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CAS No. : | 2516-34-9 | MDL No. : | MFCD00001328 |
Formula : | C4H9N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KZZKOVLJUKWSKX-UHFFFAOYSA-N |
M.W : | 71.12 | Pubchem ID : | 75645 |
Synonyms : |
|
Num. heavy atoms : | 5 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 21.94 |
TPSA : | 26.02 Ų |
GI absorption : | High |
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) : | -6.59 cm/s |
Log Po/w (iLOGP) : | 1.43 |
Log Po/w (XLOGP3) : | 0.2 |
Log Po/w (WLOGP) : | 0.5 |
Log Po/w (MLOGP) : | 0.35 |
Log Po/w (SILICOS-IT) : | 0.85 |
Consensus Log Po/w : | 0.67 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 3.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.41 |
Solubility : | 27.9 mg/ml ; 0.392 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.31 |
Solubility : | 35.2 mg/ml ; 0.495 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.26 |
Solubility : | 39.4 mg/ml ; 0.553 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Danger | Class: | 3,8 |
Precautionary Statements: | P210-P280-P305+P351+P338-P310 | UN#: | 2733 |
Hazard Statements: | H225-H314 | Packing Group: | Ⅱ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine In butan-1-ol at 95℃; | Intermediate 16 6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine. Intermediate 16 6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine. To a solution of 4,6-dichloropyrimidin-2-amine (250 mg, 1.52 mmol, 1 equiv.) in n- BuOH (5 ml_) were added cyclobutanamine (130 μΙ_, 1.52 mmol, 1 equiv.) and Hunig's base (292 μΙ_, 1.72 mmol, 1.1 equiv.). The reaction mixture was stirred overnight at 95 °C. The solvent was removed in vacuo. The crude product was diluted in EtOAc and washed with H20, brine, dried over MgS04 and concentrated to afford the desired product as a white solid (248 mg, 80 %). LCMS [M+H]+ 199. |
69% | With triethylamine In butan-1-ol Heating; | |
In methanol at 70℃; for 1h; | To a solution of 2-amino-4,6-dichloropyrimidine (1.0 g, 6.10 mmol) in CH3OH (50.0 mL) was added cyclobutanamine (3.50 mL, 41.0 mmol), and the reaction mixture was stirred for 1.0 hour at 70 0C. The solution was concentrated, and the resulting residue was partitioned between EtOAc (100 mL) and water (150 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to afford the title compound (1.44 g) as a brown solid. LC-MS (ES) m/z = 199, 201 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: orthoformic acid triethyl ester; 2-Amino-2-cyanoacetamide In acetonitrile Heating; Stage #2: cyclobutylamine In acetonitrile at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.9% | With N-ethyl-N,N-diisopropylamine In butan-1-ol at 75 - 77℃; for 5.5h; | 1 Example 1 Preparation of 2-Chloro-N-Cyclobutyl-9H-Purin-6-Amine by a Base Catalyzed Process. Example 1 Preparation of 2-Chloro-N-Cyclobutyl-9H-Purin-6-Amine by a Base Catalyzed Process. [0047] A 12 L, 4-neck, round-bottomed flask fitted with a mechanical stirrer, digital thermometer, heating and cooling capabilities, condenser, addition funnel, and nitrogen inlet and outlet, was flushed with nitrogen and charged with 492.9 g (2.61 moles) of 2,6-dichloro-9H-purine, 497.7 mL (2.87 moles) of N,N-diisopropylethylamine, and 3.65 L of anhydrous 1-butanol. The mixture was stirred and heated to 75° C. and 244.9 mL (2.87 moles) of cyclobutylamine in 1.25 L of anhydrous 1-butanol, was added during about 1 hour at a temperature of 75° C.-77° C. The reaction temperature and stirring was maintained for 4.5 hours. The mixture was cooled to 5° C. over a period of 1 hour. The product was filtered and the filter cake was washed three times with a total of 0.9 L of 1-butanol. The filter cake was collected and dried at 75° C./20 mm Hg for 24 hours to give 506.6 g of light yellow crystalline solid. Theoretical yield was 583.3 g. Actual yield was 86.9%. |
86.9% | Stage #1: 2,6 dichloropurine With N-ethyl-N,N-diisopropylamine In butan-1-ol at 75℃; for 0.416667h; Inert atmosphere; Stage #2: cyclobutylamine In butan-1-ol at 75 - 77℃; for 5.5h; Inert atmosphere; regioselective reaction; | |
With triethylamine In N,N-dimethyl-formamide at 80℃; for 5h; | 24.1 1. 3.78 g (20 mmol) of dichloropurine 4, 20 ml of DMF, 1.4 ml of cyclobutylamine, and 3.08 ml of triethylamine were mixed. The mixture was stirred at 80° C. for 5 hours. The solvent was distilled off and the residue obtained was purified by column chromatography on silica gel to afford 4.1 g of compound 14. |
With N-ethyl-N,N-diisopropylamine In ethanol at 120℃; for 0.333333h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) at 20℃; for 6h; | 562 N-methylmorpholine (48 uL, 0.43 mmol), cyclobutylamine (13 mg, 0.18 mmol), 1- hydroxybenzotriazole (30 mg, 0.22 mmol), 1- (3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol) were added to a solution of 6- (2, 3-dichloro-phenylamino)-4- trifluoromethyl nicotinic acid (Description 10) (50 mg, 0.14 mmol) in dimethylformamide (3 mL). After stirring at room temperature for 6 h, dimethylformamide was evaporated under reduced pressure and dichloromethane was added. The solution was washed with an aqueous solution of NaHCO3 5% (5 mL), with water (10 mL), then with brine (2 x 3 mL) and was evaporated under reduced pressure. The crude residue was triturated with diethyl ether, filtered and dried under vacuum to afford the title compound (46 mg, yield=81 %). 1H NMR (300 MHz, DMSO-d6) 8 : 9.27 (s br, 1H); 8.66 (d br, 1H) ; 8.27 (s, 1H) ; 7.90 (dd, 1H) ; 7.42-7. 31 (m, 3H) ; 4.30 (m, 1H) ; 2,21 (m, 2H) ; 1.97 (m, 2H) ; 1.66 (m, 2H). MS m/z (EI+); TSQ 700; source 180°C ; 70 V; 200 uA: 403 (MF), 375,332. |
81% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) at 20℃; for 6h; | 104 N-methylmorpholine (48 uL, 0.43 [MMOL),] cyclobutylamine (13 mg, 0.18 [MMOL),] 1- hydroxybenzotriazole (30 mg, 0.22 [MMOL),] 1- (3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (32 mg, 0.17 [MMOL)] were added to a solution of 6- (2, 3-dichloro- phenylamino)-4-trifluoromethyl nicotinic acid (Description 18) (50 mg, 0.14 [MMOL)] in [DIMETHYLFORMAMIDE] (3 mL). After stirring at room temperature for 6 h, dimethylformamide was evaporated under reduced pressure and [DICHLOROMETHANE] was added. The solution was washed with an aqueous solution of NaHCO3 5% (5 mL), with water (10 mL), then with brine (2 x 3 mL) and was evaporated under reduced pressure. The crude residue was triturated with diethyl ether, filtered and dried under vacuum to afford the title compound (46 mg, [YIELD=81] %). ['H] NMR (300 MHz, DMSO-d6) [6] : 9.27 (s br, 1H) ; 8.66 (d br, 1H) ; 8.27 (s, 1H) ; 7.90 (dd, [1H)] ; 7.42-7. 31 (m, 3H); 4.30 (m, [1H)] ; 2,21 (m, 2H); 1.97 (m, 2H); 1.66 (m, 2H). MS m/z [(EL+)] ; TSQ 700; source [180°C] ; 70 V; 200 uA: 403 (M+), 375,332. |
81% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) at 20℃; for 6h; | 13 Description 13; 6-(2,3-dichloro-phenylamino)-n-(cyclobutyl)-4-trifluoromethyl-nicotinamide N-methylmorpholine (48 ul, 0.43 mmol), cyclobutylamine (13 mg, 0.18 mmol), 1- hydroxybenzotriazole (30 mg, 0.22 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol) were added to a solution of 6-(2,3-dichloro-phenylamino)-4-trifluoromethyl nicotinic acid (Description 10) (50 mg, 0.14 mmol) in dimethylformamide (3 ml). After stirring at room temperature for 6 h, dimethylformamide was evaporated under reduced pressure and dichloromethane was added. The solution was washed with an aqueous solution of 5% NaHCO3 (5 ml), with water (10 ml), then with brine (2 x 3 ml) and was evaporated under reduced pressure. The crude residue was triturated with diethyl ether, filtered and dried under vacuum to afford the title compound (46 mg, yield=81 %). 1H NMR (300 MHz, DMSO-d6) δ: 9.27 (s br, 1H); 8.66 (d br, 1H); 8.27 (s, 1H); 7.90 (dd, 1H); 7.42-7.31 (m, 3H); 4.30 (m, 1H); 2,21 (m, 2H); 1.97 (m, 2H); 1.66 (m, 2H). MS m/z (EI+); TSQ 700; source 180C; 70 V; 200 uA: 403 (M+.), 375,332 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxy-7-aza-benzotriazole; 3-[(ethylimino)methylene]-amino}-N,N,N-trimethyl-1-propanaminium iodide; In chloroform; for 18h; | A mixture of 4-methyl-3-(4,4,5,5-tetramethyM,3,2-dioxaborolan-2-yl)benzoic acid(262mg) in chloroform (10ml) was stirred with 3-[(ethylimino)methylidene]amino}-/V,/V,A/-trimethyl-1-propanaminium iodide (450mg), 1-hydroxy-7-azabenzotriazole (13mg) and cyclobutylamine (102ul) for 18h. Water was added, the organic layer was separated using a20 hydrophobic filter tube and the solvent was removed under vacuum to give the title compound (210mg).NMR: [5H d6-DMSO] 8.59 (1H d, J=8Hz,), 8.08 (1H, d, J=1Hz), 7.81 (1H, dd,^8Hz J=1Hz), 7.26 (1H, d, J=8Hz), 4.47-4.37 (1H, m,), 2.50 (3H, s), 2.25-2.15 (2H, m), 2.14-2.03 (2H, m), 1.70-1.62 (2H,m), 1.32(12H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1: Preparation of 1-cyclobutyl-5-nitro-1,3-dihydro-indol-2-one (2-Fluoro-5-nitrophenyl)acetic acid (Step 1, Example 11, 2.00 g, 10.0 mmol) and cyclobutylamine (6 eq., 5.14 ml, 60.2 mmol) are mixed in dimethyl sulfoxide (10 ml) and stirred at 45 C. overnight. Excess cyclobutylamine is removed under vacuum and 2N hydrochloric acid (40 ml) added in one portion. The mixture is stirred for 1.5 hours at 45 C. and the resulting precipitate filtered, washed with water, and dried to give the title compound as a yellowish solid. HPLC r.t. 4.94 min; MS for C12H12N2O3 m/z 233.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With pyridine; In dichloromethane; at 0 - 20℃; for 2.5h; | A solution of cyclobutylamine (0.552 mL, 6.44mmol) and pyridine (0.709 mL, 8.79 mmol) in dichloromethane (15 mL) was cooled at 0 0C. After the addition of 4-chloro-3-nitrobenzenesulfonyl chloride (1.5 g, 5.86 mmol), the mixture was warmed to room temperature and stirring was continued for 2.5 h. The solvent was evaporated at reduced pressure and the residue was partitioned between 1 N HCI and ethyl acetate. The organic was washed with water, brine, dried over Na2SO4 and evaporated to give the desired product as a yellow solid (1.21 g, 71%). 1H NMR (400 MHz, CDCI3) delta ppm 8.35 (d, J=2.3 Hz, 1 H), 7.99 (dd, J=8.5, 2.2, 1 H), 7.72 (d, J=8.3 Hz, 1 H), 4.96 (d, J=8.5 Hz, 1 H), 3.87 (sext, J=8.2 Hz, 1 H), 2.26-2.19 (m, 2H), 1.90-1.80 (m, 2H), 1.73-1.62 (m, 2H). |
71% | With pyridine; In dichloromethane; at 0 - 20℃; for 2.5h; | A solution of cyclobutylamine (0.552 ml_, 6.44mmol) and pyridine (0.709 ml_, 8.79 mmol) in dichloromethane (15 ml.) was cooled at 0 0C. After the addition of 4-chloro-3- nitrobenzenesulfonyl chloride (1.5 g, 5.86 mmol), the mixture was warmed to room temperature and stirring was continued for 2.5 h. The solvent was evaporated at reduced pressure and the residue was partitioned between 1 N HCI and ethyl acetate. The organic was washed with water, brine, dried over Na2SO4 and evaporated to give the desired product as a yellow solid (1.21 g, 71 %). 1H NMR (400 MHz, CDCI3) delta ppm 8.35 (d, J=2.3 Hz, 1 H), 7.99 (dd, J=8.5, 2.2, 1 H), 7.72 (d, J=8.3 Hz, 1 H), 4.96 (d, J=8.5 Hz, 1 H), 3.87 (sext, J=8.2 Hz, 1 H), 2.26-2.19 (m, 2H), 1.90-1.80 (m, 2H), 1.73-1.62 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 6h; | Example 325A mixture of cyclobutanamine (6.4 mg) , ethyl 4-chloro- li-pyrrolo[2,3-jb]pyridine-5-carboxylate (0.030M solution in 1- methyl-2-pirrolidone, 1.00 mL) , and N,N-diisopropylethylamine (0.016 mL) was heated at 1500C for 6 days. The reaction mixture was cooled to ambient temperature, then solvent was removed in vacuo. To the residue was added 1,4-dioxane (ImL) and LiOH (0.090M solution in water, l.OOmL) . The mixture was heated at 1000C for 24 hours and it was cooled to ambient temperature, and the solvent was' removed in vacuo. To the residue was added 1,4-dioxane (1 mL) ,N,N-dimethylformamide (0.5mL) , N,N-diisoprorhoylethylamirie (O.OldeltamL), and diphenylphosphoryl azide (0.090M solution in 1,4-dioxane, l.OOmL) . The mixture was heated at 1000C for 24 hours and it was cooled to ambient temperature, and the solvent was removed in vacuo. To the residue was added chloroform (2 mL) , and IM NaOH solution (1 EPO <DP n="181"/>itiL) and was mixed with Bortex Mixer. The organic phase was separated with IPS Filter Tube (from Whatman) and evaporated. Purification by preparative high performance liquid chromatography gave l-cyclobutyl-3, 6-dihydroimidazo [4, 5-d]pyrrolo [2, 3-jb] pyridin- -2 (IH) -one (0.3mg) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; triethylamine; trifluoroacetic acid In dichloromethane; water; acetonitrile | 160 N-cyclobutyl-2-methyl-6-(trifluoromethyl)nicotinamide EXAMPLE 160 N-cyclobutyl-2-methyl-6-(trifluoromethyl)nicotinamide A suspension of 2-methyl-6-(trifluoromethyl)nicotinic acid (6 mmol) in dry dichloromethane (9 mL) was treated with thionyl chloride (12.4 mmol) at 0° C., stirred for one hour, and concentrated in vacuo. The concentrate was added dropwise to a cold solution of cyclobutylamine (6 mmol) and triethylamine (4.5 mL) in dichloromethane (20 mL). The mixture was stirred for 4 hours and then concentrated in vacuo. The residue was dissolved in dichloromethane, washed sequentially with saturated sodium bicarbonate, water, and brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by HPLC on a C-18 column using a solvent system increasing in gradient from 5% to 100% acetonitrile/water containing 0.01% TFA over 50 minutes to provide the desired product as the trifluoroacetate salt. MS m/e 259.0 (M+H)+; 1H NMR (DMSO-d6) δ 1.64-1.75 (m, 2H), 1.95-2.06 (m, 2H), 2.20-2.31 (m, 2H), 2.56 (s, 3H), 4.33-4.43 (m, 1H), 7.78 (d, 1H), 7.96 (d, 1H), 8.79 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In butan-1-ol; at 70℃; for 18h; | A solution of <strong>[900789-14-2]5-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine</strong> (142 mg, 0.530 mmol), cyclobutylamine (0.090 mL, 1.06 mmol) and TEA (0.150 mL, 1.08 mmol) in nBuOH (6 mL) was stirred at 70 C for 18 h. CH2Cl2 and H2O were added. The organic phase was separated, washed with 5% NaHCO3, then with IN HCl, dried over Na2SO4, concentrated in vacuo to give 5-bromo-2-chloro-N-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (154 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In butan-1-ol; at 70℃; for 5h; | A solution of <strong>[1053228-29-7]2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine</strong> (50 mg, 0.24 mmol), cyclobutylaniine (0.041 mL, 0.48 mmol) and TEA (0.070 mL, 0.50 mmol) in nBuOH (2 mL) was stirred at 70 C for 5 h. CH2Cl2 and H2O were added. The organic phase was separated, washed with 5% NaHCO3, then with IN HCl, dried over Na2SO4, concentrated in vacuo to give 2-chloro-N-cyclobutyl-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (54 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In butan-1-ol; at 70℃; | A solution of <strong>[1192711-71-9]2,4-dichloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (190 mg, 0.94 mmol), cyclobutylamine (0.160 mL, 1.88 mmol) and triethylamine (0.200 mL, 1.44 mmol) in nBuOH (6 mL) was stirred at 70 0C overnight. It was then purified by HPLC to give 2- chloro-N-cyclobutyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine In dichloromethane at 0 - 10℃; for 1h; | 4.1.6 General procedure for synthesis of chloroacetamides (70a-h) General procedure: To the appropriate substituted amines (83a-h, 1 equiv) in DCM was added chloroacetyl chloride 84 (1.1 equiv) followed by the addition of TEA (2.8 equiv) at 0-10°C. The reaction was continued at the same temperature for 1h. Then, the reaction mixture was washed with saturated NaHCO3 solution, HCl 2N, and brine solution. The excess of organic solvent was removed under reduced pressure and the crude compounds were purified by flash chromatography, eluting with Cyclohexane/EtOAc 1/1. 2-chloro-N-cyclobutylacetamide (70a). Cyclobutylamine 83a (240μL, 2.81mmol), chloroacetyl chloride 84 (248μL, 3.12mmol), TEA (1.09mL, 7.8mmol) in DCM (6mL) were allowed to react according to the general procedure. Clean compound was eluted with Cycloexane/EtOAc 7/3, giving 70a (380mg, 83% yield) as white solid. 1H NMR (400MHz, DMSO-d6) δ 8.43 (s, 1H), 4.28-4.09 (m, 1H), 3.98 (s, 2H), 2.21-2.08 (m, 2H), 2.00-1.80 (m, 2H), 1.70-1.59 (m, 2H) ppm. UPLC-MS (ESI, m/z) Rt=1.23min-148 [M (35Cl)+H]+. |
66% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 18h; | To a solution of cyclobutylamine (1.0 g, 14.1 mmol) in freshly distilled tetrahydrofuran (THF) (60 mL) was added triethylamine (Et3N) (2.16 mL, 15.5 mmol, 0.726 g/mL) dropwise at room temperature. The mixture was cooled to 0 °C. Chloroacetyl chloride (1.23 mL, 15.5 mmol, 1.42 g/mL) at 0 °C was then added and the reaction stirred for 1 h. The reaction mixture was allowed to reach room temperature and stirred for 17 h. The reaction mixture was concentrated, and the residue was taken up in water (70 mL) and extracted with ethyl acetate (EtOAc) (1 x 70 mL). The organic layer was washed with 1 M hydrochloric acid (HCl) (1 x 35 mL), saturated NaHCO3 (1 x 35 mL), and saturated ammonium chloride (NH4Cl) (1 x 35 mL), dried over sodium sulfate (Na2SO4), filtered and concentrated. Purification (FCC, SiO2, 10 to 100% n-heptane/EtOAc) afforded a residue that was triturated with n-heptane (10 mL) to give the title compound (1.37 g, 9.28 mmol, 66%) as a white crystalline solid. MS (ESI): mass calcd. for C6H10ClNO;147.1 m/z found, 148.1 [M+H]+ |
53% | With triethylamine In dichloromethane at 0 - 23℃; |
With triethylamine In tetrahydrofuran at 0 - 20℃; | 87 To a solution of cyclobutanamine (1.3 g) in dry THF (80 ml_) dry TEA (2.03 g) was added dropwise at room temperature. The reaction mixture was then cooled down to 0 oC and 2- chloroacetyl chloride (2.27 g) was added dropwise at the same temperature. After the addition was over, the solvent was removed under reduced pressure and the residue was diluted with water and extracted with EA. The organic layer was washed with aqueous HCI, saturated NaHCO3 and saturated NH4CI, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (eluent PE:EA = 4:1 ) to give the title compound as a colourless solid (2.1 g).1H NMR (CDCI3), δ: 0.788-0.825 (t, 3H), 1.012-1.028 (d, 2H), 1.35-1.42 (m, 2H), 3.61- 3.68 (m, 1 H), 3.96-4.02 (t, 2H), 7.98-8.00 (b, 1 H). | |
247 mg | With triethylamine In dichloromethane at 20 - 25℃; for 2h; Inert atmosphere; | 60.i i) 2-Chloro-A/-cyclobutylacetamidemide To a solution of cyclobutylamine (200 mg) and dry EbN (683 mg) in 5.6 mL of dry DCM were added 2-chloroacetyl chloride (381 mg) dropwise at 0 °C. After stirring 15 min at this temperature, the mixture was additionally stirred for 2 h at RT. After completion of the reaction as monitored by LCMS water was added and the organic phase was separated. The water phase was extracted 2-times with DCM and the combined organic layers were dried with MgS04, the solvents were removed under reduced pressure and the crude product was purified by silica gel (0878) chromatography using a gradient of ethyl acetate/cyclohexane as eluent. (0879) Yield: 247 mg MS (ES+) [M+H]+: m/e = 148.1 , RT: 0.657 min |
With triethylamine In dichloromethane at 0 - 20℃; | 4.1.2. General procedure for preparation of intermediate 7 General procedure: Chloroacetyl chloride (11 mmol) in 5 mL DCM was added slowlydropwise to a stirred solution of appropriate amines (10 mmol) and Et3N(15 mmol) in DCM (10 mL) at 0 C, then the reaction mixture was stirredat room temperature until amines were consumed. The reaction mixturewas diluted with water (10 mL) and extracted with dichloromethane (3× 10 mL). The combined dichloromethane extracts were washed successivelywith H2O and brine, dried (Na2SO4), and concentrated underreduced pressure to obtain the product without further purification. | |
With triethylamine In dichloromethane at 0 - 20℃; | 4.1.2. General procedure for preparation of intermediate 7 General procedure: Chloroacetyl chloride (11 mmol) in 5 mL DCM was added slowlydropwise to a stirred solution of appropriate amines (10 mmol) and Et3N(15 mmol) in DCM (10 mL) at 0 C, then the reaction mixture was stirredat room temperature until amines were consumed. The reaction mixturewas diluted with water (10 mL) and extracted with dichloromethane (3× 10 mL). The combined dichloromethane extracts were washed successivelywith H2O and brine, dried (Na2SO4), and concentrated underreduced pressure to obtain the product without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; chloroform; at 20℃; for 5h; | Stage 1: N-cyclobutyl-4-(hydroxymethyl)benzamide 1-hydroxybenzotriazole (HOBt) (888 mg, 1 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.26 g, 1 eq) in solution in chloroform (40 ml) then cyclobutylamine (470 mg) are successively added to 4-(hydroxymethyl)benzoic acid (1 g, 1 eq) in solution in anhydrous THF (30 ml). After stirring for 5 hours at a temperature of approximately 20 C., the reaction mixture is concentrated under reduced pressure at 40 C. The residue is taken up in dichloromethane (100 ml) and water (60 ml). After decantation and extractions, the combined organic phases are washed with water, then with salt water, dried over Na2SO4 and concentrated under reduced pressure at 40 C. Purification by flash chromatography on silica gel (eluent: heptane/ethyl acetate 40:60 to heptane/ethyl acetate 25:75) produces the expected compound in the form of a white powder (1.3 g; 67% yield). MS/LC: calculated MM=205.5; m/z=206.2 (MH+) NMR (1H, 400 MHz, DMSO-d6): delta 1.66 (m, 2H), 2.05 (m, 2H), 2.20 (m, 2H), 4.40 (m, 1H), 4.54 (d, 2H), 5.26 (t, 1H), 7.36 (AB, 2H), 2.01 (AB, 2H), 8.52 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; Cooling with ice; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.4% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; | |
92.5% | With triethylamine In dichloromethane at 20℃; for 4h; | 15 To a stirred solution of cyclobutylamine (4.3 g, 59.7 mmol) and triethylamine (11.2 mL, 79.6 mmol) in dichloromethane (300 mL) was added the solution of 4-nitro-benzenesulfonyl chloride (8.8 g, 39.8 mmol) in dichloromethane (50 mL) at 0° C. The mixture solution was stirred at room temperature for 4 h and then washed with brine (50 mL×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford N-cyclobutyl-4-nitro-benzenesulfonamide (9.4 g, 92.5%) as a white powder: MS (ESI) M+1=257.1. |
92.5% | With triethylamine In dichloromethane at 0 - 20℃; for 4h; | 15 Example 154,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamideTo a stirred solution of cyclobutylamine (4.3 g, 59.7 mmol) and triethylamine (11.2 mL, 79.6 mmol) in dichloromethane (300 mL) was added the solution of 4-nitro- benzenesulfonyl chloride (8.8 g, 39.8 mmol) in dichloromethane (50 mL) at 0 °C. The mixture solution was stirred at room temperature for 4 h and then washed with brine (50 mL x 2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford N-cyclobutyl-4-nitro-benzenesulfonamide (9.4 g, 92.5%) as a white powder:MS(ESI) M+l = 257.1.To a stirred solution of N-cyclobutyl-4-nitro-benzenesulfonamide (5.8 g, 18.4 mmol) ethanol (400 mL) was added iron powder (5.2 g, 92.0 mmol) and the solution of ammonium chloride (10 g, 184.0 mmol) in water (100 mL). After the reaction mixture was refluxed for 3 h, the iron was filtered off and the filtrate was basified to pH 9 by addition of sodium carbonate. The reaction mixture was extracted with ethyl acetate (300 mL x 2). The extract was washed with water (130 mL x 2) and brine (130 mL x 2), dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 20 - 60% ethyl acetate in petroleum ether) to afford 4-amino-N-cyclobutyl-benzenesulfonamide (3.87 g, 93%) as a yellow powder: MS(ESI) M+l = 227.0. To a stirred solution