice with water, dried over Na2 SO4, filtered and concentrated in vacuo. The solid was triturated several times with diethylether and filtered to give (27 mg, 25% yield) of a pale yellow solid, m.p. 223°-225° C. |
25% | In pyridine; water | 7 (Y=ethyl; R1 =H; A=CH; R2 =e; n=2) EXAMPLE 7 1-Ethyl-6-fluoro-1,4-dihydro- 7-(1,4-diazabicyclo[3.2.2]non-4-yl)-4-oxo-3-quinolinecarboxylic acid (Y=ethyl; R1 =H; A=CH; R2 =e; n=2) A stirred suspension of 1-ethyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (76 mg, 0.302 mmol) and 1,4-diazabicyclo[3.2.2]nonane (95 mg, 0.754 mmol) in 3 ml of dry pyridine under N2 was heated to 90° C. for 18 hours. The mixture was cooled to room temperature and diluted with 50 ml of water. The aqueous solution was extracted two times with 50 ml of chloroform. The combined organic layers were then washed twice with water, dried over Na2 SO4, filtered and concentrated in vacuo. The solid was triturated several times with diethylether and filtered to give (27 mg, 25% yield) of a pale yellow solid, m.p. 223°-225° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.4% | EXAMPLE 19 1-Cyclopropyl-6-fluoro-7-(1,4-diazabicyclo-[3.2.2]-non-4-yl)-1,4-dihydro-4-oxo-3-quinoline carboxylic acid (R1 =H; Y=cyclopropyl; A=CH; R2 =d; n=2; p=1) The title compound was prepared in 68.4percent yield according to example 9 by reacting 6,7-difluoro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid with 1,4-diazabicyclo[3,2,2]nonane, m.p. 296°-297° C. | |
68.4% | EXAMPLE 19 1-Cyclopropyl-6-fluoro-7-(1,4-diazabicyclo[3.2.2]-non-4-yl)-1,4-dihydro-4-oxo-3-quinoline carboxylic acid R1 =H; Y=cyclopropyl; A=CH; R2 =d; n=2; p=1) The title compound was prepared in 68.4percent yield according to example 9 by reacting 6,7-difluoro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid with 1,4-diazabicyclo[3,2,2]nonane, m.p. 296°-297° C. | |
68.4% | EXAMPLE 19 1-Cyclopropyl-6-fluoro-7-(1,4-diazabicyclo[3.2.2]-non-4-yl)-1,4-dihydro-4-oxo-3-quinoline carboxylic acid (R1 =H; Y=cyclopropyl; A=CH; R2 =d; n=2; p=1) The title compound was prepared in 68.4percent yield according to example 9 by reacting 6,7-difluoro-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid with 1,4-diazabicyclo[3,2,2]nonane, m.p. 296°-297° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene at 80℃; for 2h; | |
68% | 12 (Y=4-fluorophenyl; R1 =H; A=CH; R2 =d; n=2; p=1; Q=H) EXAMPLE 12 1-(4-Fluorophenyl)-6-fluoro-1,4-dihydro-7-(1,4-diazabicyclo[3.2.2]non-4-yl)-4-oxo-3-quinolinecarboxylic acid. (Y=4-fluorophenyl; R1 =H; A=CH; R2 =d; n=2; p=1; Q=H) The title compound was prepared in 68% yield according to example 9 by reacting 6,7-difluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 1,4-diazabicyclo[3.2.2]nonane, m.p. 320° C. NMR: (CDCl3 and DMSOd6, 250 MHz): 8.60 (1H, s); 7.98 (1H, d, J=13 Hz); 7.54 (2H, m); 7.41 (2H, m); 6.28 (1H, d, J=7Hz); 3.89 (1H, m); 3.26 (2H, t); 2.9-3.15 (6H, m); 1.95-2.10 (2H, m); 1.75-1.90 (2H, m). | |
68% | 12 (Y=4-fluorophenyl; R1 =H; A=CH; R2 =d; n=2; p=1; Q=H) EXAMPLE 12 1-(4-Fluorophenyl)-6-fluoro-1,4-dihydro-7-(1,4-diazabicyclo[3.2.2]non-4-yl)-4-oxo-3-quinolinecarboxylic acid. (Y=4-fluorophenyl; R1 =H; A=CH; R2 =d; n=2; p=1; Q=H) The title compound was prepared in 68% yield according to example 9 by reacting 6,7-difluoro-1(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 1,4-diazabicyclo[3.2.2]nonane, m.p. 320° C. NMR: (CDCl3 and DMSOd6, 250 MHz): 8.60 (1H, s); 7.98 (1H, d, J=13 Hz); 7.54 (2H, m); 7.41 (2H, m); 6.28 (1H, d, J=7Hz); 3.89 (1H, m); 3.26 (2H, t); 2.9-3.15 (6H, m); 1.95-2.10 (2H, m); 1.75-1.90 (2H, m). |
68% | 12 (Y=4-fluorophenyl; R1 =H; A=CH; R2 =d; n=2; p=1; Q=H) EXAMPLE 12 1-(4-Fluorophenyl)-6-fluoro-1,4-dihydro-7-(1,4-diazabicyclo[3.2.2]non-4-yl)-4-oxo-3-quinolinecarboxylic acid (Y=4-fluorophenyl; R1 =H; A=CH; R2 =d; n=2; p=1; Q=H) The title compound was prepared in 68% yield according to example 9 by reacting 6,7-difluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with 1,4-diazabicyclo[3.2.2]nonane, m.p. 320° C. NMR: (CDCl3 and DMSOd6, 250 MHz): 8.60 (1H, s); 7.98 (1H, d, J=13 Hz); 7.54 (2H, m); 7.41 (2H, m); 6.28 (1H, d, J=7 Hz); 3.89 (1H, m); 3.26 (2H, t); 2.9-3.15 (6H, m); 1.95-2.10 (2H, m); 1.75-1.90 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With sodium hydroxide; In pyridine; water; dimethyl sulfoxide; ethyl acetate; | EXAMPLE 14 10-(1,4-Diazabicyclo[3.2.2]non-4-yl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-(7H)-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid (A--Y=CH--O--CH2 --C(CH3)H; R1 =H; R2 =d; n=2; p=1; Q=H) 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-(7H)-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid (281 mg, 1.0 mmol) was dissolved in 5 ml DMSO and heated to 120 C. 1,4-Diazabicyclo[3.2.2]nonane (315 mg, 2.5 mmoles) in 1 ml dry pyridine was added and the resulting mixture was heated at 120 C. for 4.5 hours. The solution was then cooled to room temperature and poured in 250 ml water. The aqueous mixture was extracted 3 times with 250 ml chloroform. The combined chloroform extracts were further extracted 3 times with 1.0N HCl (250 ml). The aqueous acidic extracts were combined and neutralized to a pH of 7.0 with 6N NaOH, and then extracted 3 times with 250 ml chloroform. The combined chloroform extracts were dried over sodium sulfate and stripped of solvent to give a solid residue that was slurried in ethyl acetate, filtered, washed with ethyl acetate, and dried to give the title compound (55 mg, 14% yield) as a pale yellow solid, m.p. 230-232 C. |
14% | With sodium hydroxide; In pyridine; water; dimethyl sulfoxide; ethyl acetate; | EXAMPLE 14 10-(1,4-Diazabicyclo[3.2.2]non-4-yl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-(7H)-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid (A--Y=CH--O--CH2 --C(CH3)H; R1 =H; R2 =d; n=2; p=1; Q=H) 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-(7H)-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid (281 mg, 1.0 mmol) was dissolved in 5 ml DMSO and heated to 120 C. 1,4-Diazabicyclo[3.2.2]nonane (315 mg, 2.5 mmoles) in 1 ml dry pyridine was added and the resulting mixture was heated at 120 C. for 4.5 hours. The solution was then cooled to room temperature and poured in 250 ml water. The aqueous mixture was extracted 3 times with 250 ml chloroform. The combined chloroform extracts were further extracted 3 times with 1.0 N HCl (250 ml). The aqueous acidic extracts were combined and neutralized to a pH of 7.0 with 6N NaOH, and then extracted 3 times with 250 ml chloroform. The combined chloroform extracts were dried over sodium sulfate and stripped of solvent to give asolid residue that was slurried in ethyl acetate, filtered, washed with ethyl acetate, and dried to give the title compound (55 mg, 14% yield) as a pale yellow solid, m.p. 230-232 C. |
14% | With sodium hydroxide; In pyridine; water; dimethyl sulfoxide; ethyl acetate; | EXAMPLE 14 10-(1,4-Diazabicyclo[3.2.2]non-4-yl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro(7H)-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid (A--Y=CH--O--CH2 --C(CH3)H; R1 =H; R2 =d; n=2; p=1; Q=H) 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-(7H)-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid (281 mg, 1.0 mmol) was dissolved in 5 ml DMSO and heated to 120 C. 1,4-Diazabicyclo[3.2.2]nonane (315 mg, 2.5 mmoles) in 1 ml dry pyridine was added and the resulting mixture was heated at 120 C. for 4.5 hours. The solution was then cooled to room temperature and poured in 250 ml water. The aqueous mixture was extracted 3 times with 250 ml chloroform. The combined chloroform extracts were further extracted 3 times with 1.0N HCl (250 ml). The aqueous acidic extracts were combined and neutralized to a pH of 7.0 with 6N NaOH, and then extracted 3 times with 250 ml chloroform. The combined chloroform extracts were dried over sodium sulfate and stripped of solvent to give a solid residue that was slurried in ethyl acetate, filtered, washed with ethyl acetate, and dried to give the title compound (55 mg, 14% yield) as a pale yellow solid, m.p. 230-232 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene at 80℃; for 2h; | |
73% | 13 (Y=methylamino; R1 =H; A=CH; R2 =d; n=2; p=1; Q=H) EXAMPLE 13 1-Methylamino-6-fluoro-1,4-dihydro-7-(1,4-diazabicyclo[3.2.2]non-4-yl)-4-oxo-3-quinoline carboxylic acid (Y=methylamino; R1 =H; A=CH; R2 =d; n=2; p=1; Q=H) The title compound was prepared in 73% yield according to example 9 by reacting 6,7-difluoro-1-methylamino-1,4-dihydro-4-oxo-3-quinoline carboxylic acid with 1,4-diazabicyclo[3.2.2]nonane, m.p. 245°-247° C. | |
73% | 13 (Y=methylamino; R1 =H; A=CH; R2 =d; n=2; p=1; Q=H) EXAMPLE 13 1-Methylamino-6-fluoro-1,4-dihydro-7-(1,4-diazabicyclo-[3.2.2]non-4-yl)-4-oxo-3-quinoline carboxylic acid (Y=methylamino; R1 =H; A=CH; R2 =d; n=2; p=1; Q=H) The title compound was prepared in 73% yield according to example 9 by reacting 6,7-difluoro-1-methylamino-1,4-dihydro-4-oxo-3-quinoline carboxylic acid with 1,4-diazabicyclo[3.2.2]nonane, m.p. 245°-247° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With lithium aluminium tetrahydride In tetrahydrofuran for 2h; Heating; | |
90% | With lithium aluminium tetrahydride In tetrahydrofuran; 1,4-dioxane for 6h; Reflux; | C Preparation C Intermediate 6 l,4-Diazabicyclo[3.2.2]nonane To a stirred solution of l,4-diazabicyclo[3.2.2]nonan-3-one (1.0 g, 7.2 mmol) in 1,4-dioxane (7.2 mL) at room temperature was added lithium aluminum hydride [2.0M/THF] (4.1 mL, 8.2 mmol). The reaction mixture was then heated at reflux for 6 hours before cooling to room temperature. The reaction was quenched by the stepwise addition of 200 μ, of H20, 200 μ, of 15% aqueous NaOH, and 600 μ, of H20. The mixture was filtered through Celite which was subsequently washed with EtOAc. The combined filtrate was concentrated in vacuo to afford the product (0.82 g, 90%) which was used without further purification. XH NMR (400 MHz, CDC13) δ 3.28-3.25 (m, IH), 2.99-2.95 (m, 8H), 1.86-1.80 (m, 3H), 1.69-1.64 (m, 2H) ppm. |
90% | With lithium aluminium tetrahydride In tetrahydrofuran; 1,4-dioxane for 6h; Reflux; | C 1,4-Diazabicyclo[3.2.2]nonane To a stirred solution of 1,4-diazabicyclo[3.2.2]nonan-3-one (1.0 g, 7.2 mmol) in 1,4-dioxane (7.2 mL) at room temperature was added lithium aluminum hydride [2.0M/THF] (4.1 mL, 8.2 mmol). The reaction mixture was then heated at reflux for 6 hours before cooling to room temperature. The reaction was quenched by the stepwise addition of 200 L of H2O, 200 L of 15% aqueous NaOH, and 600 L of H2O. The mixture was filtered through Celite which was subsequently washed with EtOAc. The combined filtrate was concentrated in vacuo to afford the product (0.82 g, 90%) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.28-3.25 (m, 1H), 2.99-2.95 (m, 8H), 1.86-1.80 (m, 3H), 1.69-1.64 (m, 2H) ppm. |
83% | With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Inert atmosphere; Reflux; | 1,4-Diazabicyclo[3.2.2]nonane (29) Compound 28 (2 g; 14 mmol) was suspended in 20 mL anhydrous 1,4-dioxane under nitrogen. Lithium aluminium hydride (700 mg; 18 mmol) was added in portions and the resultant mixture heated to reflux for six hours. The reaction was cooled in an ice-bath and 1 mL water was added slowly, followed by 1 mL 10% aqueous NaOH and a further 1 mL of water. The grey suspension turned to a white suspension which was filtered through a sintered glass funnel. The filtrate was dried over sodium sulfate, filtered and concentrated to dryness to give the titled compound as a low melting point off-white solid (1.5 g; 83%). Rf (1:1 DCM:MeOH): 0.11. Anal. RP-HPLC: tR 2.93 min (method D), purity 91 %. νmax (Thin film, cm-1): 555.4, 624.4, 732.8, 764.3, 808.0, 855.7, 912.8, 960.1, 996.5, 1042.7, 1071.7, 1169.3, 1250.6, 1313.1, 1352.5, 1406.1, 1441.3, 1635.9, 1665.9, 2858.2, 2932.6, 3051.4, 3262.5. 1H-NMR (400 MHz, CDCl3): δ 1.55-1.74 (2H, m), 1.75-1.93 (2H, m), 2.36 (1H, br s), 2.87-3.00 (8H, m), 3.26 (1H, heptet, J = 4.5 Hz). 13C-NMR (100 MHz, CDCl3): δ 29.4, 43.7, 46.7, 47.9, 59.1. HRMS (ESI+): m/z [M + H]+ calcd for C7H15N2 127.1230, found 127.1200. |
78% | With lithium aluminium tetrahydride In 1,4-dioxane at 20℃; for 6h; Heating / reflux; | To the solution of 1, 4-diazabicyclo [3.2. 2] nonan-3-one (15.8 g ; 113 mmol) in absolute dioxane (130 mi) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then tittered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1,4- diazabicyclo [3.2. 2] nonane (11.1 g; 78%) as colourless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Heating / reflux; Stage #2: With water In 1,4-dioxane at 20℃; for 0.5h; | 1 To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colourless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane at 20℃; for 6h; Heating / reflux; Stage #2: With water In 1,4-dioxane for 0.5h; | 1 To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colourless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Heating / reflux; Stage #2: With water In 1,4-dioxane at 20℃; for 0.5h; | 1 To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colourless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Heating / reflux; Stage #2: With water In 1,4-dioxane at 20℃; for 0.5h; | 1 To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colourless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Heating / reflux; Stage #2: With water In 1,4-dioxane at 20℃; for 0.5h; | To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (1 1 .1 g; 78%) as colourless hygroscopic material. |
78% | With lithium aluminium tetrahydride; water In 1,4-dioxane at 20℃; for 6.5h; Heating / reflux; | 1 Example 1 Preparatory Example 1,4-diazabicyclo[3. 2.2]nonane (Intermediate compound) To a solution of 1, 4-DIAZABICYCLO [3.2. 2] nonan-3-one (15.8 g, 113 MMOL) in absolute dioxane (130 ML), LiAIH4 (4.9 g, 130 MMOL) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperatre. To this reaction mixture, water (5 ml in 10 ml of dioxane) was added, by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using a Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1, 4-DIAZABICYCLO [3. 2.2] nonane (11.1 g, 78%) as colourless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Heating / reflux; Stage #2: With water In 1,4-dioxane for 0.5h; | 1 1 ,4-Diazabicvclo[3.2.2]nonane (Intermediate compound) To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colourless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Heating / reflux; Stage #2: With water In 1,4-dioxane for 0.5h; | 1 1 ,4-Diazabicvclo[3.2.2]nonane (Intermediate compound) To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colourless hygroscopic material. |
