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CAS No. : | 1610028-42-6 | MDL No. : | MFCD26406720 |
Formula : | C8H18Cl2N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DTWZADKIVZIVQR-UHFFFAOYSA-N |
M.W : | 213.15 | Pubchem ID : | 71743011 |
Synonyms : |
|
Num. heavy atoms : | 12 |
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 : | 63.54 |
TPSA : | 15.27 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.32 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.81 |
Log Po/w (WLOGP) : | 1.14 |
Log Po/w (MLOGP) : | 1.52 |
Log Po/w (SILICOS-IT) : | 1.28 |
Consensus Log Po/w : | 1.15 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.3 |
Solubility : | 1.06 mg/ml ; 0.00499 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.75 |
Solubility : | 3.79 mg/ml ; 0.0178 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.56 |
Solubility : | 5.92 mg/ml ; 0.0278 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.72 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.6% | With N-ethyl-N,N-diisopropylamine In dichloromethane; dimethyl sulfoxide at 5 - 20℃; for 4.5h; | 114 Example _ 114: 4-[6-(5-chloro-2-fluorophenyl)pyridazin-4- yl]amino}quinolin-7-yl 2-methyl-2,7-diazaspiro[3.5]nonane-7-carboxylate 2-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride (Intermediate 210, 75 mg, 0.35 mmol) was added to a stirred mixture of DIPEA (0.33 mL, 1.88 mmol) and 4-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-ol hydrobromide (Intermediate 101, 105 mg, 0.23 mmol) in DCM (6.79 mL) and DMSO (0.68 mL) at RT. After 5 minutes the mixture was cooled at 5 °C and 4-nitrophenyl carbonochloridate (71 mg, 0.35 mmol) was added. After 30 minutes the reaction was warmed at RT. After 4 hrs the mixture was diluted with DCM, washed with water and NaHCO3 aqueous solution. Organic layer was separated, dried overNa2S04 and evaporated. The residue was purified by flash chromatography on Biotage silica NH cartridge (from DCM to 3% MeOH/0.3% H2O). Proper fractions were collected and further purified by HPLC preparative to afford 4-[6-(5-chloro-2- fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 2-methyl-2,7- diazaspiro[3.5]nonane-7-carboxylate (7 mg, 0.013 mmol, 5.6% yield) as a yellow solid. (1477) LC-MS (ESI): mlz (M+1): 533.2 (Method 2) 1H NMR (500 MHz, Chloroform-d) δ ppm 9.08 (d, J= 2.6 Hz, 1 H), 8.65 (d, J=4.8 Hz, 1 H), 8.19 (dd, J=6.7, 2.7 Hz, 1 H), 7.77 (d, J=9.2 Hz, 1 H), 7.70 (d, J=1.8 Hz, 1 H), 7.65 (s, 1 H), 7.47 (br. s, 1 H), 7.39 - 7.44 (m, 1 H), 7.22 - 7.26 (m, 2 H), 7.13 (dd, J=10.5, 8.9 Hz, 1 H), 3.54 - 3.79 (m, 4 H), 3.06 - 3.34 (m, 4H), 2.43 (s, 3 H), 1.84 - 1.99 (m, 4 H). |
5.6% | With N-ethyl-N,N-diisopropylamine In dichloromethane; dimethyl sulfoxide at 5 - 20℃; for 4.5h; | 114 Example _ 114: 4-[6-(5-chloro-2-fluorophenyl)pyridazin-4- yl]amino}quinolin-7-yl 2-methyl-2,7-diazaspiro[3.5]nonane-7-carboxylate 2-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride (Intermediate 210, 75 mg, 0.35 mmol) was added to a stirred mixture of DIPEA (0.33 mL, 1.88 mmol) and 4-[6-(5-chloro-2-fluorophenyl)pyridazin-4-yl]amino}quinolin-7-ol hydrobromide (Intermediate 101, 105 mg, 0.23 mmol) in DCM (6.79 mL) and DMSO (0.68 mL) at RT. After 5 minutes the mixture was cooled at 5 °C and 4-nitrophenyl carbonochloridate (71 mg, 0.35 mmol) was added. After 30 minutes the reaction was warmed at RT. After 4 hrs the mixture was diluted with DCM, washed with water and NaHCO3 aqueous solution. Organic layer was separated, dried overNa2S04 and