of 4-amino-N-cyclobutyl-benzenesulfonamide (2.8 g, 12.4 mmol) and 3-bromo-benzaldehyde (2.52 g, 13.6 mmol) in acetonitrile (150 mL) were added isobutene (2.7 mL, 37.2 mmoll) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (1.54 g, 2.5 mmol). The resulting mixture was stirred at 80 °C for 18 h in sealed tube. The mixture solution was diluted with ethyl acetate (300 mL) and washed with water (100 mL x 2) and brine (100 mL x 2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10- 40% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)- 4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (2.2 g, 40%) as a light yellow solid: MS(ESI) M+l = 449.0 & 451.0.The mixture solution of 2-(3-bromo-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- sulfonic acid cyclobutylamide (150.0 mg, 0.34 mmol), copper(I) iodide (20.0 mg, 0.1 mmol), N,N-dimethylglycine hydrochloride (37.5 mg, 0.27 mmol), morpholine (0.78 mL, 9.0 mmol) and potassium carbonate (140.0 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL). was stirred at 120°C for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL x 2), washed with water (30 mL x 3) and saturated aqueous ammonium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 4,4- dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (123.7 mg, 80.0%) as a white solid: MS(ESI) M+l = 456.2. |
With pyridine In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine; chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II); lithium hexamethyldisilazane In tetrahydrofuran at 65℃; for 4h; Inert atmosphere; Sealed vial; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; | Dichloropyrimidine 1.4 (5.9g, 27 mmol) was dissolved in acetonitrile (50 mL) and treated sequentially with diisopropylamine (5.2 mL, 30 mmol) followed by cyclobutyl amine (1.9g, 27 mmol) and stirred at rt until all starting material had been consumed. The reaction mixture was then diluted with water to a total volume of 150 mL and the precipitate collected by filtration affording the desired product as a light yellow solid (6.02g, 87%). 1H NMR (DMSOd6, 400 MHz): delta 8.60 (S, IH), 8.48 (d, IH), 4.52 (m, IH), 4.29 (q, 2H), 2.30 (m, 2H), 2.04 (m, 2H), 1.73 (m, 2H), 1.30 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium t-butanolate In toluene at 120℃; for 3h; Inert atmosphere; Microwave irradiation; | ?/-cyclobutyl-4-(4-methylpiperazin-1 -yl)quinazolin-7-amine (Cpd. 28)4-(4-methylpiperazin-1-yl)quinazoiin-7-amine (150 mg), cyclobutylamine (58 ul) and NaOtBu (66 mg) were added to a microwave tube with 3 ml of toluene. The reaction mixture was flushed with N2 for 15 minutes. Then, Pd2(dba)3 (2.2 mg) and BINAP (2.3 mg) were added and the sealed tube was flushed for another 15 minutes with N2. The reaction mixture was heated for 3 hours at 120 C by microwave irradiation. Af ter cooling to r.t., the reaction mixture was partitioned between chloroform and water (pH>10 with 1M NaOH) and the aqueous layer was extracted with chloroform. The combined organic layers were washed with brine and dried over Na2SO4, evaporation of the solvent gave the crude product that was purified by flash chromatography (SiO2, EtOAc:MeOH:TEA, 90:5:5) to yield 122 mg (0.43 mmol, 88%) of the title compound. 1H NMR (250 MHz, CDCI3) d (ppm) 8.57 (s, 1 H), 7.63 (d, J= 8.9 Hz, 1 H), 6.74 (d, J= 2.4 Hz, 1 H), 6.71 (dd, J= 8.9 Hz, J= 2.4 Hz, 1 H), 4.41-4.38 (m, 1 H), 4.04 (quin, J= 7.1 Hz, 1 H), 3.71 (t, J= 5.0 Hz, 4H), 2.58 (t, J= 5.0 Hz, 4H), 2.54-2.42 (m, 2H), 2.37 (s, 3H), 2.02-1.77 (m, 4H); MS (ESI) 298 m/z (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1-methyl-pyrrolidin-2-one at 20℃; for 3h; | Gg To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (160 mg, 0.60 mmol) in NMP (2 mL) was added cyclobutanamine (129 mg, 1.81 mmol) dropwise. The mixture was stirred at RT for 3 hrs. 8 mL of water was added to precipitate out the product. The solid was filtered out and air-dried to give a crude 2- chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (177 mg, 0.57 mmol, 94 % yield), which was used for the next step without any purification. LC- MS (M+H)+ = 300.1. | |
In 1-methyl-pyrrolidin-2-one at 20℃; for 3h; | Gg Preparation Gg2-chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amineTo a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (160 mg, 0.60 mmol) in NMP (2 mL) was added cyclobutanamine (129 mg, 1.81 mmol) dropwise. The mixture was stirred at RT for 3 hrs. 8 mL of water was added to precipitate out the product. The solid was filtered out and air-dried to give a crude 2- chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (177 mg, 0.57 mmol, 94 % yield), which was used for the next step without any purification. LC- MS (M+H)+ = 300.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; acetonitrile; at 20℃; | Genera procedure: To a solution of the corresponding alkyl amine (1.2 equiv) in THF (2.0 M) was added simultaneously a solution of <strong>[110104-60-4](E)-4-chloro-3-methoxy-but-2-enoic acid methyl ester</strong> (1 equiv) in acetonitrile (1.5 M) and a solution of triethylamine (1 equiv) in acetonitrile (3.6 M) over 30 min at room temperature. After stirring overnight at room temperature or 3 h at 55 C, the resulting precipitate in the reaction mixture was removed by filtration. The mother liquor was concentrated and purified by flash chromatography on silica gel eluting with a gradient of 20-100% ethyl acetate in hexanes to afford the title compound in greater than 75% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.5% | Stage #1: 5-nitropyrazole-3-carboxylic acid With oxalyl dichloride In tetrahydrofuran; dichloromethane at 0 - 20℃; for 3h; Stage #2: cyclobutylamine With pyridine In dichloromethane at 20℃; | 1 A solution of 2M oxalyl chloride (in dichloromethane, 7 mL, 14 mmol) was added to a suspension of 5-nitro-3-pyrazocarboxylic acid (12A) (1.10 g, 7 mmol) in dichloromethane (25 mL), THF (0.7 mL) at 0 °C. One drop of DMF was added to the reaction mixture and stirred at room temperature for 3 h. The reaction mixture was evaporated in vacuum to dryness and the residue obtained was dissolved in dichloromethane (35 mL). To the solution was added a mixture of cyclobutylamine (0.72 mL, 8.5 mmol), pyridine (1.13 mL), and dichloromethane (2 mL) over a period of 10 min. After stirring at room temperature overnight, the reaction mixture was concentrated in vacuum to dryness and the residue obtained was purified by flash column chromatography (silica gel, eluting with hexanes/ethyl acetate 0 to 100%) to furnish N- cyclobutyl-5-nitro-lH-pyrazole-3-carboxamide (13B)(0.927 g, 67.5%) as an off-white solid; mp 240.1 °C; 1H NMR (300 MHz, DMSO) δ 14.77 (s, 1H), 8.92 (d, J= 7.5 Hz, 1H), 7.65 (s, 1H), 4.55-4.24 (m, 1H), 2.33-2.15 (m, 2H), 2.13-1.95 (m, 2H), 1.79-1.60 (m, 2H). MS (ES-): 209.0 M-l. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate In acetonitrile at -10 - 20℃; | 2,5-Dichloro-N-cyclobutylpyrimidin-4-amineAt -10° C., 3.39 g (24.5 mmol) of potassium carbonate are added to a solution of 3.00 g (16.4 mmol) of 2,4,5-trichloropyrimidine in 50 ml of acetonitrile. 1.22 g (17.2 mmol) of cyclobutylamine are then added dropwise as a 20% strength solution in acetonitrile. With stirring, the reaction mixture is allowed to warm to room temperature overnight. The reaction mixture is stirred into 250 ml of ice-water/dilute hydrochloric acid (1:1). The mixture is extracted with ethyl acetate (2×200 ml), the combined organic phases are then washed with water (2×100 ml) and dried over MgSO4 and the solvent is removed under reduced pressure. This gives 3.45 g (94%) of 2,5-dichloro-N-cyclobutylpyrimidin-4-amine (V-1) (logP (pH 2.3): 2.62).1H NMR (400 MHz, MeCN-d) δ=8.00 (s, 1H), 6.31 (br. s, 1H), 4.54-4.46 (m, 1H), 2.39-2.31 (m, 2H), 2.15-2.04 (m, 2H), 1.83-1.77 (m, 2H). |