78% | With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Inert atmosphere; Reflux; | 1 1 ,4-Diazabicyclo[3.2.21nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colourless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Inert atmosphere; Reflux; Stage #2: With water In 1,4-dioxane at 20℃; | 1 1 ,4-Diazabicvclo[3.2.2]nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colourless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Inert atmosphere; Reflux; Stage #2: With water In 1,4-dioxane at 20℃; | 1 ,4-Diazabicyclo[3.2.2]nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colorless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Inert atmosphere; Reflux; Stage #2: With water In 1,4-dioxane at 20℃; | 1 1 ,4-Diazabicvclo[3.2.2]nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colourless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Inert atmosphere; Reflux; Stage #2: With water In 1,4-dioxane at 20℃; | 1 1 ,4-Diazabicvclo[3.2.2]nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 1 13 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added20 by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (1 1 .1 g; 78%) as colourless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Inert atmosphere; Reflux; Stage #2: With water In 1,4-dioxane at 20℃; for 0.5h; | 1 1 ,4-Diazabicvclo[3.2.2]nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colorless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Inert atmosphere; Reflux; Stage #2: With water In 1,4-dioxane at 20℃; for 0.5h; | 1 1 ,4-Diazabicyclo[3.2.2]nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colourless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Inert atmosphere; Reflux; Stage #2: With water In 1,4-dioxane at 20℃; for 0.5h; | 1 1 ,4-Diazabicvclo[3.2.2]nonane (Intermediate compound); To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colorless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Inert atmosphere; Reflux; Stage #2: With water In 1,4-dioxane for 0.5h; | 1,4-Diazabicvclo[3.2.21nonane (Intermediate compound). To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 1 13 mmol) in absolute dioxane (130 ml) LiAIH (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (1 1 .1 g; 78%) as colourless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Inert atmosphere; Reflux; Stage #2: With water In 1,4-dioxane at 20℃; for 0.5h; | 1 1 ,4-Diazabicvclo[3.2.21nonane (Intermediate compound)To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 1 13 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (1 1 .1 g; 78%) as colourless hygroscopic material. |
78% | With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Heating / reflux; | 1 [1,] [4-DIAZABICYCLOF3.] 2.21nonane (Intermediate compound) was prepared according to J. Med. Chem. 1993 36 2311-2320, and according to the following slightly modified method. To the solution of 1, [4-DIAZABICYCLO] [3.2. 2] nonan-3-one (15.8 g, 113 [MMOL)] in absolute dioxane (130 ml) LiAIH4 (4.9 g, 130 [MMOL)] was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperature. Water (5 ml in 10 ml of dioxane) was added by drops to the reaction mixture, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at [90°C] (0.1 mbar) to yield 1, 4-diazabicyclo [3.2. 2] nonane (11.1 g, 78%) as colourless hygroscopic material. |
78% | With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Heating / reflux; | 1 1,4-Diazabicyclo[3.2.2]nonane (Intermediate Compound) Was prepared according to J. Med. Chem. 1993 36 2311-2320 and the following slightly modified method. To a solution of 1,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g, 113 mmol) in absolute dioxane (130 ml), LiAlH4 (4.9 g, 130 mmol) was added under argon.The mixture was refluxed for 6 hours and then allowed to reach room temperatre.To this reaction mixture, water (5 ml in 10 ml of dioxane) was added, by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter.The solvent was evaporated and the residue was distilled using a Kugelrohr apparatus at 90° C. (0.1 mbar) to yield 1,4-diazabicyclo[3.2.2]nonane (11.1 g, 78%) as colourless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Heating / reflux; Stage #2: With water In 1,4-dioxane for 0.5h; | 1 To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The 20 mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colourless hygroscopic material. |
78% | Stage #1: 1,4-diaza-bicyclo[3.2.2]nonan-3-one With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Heating / reflux; Stage #2: With water In 1,4-dioxane for 0.5h; | 1 1 ,4-Diazabicyclor3.2.2lnonane (Intermediate compound)To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 1 13 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90°C (0.1 mbar) to yield 1 ,4-diazabicyclo[3.2.2]nonane (1 1 .1 g; 78%) as colourless hygroscopic material. |
78% | With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Heating / reflux; | 1 To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 1 13 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 9O0C (0.1 mbar) to yield 1 ,4- diazabicyclo[3.2.2]nonane (1 1 .1 g; 78%) as colourless hygroscopic material. |
78% | With lithium aluminium tetrahydride In 1,4-dioxane for 6h; Heating / reflux; | 1 To the solution of 1 ,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAIH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 9O0C (0.1 mbar) to yield 1 ,4- diazabicyclo[3.2.2]nonane (1 1.1 g; 78%) as colourless hygroscopic material. |
68% | With lithium aluminium tetrahydride In tetrahydrofuran for 36h; Heating / reflux; | 1 1. 4-DIAZABICYCLOR3. 2.21nonane FJ. Med. Chem. 1993 36 2311-23201 (Intermediate compound) 1, 4-DIAZABICYCLO [3.2. 2] NONAN-3-ONE (5.12 G ; 36 MMOL) was dissolved in tetrahydrofuran (50 ML), litium aluminium hydride 2.28 G (60 MMOL) was added to the solution and the reaction mixture was refluxed for 36 hours. After cooling the reaction mixture to room temperature, water (2.3 ml) was added dropwise and the mixture was filtered. The solvent was removed from the filtrate by rotavapor at reduced pressure. The formed substance was distilled with Kugelrohr (0.5 MBAR, 70 C). Yield of the title compound 3.11 G (68%). |
68% | With lithium aluminium tetrahydride In tetrahydrofuran for 36h; Heating / reflux; | 1 1. 4-Diazabicyclor3. 2. 21nonane fJ. Med. Chem. 1993 36 2311-23201 (Intermediate compound); 1, 4-Diazabicyclo [3.2. 2] nonan-3-one (5.12 g ; 36 mmol) was dissolved in tetrahydrofuran (50 ml), litium aluminium hydride 2. 28 g (60 mmol) was added to the solution and the reaction mixture was refluxed for 36 hours. After cooling the reaction mixture to room temperature, water (2.3 ml) was added dropwise and the mixture was filtered. The solvent was removed from the filtrate by rotavapor at reduced pressure. The formed substance was distilled with Kugelrohr (0.5 mBar ; 70°C). Yield of the title compound 3.11 g (68%). |
With aluminium hydride In tetrahydrofuran Ambient temperature; | ||
2.09 g (64.5%) | In tetrahydrofuran; water | 9.B B. B. 1,4-diazabicyclo[3.2.2]nonane Lithium aluminum hydride (2.0 g, 51.4 mmoles) was slurried in 250 ml of dry tetrahydrofuran and 3-oxo-1,4-diazabicyclo[3.2.2]nonane (3.6 g, 25.7 mmoles) was added carefully as a solid in one portion at room temperature. The resulting mixture was then heated to a gentle reflux for 20 hours. The reaction was cooled to room temperature and quenched by slow addition of 2.5 ml water. The salts were filtered and washed several times with diethyl ether totaling 1.0 l. These washings and the supernatant were combined, dried over magnesium sulfate and concentrated to give 2.09 g (64.5%) of the title compound as a pale yellow oil. NMR(13 C; 63 MHz, CDCl3) 59.11, 47.97, 46.67, 43.67, 29.43. |
2.09 g (64.5%) | In tetrahydrofuran; water | 9.B B. B. 1,4-diazabicyclo[3.2.2]nonane Lithium aluminum hydride (2.0 g, 51.4 mmoles) was slurried in 250 ml of dry tetrahydrofuran and 3-oxo-1,4-diazabicyclo[3.2.2]nonane (3.6 g, 25.7 mmoles) was added carefully as a solid in one portion at room temperature. The resulting mixture was then heated to a gentle reflux for 20 hours. The reaction was cooled to room tempeature and quenched by slow addition of 2.5 ml water. The salts were filtered and washed several times with diethyl ether totaling 1.0 1. These washings and the supernatant were combined, dried over magnesium sulfate and concentrated to give 2.09 g (64.5%) of the title compound as a pale yellow oil. NMR (13 C; 63 MHz, CDCl3): 59.11, 47.97, 46.67, 43.67, 29.43. |
2.09 g (64.5%) | In tetrahydrofuran; water | 9.B A. B. 1,4-diazabicyclo[3.2.2]nonane Lithium aluminum hydride (2.0 g, 51.4 mmoles) was slurried in 250 ml of dry tetrahydrofuran and 3-oxo-1,4-diazabicyclo[3.2.2]nonane (3.6 g, 25.7 mmoles) was added carefully as a solid in one portion at room temperature. The resulting mixture was then heated to a gentle reflux for 20 hours. The reaction was cooled to room tempeature and quenched by slow addition of 2.5 ml water. The salts were filtered and washed several times with diethyl ether totaling 1.0 1. These washings and the supernatant were combined, dried over magnesium sulfate and concentrated to give 2.09 g (64.5%) of the title compound as a pale yellow oil. NMR(13 C; 63 MHz, CDCl3): 59.11, 47.97, 46.67, 43.67, 29.43. |
With lithium aluminium tetrahydride In tetrahydrofuran; 1,4-dioxane for 6h; Reflux; | To a stirred solution of l,4-diazabicyclo[3.2.2]nonan-3-one (1.00 g, 7.13 mmol) in 1,4-dioxane (7.2 mL) at room temperature was added lithium aluminum hydride [2.0M/THF] (4.1 mL, 8.2 mmol). The reaction mixture was then heated at reflux for 6 hours. After cooling to room temperature, the reaction was quenched by the sequential addition of water (200 fjL), 15% a The mixture was filtered through Celite which was subsequently washed with ethyl acetate. The combined filtrate was concentrated to afford the title compound as a light brown solid (0.82 g, 90%) which was used without purification. 1H NMR (400 MHz, CDC13)□ 3.28-3.25 (m, 1H), 2.99-2.95 (m, 8H), 1.86-1.80 (m, 3H), 1.69-1.64 (m, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | A mixture of 1 ,4-diazabicyclo[3.2.2]nonane (0.87 g, 6.90 mmol), 2-chloro-5- nitro-pyrimidine (1.56 g, 6.27 mmol) and dioxane (75 ml) was stirred at room- temperature for 15 h. Aqueous sodium bicarbonate (20 ml, 10percent) was added followed by extraction with ethylacetate (3 x 20 ml). The organic phase was dried and evaporated and a yellow powder was isolated. Yield 0.86 g (55percent). Mp 135-139°C. | |
55% | A mixture of 1 ,4-diazabicyclo[3.2.2]nonane (0.87 g, 6.90 mmol), 2-chloro-5- nitro-pyrimidine (1.56 g, 6.27 mmol) and dioxane (75 ml) was stirred at room- temperature for 15 h. Aqueous sodium bicarbonate (20 ml, 10percent) was added followed by extraction with ethylacetate (3 x 20 ml). The organic phase was dried and evaporated and a yellow powder was isolated. Yield 0.86 g (55percent). Mp 135-139°C. | |
55% | 4-(5-Nitro-pyrimidin-2-yl)-1 ,4-diaza-bicvclo[3.2.2]nonane free base (Intermediate compound)A mixture of 1 ,4-diazabicyclo[3.2.2]nonane (0.87 g, 6.90 mmol), 2-chloro-5- nitro-pyrimidine (1.56 g, 6.27 mmol) and dioxane (75 ml) was stirred at room- temperature for 15 h. Aqueous sodium bicarbonate (20 ml, 10percent) was added followed by extraction with ethylacetate (3 x 20 ml). The organic phase was dried and evaporated and a yellow powder was isolated. Yield 0.86 g (55percent). Mp 135-139°C. |
55% | 4-(5-Nitro-pyrimidin-2-yl)-1 ,4-diaza-bicvclo[3.2.2]nonane free base (Intermediate compound)A mixture of 1 ,4-diazabicyclo[3.2.2]nonane (0.87 g, 6.90 mmol), 2-chloro-5- nitro-pyrimidine (1.56 g, 6.27 mmol) and dioxane (75 ml) was stirred at room- temperature for 15 h. Aqueous sodium bicarbonate (20 ml, 10percent) was added followed by extraction with ethylacetate (3 x 20 ml). The organic phase was dried and evaporated and a yellow powder was isolated. Yield 0.86 g (55percent). Mp 135-139°C. | |
55% | 4-(5-Nitro-pyrimidin-2-yl)-1 ,4-diaza-bicvclo[3.2.21nonane free base (Intermediate compound); A mixture of 1 ,4-diazabicyclo[3.2.2]nonane (0.87 g, 6.90 mmol), 2- chloro-5-nitro-pyhmidine (1.56 g, 6.27 mmol) and dioxane (75 ml) was stirred at room-temperature for 15 h. Aqueous sodium bicarbonate (20 ml, 10percent) was added followed by extraction with ethylacetate (3 x 20 ml). The organic phase was dried and evaporated and a yellow powder was isolated. Yield 0.86 g (55percent). Mp 135-139°C. | |
55% | A mixture of 1 ,4-diazabicyclo[3.2.2]nonane (0.87 g, 6.90 mmol), 2-chloro-5- nitro-pyrimidine (1.56 g, 6.27 mmol) and dioxane (75 ml) was stirred at room- temperature for 15 h. Aqueous sodium bicarbonate (20 ml, 10percent) was added followed by extraction with ethylacetate (3 x 20 ml). The organic phase was dried and evaporated and a yellow powder was isolated. Yield 0.86 g (55percent). Mp 135-139or V"y . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With N-ethyl-N,N-diisopropylamine at 100℃; for 4h; | 1.A Method A4-r5-(5-Bromo-furan-2-ylH1 ,3,4loxadiazol-2-yll-1 ,4-diaza-bicyclor3.2.21nonane free base (Compound ADA mixture of 1 ,4-diazabicyclo[3.2.2]nonane (4.05 g, 32.1 mmol), 2- benzylsulfanyl-5-(5-bromo-furan-2-yl)-[1 ,3,4]oxadiazole (10.3 g, 30.5 mmol) and N, N- diisopropylethylamine (8.29 g, 64.1 mmol) was stirred at 100°C for 4 hours. Aqueous sodium hydroxide (30 ml, 1 M) was added followed by extraction with chloroform (3 x 30 ml). The organic phase was dried and evaporated. The crude solid mixture was solved in hot ethyl acetate (100 ml), some red, glue-like impurities where removed by filtration. The filtrate was evaporated and finally the crystalline product was triturated with diethylether. Yield 3.43 g (33%). LC-ESI-HRMS of [M+H]+ shows 339.0453 Da. CaIc. 339.045664 Da, dev. -1.1 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: C14H7ClO3; 1,4-diazabicyclo[3.2.2]nonane In 1,2-dimethoxyethane at 20℃; for 144h; Stage #2: With sodium hydroxide In 1,2-dimethoxyethane; water | 1.A Phosgen, 20% in toluene (2.87 g, 29.0 mmol) was solved in anhydrous dichloromethane (15 ml) at O0C. A mixture of 2-hydroxy-fluoren-9-one (1 .14 g, 5.81 mmol) and pyridine (0.61 g, 7.73 mmol), solved in dichloromethane (25 ml) was added to the mixture at O0C. The mixture was stirred for 30 minutes at O0C and was then allowed to reach room-temperature and was stirred over-night. The reaction-mixture30 was evaporated and was co-evaporated with toluene (25 ml). The crude intermediate, 1 ,4-diazabicyclo[3.2.2]nonane (0.73 g 5.81 mmol) and 1 ,2-dimethoxyethane (40 ml) was stirred at room-temperature for 6 days. Aqueous sodium hydroxide (50 ml, 1 M) was added followed by extraction with chloroform (3 x 30 ml). Chromatography on silica gel with chloroform, 10% methanol and 1 % aqueous ammonia as solvent gave35 the title compound as an oil. The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1 ) saturated with fumaric acid. Yield 1 .40 g, 0.51 %. LC-ESI-HRMS of [M+H]+ shows 349.1562 Da. CaIc. 349.155218 Da, dev. 2.8 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With N-ethyl-N,N-diisopropylamine In methanol at 20℃; for 4.5h; Inert atmosphere; | |