evaporated. The residue was purified by flash chromatography on Biotage silica NH cartridge (from DCM to 3% MeOH/0.3% H2O). Proper fractions were collected and further purified by HPLC preparative to afford 4-[6-(5-chloro-2- fluorophenyl)pyridazin-4-yl]amino}quinolin-7-yl 2-methyl-2,7- diazaspiro[3.5]nonane-7-carboxylate (7 mg, 0.013 mmol, 5.6% yield) as a yellow solid. (1477) LC-MS (ESI): mlz (M+1): 533.2 (Method 2) 1H NMR (500 MHz, Chloroform-d) δ ppm 9.08 (d, J= 2.6 Hz, 1 H), 8.65 (d, J=4.8 Hz, 1 H), 8.19 (dd, J=6.7, 2.7 Hz, 1 H), 7.77 (d, J=9.2 Hz, 1 H), 7.70 (d, J=1.8 Hz, 1 H), 7.65 (s, 1 H), 7.47 (br. s, 1 H), 7.39 - 7.44 (m, 1 H), 7.22 - 7.26 (m, 2 H), 7.13 (dd, J=10.5, 8.9 Hz, 1 H), 3.54 - 3.79 (m, 4 H), 3.06 - 3.34 (m, 4H), 2.43 (s, 3 H), 1.84 - 1.99 (m, 4 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With anhydrous sodium carbonate In dimethyl sulfoxide at 100℃; for 2.5h; | Intermediate _ 154: N-(4-bromopyridin-2-yl)-2-methyl-2,7- diazaspiro[3.5]nonane-7-carboxamide A mixture of N-(4-bromopyridin-2-yl)-2,2,2-trichloroacetamide (Intermediate 153, 200 mg, 0.63 mmol), commercially available 2-methyl-2,7- diazaspiro[3.5]nonane dihydrochloride (147 mg, 0.69 mmol) in DMSO (4.2 mL), and Na2CO3 (233 mg, 2.2 mmol) was stirred at 100 °C for 2.5 hrs. The mixture was treated with saturated NaHCO3 solution and extracted with DCM. The organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on Biotage silica NH (from DCM to 5% MeOH) to afford N-(4-bromopyridin-2-yl)-2-methyl-2,7- diazaspiro[3.5]nonane-7-carboxamide (90 mg, 0.265 mmol, 42% yield) as a colourless oil. (0686) LC-MS (ESI): mlz (M+1): 341.1 (Method 2) |
42% | With anhydrous sodium carbonate In dimethyl sulfoxide at 100℃; for 2.5h; | Intermediate _ 154: N-(4-bromopyridin-2-yl)-2-methyl-2,7- diazaspiro[3.5]nonane-7-carboxamide A mixture of N-(4-bromopyridin-2-yl)-2,2,2-trichloroacetamide (Intermediate 153, 200 mg, 0.63 mmol), commercially available 2-methyl-2,7- diazaspiro[3.5]nonane dihydrochloride (147 mg, 0.69 mmol) in DMSO (4.2 mL), and Na2CO3 (233 mg, 2.2 mmol) was stirred at 100 °C for 2.5 hrs. The mixture was treated with saturated NaHCO3 solution and extracted with DCM. The organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on Biotage silica NH (from DCM to 5% MeOH) to afford N-(4-bromopyridin-2-yl)-2-methyl-2,7- diazaspiro[3.5]nonane-7-carboxamide (90 mg, 0.265 mmol, 42% yield) as a colourless oil. (0686) LC-MS (ESI): mlz (M+1): 341.1 (Method 2) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere; | Intermediate _ 176: tert- butyl 4-[(4-bromopyridin-2- yl)carbamoyl]methyl}piperazine-l-carboxylate General procedure: A mixture of N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 159, (0738) 150 mg, 0.60 mmol), 1-piperazinecarboxylic acid tert- butyl ester (224 mg, 1.2 mmol) and K2CO3 (249 mg, 1.8 mmol) in dry DMF (6 mL) was stirred under nitrogen at RT for 18 hrs. Water and EtOAc were added, the organic phase was separated and the aqueous phase was extracted with EtOAc The combined organic layers were washed several times with brine, dried over Na2S04 and filtered. The solvent was evaporated, the crude material was purified by flash chromatography on Biotage silica NH cartridge (from cHex to 45% EtOAc) to afford tert-butyl 4-[(4- bromopyridin-2-yl)carbamoyl]methyl (piperazine- 1-carboxylate (150 mg, 0.38 mmol, y= 62%) as a white sticky solid. LC-MS (ESI): mlz (M+1): 399.2 (Method 1) |
57% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere; | Intermediate _ 176: tert- butyl 4-[(4-bromopyridin-2- yl)carbamoyl]methyl}piperazine-l-carboxylate General procedure: A mixture of N-(4-bromopyridin-2-yl)-2-chloroacetamide (Intermediate 159, (0738) 150 mg, 0.60 mmol), 1-piperazinecarboxylic acid tert- butyl ester (224 mg, 1.2 mmol) and K2CO3 (249 mg, 1.8 mmol) in dry DMF (6 mL) was stirred under nitrogen at RT for 18 hrs. Water and EtOAc were added, the organic phase was separated and the aqueous phase was extracted with EtOAc The combined organic layers were washed several times with brine, dried over Na2S04 and filtered. The solvent was evaporated, the crude material was purified by flash chromatography on Biotage silica NH cartridge (from cHex to 45% EtOAc) to afford tert-butyl 4-[(4- bromopyridin-2-yl)carbamoyl]methyl (piperazine- 1-carboxylate (150 mg, 0.38 mmol, y= 62%) as a white sticky solid. LC-MS (ESI): mlz (M+1): 399.2 (Method 1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With hydrogenchloride In 1,4-dioxane; methanol at 20℃; for 2h; | Intermediate 173: methyl 1-methylpiperazine-2-carboxylate hydrochloride General procedure: A solution of l-tert-butyl 3-methyl 4-methylpiperazine-l,3-dicarboxylate (Intermediate 172 (124 mg, 0.48 mmol) in HC1 solution, 4 M in dioxane (1.2 mL, 4.8 mmol) and MeOH (1.2 mL) was stirred at RT for 2 hrs. Volatiles were removed under vacuum, to afford methyl 1-methylpiperazine-2-carboxylate hydrochloride (Intermediate 173, 160 mg, 0.82 mmol, recovery assumed quantitative) that was used in the next step without further purification. (0732) LC-MS (ESI): mlz (M+1): 159.1 (Method 2) |
94% | With hydrogenchloride In 1,4-dioxane; methanol at 20℃; for 2h; | Intermediate 173: methyl 1-methylpiperazine-2-carboxylate hydrochloride General procedure: A solution of l-tert-butyl 3-methyl 4-methylpiperazine-l,3-dicarboxylate (Intermediate 172 (124 mg, 0.48 mmol) in HC1 solution, 4 M in dioxane (1.2 mL, 4.8 mmol) and MeOH (1.2 mL) was stirred at RT for 2 hrs. Volatiles were removed under vacuum, to afford methyl 1-methylpiperazine-2-carboxylate hydrochloride (Intermediate 173, 160 mg, 0.82 mmol, recovery assumed quantitative) that was used in the next step without further purification. (0732) LC-MS (ESI): mlz (M+1): 159.1 (Method 2) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate In dimethyl sulfoxide at 100℃; | 9.1 Step 1 : Preparation of 7-(5-methoxy-2-methyl-4-nitrophenyl)-2-methyl-2,7-diazaspiro[3.5]nonane To a solution of 2-methyl-2,7-diazaspiro[3.5]nonane (250 mg, 1 .17 mmol, 1 eq, 2HCI) and 1 -fluoro-5-methoxy-2-methyl-4-nitro-benzene (217 mg, 1.17 mmol, 1 eq) in DMSO (5 mL) was added K2CO3 (486 mg, 3.52 mmol, 3 eq). The solution was stirred at 100 °C for 12 h. The solution was purified by reverse phase column chromatography (0.1% NH3.H2O) to give a desired product (290 mg, 74% yield) as a yellow solid. LC/MS: 306.2 [M+H]+. |
74% | With potassium carbonate In dimethyl sulfoxide at 100℃; | 9.1 Step 1 : Preparation of 7-(5-methoxy-2-methyl-4-nitrophenyl)-2-methyl-2,7-diazaspiro[3.5]nonane To a solution of 2-methyl-2,7-diazaspiro[3.5]nonane (250 mg, 1 .17 mmol, 1 eq, 2HCI) and 1 -fluoro-5-methoxy-2-methyl-4-nitro-benzene (217 mg, 1.17 mmol, 1 eq) in DMSO (5 mL) was added K2CO3 (486 mg, 3.52 mmol, 3 eq). The solution was stirred at 100 °C for 12 h. The solution was purified by reverse phase column chromatography (0.1% NH3.H2O) to give a desired product (290 mg, 74% yield) as a yellow solid. LC/MS: 306.2 [M+H]+. |
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