94% | With potassium carbonate In acetonitrile at -10 - 20℃; | 2,5-Dichloro-N-cyclobutylpyrimidin-4-amine (V-1)At -10° C., 3.39 g (24.5 mmol) of potassium carbonate are added to a solution of 3.00 g (16.4 mmol) of 2,4,5-trichloropyrimidine in 50 ml of acetonitrile. Thereafter, 1.22 g (17.2 mmol) of cyclobutylamine are added dropwise as a 20% strength acetonitrile solution. The reaction mixture is allowed to come to room temperature overnight, with stirring. The reaction mixture is stirred into 250 ml of ice-water/dilute hydrochloric acid (1:1). The mixture is extracted with ethyl acetate (2×200 ml), the combined organic phases are then washed with water (2×100 ml), and dried over MgSO4, and the solvent is removed under reduced pressure. This gives 3.45 g (94%) of 2,5-dichloro-N-cyclobutylpyrimidin-4-amine (V-1).logP (pH2.3): 2.62; 1 H NMR (400 MHz, MeCN-d) δ=8.00 (s, 1H), 6.31 (br. s, 1H), 4.54-4.46 (m, 1H), 2.39-2.31 (m, 2H), 2.15-2.04 (m, 2H), 1.83-1.77 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; at 100℃; | In a 50-mL,3Nround-bottomed flask equipped with nitrogen inlet and a rubber septum, 3-fluoro-5-trifluorobenzonitrile (1.5 g, 1.0 eq.) was dissolved in DMSO (30 mL) and cyclobutanamine (1.128 g, 2.0 eq.) and potassium carbonate(3.81 g, 3.5 eq.) was added. The reaction mixture was heated at 100 C for 4-5 h. The progress of reaction was followed by TLC analysis on silica gel with 20% Ethyl acetate- hexane as mobile phase. SM f=0.6 and Product Rf=0.4. eaction mixture was poured into ice water (150 mL) and extracted with EtOAc ( 3x50 mL). The combined organic layers were washed with brine solution(3x50mL) and dried over anhydrous MgS04, filtered, and concentrated by rotary evaporation (25C, 20mmHg) to afford 1.8g of crude compound which was used for next step without any purification. Yield (94.7%). Mass: 240.90. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
hydrogenchloride; In butan-1-ol; at 130℃; for 0.5h;Microwave; | Synthesis of Intermediate (1) 1.21[00654] In a25-mL microwave seal tube <strong>[1196155-38-0]2-chloro-6-trifluoromethylisonicotinonitrile</strong> (lg) Isopropyl amine(0.517g) was dissolved in n-butanol(lOmL) and one drop of con. HC1 was added. Reaction mixture was irradiated at 130°C for 30 min in Microwave. The Completion of the reaction was confirmed by TLC using 10percent EtOAc-n-hexane as mobile phase. Reaction mixture was quenched into ice water slurry. Extract compound in ethyl acetate, organic layer washed with water two times dried over Nu3/4804, filtered, and concentrated by rotary evaporation(40°C,20 mmHg) to afford 8g of a yellow oil. The resulting crude compound was purified by column chromatography. The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate :n-hexane as mobile phase. The columnwas packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection(25 -mL fractions) from 1-3 percent ethyl acetate in hexane. Compound started eluting with 2 percent ethylacetate in hexane. Fraction containing such TLC profile was collected together to obtain pure compound(0.8 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 48h; | Dichloro ester 1.2 (2.0 g, 9.7 mmol) was diluted with 20 mL of acetonitrile then treated with diisopropyl ethyl amine (1.9 mL, 10.7 mmol) followed by cyclobutyl amine (0.75 mL, 9.7 mmol). The reaction as then stirred at room temperature for two days during which time a precipitate formed. When the progress was checked by UPLC the reaction was found to be only 50% complete with an 4:1 ratio of the 2-amino to 6-amino isomers. The solids were removed by filtration affording 0.40 g of the desired product. The filtrate was then diluted with water to 100 mL total volume affording an additional 0.50 g of the desired product. MS found for C11H13ClN2O2 as (M+H)+ 241.0, 243.0. UV lambda=263 (major), 288 (minor). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 140℃; for 0.5h;Microwave irradiation; | General procedure: A solution of <strong>[1187-59-3]N-methylacrylamide</strong> (2) (1.88 g, 22.0 mmol) and cyclopentylamine (1.98 mL, 20.0 mmol) in MeOH (14 mL) was heated under microwave irradiation to 140 C for 30 min (Biotage Initiator). The volatiles were removed under reduced pressure, the residue diluted with MeOH (20 mL) and purified by strong cation exchange filtration (50 g SCX-2 cartridge) washing with MeOH (100 mL) and eluting with 7 M methanolic NH3 (100 mL). The eluted product was concentrated under reduced pressure to afford the title compound 3 as a brown oil (3.09 g, 18.2 mmol, 91%). This was used directly with no further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 2h; | Example 611-cyclobutyl-4-[6-cyclopropyM-methyl-4-(trifluoromethyl)-1H-benztoyl]carbonyl}-5-ethyl-2-piperazinoneStep A1, 1 -dimethyl ethyl {1-[(cyclobutylamino)carbonyl ]propyl}carbamate[00284] To a solution of 2-([(1 ,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (4.0 g, 20 mmol) in N,N-dimethylformamide (100 mL) was added cyclobutylamine (1.9 mL, 22 mmol), N,N-diisopropylethylamine (10.3 mL, 59.0 mmol), and N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5- b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (8.23 g, 21.7 mmol). The mixture was stirred for 2 hours, quenched with water, and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, washed with 5% lithium chloride, dried over sodium sulfate and concentrated. The residue was slurried in ethyl ether, stirred for 30 minutes, and the solids collected by filtration. The product was purified by passing through a silica gel plug, eluting with 25% ethyl acetate in dichloromethane. Fractions were concentrated to give the title compound (3.1 g; 62%). 1H NMR (400 MHz, CHLOROFORM- d) 5 ppm 6.00 - 6.39 (m, 1 H), 4.85 - 5.19 (m, 1 H), 4.27 - 4.53 (m, 1 H), 3.78 - 4.03 (m, 1 H), 2.26 - 2.46 (m, 2 H), 1.78 - 1.96 (m, 3 H), 1.52 - 1.78 (m, 3 H), 1.45 (s, 9 H), 0.94 (t, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 70℃; for 2.5h; | Step AK4: 1-Cvclobutyl-1 H-imidazole-4-carboxylic acid ethyl ester The stirred mixture of <strong>[72130-97-3](Z)-3-dimethylamino-2-isocyano-acrylic acid ethyl ester</strong> (17.0 g, 100 mmol) and cyclobutaneamine (21.79 g, 300 mmol) was heated for 2.5 h at 70 C. The reaction mixture was cooled to rt and concentrated. The residue was purified by flash chromatography (EtOAc/hexane, 5:1 ) to afford the title compound as an orange oil. tR: 0.70 min (LC-MS 2); ESI-MS: 195.2 [M+H]+ (LC-MS 2); H-NMR (DMSO-c 6, 400 MHz) delta ppm 8.03 (s, 1 H), 7.83 (s, 1 H), 4.73 (m, 1 H), 4.18 (q, 2H), 2.36 (m, 4H), 1.74 (m, 2H), 1.24 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium t-butanolate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; for 4h;Reflux; | A mixture of <strong>[175358-02-8]4,6-dichloropyrido[3,2-d]pyrimidine</strong> (Intermediate 1, step D) (0.100 g, 0.500 mmol), cyclobutanamine (0.047 ml, 0.550 mmol), PdCl2(dppf)-CH2Cl2Adduct (4.08 mg, 5.00 mmol) and sodium tert-butoxide (0.096 g, 1.00 mmol) in dioxane (2.50 ml) was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give 6-chloro-N-cyclobutylpyrido[3,2-d]pyrimidin-4-amine (0.098 g, 84%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.79-1.89 (2H, m), 2.06-2.17 (2H, m), 2.48-2.56 (2H, m), 4.71-4.82 (1H, m), 7.11 (1H, brs), 7.61 (1H, d, J=8.8 Hz), 8.03 (1H, d, J=8.8 Hz), 8.61 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 60℃; for 2h; | To a stirring solution of <strong>[33089-15-5]4-chloro-2-(methylthio)pyrimidine-5-carbonitrile</strong> (2 g, 10.8 mmol) in DMF (10 mL) was added DIEA (4.2 g, 32.4 mmol) and cyclobutanamine (2.3 g, 32.4 mmol) at 0 C. The resulting mixture was stirred at 60 C for 2 h. The reaction mixture was poured into saturated sodium chloride, and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product. The crude product was purified via silica gel column chromatography (10% ethyl acetate in petroleum ether) to get the desired product as a white solid (1.7 