35% | Stage #1: 2-chloro-1,3-benzoxazole; 1,4-diazabicyclo[3.2.2]nonane In methanol at 0 - 20℃; for 16h; Stage #2: With N-ethyl-N,N-diisopropylamine In methanol at 20℃; for 4.5h; | |
With ammonium hydroxide; IPr2NEt In methanol; chloroform | 1 4-BENZOOXAZOL-2-YL-1,4-DIAZA-BICYCLO[3.2.2]NONANE EXAMPLE 1 4-BENZOOXAZOL-2-YL-1,4-DIAZA-BICYCLO[3.2.2]NONANE 2-Chlorobenzoxazole (Aldrich, 99 μL, 0.87 mmol) was added to a solution of 1,4-diazabicyclo[3.2.2]nonane (100 mg, 0.79 mmol) in methanol (2.65 mL) at 0° C. The reaction mixture was allowed to slowly warm to RT. After a period of 16 h iPr2NEt (138 μL, 0.79 mmol) was added and the mixture was stirred at RT for 4.5 h at which time it was diluted with CHCl3 and NaHCO3. The layers were partitioned and the aqueous layer was extracted with CHCl3 (*3). The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by chromatography (Biotage, 12L) eluding with 4% MeOH in CHCl3 containing 20 drops of NH4OH per liter of eluent to afford 67 mg (35%) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.30 (d, 1H, J=7.5 Hz), 7.19 (d, 1H, J=7.9 Hz), 7.10 (t, 1H, J=7.5 Hz), 6.94 (t, 1H, J=7.9 Hz), 4.46, (s, 1H), 3.87, (t, 2H, J=5.8 Hz), 3.12-2.92 (m, 6H), 2.15-2.05 (m, 2H), 1.79-1.70 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 161.8, 148.9, 143.7, 124.1, 120.3, 116.1, 108.7, 57.3, 50.3, 46.5, 44.4, 27.1; MS (Cl) m/z 244.3 (M+1). The hydrochloride salt was prepared by dissolving the title compound in iPrOH and adding 0.1 mL of 6 M hydrochloric acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine In isopropyl alcohol at 90℃; for 18h; Inert atmosphere; Neat (no solvent); | |
55% | In isopropyl alcohol at 90℃; for 18h; | |
With ammonium hydroxide In 2-methyl-propan-1-ol; chloroform | 9 4-(5-BROMO-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE EXAMPLE 9 4-(5-BROMO-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE 1,4-Diazabicyclo[3.2.2]nonane (57%, 731 mg, 3.31 mmol) was added to a solution of 5-bromo-2-methylsulfanyl-benzooxazole (538 mg, 2.20 mmol) in iPrOH (4.4 mL). The mixture was placed in an oil bath at 90° C. and the solvent was evaporated. The mixture was allowed to stir neat at 90° C. for 18 h. Upon cooling to RT the mixture was purified by chromatography (Biotage, 25M) eluding with 4% MeOH in CHCl3 with 20 drops of NH4OH per liter of eluent to afford 392 mg (55%) of the title compound as an oil: 1H NMR (CDCl3, 400 MHz) δ 7.40 (t, 1H, J=1.2 Hz), 7.05 (d, 2H, J=1.2 Hz), 4.46-4.43 (m, 1H), 3.87 (t, 2H, J=5.8 Hz), 3.14-2.93 (m, 6H), 2.13-2.06 (m, 2H), 1.81-1.73 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 162.3, 148.0, 145.6, 122.9, 119.0, 116.8, 109.8, 57.2, 50.5, 46.5, 44.4, 27.0; MS (Cl) m/z 322.0 (M+1); HPLC retention time=3.36 min. The hydrochloride salt was prepared by diluting in ethyl acetate and adding a solution of 2.5 N HCl in ethyl acetate: mp>300° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With sodium hydroxide; In water; at 100℃; for 0.5h; | A mixture of <strong>[17973-86-3]3,6-dibromo-pyridazine</strong> (3.77 g, 15.85 MMOL) 1,4- diazabicyclo [3.2. 2] nonane (2.00 g, 15.85 MMOL) and aqueous sodium hydroxide (10 ml, 4M) was stirred at 100C for 30 minutes. The mixture was extracted with dichloromethane (3 x 20 ML). Chromatography on silica gel with DICHLOROMETHANE, 10% methanol and 1% aqueous ammonia as solvent gave the title compound as an oil. Yield 0.88 g, 20%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4-[5-Phenyl-(1,2,4-oxadiazol-3-yl)]-1,4-diazabicyclo[3.2.2]nonane hydrobromide 1:2 A 10 ml reactor is charged in succession with 0.2 g (1.6 mmol) of 1,4-diazabicyclo[3.2.2]nonane, 6 ml of tetrahydrofuran, 0.22 g (1.6 mmol) of 3-bromo-5-phenyl-(1,2,4)oxadiazole and 0.24 ml (1.7 mmol) of triethylamine and the mixture is heated at reflux for 20 hours. It is poured into water, the aqueous phase is extracted with chloroform and the organic phases are dried, filtered and concentrated under reduced pressure. The residue is purified by chromatography on an alumina column, eluding with a 60/40 mixture of cyclohexane and ethyl acetate. This gives 0.11 g of product, which is dissolved in 20 ml of acetone, and then ml of a 33% strength solution of hydrobromic acid in acetic acid are added. The crystals obtained are recovered by filtration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | With potassium <i>tert</i>-butylate In 1,4-dioxane at 100℃; for 15h; | 1.B [0295] A mixture of 1,4-diazabicyclo[3.2.2]nonane (1.0 g, 7.9 mmol), 4-bromobiphenyl (1.85 g, 7.9 mmol), potassium tert-butoxide (1.85 g, 15.8 mmol), Pd(0)(PPh3)4 (0.27 g, 0.24 mmol) and dioxane (10 ml) was stirred at 100° C. for 15 hours. The mixture was evaporated. Aqueous sodium hydroxide (10 ml, 4M) was added. The mixture was extracted with dichloromethane (3x20 ml). Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound as an oil. Yield 65 mg, 3%. [0296] The corresponding salt was obtained by addition of a diethyl ether and 10 methanol mixture (9:1) saturated with fumaric acid. Mp 196.3-196.9° C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With sodium hydroxide; In water; at 100℃; for 0.5h; | 4-(6-Bromo-pyridazin-3-yl)-1.4-diazabicyclo[3.2.2]nonane Fumaric Acid Salt (Intermediate Compound) A mixture of <strong>[17973-86-3]3,6-dibromo-pyridazine</strong> (3.77 g, 15.85 mmol) 1,4-diazabicyclo[3.2.2]nonane (2.00 g, 15.85 mmol) and aqueous sodium hydroxide (10 ml, 4M) was stirred at 100 C. for 30 minutes.The mixture was extracted with dichloromethane (3*20 ml).Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound as an oil.Yield 0.88 g, 20%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine In 1,2-dimethoxyethane at 20℃; | 1.A Method A (1, 4-DIAZA-BICVCLO3. 2. 21NON-4-Y)-FURAN-2-VL-METHANONE HVDROCHLORIC acid salt (Compound A1) A mixture of 1, 4-DIAZA-BICYCLO [3.2. 2] nonane (0.50 G ; 4.0 MMOL), 2-furoyl chloride (0.52 mg; 4.0 MMOL), diisopropylethylamine (1.02 G ; 7.9 MMOL) and 1,2- dimethoxyethane (25 ML) was stirred at room-temperatue over night. The product precipitated as hydrochloric acid salt and was filtered and washed with 1,2- dimethoxyethane (5 ML). Yield 0.84 G (82%). Mp. 279-283 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; In DMF (N,N-dimethyl-formamide); at 110℃; for 20.0h; | 1 g (5 mmol) of <strong>[76006-13-8]3-bromo-1H-pyrazolo[3,4-c]-pyridine</strong>, 0.53 g (0.75 mmol) of bis(triphenyl-phosphino)dichloropalladium, 1.9 g (15.1 mmol) of 1,4-diazabicyclo[3.2.2]nonane and 3.5 ml (25 mmol) of triethylamine dissolved in 15 ml of N,N-dimethyl-formamide are successively introduced into a 50 ml reactor. The mixture is then purged with carbon monoxide and heated at 110 C. for 20 hours. The reaction medium is poured into 100 ml of water and the aqueous phase is extracted with chloroform. After drying the organic phases, they are dried, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of chloroform, methanol and aqueous ammonia in 90/10/1 proportions. 0.41 g of product in the form of a crystalline solid is thus obtained. Melting point: 232-234 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1H-Indazole-3-carboxylic acid With 1,1'-carbonyldiimidazole In DMF (N,N-dimethyl-formamide) at 20℃; for 0.75h; Stage #2: 1,4-diazabicyclo[3.2.2]nonane In DMF (N,N-dimethyl-formamide) at 20℃; for 15h; | 1 3-(1,4-Diazabicyclo[3.2.2]non-4-ylcarbonyl)-1H-indazole hydrochloride 2.4 g (14.8 mmol) of 1H-indazole-3-carboxylic acid dissolved in 30 ml of N,N-dimethylformamide and 2.4 g (14.8 mmol) of N,N'-carbonyldiimidazole are introduced into a 100 ml reactor. The mixture is stirred at room temperature for 45 minutes, 1.7 g (13.4 mmol) of 1,4-diazabicyclo[3.2.2]nonane dissolved in 20 ml of N,N-dimethylformamide are then added and the mixture is stirred at room temperature for 15 hours. The resulting mixture is diluted in 100 ml of ethyl acetate and the organic phase is washed with 100 ml of saturated aqueous sodium chloride solution, dried and filtered. The solvent is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of chloroform, methanol and aqueous ammonia in 85/15/1.5 proportions. 1.7 g of product are obtained, and are dissolved in 30 ml of isopropyl alcohol, followed by addition of 1.5 ml of a 5N solution of hydrogen chloride in isopropyl alcohol. The crystals obtained are collected by filtration and dried under reduced pressure. 1.2 g of hydrochloride are obtained. Melting point: 282-283° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | In monoethylene glycol diethyl ether at 135℃; for 18h; | 1.E A mixture of 1, 4-diazabicyclo [3.2. 2] nonane (20.2 g, 160 mmol), 1-fluoro-4- nitrobenzene (17.5 ml, 163.3 mmol) and ethylene glycol diethyl ether (160 mi) was stirred at 135°C for 18 hours. The mixture was cooled to room-temperature and diethyl ether (100 mi) was added. The mixture was filtered and the product was isolated by filtration. Yield 24.8 g (58 %). Mp. 122-129°C. |
58% | In monoethylene glycol diethyl ether at 135℃; for 18h; | 1.A 4-(4-Nitro-phenyl)-1 ,4-diaza-bicvclo[3.2.2]nonane hydrofluoric acid salt(Intermediate compound); A mixture of 1 ,4-diazabicyclo[3.2.2]nonane (20.2 g, 160 mmol), 1 -fluoro- 4-nitrobenzene (17.5 ml, 163.3 mmol) and ethylene glycol diethyl ether (160 ml) was stirred at 135°C for 18 hours. The mixture was cooled to room-temperature and diethyl ether (100 ml) was added. The mixture was filtered and the product was isolated by filtration. Yield 24.8 g (58%). Mp. 122-129°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In 1,2-dimethoxyethane at 20℃; for 15h; | 1.A (1. 4-Diaza-bicyclo[3. 2. 2]non-4-yl)-5-(4-nitrophenyl)-furan-2-yl-methanone hydrochloric acid salt (intermediate Compound); A mixture of 5-(4-nitrophenyl)-2 ; furoyl chloride (1.0 g ; 4,0 mmol), 1,4- diazabicyclo [3. 2. 2] nonane (0.50 g; 4.0 mmol) and 1, 2-dimethoxyethane (20 mi) was stirred for 15 hours at room temperature. The title compound was filtered. Yield 1.4 g (93%). Mp. 298. 2°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In 1,4-dioxane; water at 0 - 20℃; | 1.E 1, 4-diazabicyclo [3.2. 2] nonane (6.3 g, 50 mmol) was added to a mixture of 2- chloro-nitropyridine (11.9, 75 mmol), and dioxane (250 mi) at 0°C. The reaction mixture was allowed to reach room-temperature. Water (100 mi) was added. The mixture was extracted with dichloromethane (3 x 50 ml). Chromatography on silica gel with dichloromethane and 10% methanol as solvent gave the title compound as an oil. Yield 8.1 g (65%). Mp. 143-146°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 100℃; for 0.166667h; | 7.3 375 mg (2 mmol) of the derivative from the preceding step, 760 mg (4 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 50 mg of dimethylaminopyridine, 5 ml of acetonitrile and 500 mg (4 mmol) of diazabicyclononane are placed in a microwave tube (Personal Chemistry), and the tube is stoppered and heated at 100° C. for 10 minutes. The mixture is immersed in 50 ml of water and extracted with dichloromethane, and the organic phase is evaporated. By trituration in isopropyl ether, 310 mg of a crystalline compound are obtained. Melting point: 228-229° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; caesium carbonate In tetrahydrofuran; methanol; dichloromethane | 4 4.2 4-(6-Chloroquinolin-3-yl)-1,4-diazabicyclo[3.2.2]_nonane 4.2 4-(6-Chloroquinolin-3-yl)-1,4-diazabicyclo[3.2.2]_nonane 0.53 g (2.18 mmol) of 3-bromo-6-chloro_quinoline, 0.25 g (2 mmol) of 1,4-diazabicyclo[3.2.2]_nonane, 0.018 g (0.08 mmol) of palladium diacetate, 0.91 g (2.8 mmol) of cesium carbonate and 0.05 g (0.08 mmol) of 2,2'-bis(diphenylphosphino)-1,1'-bi_naphthyl, in 15 ml of tetrahydrofuran, are introduced consecutively into a 50 ml three-necked round-bottomed flask and the reaction mixture is heated at reflux for 26 h. The inorganic products are separated off by filtration and the solvent is evaporated under reduced pressure; the residue is then purified by chromatography on a silica gel column, with the elution being carried out using a 95/5/0.5, and then a 90/10/1, mixture of dichloromethane, methanol and ammonia. 0.40 g of solid is obtained, with this solid being recrystallized in diisopropyl ether. Melting point: 134-135° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