g, 7.7 mmol, 71% yield). MS (ESI) m/z = 221.2[M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: cyclobutylamine; 8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-one In toluene for 2h; Reflux; Stage #2: With sodium tris(acetoxy)borohydride In ethanol; toluene at 30℃; for 72h; | S.1.iii iii) 8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-N-cyclobutyl-8-azabicyclo[3.2.1]octan-3- amine iii) 8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-N-cyclobutyl-8-azabicyclo[3.2.1]octan-3- amine8-(5-Bromothieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-one (1.5 g, 4.43 mmol) in toluene (60 mL) was treated with cyclobutylamine (3.145 g, 44.3 mmol) and heated with stirring to reflux for 2h. Ethanol (100 mL) and sodium triacetoxyborohydride (9.347 g, 44.3 mmol) were added and the reaction stirred and warmed at 30 °C over 3 days. The reaction was then concentrated in vacuum to a gum, diluted with ethyl acetate (100 mL) and saturated sodium hydrogen carbonate solution (50 mL) and shaken. The ethyl acetate layer was then separated, dried over sodium sulphate and concentrated in vacuum to give 8-(5- bromothieno[2,3-d]pyrimidin-4-yl)-N-cyclobutyl-8-azabicyclo[3.2.1]octan-3-amine as a yellow solid (1.799 g, 3.97 mmol, 89%). 1H NMR (CDC13) δ: 1.5 (3H, d, J = 12 Hz), 1.65 (3H, br s), 1.93 (2H, br s), 2.1 (2H, d, J = 6 Hz), 2.22 (2H, m), 2.4 (2H, m), 3.0 (1H, br s), 3.3 (1H, m), 4.63 (2H, br s), 7.3 (1H, s), 8.45 (1H, s). |
89% | Stage #1: cyclobutylamine; 8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-one With sodium tris(acetoxy)borohydride In toluene for 2h; Reflux; Stage #2: With sodium tris(acetoxy)borohydride In ethanol; toluene at 30℃; for 72h; | S.1.iii iii) 8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-N-cyclobutyl-8-azabicyclo[3.2.1]octan-3-amine iii) 8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-N-cyclobutyl-8-azabicyclo[3.2.1]octan-3-amine 8-(5-Bromothieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-one (1.5 g, 4.43 mmol) in toluene (60 mL) was treated with cyclobutylamine (3.145 g, 44.3 mmol) and heated with stirring to reflux for 2 h. Ethanol (100 mL) and sodium triacetoxyborohydride (9.347 g, 44.3 mmol) were added and the reaction stirred and warmed at 30° C. over 3 days. The reaction was then concentrated in vacuum to a gum, diluted with ethyl acetate (100 mL) and saturated sodium hydrogen carbonate solution (50 mL) and shaken. The ethyl acetate layer was then separated, dried over sodium sulphate and concentrated in vacuum to give 8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-N-cyclobutyl-8-azabicyclo[3.2.1]octan-3-amine as a yellow solid (1.799 g, 3.97 mmol, 89%). 1H NMR (CDCl3) δ: 1.5 (3H, d, J=12 Hz), 1.65 (3H, br s), 1.93 (2H, br s), 2.1 (2H, d, J=6 Hz), 2.22 (2H, m), 2.4 (2H, m), 3.0 (1H, br s), 3.3 (1H, m), 4.63 (2H, br s), 7.3 (1H, s), 8.45 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium tris(acetoxy)borohydride; acetic acid In 1,1-dichloroethane at 20℃; for 16h; | 1.3 Step 3: l-(4-(4-((Cyclobutylamino)methyl)-3-fluorophenyl)piperazin-l-yl)ethanone Step 3: l-(4-(4-((Cyclobutylamino)methyl)-3-fluorophenyl)piperazin-l-yl)ethanone To a solution of cyclobutanamine (1.26 mL, 14.7 mmol) and 4-(4-acetylpiperazin-l-yl)- 2-fluoro-benzaldehyde (3.68 g, 14.7 mmol) in dichloroethane (50 mL) was added sodium tnacetoxyborohydride (4.39 g, 20.6 mmol) followed by acetic acid (0.84 mL, 14.7 mmol) and the reaction was stirred at ambient temperature for 16 hours. 1 N aqueous NaOH was then added to basify the reaction and the product was extracted with Et20 (x3), washed with brine, dried with MgS04, concentrated and dried in vacuo to give l-[4-[4- [(cyclobutylamino)methyl]-3-fluoro-phenyl]piperazin-l-yl]ethanone (4.76 g, 99% yield). The product was used without purification. LCMS (m/z) ES+ 306 [M+l]+. |
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 23℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridine; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; | 70 Preparation 70 N-Cyclobutylmethanesulfonamide Preparation 70 N-Cyclobutylmethanesulfonamide To a stirred solution of cyclobutylamine (0.400 g, 5.6 mmol), N,N-diisopropylethylamine (0.930 mL, 5.6 mmol) and pyridine (0.455 mL, 5.6 mmol) in methylene chloride (10 mL) at 0° C. was slowly added methanesulfonyl chloride (0.435 mL, 5.6 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was concentrated and the residue purified by silica gel chromatography (0-80% ethyl acetate/hexane) to afford the product as a low melting solid (0.82 g, 98%). 1H NMR (300 MHz, CDCl3) δ 4.62 (br s, 1H), 3.94 (m, 1H), 2.94 (s, 3H), 2.50-2.30 (m, 2H), 2.10-1.85 (m, 2H), 1.85-1.60 (m, 2H). |
In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.3% | With triethylamine; In 1,4-dioxane; hexane; at 90℃; for 0.45h;Microwave irradiation; | Step 1. 6-Bromo-N-cyclobutylpyridazin-3-amine Into a solution of <strong>[17973-86-3]3,6-dibromopyridazine</strong> (1.19 g, 5 mmol) in dioxane (5 mL) was added cyclobutylamine (0.39 g, 5.5 mmol), and Et3N (0.60 g, 6 mmol). The reaction was microwave at 90 C., 150W for 0.45 h. The reaction was monitored by TLC and the crude product was purified by silica gel chromatography (eluent: 30% Ethyl acetate in n-hexane), to give the desired product (0.63 g, 55.3%). 1H NMR (300 MHz, CDCl3) delta: 7.25-7.28 (1H, d, J=9.0 Hz), 6.49-6.52 (1H, d, J=9.0 Hz), 5.27 (1H, s), 4.16-4.24 (1H, m), 2.40-4.49 (2H, m), 1.87-1.95 (2H, m), 1.75-1.84 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethyl sulfoxide; at 60℃; for 12h; | Step 1: A mixture of 33-1 (Ri, R2 = H) (2.4 g, 14 mmol) and cyclobutanamine (2 g, 28 mmol) in DMSO (30 mL) was stirred at 60 C for 12 hrs. The reaction was poured into ice water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL) and dried over Na2S04. After being concentrated, the crude product was purified by flash column chromatography eluting with PE/EA = 10/1 to give 33- 2 as a white solid, *H NMR (300 MHz, CDC13) delta 7.72 - 7.68 (m, 1H), 7.63 - 7.58 (m, 1H), 6.60 - 6.54 (m, 1H), 4.01 - 3.96 (m, 1H), 3.85 (s, 3H), 2.48 - 2.42 (m, 2H), 1.97 - 1.83 (m, 4H). LC-MS: m/z = 224.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 16h;Sealed tube; | To a solution of <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (10.0 g, 44.24 mmol), K2003 (8.3 g, 60.05 mmol) in DMSO (50 mL) was added cyclobutylamine (4.51 mL, 52.82 mmol) and maintained at 100 C for 16 h in sealed tube. The reaction mixture was diluted with water and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with water, brine solution, dried over an hydrous Na2SO4 and concentrated. The crude product was purified by column chromatography over silica gel (100 - 200 mesh) using a solvent gradient of 20 % ethyl acetate in pet-ether to afford 8.0 g (84 %) of N-cyclobutyl-5- (trifluoromethyl)pyridin-2-amine 160-1 as a white solid. 1H-NMR (400 MHz, DMSO-d6): c5 8.26 (5, 1H), 7.55-7.63 (m, 2H), 6.50 (d, J= 11.6 Hz, 1H), 4.30-4.33 (m, 1H), 2.23-2.31 (m, 2H), 1.82-1.93 (m, 2H), 1.64-1.72 (m, 2H). ESI-LC/MS: m/z217.06 (M+H); R = 2.85 mm [Waters Acquity UPLC with SOD; Waters Acquity UPLC BEH 018, 1.7 pm, 2.1 X 50 mm column; gradient of 98:02 H20 (0.1% H000H): CH3CN (0.1% H000H) hold for 0.8 mm and to 45:55 H2Q (0.1% H000H):CH3CN (0.1% H000H) in 2.0 mm and hold for 1.0 mm and to 0:100 H2Q (0.1% H000H):CH3CN (0.1% H000H) in 0.5 mm and hold for 1.5 mm with flow rate of 0.4 mLlmin]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | In water at 125℃; for 4h; Microwave irradiation; | 98 5-Chloro-N3-cyclobutylpyridazine-3,4-diamine A mixture of 3,5-dichloro-4-aminopyridazine (Preparation 4, 200 mg, 1.22 mmol), cyclobutyl amine (0.56 mL) and water (1.12 mL) was heated under microwave irradiation at 125° C. for 4 hours. The reaction mixture was concentrated in vacuo and the crude residue was purified by silica gel column chromatography eluting with CH2Cl2:MeOH 98:2 to afford the title compound as a brown solid in 58% yield, 140 mg. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.68-1.75 (m, 2H), 1.84-1.92 (m, 2H), 2.30-2.37 (m, 2H), 4.40-4.46 (m, 1H), 6.15 (br s, 2H), 6.33 (br s, 1H), 8.10 (s, 1H). LCMS (System 7): Rt=2.17 minutes MS m/z 199 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(Step 1) [0308] Toluene (30 mL) and cyclobutylamine (2.25 mL) were added to <strong>[148625-35-8]methyl 3-formyl-4-nitrobenzoate</strong> (5.00 g), and the reaction solution was stirred at room temperature for 5 minutes. The solvent was evaporated under vacuum, then triethyl phosphite (11.3 mL) was added to the residue, and the reaction solution was stirred at 100°C for 7 hours. The solvent was evaporated under vacuum, the resultant residue was purified by column chromatography on silica gel [0309] (developing solvent: hexane/ethyl acetate). Ethanol (2 mL) and a 5 N aqueous sodium hydroxide solution (5.0 mL) were added to the resultant crude product, and the reaction solution was stirred at room temperature for 1 hour. A 10percent aqueous phosphoric acid solution was added to acidify the reaction solution. Furthermore, water was added, and the deposited precipitate was filtrated to obtain 2-cyclobutyl-2H-indazole-5-carboxylate as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With acetic acid; at 160℃;Inert atmosphere; Autoclave; | General procedure: To a pressure bottle containing <strong>[82437-64-7]methyl 3-amino-4-phenylthiophene-2-carboxylate</strong> (100 mg, 0.43 mmol), CH(OEt)3 (1 mL) was added, followed by allylamine hydrochloride (93 mg, 0.99 mmol) and AcOH (0.1 mL). The reaction mixture was stirred and refluxed at 160 C overnight. After the reaction, the mixture was evaporated then solidified with ether. The produced white crystals were filtered and dried in vacuo to give the title compound 4-1 (66 mg, 0.25 mmol, 58 % yield): 1HNMR (300 MHz, CDCl3) delta 8.11 (s, 1H), 7.84-7.79 (m, 3H), 7.50-7.44 (m, 2H), 7.41-7.36 (m, 1H), 6.08-5.95 (m, 1H), 5.34-5.24 (m, 2H), 4.72-4.67 (m, 2H); 13C NMR (100 MHz, CDCl3) delta 157.3, 154.3, 147.3, 138.1, 133.7, 131.9, 130.5,128.7, 128.3, 128.0, 124.9, 119.1, 48.0; LC/MS (ESI+): m/z: calcd for C15H12N2OS: 268.34, [M + H]+; found: 269.05 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a mixture of N-hydroxy-3-phenylpropanamide (1j) (0.198 g, 1.2 mmol), K2CO3 (0.166 g, 1.2 mmol), and DMSO (0.5 mL) was added acetic anhydride (1.1 mL, 0.012 mmol) and heated to 50 C. After stirring at that temperature for 10 min,the reaction mixture was cooled to 0 C and then treated with 2 M HCl (ca. 1mL). After the mixture became the clear solution, 2 M NaOH (ca. 2 mL) and di-t-butyl dicarbonate (0.55 mL, 2.4 mmol) was added successively. After stirring for 12 h, the mixture was extracted with Et2O (15 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/Et2O,1:1) to yield t-butyl 3-phenylpropylcarbamate (2j) (0.122 g, 46%) as a colorless liquid. | ||
General procedure: A 10 mL test tube was charged with 3-phenylpropanoic acid (1l) (0.300 g, 2.00 mmol) and anhydrous DMSO (2 mL) and placed under an argon atmosphere. CDI (0.486 g, 3.00 mmol) was added and the resulting mixture was stirred at rt for 1 h. DMAP (24.0 mg, 0.200 mmol) and NH2OTMS (0.420 g, 4.00 mmol) was added at rt and stirred at ambient temperature for 18 h. After addition of anhydrous K2CO3 (0.696 g, 5.04 mmol), the resulting mixture was heated to 90 C and stirred at that temperature for 3 h. After cooling of the reaction mixture to rt, 2 M HCl (2 mL) was added and stirred for 1 h. 2 M NaOH (3 mL) was added to the reaction mixture at 0 C and then Z-chloride (0.51 mL, 3.6 mmol) was added. After stirred for 16 h, the mixture was extracted with CH2Cl2 (15 mL× 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/Et2O = 2:1) to yield the pure N-Boc-(2-phenylethyl)amine (3a) (0.180 g, 41%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1: Preparation of 2,6-dichloro-N-cyclobutyl-5-nitropyrimidin-4-amine Cyclobutanamine (0.485 mL, 5.68 mmol) in iPrOH (20 mL) was added to a solution of <strong>[4359-87-9]2,4,6-trichloro-5-nitropyrimidine</strong> (1.29 g, 5.65 mmol) in iPrOH (40 mL) at -78 C. dropwise via addition funnel. After complete addition, the mixture was allowed to warm to rt over 30 min, then DIEA (0.940 mL, 5.66 mmol) was added and the mixture stirred at rt for 10 min. The solvent was removed under reduced pressure and dried to give the title compound as a pale yellow oil which was used without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; at 140℃; for 1.5h;Microwave irradiation; | 1.00 g (5.04 mmol) <strong>[351-32-6]N-(4-fluoro-3-nitrophenyl)acetamide</strong> (for preparation see: WO2005/72741 page 26, Example 117A) and 0.86 ml (10.09 mmol) of cyclobutylamine were initially charged in 40 ml of ethanol, then 1.40 ml (10.09 mmol) of triethylamine were added and the reaction mixture was stirred in a microwave at 140 C. for 1.5 h. For workup, the mixture was concentrated under reduced pressure, the residue was stirred with MTBE, and the solid formed was filtered off and dried under high vacuum. This gave 185 mg (69% purity, 10% of theory) of the target compound. The remaining filtrate was concentrated, and the residue was taken up in ethyl acetate, washed once each with water and saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. After drying under high vacuum, this gave a further 1.01 g (78% of theory) of the target compound. LC-MS (Method 3): Rt=1.31 min; MS (ESIpos): m/z=250 (M+H)+. 1H NMR (400 MHz, DMSO-d6): delta [ppm]=1.70-1.85 (m, 2H), 1.93-2.04 (m, 5H), 2.39-2.47 (m, 2H), 4.12 (sxt, 1H), 6.92 (d, 1H), 7.65 (dd, 1H), 7.93 (d, 1H), 8.46 (d, 1H), 9.97 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 3.0h; | [0184j To compound 5-6 (220 mg, 1 mmol) in acetonitrile (2 ml) was added cyclobutamine (102 iL, 1.2 mmol) and DIEA (213 iL, 1.2 mmol) and the reaction mixture stirred at room temperature for 3 hr. After work up and extraction with ethyl acetate the crude compound 6-2 was isolated. To the THF solution of crude 6-2 added LiOH (84 mg) and stirred for 4hr. The reaction mixture was acidified and extracted the desired product 6-3 as white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.2% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 1h; | Synthesis of compound 222.1. To a solution of 220.1 (0.275g, 1.936mmol, l .Oeq) in DMSO (5ml) was added cyclobutyl amine (0.165 g, 2.323 mmol, 1.2 eq.) and DIPEA (2.5 g, 19.4 mmol, 10 eq.). Reaction mixture was heated at 100 C for lh. After completion of reaction, mixture was poured in water, quenched with ammonium chloride solution and product was extracted with EtOAc. Organic layers were combined,dried over sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by column chromatography to get pure 222.1 (0.3 g, 80.2 %). MS(ES): m/z 193.21 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; | N-(2-(Dimethylamino)ethyl)-4-phenoxybenzamide (5a) To a solution of N,N-dimethylethylenediamine (51 μL, 0.47 mmol) and compound 4 (100 mg, 0.47 mmol) in CH2Cl2 (5 mL) at 0 °C were added 1-hydroxybenzotriazole HOBt (76 mg, 0.56 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI (107 mg, 0.56 mmol) and 4-methylmorpholine (155 μL, 1.41 mmol). The reaction mixture was stirred at room temperature for overnight, then washed with 10 % aqueous HCl, 5 %aqueous NaHCO3, H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography to provide the title compound (97 %) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hydrogencarbonate; In ethanol; for 0.666667h; | Step A. Alternative preparation of N-cyclobutyl-3-nitro-5-(trifluoromethyl)pyridin-2-amine To a mixture of <strong>[72587-15-6]2-chloro-3-nitro-5-(trifluoromethyl)pyridine</strong> (1.00 g, 4.41 mmol) and NaHCO3 (1.12 g, 13.2 mmol) in EtOH (10 