104 mg (34%) | With ammonium hydroxide; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In chloroform; toluene; | 2-Chloro-benzoimidazole-1-carboxylic acid tert-butyl ester (333 mg, 1.32 mmol), 1,4-diazabicyclo[3.2.2]nonane (57%, 195 mg, 0.88 mmol), tris(dibenzylideneacetone)dipalladium (28 mg, 0.031 mmol), racemic-2,2'-bis(diphenylphosphino)-1,1 '-binaphthyl (58 mg, 0.093 mmol), sodium tert-butoxide (208 mg, 2.17 mmol) and toluene (1.55 mL) were added to a flame dried round bottom flask purged with nitrogen. The mixture was placed in an oil bath at 80 C. for 18 h and then cooled to RT. The mixture was filtered through a pad of celite and washed with chloroform and methanol. The filtrate was concentrated and the residue was purified by chromatography (Biotage, 12M) eluding with 8% methanol in chloroform with 20 drops of NH4OH per liter of eluent to afford 104 mg (34%) of 2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-benzoimidazole-1-carboxylic acid tert-butyl ester: MS (Cl) m/z 343.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In 1,2-dimethoxyethane at 20℃; for 15h; | 1.B Method B; 1 ,4-diaza-bicvclo[3.2.2lnonane-4-carboxylic acid 4-bromo-phenyl ester hydrochloric acid salt (Intermediate compound); 1 ,4-Diaza-bicyclo[3.2.2]nonane (5.49 g, 43.5 mmol), obtained according to literature, was slowly added to a mixture of 4-bromophenyl chloroformate (10.25 g, 43.5 mmol) and 1 ,2-dimethoxyethane (100 ml). The mixture was allowed to stir at room temperature for 15 hours. The precipitated product was filtered and washed with 1 ,2- dimethoxyethane. Yield 11.3 g (72%). Mp. 2420C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In 1,2-dimethoxyethane at 20℃; for 21h; | 1.C 1 ,4-Diaza-bicvclo[3.2.2lnonane-4-carboxylic acid 4-nitro-phenyl ester hydrochloric acid salt (Intermediate compound); A mixture of 1 ,4-diaza-bicyclo[3.2.2]nonane (6.31 g, 50 mmol) and 1 ,2- dimethoxyethane (40 ml) was added to a mixture of 4-nitrophenylchloroformate (10.1 g, 50 mmol) and 1 ,2-dimethoxyethane (100 ml) at room temperature. The mixture was stirred at room temperature for 21 hours. The precipitated solid was filtered and was purified by stirring in 1 ,2-dimethoxyethane (100 ml) followed by fitration. Yield 12.3 g(75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.2 N-[2-(1,4-Diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]-4-methoxybenzamide 0.42 g (2 mmol) of <strong>[13214-64-7]N-(4-methoxybenzoyl)_glycine</strong> dissolved in 20 ml of dioxane is placed in a 50 ml round-bottomed flask, 0.45 g (2.2 mmol) of dicyclohexylcarbodiimide is added, the mixture is stirred at room temperature for 30 minutes, 0.25 g (2 mmol) of 1,4-diazabicyclo[3.2.2]nonane is added and the mixture is stirred for a further one hour. 20 ml of water are added, the precipitate formed is filtered off, the filtrate is extracted with chloroform, the organic phase is extracted with aqueous 0.1N hydrochloric acid solution and the aqueous extraction phase is basified to pH 10 by addition of concentrated aqueous sodium hydroxide solution and extracted with chloroform. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. 0.49 g of product is obtained in the form of an amorphous solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: Hippuric Acid With 1,1'-carbonyldiimidazole In chloroform at 20℃; for 1h; Stage #2: 1,4-diazabicyclo[3.2.2]nonane In chloroform for 24h; | 1.1 1.1 N-[2-(1,4-Diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]benzamide 1.1 N-[2-(1,4-Diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]benzamide 1.06 9 (5.9 mmol) of N-benzoylglycine (hippuric acid) dissolved in 20 ml of chloroform are placed in a 50 ml round-bottomed flask and 2.9 g (17.9 mmol) of 1,1'-carbonylbis-1H-imidazole are added, and the mixture is then stirred at room temperature for one hour. 0.75 g (5.9 mmol) of 1,4-diazabicyclo[3.2.2]_nonane dissolved in 5 ml of chloroform is added and the mixture is stirred for 24 hours. The solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluding with a 90/10/1 mixture of chloroform, methanol and aqueous ammonia. 1.3 g of product are obtained in the form of an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.1 N-[2-(1,4-Diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]-2-methylbenzamide 0.47 g (2.28 mmol) of dicyclohexylcarbodi_imide dissolved in 20 ml of dioxane is placed in a 50 ml round-bottomed flask at room temperature. 0.4 g (2.07 mmol) of N-(o-toluyl)glycine is then added and the mixture is stirred for 30 minutes at room temperature. 0.26 g (2.07 mmol) of 1,4-diazabicyclo-[3.2.2]nonane dissolved in 5 ml of dioxane is added and the mixture is stirred for one hour. 50 ml of water are added, the precipitate formed is filtered off and the aqueous phase is extracted with chloroform. The organic phase is extracted with-aqueous 0.1N hydrochloric acid solution and the aqueous phase is basified to pH 10 by addition of concentrated aqueous sodium hydroxide solution and extracted with chloroform. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. 0.41 g of product is obtained in solid form. Melting point: 177 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N-3-methoxybenzoylglycine With dicyclohexyl-carbodiimide In 1,4-dioxane at 20℃; for 0.5h; Stage #2: 1,4-diazabicyclo[3.2.2]nonane In 1,4-dioxane for 2h; | 3.2 3.2 N-[2-(1,4-Diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]-3-methoxybenzamide 3.2 N-[2-(1,4-Diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]-3-methoxybenzamide 0.42 g (2 mmol) of N-(3-methoxybenzoyl)_glycine dissolved in 20 ml of dioxane is placed in a 50 ml round-bottomed flask, 0.45 g (2.2 mmol) of dicyclohexylcarbodiimide is added and the mixture is stirred at room temperature for 30 minutes, 0.25 g (2 mmol) of 1,4-diazabicyclo[3.2.2]nonane is added and the mixture is stirred for a further two hours. 20 ml of water are added, the precipitate formed is filtered off and the filtrate is extracted with chloroform. The organic phase is extracted with aqueous 0.1N hydrochloric acid solution and the aqueous extraction phase is basified to pH 10 by addition of concentrated aqueous sodium hydroxide solution and extracted with chloroform. The organic phase is dried over sodium sulfate-and concentrated under reduced pressure. 0.43 g of product is obtained in the form of an amorphous solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-[(3-bromobenzoyl)amino]acetic acid With dicyclohexyl-carbodiimide In 1,4-dioxane at 20℃; for 0.5h; Stage #2: 1,4-diazabicyclo[3.2.2]nonane In 1,4-dioxane for 2h; | 5.2 5.2 N-[2-(1,4-Diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]-3-bromobenzamide 5.2 N-[2-(1,4-Diazabicyclo[3.2.2]non-4-yl)-2-oxoethyl]-3-bromobenzamide 0.77 g (3 mmol) of N-(3-bromobenzoyl)glycine dissolved in 30 ml of dioxane is placed in a 100 ml round-bottomed flask, 0.68 g (3.3 mmol) of dicyclohexylcarbodiimide is added and the mixture is stirred at room temperature for 30 minutes, 0.38 g (3 mmol) of 1,4-diazabicyclo[3.2.2]nonane is added and the mixture is stirred for a further two hours. 30 ml of water are added and the precipitate formed is filtered off, the filtrate is extracted with chloroform and the organic phase is then extracted with aqueous 0.1N hydrochloric acid solution. The aqueous extraction phase is basified to pH 10 by addition of concentrated aqueous sodium hydroxide solution and extracted with chloroform. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. 0.95 g of product is obtained in the form of an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In 1,4-dioxane at 20℃; for 3h; | 1.A A mixture of 5-bromo-2-chloropyrimidine (2.5 g, 12.92 mmol), 1 ,4- diazabicyclo[3.2.2]nonane (1.4 g, 18.09 mmol), triethylamine (1.3 g, 12.92 mmol) and dioxane (100 ml) was stirred for 3 hours at room-temperature. Water (100 ml) was added. The mixture was extracted with ethyl acetate (3 x 100 ml). The organic phase was washed with sodium carbonate (100 ml, 1 %) and saturated sodium chloride (75 ml). The product was isolated as an oil. | |
With triethylamine In 1,4-dioxane at 20℃; for 3h; | 1 4-(5-Bromo-pyrimidin-2-yl)-1 ,4-diaza-bicvclo[3.2.21nonane (Intermediate compound); A mixture of 5-bromo-2-chloropyrimidine (2.5 g, 12.92 mmol), 1 ,4- diazabicyclo[3.2.2]nonane (1 .4 g, 18.09 mmol), triethylamine (1 .3 g, 12.92 mmol) and dioxane (100 ml) was stirred for 3 hours at room-temperature. Water (100 ml) was added. The mixture was extracted with ethyl acetate (3 x 100 ml). The organic phase was washed with sodium carbonate (100 ml, 1 %) and saturated sodium chloride (75 ml). The product was isolated as an oil. | |
With triethylamine In 1,4-dioxane at 20℃; for 3h; | 1 4-(5-Bromo-pyrimidin-2-yl)-1 ,4-diaza-bicvclo[3.2.21nonane fumaric acid salt (Compound 1 ); A mixture of 5-bromo-2-chloropyhmidine (2.5 g, 12.92 mmol), 1 ,4- diazabicyclo[3.2.2]nonane (1 .4 g, 18.09 mmol), triethylamine (1 .3 g, 12.92 mmol) and dioxane (100 ml) was stirred for 3 hours at room-temperature. Water (100 ml)30 was added. The mixture was extracted with ethyl acetate (3 x 100 ml). The organic phase was washed with sodium carbonate (100 ml, 1 %) and saturated sodium chloride (75 ml). The product was isolated as an oil. The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1 ) saturated with fumaric acid.35 LC-ESI-HRMS of [M+H]+ shows 283.0543557 Da. CaIc. 283.055289Da, dev. -3.3 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 100℃; for 15h; | 1.A A mixture of 2-benzylsulfanyl-5-(2-phenoxy-phenyl)-[1 ,3,4]oxadiazole (4.9 g, 13.6 mmol), 1 ,4-diazabicyclo[3.2.2]nonan (1.80 g, 14.3 mmol), diisopropylethylamine (3.5 g, 27.2 mmol) and DMF (5 ml) was stirred for 15 hours at 100°C. The mixture was co-evaporated twice with toluene. The oil obtained was solved in chloroform (10 ml) and was evaporated on celite. The crude mixture was purified by silica gel chromatography, using a 10 : 1 + 1 % dichloromethane : methanol + aqueous ammonia mixture as eluent. Yield 1.1 g (22%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1,4-diazabicyclo[3.2.2]nonane; 4-phenylazo-phenylchloroformate In 1,2-dimethoxyethane at 20℃; Stage #2: With sodium hydroxide In 1,2-dimethoxyethane; water | A mixture of 4-phenylazophenol (1 .0 g, 5.04 g), pyridine (0.52 g, 6.6 mmol) and dichloromethane (40 ml) was added dropwise to a mixture of phosgene in toluene (12.5 g, 25,2 mmol) and dicloromethane (25 ml) at 0 °C and was stirred for 1 h at the same temperature. The mixture was stirred at room-temperature for 15 h. The mixture was evaporated and co-evaporated with toluene. The formed 4- phenylazo-phenylchloroformate was solved in DME (50 ml), followed by addition of 1 ,4-diazabicyclo[3.2.2]nonane (0.64 g, 5.04 mmol) at room-temperature, followed by stirring over-night at room temperature. Aqueous sodium hydroxide (1 M) was added, DME was evaporated and the mixture was extracted with chloro- form. Chromatography on silica gel with chloroform, 10% methanol and 1 % aqueous ammonia as solvent gave a crude product. Yield 1 .68 g (95 %). The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1 ) saturated with fumaric acid. Yield 1.39 g (62 %). LC-ESI-HRMS of [M+H]+ shows 351.1827 Da. CaIc. 351.182101 Da, dev. 1.7 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 16h; | 3.A A mixture of 2-fluoro-5-nitrotoluene (1.08 g, 6.98 mmol), 1 ,4- diazabicyclo[3.2.2]nonane (0.8 g, 6.34 mmol) and K2CO3 (2.2 g, 15.86 mmol) in 8 ml. of DMF was stirred at 100 0C for 16 h. After cooling to ambient temperature, water (40 ml.) was slowly added to the mixture. The resulting (yellow) solid was filtered and washed three times with water. Thin layer chromatography showed trace amount of starting aryl fluoride. The solid 4-(2-methyl-4-nitrophenyl)-1 ,4-diazabicyclo[3.2.2]nonane was suspended in 25 ml. of Et2O, sonicated for 10 min, collected by filtration and washed with Et2O; 950 mg; Purity (LC-MS): >97%; MS (m/e): 262.4 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 100℃; for 20h; | 4-(5-Benzo[1.31dioxol-5-yl-H .3.41oxadiazol-2-yl)-1 ,4-diaza-bicvclor3.2.21nonane fumaric acid salt (Intermediate compound); A mixture of 1 ,4-diazabicyclo[3.2.2]nonane (6.36 g, 50.4 mmol), 2- benzo[1 ,3]dioxol-5-yl-5-benzylsulfanyl-[1 ,3,4]oxadiazole (15.0 g, 48.0 mmol), DMF (20 ml) and N,N-diisopropylethylamine (13.0 g, 100.8 mmol) was stirred at 100°C for 20 hours. Chromatography on silica gel with chloroform, 10% methanol and 1 % aqueous 5 ammonia as solvent gave a crude product (7.9 g). Repeated chromatography on silica gel with chloroform, 10% methanol and 1 % aqueous ammonia as solvent gave the product as an amorphous solid. Yield 4.4 g (29%). The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1 ) saturated with fumaric acid. The product fumarate salt was recrystalized from isopropanol. Yield from 10 free base 3.2 g (61 %). LC-ESI-HRMS of [M+H]+ shows 315.1463 Da. CaIc. 315.145716 Da, dev. 1.9 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol; 1,4-diazabicyclo[3.2.2]nonane In pentan-1-ol at 130℃; for 15h; Stage #2: With sodium hydroxide In pentan-1-ol; chloroform; water | 1.A Method A4-r5-(2,3-Dihvdro-benzofuran-5-ylH1 ,3,41oxadiazol-2-yl1- 1 ,4diazabicvclo[3.2.2]nonane fumaric acid salt (Compound 1 )A mixture of 1 ,4-diaza-bicyclo[3.2.2]nonane (0.69 g, 5.45 mmol), 5-(2,3- dihydro-benzofuran-5-yl)-[1 ,3,4]oxadiazole-2-thiol (1.5 g, 6.81 mmol) and n- pentanol (15 ml) was stirred for 15 h at 130 °C. Chloroform (25 ml) and aqueous sodium hydroxide (25 ml, 1 M) was added and stirred. The phases were separated and the organic phase was washed with aqueous sodium hydroxide (25 ml, 1 M). The collected aqueous sodium hydroxide phases was extracted with chloroform (25 ml). The collected organic phases was extracted with aqueous hydrochloric acid (2 x 25 ml, 1 M). The acidic phase was washed with chloroform (25 ml). The acidic phase was made alkaline by adding aqueous sodium hydroxide (25 ml, 4 M). The alkaline aqueous phase was extracted with chloroform (2 x 25 ml). The organic phase was washed with aqueous sodium hydroxide (25 ml, 1 M). The organic phase was dried and evaporated. Yield 1.0 g (59%). The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1 ) saturated with fumaric acid. Yield 1.0 g (73%). LC-ESI-HRMS of [M+H]+ shows 5 313.1654 Da. CaIc. 313.166451 Da, dev. -3.4 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | Stage #1: 4-bromo-1,1'-biphenyl; 1,4-diazabicyclo[3.2.2]nonane With potassium <i>tert</i>-butylate In 1,4-dioxane; water at 100℃; for 15h; Stage #2: (2E)-but-2-enedioic acid In methanol; diethyl ether | 1 Example 1 Preparatory Example 4-BIPHENYL-4-YL-114-DIAZABICYCLO[3. 2. 2]nonane fumaric acid salt (Compound 34) A mixture of 1, 4-diazabicyclo [3.2. 2] nonane (1. 0 g, 7.9 MMOL), 4- bromobiphenyl (1.85 g, 7.9 MMOL), potassium ferf-butoxide (1.85 G, 15.8 MMOL), Pd (0) (PPh3) 4 (0.27 g, 0.24 MMOL) and dioxane (10 ml) was stirred at 100°C for 15 hours. The mixture was evaporated. Aqueous sodium hydroxide (10 ML, 4M) was added. The mixture was extracted with DICHLOROMETHANE (3 x 20 ML). Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound as an oil. Yield 65 mg, 3%. The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9: 1) saturated with fumaric acid. MP 196.3-196. 9°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: 5-indan-2-yl-[1,3,4]oxadiazole-2-thiol; 1,4-diazabicyclo[3.2.2]nonane In pentan-1-ol at 130℃; for 15h; Stage #2: (2E)-but-2-enedioic acid In methanol; diethyl ether | 1.A A mixture of 1 ,4-diaza-bicyclo[3.2.2]nonane (0.80 g, 5.13 mmol), 5- indan-2-yl-[1 ,3,4]oxadiazole-2-thiol (1.4 g, 6.41 mmol) and n-pentanol (15 ml) was stirred for 15 h at 130 °C. Chloroform (25 ml) and aqueous sodium hydroxide (25 ml, 1 M) was added and stirred. The phases were separated and the organic phase was washed with aqueous sodium hydroxide (25 ml, 1 M). The collected aqueous sodium hydroxide phases were extracted with chloroform (25 ml). The collected organic phases were extracted with aqueous hydrochloric acid (2 x 25 ml, 1 M). The acidic phase was washed with chloroform (25 ml). The acidic phase was made alkaline by adding aqueous sodium hydroxide (25 ml, 4 M). The alkaline aqueous phase was extracted with chloroform (2 x 25 ml). The organic phase was washed with aqueous sodium hydroxide (25 ml, 1 M). The organic phase was dried and evaporated. Yield 1.0 g (59%). The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1 ) saturated with fumaric acid. Yield 1.3 g (59%). LC-ESI-HRMS of [M+H]+ shows 311.1886 Da. CaIc. 311.187186 Da, dev. 4.5 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.8% | With triethylamine In isopropyl alcohol at 100℃; | 1.4 (4) Synthesis of compound I-6 To the reaction flask was added 1,4-diazabicyclo [3.2.2] nonane (200 mg, 1.58 mmol)Compound I-5 (466 mg, 1.9 mmol),Triethylamine (321 mg, 3.17 mmol) and10 mL isopropanol,Heating the system while heating to 100 ,After the solvent was evaporated, stirring was continued overnight.TLC After the reaction was complete (ethyl acetate / methanol = 10: 1)Directly eluting with ethyl acetate (containing 1% methanol and 1 ‰ triethylamine) as eluent,To a solution of pale yellow solid I-6 (250 mg, 48.8%). |
48.8% | With triethylamine In isopropyl alcohol at 100℃; | 4.2.17. 5-Bromo-2-(methylthio)oxazolo[4,5-b]pyridine (21) 1,4-Diazabicyclo[3.2.2]nonane (200 mg, 1.58 mmol) was addedto a solution of 5-bromooxazolo[4,5-b]pyridine-2-thiol (20)(466 mg, 1.9 mmol) and NEt3 (321 mg, 3.17 mmol) in i-PrOH(10 mL). The mixture was placed in an oil bath at 100 C and thesolvent was evaporated. The mixture was allowed to stir neat at90 C overnight. Upon cooling to RT, the mixture was purified byflash column chromatography (EA) to provide the title compound5-bromo-2-(methylthio)oxazolo[4,5-b]pyridine (21) (250 mg,48.8%). 1H NMR (400 MHz, DMSO) d 7.68 (d, J 8.12 Hz, 1H), 7.15 (d,J 8.12 Hz, 1H), 4.43e4.42 (m, 1H), 3.90 (t, J 5.56 Hz, 2H), 3.09 (t,J 5.76 Hz, 2H), 3.04e2.95 (m, 4H), 2.10e2.07 (m, 2H), 1.84e1.76(m, 2H); MS (M H): m/z 323.905. |
With triethylamine In isopropyl alcohol at 90℃; Neat (no solvent); Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | In pentan-1-ol at 130℃; for 15h; | 1 4-(5-Dibenzofuran-4-yl-[1 ,3,41oxadiazol-2-yl)-1 ,4-diaza-bicvclo[3.2.2]nonane fumaric acid salt (Compound 1 ); A mixture of 5-dibenzofuran-4-yl-[1 ,3,4]oxadiazole-2-thiol (1.5 g, 5.91 mmol), 1 ,4-diazabicyclo[3.2.2]nonane (0.56 g, 4.47 mmol) and 1-pentanol (10 ml) was stirred for 15 h at 130°C. The reaction-mixture was allowed to cool to room- temperature. Aqueous sodium hydroxide (1 M) was added and the mixture was extracted twice with chloroform. The organic mixture was extracted twice with aqueous hydrochloric acid. The aqueous phase was washed with chloroform and was made alkaline by adding sodium hydroxide (4 M), followed by extraction three times with chloroform. The free base was isolated as a yellow oil (1.1 g 69%). The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1 ) saturated with fumaric acid. Yield 1.3 g (89%). LC-ESI-HRMS of [M+H]+ shows 361.1663 Da. CaIc. 361.166451 Da, dev. -0.4 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In pentan-1-ol at 130℃; for 15h; | 1 4-(5-Furan-3-yl-[1 ,3,41oxadiazol-2-yl)-1 ,4-diaza-bicvclo[3.2.2]nonane (Intermediate compound); 5-Furan-3-yl-[1 ,3,4]oxadiazole-2-thiol (1.0 g, 5.95 mmol), 1 ,4- diazabicyclo[3.2.2]nonane (0.70 g, 4.16 mmol) and 1 -pentanol (15 ml) was stirred at 130°C for 15 h. The reaction-mixture was allowed to cool to room-temperature. Aqueous sodium hydroxide (1 M) was added and the mixture was extracted twice with chloroform. The organic mixture was extracted twice with aqueous hydrochloric acid. The aqueous phase was washed with chloroform and was made alkaline by adding sodium hydroxide (4 M), followed by extraction three times with chloroform. The free base was isolated. Yield 950 mg (88%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In methanol;Inert atmosphere; | Intermediate 27A: Methyl 2-(1 ,4-diazabicvclo[3.2.2lnonan-4-yl)-5-nitroisonicotinateTo a solution of <strong>[777899-57-7]methyl 2-chloro-5-nitroisonicotinate</strong> (Intermediate 26A) (0.1 g, 0.46 mmol) in methanol (3 mL) under nitrogen was added 1 ,4-diazabicyclo[3.2.2]nonane (0.18 g, 0.55 mmol) and triethylamine (7 mg, 0.69 mmol), reaction then stirred overnight. The reaction mixture was concentrated and purified by a 10g silica column eluting with 40% ethylacetate in hexane to afford methyl 2-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-5- nitroisonicotinate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In dimethyl sulfoxide at 90℃; for 96h; | 15 Intermediate 15A: 4-(1 ,4-Diazabicyclo[3.2.21nonan-4-yl)-/V-methyl-2-nitrobenzamideTo a solution of 4-fluoro-/V-methyl-2-nitrobenzamide (Intermediate 3L) (0.65 g, 3.3 mmol) in dimethylsulfoxide (50 mL) was added 1 ,4-diazabicyclo[3.2.2]nonane (0.62 g, 4.9 mmol) and potassium carbonate (1 .36g, 9.8 mmol). The resulting suspension was heated at 90 °C for 4 days. The mixture was filtered and the filtrate purified using a 20g SCX cartridge to afford 4-(1 ,4-diazabicyclo[3.2.2]nonan-4-yl)-/V-methyl-2-nitrobenzamide (0.8 g, 2.7 mmol).1H NMR (400 MHz, CDCI3): 7.35 (1 H, d J=16.8Hz), 7.1 (1 H, d J=2.8Hz), 6.85 (1 H, dd J=8.8, 2.8 Hz) 5.68-5.76 (1 H, bs), 4.03-4.09 (1 H, bs), 3.58-3.61 (2H, m), 3.06-3.18 (4H, m), 2.95-3.03 (2H, m), 3.0 (3H, d J=4.8Hz), 2.06-2.13 (2H, m), 1 .71 -1.81 (2H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate In 1,4-dioxane at 85℃; Inert atmosphere; Sealed vessel; | 7A EXAMPLE 7A: 7-(1 ,4-Diazabicvclor3.2.21nonan-4-yl)-3-(3-chlorophenyl)-2- methylisoquinolin-1 (2H)-oneA mixture of 7-bromo-3-(3-chlorophenyl)-2-methylisoquinolin-1 (2/-/)-one (Intermediate 24A) (50 mg, 0.143 mmol), 1 ,4-diazabicyclo[3.2.2]nonane (27.2 mg, 0.215 mmol), sodium t-butoxide (55.1 mg, 0.574 mmol), tris(dibenzylideneacetone)dipalladium(0) (13.13 mg, 0.014 mmol) and (+/-) BINAP (26.8 mg, 0.043 mmol) in degassed dioxane (1 mL) was heated to 85° C under N2 in a sealed vessel overnight. Reaction mixture allowed to cool to room temperature, diluted with water and the product extracted into ethyl acetate. Organics washed several times with water, dried (MgS04), filtered and then evaporated to dryness. The crude product was added to a silica gel column (25g) and was eluted with 0-50% 2M ammonia in methanol in ethylacetate to afford 7-(1 ,4-diazabicyclo[3.2.2]nonan- 4-yl)-3-(3-chlorophenyl)-2-methylisoquinolin-1 (2/-/)-one (19.4 mg, 0.05 mmol).MS (ESI) m/z 394 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 6-bromo-3-methylthieno[2,3-d]pyrimidin-4(3H)-one; 1,4-diazabicyclo[3.2.2]nonane With potassium phosphate In dimethyl sulfoxide at 90℃; for 72h; Sealed vessel; Stage #2: With acetic acid In dimethyl sulfoxide | 12A Example 12A: 6-(1 ,4-Diazabicyclo[3.2.2lnonan-4-yl)-3-methylthieno[2,3-dlpyrimidin- 4(3H)-one A mixture of 6-bromo-3-methylthieno[2,3-d]pyrimidin-4(3/-/)-one (70 mg, 0.28 mmol), copper(l) iodide (13.6 mg, 0.071 mmol), L-proline (16.4 mg, 0.143 mmol), 1 ,4- diazabicyclo[3.2.2]nonane (54.1 mg, 0.428 mmol) and potassium phosphate (132 mg, 5 0.571 mmol) in DMSO (1 mL) was heated at 90 °C in a sealed vessel for 3 days. The reaction was acidified with acetic acid, diluted with methanol and purified on a sex cartridge (1 g), further purified by acid prep HPLC, passed through a sex cartridge (500 mg) and evaporated to dryness to afford 6-(1 ^-DiazabicyclotS^^nonan^-y -S- methylthieno^S-d^yrimidin^S -one (1.8 mg, 0.006 mmol).10 .MS (ESI) m/z 291.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: 2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]benzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.666667h; Stage #2: 1,4-diazabicyclo[3.2.2]nonane In N,N-dimethyl-formamide at 20℃; for 1.5h; Cooling with ice; | 5.1 Step (1): Compound 2d + Compound 5a → Compound 5b Compound 2d (2.55 g, 5.9 mmol) was dissolved in N,N-dimethylformamide (25 mL), and then hydrochloric acid salt of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (1.25g, 6.54 mmol) followed by 1-hydroxybenzotriazole (883mg, 6.54mmol) were added, followed by stirring at room temperature for 40 minutes. After the reaction temperature was ice-cooled, a solution of Compound 5a (900 mg, 7.13 mmol), which was synthesized as described in Synth. Commun. 2006, 36, 321, inN,N-dimethylformamide (3mL) wasaddedthereto, and then stirred at room temperature for 90 minutes. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution, water, and then saturated brine. The organic layer was dried with magnesium sulfate, and then magnesium sulfate was removed by filtration, followed by concentration in vacuo. The resulting residue was subjected to silica gel column chromatography, eluting with methanol-chloroform. Fractions containing the desired compound were concentrated in vacuo to yield Compound 5b (1.64 g, 51%).MS: 537.19 (M+H).1H-NMR (CDCl3) δ: 7.34 (4H, t, J = 9.3 Hz), 6.98-6.87 (4H, m), 6.81 (2H, d, J = 8.4 Hz), 5.07 (2H, s), 4.99 (2H, dd, J = 26.2, 10.3 Hz), 4.79 (0.8H, m), 4.34-4.26 (0.2H, m), 3.84 (3H, s), 3.79 (3H, s), 3.67-2.80 (8H, m), 2.23-2.00 (2H, m), 1.70-1.86 (2H, m). |
51% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; | [Method A] General procedure: To a solution of 1.0 equivalent of the acid derivative and 1.1 equivalent of amine in DMF were added 1.1 equivalent of HOBt and EDC·HCl, and stirred at room temperature for 1h. The solvent was evaporated in vacuo, the resulting residue was diluted with a mixture of aq. 2mol/L NaOH and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc and the combined extracts were washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting residue was subjected to silica gel chromatography, eluting with EtOAc (containing 5% of Et3N)-MeOH. The eluted fractions containing the desired compound were concentrated in vacuo to afford a target amide derivative. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With water; sodium hydroxide at 17℃; | 4 1 ,4-diazabicyclo[3.2.2]nonane dihydrochloride (0.81 g; 4.1 mmol) was taken up in water (4 mL; 222 mmol). The solution was cooled to 17°C. Next was added sodium hydroxide (50 mass% in H20; 10 mmol) and the pH was measured as ~13+. The solution was extracted thrice with 2- methyltetrahydrofuran (15 mL total) and the combined extract solvent was removed in vacuo to yield colorless oil 1 ,4-diazabicyclo[3.2.2]nonane (391 mg; 3.0983 mmol; 76% Yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl acetamide at 20℃; for 0.75h; | 8.1 To a solution of compound 8a (851 mg, 2.0 mmol) in N,N-dimethylacetamide (9 ml), triethylamine (665 μl, 4.8 mmol) and compound 8b (252 mg, 2.0 mmol) were added, under ice-cooling, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphite (913 mg, 2.4 mmol) was added, and then stirred at room temperature for 45 minutes. After the solvent was evaporated under reduced pressure, aqueous 5% sodium bicarbonate was added to the resulting concentrated residue, followed by extraction with mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with aqueous 5% sodium bicarbonate, then saturated brine, and then dried with anhydrous sodium sulfate. The inorganic substance was removed by filtration, followed by concentration under reduced pressure. The resulting crude product was purified by silica gel column chromatography to yield compound 8c as a brown foam. Yield 565 mg, (53%). MS (m+1)=534.25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 105℃; for 48h; Inert atmosphere; | |
55% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 105℃; for 48h; Inert atmosphere; | 3-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-6-nitrodibenzo[b,d]-thiophene 5,5-Dioxide (10) 3-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-6-nitrodibenzo[b,d]-thiophene 5,5-Dioxide (10) The typical procedure for Buchwald-Hartwig cross-coupling reaction was followed starting with 8 (0.129 g, 0.38 mmol). Note that the reaction mixture was heated at 105° C. for 48 h. The title compound 10 was obtained as a reddish solid (80 mg, 55% yield). 1H NMR (DMSO-d6, 400 MHz) δ 8.40 (d, J=4.0 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.15 (d, J=4.0 Hz, 1H), 4.21 (s, 1H), 3.71 (m, 2H), 3.00-2.85 (m, 6H), 2.00 (s, 2H), 1.71 (m, 2H); HRMS calculated for C19H2ON3O4S ([M+H]) 386.1169. found, 386.1150. Elemental analysis for C19H19N3O4S.H2O, calcd: C, 56.56; H, 5.25; N, 10.42. Found: C, 56.65; H, 4.99; N, 10.50. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 80 - 85℃; Inert atmosphere; | |
53% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 90℃; for 24.5h; Inert atmosphere; | 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-fluorodibenzo[b,d]thiophene 5,5-dioxide (10a) General procedure: Representative procedure for Buchwald-Hartwig amination. A mixture of Pd2(dba)3 (11 mg, 0.012 mmol) and BINAP (15 mg, 0.024 mmol) in toluene (1.5 mL) was stirred for 30 min at 90° C. The red-orange colored solution of the catalyst was allowed to cool (22 °C) and added to a mixture of 1,4-diazabicyclo[3.2.2]nonane (9a,53 mg, 0.42 mmol) and 8a (0.126 g, 0.40 mmol) in toluene (2 mL). Cs2CO3 (0.39 g, 1.2 mmol; AlfaAesar, Karlsruhe, Germany), which was previously dried (4 mbar, 2 h at 120 °C) was then added, andthe reaction mixture was stirred under an atmosphere of argon for 24 h at 90° C. After cooling to roomtemperature, the solid was filtered off and washed with CH2Cl2 (2 × 4 mL). The filtrate was evaporatedand purified by dry-column flash chromatography (silica gel 15-40 μm, 8 g) with a gradient from CHCl3(100%) to CHCl3/MeOH/NH3 (aq) (100:8:0.8, 100%). The fractions containing the product werecombined, evaporated and the solid residue was recrystallized from EtOH to afford the title compound10a (0.075 g, 0.21 mmol, 52% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 90℃; for 24.5h; Inert atmosphere; | 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-fluorodibenzo[b,d]thiophene 5,5-dioxide (10a) General procedure: Representative procedure for Buchwald-Hartwig amination. A mixture of Pd2(dba)3 (11 mg, 0.012 mmol) and BINAP (15 mg, 0.024 mmol) in toluene (1.5 mL) was stirred for 30 min at 90° C. The red-orange colored solution of the catalyst was allowed to cool (22 °C) and added to a mixture of 1,4-diazabicyclo[3.2.2]nonane (9a,53 mg, 0.42 mmol) and 8a (0.126 g, 0.40 mmol) in toluene (2 mL). Cs2CO3 (0.39 g, 1.2 mmol; AlfaAesar, Karlsruhe, Germany), which was previously dried (4 mbar, 2 h at 120 °C) was then added, andthe reaction mixture was stirred under an atmosphere of argon for 24 h at 90° C. After cooling to roomtemperature, the solid was filtered off and washed with CH2Cl2 (2 × 4 mL). The filtrate was evaporatedand purified by dry-column flash chromatography (silica gel 15-40 μm, 8 g) with a gradient from CHCl3(100%) to CHCl3/MeOH/NH3 (aq) (100:8:0.8, 100%). The fractions containing the product werecombined, evaporated and the solid residue was recrystallized from EtOH to afford the title compound10a (0.075 g, 0.21 mmol, 52% yield) |
40% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 80 - 85℃; for 24h; Inert atmosphere; | |
40% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene Inert atmosphere; | 3-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-6-fluorodibenzo[b,d]thiophene 5,5-Dioxide (7a) 3-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-6-fluorodibenzo[b,d]thiophene 5,5-Dioxide (7a) A catalyst solution was prepared by mixing tris(dibenzylideneacetone)dipalladium (Pd2(dba)3, 58 mg, 0.063 mmol; Aldrich) and racemic BINAP (39 mg, 0.125 mmol; Strem) in toluene (4 mL) and heating the mixture to 90° C. for 15 min. The solution was cooled and then added to a mixture of 1,4-diazabicyclo[3.2.2]nonane (200 mg, 1.58 mmol) and 6a (0.492 g, 1.58 mmol), in toluene (12 mL). Cs2CO3 (766 mg, 2.4 mmol; Aldrich) was then added, and the reaction mixture was flushed with nitrogen and heated overnight at 80-85° C. After cooling to room temperature, the mixture was concentrated and purified by silica gel flash chromatography (CHCl3/i-PrOH/Et3N 10:1:0.2). The title compound 7a (227 mg, 40% yield) was obtained as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.89 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.29-7.24 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 4.19 (s, 1H), 3.70-3.67 (m, 2H), 2.98-2.91 (m, 4H), 2.88-2.82 (m, 2H), 1.99 (m, 2H), 1.72-1.66 (m, 2H); HRMS calculated for C19H2OFN2O2S ([M+H]) 359.1224. found, 359.1240. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 80 - 85℃; for 24h; Inert atmosphere; | |
52% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 90℃; for 24.5h; Inert atmosphere; | 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-fluorodibenzo[b,d]thiophene 5,5-dioxide (10a) General procedure: Representative procedure for Buchwald-Hartwig amination. A mixture of Pd2(dba)3 (11 mg, 0.012 mmol) and BINAP (15 mg, 0.024 mmol) in toluene (1.5 mL) was stirred for 30 min at 90° C. The red-orange colored solution of the catalyst was allowed to cool (22 °C) and added to a mixture of 1,4-diazabicyclo[3.2.2]nonane (9a,53 mg, 0.42 mmol) and 8a (0.126 g, 0.40 mmol) in toluene (2 mL). Cs2CO3 (0.39 g, 1.2 mmol; AlfaAesar, Karlsruhe, Germany), which was previously dried (4 mbar, 2 h at 120 °C) was then added, andthe reaction mixture was stirred under an atmosphere of argon for 24 h at 90° C. After cooling to roomtemperature, the solid was filtered off and washed with CH2Cl2 (2 × 4 mL). The filtrate was evaporatedand purified by dry-column flash chromatography (silica gel 15-40 μm, 8 g) with a gradient from CHCl3(100%) to CHCl3/MeOH/NH3 (aq) (100:8:0.8, 100%). The fractions containing the product werecombined, evaporated and the solid residue was recrystallized from EtOH to afford the title compound10a (0.075 g, 0.21 mmol, 52% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | In tetrahydrofuran at 20℃; for 2h; | 124 Preparation of Compound 2B To a solution of Compound 2A (0.300 g, 2.38 mmol) in tetrahydrofuran (6mL), di-tert-butyl bicarbonate (0.828mL, 3.57 mmol) was added and stirred at room temperature for two hours. The suspension was filtered, washed with methanol, added with silica gel, concentrated and then subjected to silica gel chromatography. The fraction containing desired compound was concentrated and freeze-dried to yield Compound 2B (0.262g, 49%). 1H-NMR (DMSO-d6) δ: 4.07-4.01 (1H, m), 3.49 (2H, t, J = 5.8 Hz), 2.89-2.77 (6H, m), 1.88-1.79 (2H, m), 1.62-1.51 (2H, m), 1.39 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | In chloroform at 20℃; for 18h; Molecular sieve; | P; 46 N-(2-(3-(prop-1-en-2-yl)phenyl)propan-2-yl)-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide To a solution of 1,4-diazabicyclo[3.2.2]nonane (350 mg, 2.77 mmol) and 1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (1.09 mL, 5.55 mmol) in chloroform (2 mL) was added 3-4 pieces of molecular sieves. ;The reaction mixture was stirred at room temperature for 18 h and then concentrated. ;The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the corresponding urea as an off-white solid (650 mg, 36%). ;1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.31-7.26 (m, 3H), 5.34(s, 1H), 5.07 (s, 1H), 4.73 (br s, 1H), 4.03 (BR s, 1H), 3.64 (m, 2H), 3.14-3.03 (m, 6H), 2.15 (s, 3H) 2.06 (m, 2H), 1.72 (m, 8H) ppm. 13C NMR (100 MHz, CDCl3) δ 155.7, 148.3, 143.8, 141.3, 128.5, 124.1, 123.9, 122.0, 112.5, 57.8, 55.8, 48.1, 46.4 (2*), 41.2, 30.2 (2*), 27.3 (2*), 22.1 ppm. Purity: >98% UPLCMS (210 nm); retention time 0.71 min; (M+1) 328 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 90℃; for 24.5h; Inert atmosphere; | 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-fluorodibenzo[b,d]thiophene 5,5-dioxide (10a) General procedure: Representative procedure for Buchwald-Hartwig amination. A mixture of Pd2(dba)3 (11 mg, 0.012 mmol) and BINAP (15 mg, 0.024 mmol) in toluene (1.5 mL) was stirred for 30 min at 90° C. The red-orange colored solution of the catalyst was allowed to cool (22 °C) and added to a mixture of 1,4-diazabicyclo[3.2.2]nonane (9a,53 mg, 0.42 mmol) and 8a (0.126 g, 0.40 mmol) in toluene (2 mL). Cs2CO3 (0.39 g, 1.2 mmol; AlfaAesar, Karlsruhe, Germany), which was previously dried (4 mbar, 2 h at 120 °C) was then added, andthe reaction mixture was stirred under an atmosphere of argon for 24 h at 90° C. After cooling to roomtemperature, the solid was filtered off and washed with CH2Cl2 (2 × 4 mL). The filtrate was evaporatedand purified by dry-column flash chromatography (silica gel 15-40 μm, 8 g) with a gradient from CHCl3(100%) to CHCl3/MeOH/NH3 (aq) (100:8:0.8, 100%). The fractions containing the product werecombined, evaporated and the solid residue was recrystallized from EtOH to afford the title compound10a (0.075 g, 0.21 mmol, 52% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 90℃; for 24.5h; Inert atmosphere; | 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-fluorodibenzo[b,d]thiophene 5,5-dioxide (10a) General procedure: Representative procedure for Buchwald-Hartwig amination. A mixture of Pd2(dba)3 (11 mg, 0.012 mmol) and BINAP (15 mg, 0.024 mmol) in toluene (1.5 mL) was stirred for 30 min at 90° C. The red-orange colored solution of the catalyst was allowed to cool (22 °C) and added to a mixture of 1,4-diazabicyclo[3.2.2]nonane (9a,53 mg, 0.42 mmol) and 8a (0.126 g, 0.40 mmol) in toluene (2 mL). Cs2CO3 (0.39 g, 1.2 mmol; AlfaAesar, Karlsruhe, Germany), which was previously dried (4 mbar, 2 h at 120 °C) was then added, andthe reaction mixture was stirred under an atmosphere of argon for 24 h at 90° C. After cooling to roomtemperature, the solid was filtered off and washed with CH2Cl2 (2 × 4 mL). The filtrate was evaporatedand purified by dry-column flash chromatography (silica gel 15-40 μm, 8 g) with a gradient from CHCl3(100%) to CHCl3/MeOH/NH3 (aq) (100:8:0.8, 100%). The fractions containing the product werecombined, evaporated and the solid residue was recrystallized from EtOH to afford the title compound10a (0.075 g, 0.21 mmol, 52% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.4% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In 1,4-dioxane at 80 - 85℃; for 16h; Inert atmosphere; | 3.3 (3) Synthesis of Compound II-4 2-bromo-7-nitro-9-fluorenone (II-3) (9.0 g, 0.03 mol) was added successively to a 500 mL reaction flask,Pd2 (dba) 3 (0.6 g, 0.655 mmol),BINAP (1.3 g, 2.087 mmol),Sodium tert-butoxide (3.3 g, 0.0343 mol)1,4-diazabicyclo [3.2.2] nonane (3.0g, 0.024mol) and1,4-dioxane (150 mL),After replacing the nitrogen three times,The reaction system was heated to 80-85 ° C,Under nitrogen protection for 16 h;After completion of the reaction, 150 mL of ethyl acetate was added and passed through a padWith diatomite funnel filter to remove insoluble material; in the filtrate by adding 10% K2CO3 solution to adjust the pH to 8.0 or so, and thenThe mixture was extracted with CH2Cl2 until the aqueous phase had no color. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to giveBlue Purple Products (II-4) (2.1g, 20.4%), |
20.4% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In 1,4-dioxane at 80 - 85℃; Inert atmosphere; | 4.2.3. 2-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-7-nitro-9H-fluoren-9-one (4) [41] 2-bromo-7-nitro-9H-fluoren-9-one (3) (9.0 g, 0.03 mol),Pd2(dba)3 (0.6 g, 0.655 mmol), BINAP (1.3 g, 2.087 mmol), t-BuONa(3.3 g, 0.0343 mol), and 1,4-diazobicylco[3.2.2]nonane (3.0 g,0.024 mol) were added to anhydrous 1,4-dioxane (150 mL)sequentially and the reaction mixture was stirred overnight at80e85 C under an atmosphere of nitrogen. After cooling to roomtemperature, the mixture was diluted with ethyl acetate (150 mL)and filtered through Celite. The filtrate was adjusted to pH 8.0with 10% K2CO3 and then extracted with CH2Cl2. The combinedorganic layers were dried over MgSO4, filtered and concentrated.The crude product 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-7-nitro-9H-fluoren-9-one (4) was obtained as bluish violet solid (2.1 g,20.4%) and used without further purification. 1H NMR (400 MHz,CDCl3) d 7.56 (d, J 7.24 Hz, 1H), 7.38 (d, J 6.56 Hz, 1H), 7.34 (d, J 2.8 Hz, 1H), 7.14e7.09 (m, 2H), 6.78 (d, J 8.16 Hz, 1H), 4.13e4.11(m, 1H), 3.67e3.65 (m, 1H), 3.61e3.58 (m, 1H), 3.15e3.14 (m, 4H),3.04 (m, 2H), 2.14 (m, 2H), 1.78 (m, 2H); MS (M H): m/z 350.16. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 90℃; Inert atmosphere; | 2-(1,4-Diaza-bicyclo[3.2.2]nonan-4-yl)-6-fluoro-9H-fluoren-9-one (8c) Representative procedure for Buchwald-Hartwig amination General procedure: A mixture of Pd2(dba)3 (9.6 mg, 10.5 µmol) and BINAP (13.1 mg, 21 µmol) in toluene (1.5 mL) was stirred for 30 min at 90° C. The red-orange solution was allowed to cool (22 °C) and added to a mixture of 1,4-diazabicyclo[3.2.2]nonane (7a, 46 mg, 0.364 mmol) and 6c (97 mg, 0.35 mmol) in toluene (2 mL). Cs2CO3 (300 mg, 0.91 mmol) was added, and the reaction mixture was stirred under an atmosphere of argon for 28 h at 90° C. After cooling to room temperature, the solid was filtered off and washed with CH2Cl2 (2x4 mL). The filtrate was evaporated (→ 143 mg) and purified by DCVC (silica gel 15-40 µm, 8 g) with a gradient from CHCl3 (100%) to CHCl3/MeOH/NH3(aq) (100:8:0.8, 100%). Fractions containing product were combined and evaporated to give 8c (89 mg, 0.275 mmol, 80% yield, Rf = 0.29, CHCl3/MeOH/NH3(aq), 100:10:1) as dark red solid residue. A portion (48 mg, 150 µmol) was dissolved in EtOH (1 mL), treated with ethanolic HCl (8.3%, 80 mg, 180 µmol) and evaporated. The solid obtained was triturated with EtOH/MTBE to give 42 mg of 8c.HCl salt as red powder. |
41.8% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 20 - 90℃; for 14h; Inert atmosphere; | 5.6 (6) Synthesis of compound II-13 Compound II-12 (100 mg, 0.329 mmol),Diazabicyclo [3.2.2] nonane (125 mg, 0.989 mmol) andCesium carbonate (426 mg, 1.31 mmol)Dissolved in 2mL re-distilled anhydrous toluene, stand-by;Under argon protection,Pd2 (dba) 3 (30 mg, 0.033 mmol) and(±) -BINAP (61 mg, 0.099 mmol)Dissolved in 2 mL of re-evaporated anhydrous toluene,90 under the conditions of stirring 15min (the reaction mixture from deep purple turbidity into orange yellow clear liquid),Cooled to room temperature;The solution was then added to the reaction system,Argon protection, stirring at 60 ° C for 14 h (the reaction mixture consists ofOrange yellow to clarify the liquid into a brown red liquid), cooled to room temperature, add 10mL water quenching reaction, extraction with methylene chloride,The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure and purified by silica gel column chromatography (CH2Cl2: CH3OH= 20: 1) to give a dark purple solid II-13 (48 mg, 41.8%). |
41.8% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 80 - 85℃; Inert atmosphere; | 4.2.11. 7-(1,4-Diaza-bicyclo[3.2.2]nonan-4-yl)-1-nitro-9H-fluoren-9-one (13) Under an atmosphere of nitrogen, Pd2(dba)3 (0.6 g, 0.655 mmol)and BINAP (61 mg, 0.099 mmol) were stirred in anhydrous toluene(2 mL) for 15 min at 90 C. The solution was cooled to RT, and amixture of 7-bromo-1-nitro-9H-fluoren-9-one (12) (100 mg,0.329 mmol), Cs2CO3 (426 mg, 1.31 mmol), and 1,4-diazobicylco[3.2.2]nonane (125 mg, 0.989 mmol) in anhydrous toluene (2 mL)was added. The reaction mixture was heated to 80e85 C andstirred overnight. After cooling to room temperature, the mixturewas quenched by adding water. The phases separated and theaqueous layer extracted three times with CH2Cl2. The combinedorganic layers were dried over Na2SO4, filtered and concentratedunder vacuum. The crude product was purified by flash columnchromatography (CH2Cl2:CH3OH 20:1) to provide the title compound7-(1,4-diaza-bicyclo[3.2.2]nonan-4-yl)-1-nitro-9H-fluoren-9-one (13) (48 mg, 41.8%). 1H NMR (400 MHz, CDCl3) d 7.52e7.49(m, 2H), 7.36 (d, J 7.9 Hz, 2H), 7.10 (s, 1H), 6.82 (t, J 7.6 Hz, 1H), 4.13 (s, 1H), 3.63e3.62 (m, 2H), 3.18e3.04 (m, 6H), 2.31 (s, 2H),1.83e1.82 (m, 2H); MS (M H): m/z 350.37. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | A solution of compound III-2 (3.2 g, 13.7 mmol)Was dissolved in 20 mL of CH2Cl2,Diisopropylethylamine (1.77 g, 13.7 mmol)Was dissolved in 120 mL of tetrahydrofuran,Mixed with both,The mixed solution was then slowly added to triphosgene (1.3 g, 4.38 mmol)In CH2Cl2 (100 mL)After stirring at room temperature for 1 h,A mixture of 1,4-diazabicyclo [3.2.2] nonane (1.72 g, 13.7 mmol)Of the CH2Cl2 solution was slowly added thereto,Reaction at room temperature for 4 h;After completion of the reaction, add H2O dilution withCHCl3, the organic phase was collected, washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, the solvent was removed to give the crude product;CHCl3 and CH3OH (90:10) as the developing solvent. The product III-3 (2.4 g, 45%) was isolated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | The compound III-9 (3.2 g, 13.7 mmol)Was dissolved in 20 mL of CH2Cl2,Diisopropylethylamine (1.77 g, 13.7 mmol)Dissolved in 120 mL of tetrahydrofuran, the two were mixed,The mixed solution was then slowly added to triphosgene (1.3 g, 4.38 mmol)In CH2Cl2 (100 mL)After stirring at room temperature for 1 h,A mixture of 1,4-diazabicyclo [3.2.2] nonane (1.72 g, 13.7 mmol)CH2Cl2 solution was slowly added thereto,Reaction at room temperature for 4 h;After completion of the reaction, the solution was diluted with H2O and extracted with CHCl3. The organic phase was collected, washed with saturated aqueous solution of NaCl,Dried over anhydrous NaSO4 to remove the crude product;The product III-10 (2.4 g, 45%) was isolated by column eluting with CHCl3 and CH3OH (90:10) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20 - 110℃; for 12h; Inert atmosphere; | 2.2 2 N,N-diisopropylethylamine (0.7 mL, 2.213 mmol) at room temperatureAnd 1,4-diazabicyclo[3.2.2]nonane (0.252 g, 2 mmol)Dissolved in 5ml DMFTo this mixed solution, a solution of 2-chloro-5-bromobenzothiazole (0.494 g, 2.012 mmol) in DMF (1 ml) was added dropwise in a steady stream of nitrogen.Then warmed to 110 °C, reaction 12h.After the reaction is complete, the reaction is cooled to room temperature.Extract with ethyl acetate and water,Have an organic phase,After drying, the mixture was passed through a column of dichloromethane and methanol to give compound I. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.6% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 110℃; for 12h;Inert atmosphere; | at room temperature N, N- diisopropylethylamine (0.7mL, 2.213mmol)And 1,4-diazabicyclo[3.2.2]nonane (0.252g, 2mmol) was dissolved in 5ml DMF.A solution of 2-chloro-5-bromobenzothiazole (0.5 g, 2.012 mmol) in DMF (1 ml) was added dropwise to the mixed solution in a steady stream of nitrogen.Then warm up to 110 C,Reaction 12h; after completion of the reaction, the reaction is cooled to room temperature,Extract with ethyl acetate and water,Have an organic phase,After drying, the column was diluted with dichloromethane and methanol to give 220 mg of pale yellow oil I.Yield 32.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 90℃; Inert atmosphere; | 2-(1,4-Diaza-bicyclo[3.2.2]nonan-4-yl)-6-fluoro-9H-fluoren-9-one (8c) Representative procedure for Buchwald-Hartwig amination General procedure: A mixture of Pd2(dba)3 (9.6 mg, 10.5 µmol) and BINAP (13.1 mg, 21 µmol) in toluene (1.5 mL) was stirred for 30 min at 90° C. The red-orange solution was allowed to cool (22 °C) and added to a mixture of 1,4-diazabicyclo[3.2.2]nonane (7a, 46 mg, 0.364 mmol) and 6c (97 mg, 0.35 mmol) in toluene (2 mL). Cs2CO3 (300 mg, 0.91 mmol) was added, and the reaction mixture was stirred under an atmosphere of argon for 28 h at 90° C. After cooling to room temperature, the solid was filtered off and washed with CH2Cl2 (2x4 mL). The filtrate was evaporated (→ 143 mg) and purified by DCVC (silica gel 15-40 µm, 8 g) with a gradient from CHCl3 (100%) to CHCl3/MeOH/NH3(aq) (100:8:0.8, 100%). Fractions containing product were combined and evaporated to give 8c (89 mg, 0.275 mmol, 80% yield, Rf = 0.29, CHCl3/MeOH/NH3(aq), 100:10:1) as dark red solid residue. A portion (48 mg, 150 µmol) was dissolved in EtOH (1 mL), treated with ethanolic HCl (8.3%, 80 mg, 180 µmol) and evaporated. The solid obtained was triturated with EtOH/MTBE to give 42 mg of 8c.HCl salt as red powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 90℃; Inert atmosphere; | 2-(1,4-Diaza-bicyclo[3.2.2]nonan-4-yl)-6-fluoro-9H-fluoren-9-one (8c) Representative procedure for Buchwald-Hartwig amination General procedure: A mixture of Pd2(dba)3 (9.6 mg, 10.5 µmol) and BINAP (13.1 mg, 21 µmol) in toluene (1.5 mL) was stirred for 30 min at 90° C. The red-orange solution was allowed to cool (22 °C) and added to a mixture of 1,4-diazabicyclo[3.2.2]nonane (7a, 46 mg, 0.364 mmol) and 6c (97 mg, 0.35 mmol) in toluene (2 mL). Cs2CO3 (300 mg, 0.91 mmol) was added, and the reaction mixture was stirred under an atmosphere of argon for 28 h at 90° C. After cooling to room temperature, the solid was filtered off and washed with CH2Cl2 (2x4 mL). The filtrate was evaporated (→ 143 mg) and purified by DCVC (silica gel 15-40 µm, 8 g) with a gradient from CHCl3 (100%) to CHCl3/MeOH/NH3(aq) (100:8:0.8, 100%). Fractions containing product were combined and evaporated to give 8c (89 mg, 0.275 mmol, 80% yield, Rf = 0.29, CHCl3/MeOH/NH3(aq), 100:10:1) as dark red solid residue. A portion (48 mg, 150 µmol) was dissolved in EtOH (1 mL), treated with ethanolic HCl (8.3%, 80 mg, 180 µmol) and evaporated. The solid obtained was triturated with EtOH/MTBE to give 42 mg of 8c.HCl salt as red powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
127 mg | With caesium carbonate In toluene at 90 - 100℃; | 1-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-7-bromo-9H-fluoren-9-one (12a) A mixture of amine 7a (61 mg, 0.48 mmol), Cs2CO3 (300 mg, 0.92 mmol) and 6a (97 mg, 0.35 mmol) in toluene (4 mL) was stirred at 100 °C for 48 h. After cooling, the solid was filtered off and washed with CH2Cl2 (2x4 mL). The filtrate was evaporated and the residue (165 mg) chromatographically purified (silica gel 15-40 µm, 8 g) with a gradient from CHCl3 (100%) to CHCl3/MeOH/NH3(aq) (100:8:0.8, 100%) to afford the title compound (127 mg, Rf = 0.25, CHCl3/MeOH/NH3(aq), 100:10:1) as orange-yellow residue. It was converted into the hydrochloride salt by treatment with ethanolic HCl to give 115 mg (0.27 mmol, 78% yield) of 12a.HCl as yellow powder. Free base: 1H NMR (300 MHz, CDCl3) δH 7.68 (d, J = 1.8 Hz, 1HAr, 8-H), 7.53 (ddd, J = 7.9, 1.9, 0.8 Hz, 1HAr, 6-H), 7.34 (dd, J =7.4, 0.9 Hz, 1HAr, 5-H), 7.32 - 7.27 (m, 1HAr, 3-H), 6.93 (dt, J = 7.1, 0.9 Hz, 1HAr, 4-H), 6.86 (d, J =8.6 Hz, 1HAr, 2-H), 4.22 (td, J = 4.9, 2.3 Hz, 1Htert, 5’-H), 3.61 (t, J = 5.6 Hz, 2Hsec, 3’-H2), 3.20 - 3.14 (m, 2Hsec, 2’-H2), 3.06 (td, J = 12.8, 10.8, 6.0 Hz, 4Hsec, 7’-H2, 8’-H2), 2.25 - 2.08 (m, 2Hsec, 6’-Ha, 9’-Ha), 1.83 (ddt, J = 14.5, 10.2, 5.5 Hz, 2Hsec, 6’-Hb, 9’-Hb); 13C NMR (75 MHz, CDCl3) δC 189.54 (1C, C=O), 150.77 (1CAr, 1-C), 146.05 (1CAr, 4a-C), 141.57 (1C Ar, 5a-C), 136.83 (1CAr, 8a-C), 135.81(1CArH, 6-C or 3-C), 135.78 (1CArH, 3-C or 6-C), 126.56 (1CArH, 8-C), 122.66 (1CAr, 7-C), 121.22 (1CArH, 5-C), 119.45 (1CArH, 2-C), 118.74 (1CAr, 9a-C), 111.11 (1CArH, 4-C), 55.77 (1Csec, 2’-C), 54.13 (1Ctert, 5’-C), 49.70 (1Csec, 3’-C), 46.73 (2Csec, 7’-C, 8’-C), 27.39 (2Csec, 6’-C, 9’-C); HCl salt: LRMS m/z (ESI) 383.0, 385.0 ([79Br]M + H)+, ([81Br]M + H)+; HRMS m/z (ESI) calcd for C20H19BrN2O (M + H)+ 383.07535, found 383.07520. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87 mg | Stage #1: 7-bromo-1-fluoro-9H-fluoren-9-one; 1,4-diazabicyclo[3.2.2]nonane With caesium carbonate In toluene at 90 - 100℃; Stage #2: With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 90 - 100℃; | 1,7-Di(1,4-diazabicyclo[3.2.2]nonan-4-yl)-9H-fluoren-9-one (13) A mixture of amine 7a (95 mg, 0.75 mmol), Cs2CO3 (520 mg, 1.6 mmol) and 6a (97 mg, 0.35 mmol) in toluene (2 mL) was stirred at 100 °C. After 3 h, a toluene solution (2 mL) of a complex made from Pd2(dba)3 (6.4 mg, 7 µmol) and BINAP (8.8 mg, 14 µmol) was added, and the heating was continued for 40 h. TLC (CHCl3/MeOH/NH3(aq), 100:10:1) indicated starting material 6a was completely consumed and the desired product was observed as main spot (Rf = 0.07) along with a minor of 12a (Rf = 0.16). After cooling, the solid was filtered off and washed with CH2Cl2 (2x4 mL). The filtrate was evaporated and the residue (213 mg) chromatographically purified (silica gel 15-40 µm, 8 g) witha gradient from CHCl3 (100%) to CHCl3/MeOH/NH3(aq) (100:16:2, 100%) to afford the title compound (87 mg) as orange-red residue. It was converted into the dihydrochloride salt by treatment with ethanolic HCl to give 71 mg (0.142 mmol, 40% yield) of 13.2HCl as red powder. Free base: 1H NMR (300 MHz, CDCl3) δH 7.28 (d, J = 8.6 Hz, 1HAr, 5-H), 7.22 (dd, J = 8.5, 7.0 Hz, 1HAr, 3-H), 7.02 (d, J = 2.5 Hz, 1HAr, 8-H), 6.80 (d, J = 7.0 Hz, 1HAr, 4-H), 6.74 (dd, J = 8.3, 2.6 Hz, 1HAr, 6-H), 6.70 (d, J = 8.7 Hz, 1HAr, 2-H), 4.21 (tt, J = 5.1, 2.0 Hz, 1Htert, 5‘‘-H), 4.06 (tt, J = 4.5, 2.3 Hz, 1Htert, 5‘-H), 3.56 (dt, J = 8.9, 5.3 Hz, 4Hsec, 3‘‘-H2, 3‘-H2), 3.19 (dd, J = 6.6, 4.7 Hz, 2‘‘-H2), 3.15 - 2.87 (m, 10Hsec, 2‘-H2, 7‘‘-H2, 8‘‘-H2, 7‘-H2, 8‘-H2), 2.26 - 2.02 (m, 4Hsec, 6‘‘-Ha, 9‘‘-Ha, 6‘-Ha, 9‘-Ha), 1.82 (ddd, J = 15.0, 9.4, 5.3 Hz, 2Hsec, 6‘‘-Hb, 9‘‘-Hb), 1.70 (ddd, J = 14.4, 9.8, 4.9 Hz, 2Hsec, 6‘-Hb, 9‘-Hb); 13C NMR (75 MHz, CDCl3) δC 192.27 (1C, C=O), 150.78 (1CAr, 1-C), 150.43 (1CAr, 1-C), 148.27(1CAr, 4a-C), 136.74 (1CAr, 5a-C), 135.78 (1CArH, 3-C), 130.96 (1CAr, 8a-C), 120.87 (1CArH, 5-C), 119.78 (1CAr, 9a-C), 117.41 (1CArH, 2-C), 116.72 (1CArH, 6-C), 110.19 (1CArH, 4-C), 108.53 (1C ArH, 8-C), 57.18 (1Csec, 2’-C), 55.75 (1Csec, 2’’-C), 54.31 (1Ctert, 5’’-C), 52.00 (1Ctert, 5’-C), 49.26 (1Csec, 3’’-C), 46.84 and 46.69 (4Csec, 7’-C, 8’-C, 7’’-C, 8’’-C), 44.73 (1Csec, 3’-C), 27.37 and 27.01 (4Csec, 6’-C, 9’-C, 6’’-C, 9’’-C); 2HCl salt: LRMS m/z (ESI+) 429.0 (M + H)+; HRMS m/z (ESI) calcd forC27H32N4O (M + H)+ 429.26489, found 429.26483. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 90℃; Inert atmosphere; | 2-(1,4-Diaza-bicyclo[3.2.2]nonan-4-yl)-6-fluoro-9H-fluoren-9-one (8c) Representative procedure for Buchwald-Hartwig amination General procedure: A mixture of Pd2(dba)3 (9.6 mg, 10.5 µmol) and BINAP (13.1 mg, 21 µmol) in toluene (1.5 mL) was stirred for 30 min at 90° C. The red-orange solution was allowed to cool (22 °C) and added to a mixture of 1,4-diazabicyclo[3.2.2]nonane (7a, 46 mg, 0.364 mmol) and 6c (97 mg, 0.35 mmol) in toluene (2 mL). Cs2CO3 (300 mg, 0.91 mmol) was added, and the reaction mixture was stirred under an atmosphere of argon for 28 h at 90° C. After cooling to room temperature, the solid was filtered off and washed with CH2Cl2 (2x4 mL). The filtrate was evaporated (→ 143 mg) and purified by DCVC (silica gel 15-40 µm, 8 g) with a gradient from CHCl3 (100%) to CHCl3/MeOH/NH3(aq) (100:8:0.8, 100%). Fractions containing product were combined and evaporated to give 8c (89 mg, 0.275 mmol, 80% yield, Rf = 0.29, CHCl3/MeOH/NH3(aq), 100:10:1) as dark red solid residue. A portion (48 mg, 150 µmol) was dissolved in EtOH (1 mL), treated with ethanolic HCl (8.3%, 80 mg, 180 µmol) and evaporated. The solid obtained was triturated with EtOH/MTBE to give 42 mg of 8c.HCl salt as red powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 90℃; Inert atmosphere; | 2-(1,4-Diaza-bicyclo[3.2.2]nonan-4-yl)-6-fluoro-9H-fluoren-9-one (8c) Representative procedure for Buchwald-Hartwig amination A mixture of Pd2(dba)3 (9.6 mg, 10.5 µmol) and BINAP (13.1 mg, 21 µmol) in toluene (1.5 mL) was stirred for 30 min at 90° C. The red-orange solution was allowed to cool (22 °C) and added to a mixture of 1,4-diazabicyclo[3.2.2]nonane (7a, 46 mg, 0.364 mmol) and 6c (97 mg, 0.35 mmol) in toluene (2 mL). Cs2CO3 (300 mg, 0.91 mmol) was added, and the reaction mixture was stirred under an atmosphere of argon for 28 h at 90° C. After cooling to room temperature, the solid was filtered off and washed with CH2Cl2 (2x4 mL). The filtrate was evaporated (→ 143 mg) and purified by DCVC (silica gel 15-40 µm, 8 g) with a gradient from CHCl3 (100%) to CHCl3/MeOH/NH3(aq) (100:8:0.8, 100%). Fractions containing product were combined and evaporated to give 8c (89 mg, 0.275 mmol, 80% yield, Rf = 0.29, CHCl3/MeOH/NH3(aq), 100:10:1) as dark red solid residue. A portion (48 mg, 150 µmol) was dissolved in EtOH (1 mL), treated with ethanolic HCl (8.3%, 80 mg, 180 µmol) and evaporated. The solid obtained was triturated with EtOH/MTBE to give 42 mg of 8c.HCl salt as red powder. Free base: 1H NMR (300 MHz, CDCl3) δH 7.52 (dd, J = 8.1, 5.3 Hz, 1HAr, 8-H), 7.26 (d, J =8.3 Hz, 1HAr, 4-H), 7.07 (d, J = 2.6 Hz, 1HAr, 1-H), 6.97 (dd, J = 8.7, 2.2 Hz, 1HAr, 5-H), 6.79 - 6.70 (m, 2HAr, 3-H, 7-H), 4.07 (tt, J = 4.5, 2.3 Hz, 1Htert, 5’-H), 3.57 (dd, J = 6.4, 4.9 Hz, 2Hsec, 3’-H2), 3.18- 3.05 (m, 4Hsec, 7’-Ha, 8’-Ha, 2’-H2), 2.99 (dddd, J = 15.0, 9.7, 5.3, 2.2 Hz, 2Hsec, 7’-Hb, 8’-Hb), 2.18- 1.98 (m, 2Hsec, 6’-Ha, 9’-Ha), 1.74 (ddt, J = 14.3, 9.8, 4.7 Hz, 2Hsec, 6’-Hb, 9’-Hb); 13C NMR (75MHz, CDCl3) δC 193.26 (1C, C=O), 167.65 (d, J = 254.5 Hz, 1CAr, 6-C), 150.72 (1CAr, 2-C), 149.13 (d, J = 10.5 Hz, 1CAr, 5a-C), 136.66 (1CAr, 9a-C), 130.35 (d, J = 2.8 Hz, 1CAr, 8a-C), 130.27 (d, J =2.3 Hz, 1CAr, 4a-C), 126.32 (d, J = 10.4 Hz, 1CArH, 8-C), 121.85 (1CArH, 4-C), 117.21 (1CArH, 3-C), 113.17 (d, J = 23.6 Hz, 1CArH, 7-C), 109.27 (1CArH, 1-C), 107.10 (d, J = 24.3 Hz, 1CArH, 5-C), 57.16 (1Csec, 2’-C), 51.76 (1C tert, 5’-C), 46.62 (2Csec, 7’-C, 8’-C), 44.67 (1Csec, 3’-C), 26.93 (2Csec, 6’-C, 9’-C); 19F NMR (282 MHz, CDCl3) δF -103.22 (td, J = 8.8, 5.1 Hz, 1FAr); HCl salt: HRMS m/z (ESI)calcd for C20H19FN2O (M + H)+ 323.15542, found 323.15525. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53 mg | With caesium carbonate; In toluene; at 90 - 100℃; | A mixture of amine 7a (58 mg, 0.46 mmol), Cs2CO3 (350 mg, 1.06 mmol) and 6d (80 mg, 0.4 mmol) in toluene (4 mL) was stirred at 100 C for 24 h. During this time the color changed from yellow to orange. A further portion 7a (10 mg, 0.08 mmol) was added and heating was continued for 16 h. After cooling, the solid was filtered off and washed with CH2Cl2 (2x4 mL). The filtrate was evaporated and the residue (240 mg) chromatographically purified (silica gel 15-40 mum, 10.5 g) with a gradient from CHCl3 (100%) to CHCl3/MeOH/NH3(aq) (100:8:0.8, 100%) to afford the title compound (53 mg, Rf = 0.20, CHCl3/MeOH/NH3(aq), 100:10:1) as orange-yellow viscous residue. It was converted into the hydrochloride salt by treatment with ethanolic HCl to give in 51 mg (0.15 mmol, 38% yield) of 12.HCl as yellow powder. Free base: 1H NMR (300 MHz, CDCl3) deltaH 7.58 (dt, J = 7.3, 1.0 Hz, 1HAr, 8-H), 7.48 (ddd, J = 7.4, 1.2, 0.8 Hz, 1HAr, 5-H), 7.42 (td, J = 7.4, 1.2 Hz, 1HAr, 6-H), 7.34 - 7.27 (m, 1HAr, 3-H), 7.29 - 7.22 (m, 1HAr, 7-H), 6.98 (dd, J = 7.0, 0.8 Hz, 1HAr, 4-H), 6.85 (dd, J = 8.6, 0.8 Hz,1HAr, 2-H), 4.24 (tt, J = 5.0, 2.1 Hz, 1Htert, 5?-H), 3.62 (dd, J = 6.5, 4.8 Hz, 2Hsec, 3?-H2), 3.22 - 3.16 (m, 2Hsec, 2?-H2), 3.15 - 2.92 (m, 4H sec, 7?-H2, 8?-H2), 2.27 - 2.09 (m, 2Hsec, 6?-Ha, 9?-Ha), 1.83 (ddt, J= 14.5, 9.5, 5.3 Hz, 2Hsec, 6?-Hb, 9?-Hb); 13C NMR (75 MHz, CDCl3) deltaC 191.37 (1C, C=O), 150.69 (1CAr, 1-C), 146.97 (1CAr, 4a-C), 143.05 (1CAr, 5a-C), 135.56 (1CArH, 3-C), 135.07 (1CAr, 5a-C), 133.41 (1CArH, 6-C), 128.92 (1CArH, 7-C), 123.33 (1CArH, 8-C), 119.76 (1CArH, 5-C), 119.50 (1CAr, 9a-C), 119.28 (1CArH, 2-C), 111.20 (1CArH, 4-C), 55.79 (1Csec, 2?-C), 54.23 (1Ctert, 5?-C), 49.52 (1Csec, 3?-C), 46.80 (2Csec, 7?-C, 8?-C), 27.39 (2Csec, 6?-C, 9?-C); HCl salt: HRMS m/z (ESI) calcd for C20H20N2O (M + H)+ 305.16484, found 305.16473. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 90℃; Inert atmosphere; | 2-(1,4-Diaza-bicyclo[3.2.2]nonan-4-yl)-6-fluoro-9H-fluoren-9-one (8c) Representative procedure for Buchwald-Hartwig amination General procedure: A mixture of Pd2(dba)3 (9.6 mg, 10.5 µmol) and BINAP (13.1 mg, 21 µmol) in toluene (1.5 mL) was stirred for 30 min at 90° C. The red-orange solution was allowed to cool (22 °C) and added to a mixture of 1,4-diazabicyclo[3.2.2]nonane (7a, 46 mg, 0.364 mmol) and 6c (97 mg, 0.35 mmol) in toluene (2 mL). Cs2CO3 (300 mg, 0.91 mmol) was added, and the reaction mixture was stirred under an atmosphere of argon for 28 h at 90° C. After cooling to room temperature, the solid was filtered off and washed with CH2Cl2 (2x4 mL). The filtrate was evaporated (→ 143 mg) and purified by DCVC (silica gel 15-40 µm, 8 g) with a gradient from CHCl3 (100%) to CHCl3/MeOH/NH3(aq) (100:8:0.8, 100%). Fractions containing product were combined and evaporated to give 8c (89 mg, 0.275 mmol, 80% yield, Rf = 0.29, CHCl3/MeOH/NH3(aq), 100:10:1) as dark red solid residue. A portion (48 mg, 150 µmol) was dissolved in EtOH (1 mL), treated with ethanolic HCl (8.3%, 80 mg, 180 µmol) and evaporated. The solid obtained was triturated with EtOH/MTBE to give 42 mg of 8c.HCl salt as red powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | Stage #1: 5-chloro-6,7-bis((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 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 at 30℃; for 0.5h; Stage #2: 1,4-diazabicyclo[3.2.2]nonane In N,N-dimethyl-formamide at 20℃; for 1h; | 160.1 Compound 160a: 3-(1, 4-diazabicyclo[3.2. 2]nonane-4-carbonyl)-5-chloro-6,7-bis((4-methoxybenzyl)oxy)-1-methylquinolin-4(1H) -one HATU (2.80 g, 7.35 mmol) and DIPEA (3.43 mL, 19.6 mmol) were added to a solution of compound 149 j (2.5 g, 4.9 mmol) in DMF (50 mL) and the resulting mixture was treated with And the mixture was stirred at room temperature for 30 minutes. Next, 1,4-diazabicyclo [3.2.2] nonane (0.804 g, 6.37 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. Water and EtOAc were added to the mixture. The organic phase was separated and the aqueous phase was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by automated silica gel chromatography (0 to 10% solvent B in solvent A; solvent A = DCM, solvent B = 10: 90: 1 MeOH: DCM: NH 4 OH, 24 g column). The recovered brown solid was dissolved in DCM, washed with water, and then the organic layer was concentrated. The residue was further purified by automated silica gel chromatography (0 to 10% MeOH in DCM, 4 g column) to afford compound 160a (1.17 g, 39% yield) as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: 6,7-bis((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 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 for 0.5h; Stage #2: 1,4-diazabicyclo[3.2.2]nonane In N,N-dimethyl-formamide for 1h; | 159.3 Compound 159c: 3- (1, 4-diazabicyclo [3.2. 2]Nonane-4-carbonyl) -6,7-bis((4-methoxybenzyl) oxy) -1-methylquinolin-4 (1 H) -one To a solution of compound 159b (3.0 g, 5.5 mmol) in DMF (30 mL) was added HATU (3.13 g, 8.23 mmol) and DIPEA (2.88 mL, 16.5 mmol). The mixture was stirred for 0.5 h and 1,4-diazabicyclo [3.2.2] nonane (1.16 mL, 8.23 mmol) was added. The reaction mixture was stirred for 1 hour. Water was added and the product was extracted with DCM and washed with sodium bicarbonate. The crude material was purified by automated silica gel chromatography using a 24 g column and eluting with 0 to 20% MeOH in DCM to afford compound 159c (1.8 g, 56% yield) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: 6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydroquinoline-3-carboxylic acid 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 at 20℃; for 0.5h; Stage #2: 1,4-diazabicyclo[3.2.2]nonane In N,N-dimethyl-formamide at 20℃; for 1h; | 174.5 Compound 174e: 3-(1,4-diazabicyclo[3.2.2]nonane-4-carbonyl) -6,7-bis((4-methoxybenzyl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl) quinolin-4 (1 H) -one To a solution of compound 174d (24.0 g, 40.6 mmol) in DMF (250 mL) was added HATU (18.5 g, 48.7 mmol) and DIPEA (28.3 mL, 162 mmol) and the resulting mixture was stirred at room temperature And the mixture was stirred for 30 minutes. Next, 1,4-diazabicyclo [3.2.2] nonane (5.63 g, 44.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. Water and EtOAc were added and the aqueous phase was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by normal phase chromatography (24 g column, 0 to 10% solvent B in solvent A; solvent A = DCM, solvent B = 10: 90: 1 MeOH: DCM: NH 4 OH). The isolated solid was dissolved in DCM, washed with water, and then the organic layer was concentrated. The residue was eluted from a small silica gel column (4 g, 0-10% MeOH / DCM) to give compound 174e (16.4 g, 58% yield) as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.3% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 80℃; for 14h; Inert atmosphere; | 15.1 Step (1) Synthesis of Compound 3-27 Intermediate compound 3-26 (413.3 mg, 1.0 mmol), 1,4-diazabicyclo[3.2.2]nonane (146.4 mg, 1.2 mmol) and cesium carbonate (651.6 mg, 2.0 mmol) were dissolved in 30 mL Re-steamed anhydrous toluene, ready to use; under argon, Pd2(dba)3(45.8 mg, 0.05 mmol) and (±)-BINAP (61 mg, 0.099 mmol) were dissolved in 10 mL of re-steamed In water toluene, after stirring at 90 ° C for 15 min (the reaction mixture changed from dark purple turbid liquid to orange yellow clear liquid), cooled to room temperature; then the above solution was added to the reaction system, argon gas protection, at 80 ° C After stirring for 14 h (the reaction mixture was changed from an orange-yellow clarified liquid to a brown-brown liquid), cooled to room temperature, quenched with 10 mL of water, and extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate the solvent was removed by rotary evaporation, purified by silica gel column chromatography (CH was2CI2: CH. 3OH = 20 is:. 1), the red solid to obtain 3-27 (300.1mg, 65.3%). |
65.3% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 85℃; for 24h; Inert atmosphere; | 1.1.1 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-1-(3,3-dibutyltriaz-1-en-1-yl)-9H-fluoren-9-one (9) Tris(dibenzylideneacetone)dipalladium (Pd2(dba)3; 45.79 mg, 0.05 mmol, 5% eq (BINAP; 62.3 mg, 0.10 mmol, 10% eq), and Cs2CO3 (651.6 mg, 2.0 mmol) were added to a solution of 1,4-diazabicyclo[3.2.2]nonane (146.4 mg, 1.2 mmol) and 7-bromo-1-(3,3-dibutyltriaz-1-en-1-yl)-9H-fluoren-9-one (8) (413.1 mg, 1.0 mmol) in anhydrous toluene (50 mL). The mixture was flushed with nitrogen and heated to 85 °C for 24 h. After cooling to room temperature, the mixture was concentrated under vacuum and purified by chromatography on silica gel (DCM/MeOH/Et3N = 30/1/0.1). The desired red fractions containing product were combined and evaporated to remove solvents and yield 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-1-(3,3-dibutyltriaz-1-en-1-yl)-9H-fluoren-9-one (9) as a red solid (300.1 mg, 65.3%). 1H NMR (CDCl3, 600M) δ 7.29 (t, J = 6.0 Hz, 1H), 7.28-7.25 (m, 1H), 7.14 (dd, J = 12.0, 6.0 Hz, 1H), 7.07-7.05 (m, 2H), 6.75 (dd, J = 12.0, 6.0 Hz, 1H), 4.07-4.05 (m, 1H), 3.79 (dt, J = 30.0, 6.0 Hz, 4H), 3.55 (t, J = 6.0 Hz, 2H), 3.12-3.07 (m, 4H), 3.01-2.95 (m, 2H), 2.12-2.07 (m, 2H), 1.82-1.77 (m, 2H), 1.74-1.68 (m, 4H), 1.46-1.35 (m, 4H), 0.97 (t, J = 6.0 Hz, 6H). 13C NMR (150 MHz, CDCl3) δ 150.36, 150.10, 146.61, 136.75, 134.98, 131.83, 125.11, 120.99, 117.02, 115.06, 108.90, 77.29, 77.08, 76.87, 57.14, 51.94, 46.64, 44.71. MS (ESI+): m/z calcd for C28H37N5O, 459.30; found, 460.2950 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.8% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 60℃; for 14h; Inert atmosphere; | 13.1 Step (1) Synthesis of Intermediate Compound 4-2 Compound 4-1 (100 mg, 0.296 mmol), 1,4-diazabicyclo[3.2.2]nonane (46.9 mg, 0.384 mmol) and cesium carbonate (426 mg, 1.31 mmol) were dissolved in 2 mL. Water toluene, ready to use; under argon, Pd2(dba)3(30 mg, 0.033 mmol) and (±)-BINAP (61 mg, 0.099 mmol) were dissolved in 2 mL of re-steamed anhydrous toluene, 90 After stirring for 15 min at ° C (the reaction mixture changed from dark purple turbid liquid to orange yellow clear liquid), cooled to room temperature; then the above solution was added to the reaction system, argon-protected, and stirred at 60 ° C for 14 h (reaction) The mixture was changed from an orange-yellow clarified liquid to a brown-brown liquid. The mixture was cooled to room temperature. The mixture was evaporated to dryness. purification by silica gel column chromatography (CH2CI2: CH. 3OH = 20 is:. 1), the purple solid was obtained 4-2 (37mg, 36.8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium carbonate In dimethyl sulfoxide at 100℃; | |
52% | With potassium carbonate In dimethyl sulfoxide at 100℃; | 1.1 Step 1 : Synthesis of 30b: General procedure: (Ref: WO 2015038417): To a stirred mixture of compound 30a (2.0 g, 16.9 mmol) in DMF (50 ml.) at room temperature were added 26b (3.0 g, 18.9 mmol) and K2CO3 (13.1 g, 94.5 mmol). The resulting mixture was stirred at 1 10 °C for 16 h. After cooling down to room temperature, the reaction mixture was diluted with water (200 ml.) and extracted with EtOAc (3 x 150 ml_). The organic layer was washed with brine solution (50 ml_), dried (Na2SC>4), and concentrated to provide crude residue. The crude was triturated with n-hexane and filtered to give compound 30b as a yellow solid (3.8 g, 80% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,4-dioxane for 120h; Inert atmosphere; Reflux; | 4-(3-Nitrophenyl)-1,4-diazabicyclo[3.2.2]nonane (23b) A suspension of 1-bromo-3-nitrobenzene (8.7 g; 43.0 mmol), Pd2dba3 (1.0 g; 1.1 mmol), (+/-)-BINAP (1.4 g; 2.2 mmol) and Cs2CO3 (9.8 g; 30.0 mmol) in 75 mL anhydrous and deoxygenated 1,4-dioxane had 29 1,4-diazabicyclo[3.2.2]nonane (3.8 g; 30.0 mmol) added. The mixture was refluxed for 5 days under nitrogen. After completion of the reaction, the mixture was filtered through Celite, absorbed onto silica, and purified by flash column chromatography (95:5 DCM:MeOH " 4:1 DCM:MeOH) to give the titled compound as a dark brown oil (3.1 g; 42%). Rf (9:1 DCM:MeOH): 0.16. νmax (Thin film, cm-1): 626.7, 672.3, 699.6, 734.5, 752.5, 783.6, 822.6, 846.1, 867.8, 916.4, 952.7, 977.4, 996.2, 1039.9, 1078.6, 1105.9, 1135.9, 1173.8, 1245.0, 1265.7, 1345.9, 1394.4, 1451.0, 1489.5, 1524.6, 1615.1, 2862.9, 2943.6. 1H-NMR (400 MHz, CDCl3): δ 1.63-1.87 (2H, m), 2.00-2.18 (2H, m), 2.91-3.06 (2H, m), 3.08-3.12 (2H, m), 3.12-3.20 (2H, m), 3.58 (2H, t, J = 5.8 Hz), 4.02-4.12 (1H, m), 7.01 (1H, dd, J = 8.3 & 2.5 Hz), 7.31 (1H, t, J = 8.2 Hz), 7.48 (1H, ddd, J = 8.0, 2.1 & 0.8 Hz), 7.55 (1H, t, J = 2.4 Hz). 13C-NMR (100 MHz, CDCl3): δ 26.6, 44.3, 46.4, 51.6, 56.9, 107.1, 110.8, 118.5, 129.7, 149.5, 149.7. MS: m/z 248.4 [M+H]+ (100%), 289.2 [M+ACN+H]+ (45%). HRMS (ESI+): m/z [M+ACN+H]+calcd for C17H24N5O2 289.1659, found 289.1689. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: oleanolic acid 3-acetate With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 25℃; Heating; Stage #2: 1,4-diazabicyclo[3.2.2]nonane With dmap; triethylamine In dichloromethane at 0 - 23℃; for 24h; | 4.4. General Procedure for the Synthesis of Amides 9-31 (GPB) General procedure: To the solution of the acetylated triterpenoic acid (1-4, 1 eq.) in dry DCM, a drop of dryDMF and oxalyl chloride (4 eq.) were added at 0 C. Stirring at 25 C was continued untilthe evolution of gases had ceased. The volatiles were removed under reduced pressure.The corresponding amine (3 eq.) was dissolved in dry DCM (20 mL), and a solution of TEA (4.2 eq.), DMAP (cat.) in dry DCM (10 mL) was added. To this mixture, the reactionmixture (dissolved in dry DCM) from above was slowly added at 0 C, and stirring at23 C was continued for 1 day. The usual aqueous workup followed by liquid columnchromatography (CHCl3/MeOH) gave the products 9-31, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-O-acetylbetulinic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 25℃; Heating; Stage #2: 1,4-diazabicyclo[3.2.2]nonane With dmap; triethylamine In dichloromethane at 0 - 23℃; for 24h; | 4.4. General Procedure for the Synthesis of Amides 9-31 (GPB) General procedure: To the solution of the acetylated triterpenoic acid (1-4, 1 eq.) in dry DCM, a drop of dryDMF and oxalyl chloride (4 eq.) were added at 0 C. Stirring at 25 C was continued untilthe evolution of gases had ceased. The volatiles were removed under reduced pressure.The corresponding amine (3 eq.) was dissolved in dry DCM (20 mL), and a solution of TEA (4.2 eq.), DMAP (cat.) in dry DCM (10 mL) was added. To this mixture, the reactionmixture (dissolved in dry DCM) from above was slowly added at 0 C, and stirring at23 C was continued for 1 day. The usual aqueous workup followed by liquid columnchromatography (CHCl3/MeOH) gave the products 9-31, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (3β)-3-acetyloxy-20-oxo-30-norlupan-28-oic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 25℃; Heating; Stage #2: 1,4-diazabicyclo[3.2.2]nonane With dmap; triethylamine In dichloromethane at 0 - 23℃; for 24h; | 4.4. General Procedure for the Synthesis of Amides 9-31 (GPB) General procedure: To the solution of the acetylated triterpenoic acid (1-4, 1 eq.) in dry DCM, a drop of dryDMF and oxalyl chloride (4 eq.) were added at 0 C. Stirring at 25 C was continued untilthe evolution of gases had ceased. The volatiles were removed under reduced pressure.The corresponding amine (3 eq.) was dissolved in dry DCM (20 mL), and a solution of TEA (4.2 eq.), DMAP (cat.) in dry DCM (10 mL) was added. To this mixture, the reactionmixture (dissolved in dry DCM) from above was slowly added at 0 C, and stirring at23 C was continued for 1 day. The usual aqueous workup followed by liquid columnchromatography (CHCl3/MeOH) gave the products 9-31, respectively. |
Tags: 283-38-5 synthesis path| 283-38-5 SDS| 283-38-5 COA| 283-38-5 purity| 283-38-5 application| 283-38-5 NMR| 283-38-5 COA| 283-38-5 structure
[ 913812-09-6 ]
(R)-1-(Pyrrolidin-3-yl)piperidine
Similarity: 0.92
[ 436099-90-0 ]
1-Methyl-4-(piperidin-4-yl)piperazine hydrochloride
Similarity: 0.92
[ 1217074-64-0 ]
1-(Piperidin-4-yl)piperazine trihydrochloride
Similarity: 0.92
[ 73579-08-5 ]
1-Methyl-4-(methylamino)piperidine
Similarity: 0.91
[ 76272-56-5 ]
endo-3-Amine-9-methyl-9-azabicyclo[3,3,1]nonane
Similarity: 0.91
[ 4430-75-5 ]
Octahydro-2H-pyrido[1,2-a]pyrazine
Similarity: 0.88
[ 135906-03-5 ]
Endo-9-Methyl-9-azabicyclo[3.3.1]nonan-3-amine dihydrochloride
Similarity: 0.88
[ 87571-88-8 ]
endo-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine
Similarity: 0.88
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 :