mL) was added cyclobutylamine (0.94 g, 13.2 mmol) drop-wise over 10 minutes. The mixture was stirred for 30 min, absorbed onto silica and purified on a 40 g ISCO gold silica gel column, eluting with a hexanes (100%) to hexanes (95%)/EtOAc (5%) gradient, to provide the desired compound (1.05 g, 91%) as a bright yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In tetrahydrofuran; at 20 - 50℃; for 32h;Sealed tube; | Intermediate 1-10-4A solution of <strong>[3939-14-8]2-fluoro-4-cyanopyridine</strong> (1.1 g, 9.1 mmol) and cyclobutylamine (1.89 g, 18.1 mmol) in THF (10 mL) was stirred at RT for 16h, then heated in a sealed tube at 50C for 16h. Allowed to cooled, diluted with water and extracted with EtOAc, the organics were combined, washed with water, sat. NaCI, dried over Na2S04 and concentrated. Purified by silica chromatography to give Intermediate 1 -10-4 2-(cyclobutylamino)isonicotinonitrile (1 .047 g, 67%).1 H-NMR (400 MHz ,DMSO-d6), Shift [ppm]= 1 .57-1 .74 (2H), 1 .79-1 .92 (2H), 2.21 -2.33 (2H), 4.24 (1 H), 6.68-6.78 (2H), 7.34 (1 H), 8.13 (1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | 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℃; | A solution of <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (2.0 g, 9.3 mmol) and cyclobutylamine (0.87 ml, 10.2 mmol) in DMF (60 ml) was treated with N, N-diisopropylamine (3.6 ml, 20.5 mmol) and a solution of HATU (4.24 g, 11.2 mmol) in DMF (30 ml) was added thereto.The reaction mixture was stirred at RT overnight (ca. 16 h).The solvent was removed at high vacuum and the residue was added, stirred and sucked with water.The residue was washed thoroughly with water and dried under high vacuum.This gave 2:35 g (94% d. Th.) Of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium tetrahydroborate In methanol at 20℃; Inert atmosphere; | General procedure: Typical procedure for reductive amination with cyclobutyl or cyclopentyl amine: Aldehyde (1 equiv) was dissolved in anhydrous MeOH under N2. Cyclobutyl amine (1.05 equiv) was added and the reaction stirred overnight at room temperature. NaBH4 (1.6 equiv) was added and the reaction stirred for 1 hour. The reaction was quenched with saturated NH4Cl, taken up in ethyl acetate, washed with brine, dried over MgSO4, concentrated, and taken directly to the next step without further purification. |
With sodium tetrahydroborate In methanol at 20 - 25℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; In methanol; at 20℃;Inert atmosphere; | General procedure: Typical procedure for reductive amination with cyclobutyl or cyclopentyl amine: Aldehyde (1 equiv) was dissolved in anhydrous MeOH under N2. Cyclobutyl amine (1.05 equiv) was added and the reaction stirred overnight at room temperature. NaBH4 (1.6 equiv) was added and the reaction stirred for 1 hour. The reaction was quenched with saturated NH4Cl, taken up in ethyl acetate, washed with brine, dried over MgSO4, concentrated, and taken directly to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dmap; triethylamine In tetrahydrofuran at 45℃; for 0.75h; | Intermediate 51: 2-(Benzyloxv)-N5-cvclobutvl-N3-methylpyridine-3,5- dicarboxamide 2,4,6-Trichlorophenyl 6-(benzyloxy)-5-(methylcarbamoyl)nicotinate (1.65 g, 3.54 mmol) was dissolved in THF (20 mL) and Et3N (0.988 mL, 7.09 mmol) was added. Cyclobutanamine (0.605 mL, 7.09 mmol) and DMAP (0.022 g, 0.177 mmol) were added and the reaction mixture heated at 45 °C for 15 mm. The reaction was heated for a further 30 mm, then allowed to cool and concentrated in vacuo. The crude colourless oil was then partitioned between ethyl acetate (30 mL) and water (30mL). The product was extracted with ethyl acetate (2 x 30 mL) and the combined ethyl acetate layers were dried (Na2SO4) and evaporated in vacuo. The crude residue was loaded in dichloromethane and purified via Biotage SP4 flash chromatography eluting from 20-100 % ethyl acetate/cyclohexane. The relevant fractions were combined and evaporated in vacuo to yield the product - 2-(benzyloxy)-N5-cyclobutyl-N3-methylpyridine-3,5-d icarboxamide (1.025 g, 3.02 mmol,85 % yield) as a white solid.LCMS (2 mm Formic): Rt = 1.01 mi [MH] = 340.0. |
85% | With dmap; triethylamine In tetrahydrofuran at 45℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap; triethylamine In tetrahydrofuran at 45℃; for 3h; Inert atmosphere; | 2 Example 2: 1-Benzyl-N5-cvclobutvl-N3-methyl-2-oxo-1,2-dihydropyridine-3,5- dicarboxamide 2,4,6-Trichlorophenyl 1-benzyl-5-(methylcarbamoyl)-6-oxo- 1,6-dihyd ropyrid ine-3- carboxylate (401 mg, 0.861 mmol), cyclobutanamine (0.15 mL, 1.757 mmol), N,N-dimethylpyridin-4-amine (23 mg, 0.188 mmol), triethylamine (0.48 mL, 3.44 mmol) and THF (8 mL) were stirred at 45°C under N2 for 3 h. The reaction mixture was concentrated to give 600 mg of an off white solid which was purified by chromatography on Si02 (Biotage SNAP 50 g cartridge, eluting with O-100% ethylacetate/cyclohexa ne). The desired fractions were concentrated to give 1 -benzyl-N 5-cyclobutyl- N3-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarboxamide (295 mg, 0.782 mmol, 91 % yield) as anoff white solidLCMS (2 mm Formic): Rt=0.91 mi [MH] = 340. |
91% | With dmap; triethylamine In tetrahydrofuran at 45℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Ice bath,(COCl) 2 (7.5 mL) and DMF (0.4 mL)Was slowly added dropwise to a solution of 2-bromo-5H-pyrrolo [2,3-b] pyrazine-7-carboxylic acid (60%, 4.00 g, 8.26 mmol) in dichloromethane (150 mL)Reaction at room temperature for 2 h. Concentrated under reduced pressure,The residue was dissolved in dichloromethane (120 mL)Cyclobutylamine (2.2 mL, 26 mmol) and triethylamine were added(2.4 mL) was added and the reaction was carried out overnight. The reaction was quenched with water (150 mL)Dichloromethane (150 mL x 3), and the organic layer was dried over anhydrous Na2SO4, (Eluent: Cl2CH2 / MeOH (v / v) = 30/1) to give 1.20 g of a tan solid Rate: 49.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | In tetrahydrofuran; at 25℃; for 12h; | To a solution of compound N,N-di-CBZ- 1H-pyrazole- 1 -carbamidine (5.0 g, 13.2 mmol) in THF (20 mL) was added cyclobutylamine (1.1 g, 15.8 mmol) at 25 C. The reaction was stirred for 12 hrs at 25 C. The mixture was concentrated in vacuo to get a residue. The residue was purified by silica gel column to obtain compound 64 (2.5 g, 44% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With oxygen; potassium carbonate; eosin y; In toluene; at 20℃;Irradiation; Green chemistry; | General procedure: A flame-dried 10 mL flask was charged with amine 2 (0.5 mmol), potassium acetic acid 1 (1.5 mmol), potassium carbonate (2.0 mmol) and toluene (3 mL). Eosin Y (0.01 mmol) was added to the mixture. The mixture was allowed to stir at room temperature opening in air, and be irradiated with a Luxeon Rebel high power green LEDs [2.50 W, lambda = 535 nm] for 60-180 min. at room temperature, until all of the starting material disappeared. Then, the mixture was poured into water (10 mL), extracted with EtOAc (4 * 10 mL), washed with brine (15 mL), and dried over Na2SO4. The crude organic phase was concentrated in vacuo and purified with a short flash column chromatography (silica gel, hexane/EtOAc = 5:1) to afford the corresponding product 3(a-n) in high yield (71-95%) in Table 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In ethanol; at 120℃; for 48h;Inert atmosphere; Sealed tube; | In a sealed tube, compound 1[1] (500 mg, 1.75 mmol) was dissolved in a mixture of EtOH (2 mL) and cyclobutanamine (2 mL) and heated at 120C for 48 h. The resulting mixture was evaporated to dryness and the residue was purified with flash chromatography on silica gel (8 : 1 : 0.01, DCM - MeOH - sat. aq. NH3) to afford product 10 (brown amorphous solid, 449 mg, 80%). Compound 10: Rf 0.22 (8 : 1 : 0.01, DCM - MeOH - NH4OH); [alpha] D20 -10.86 (c 0.175 CH3OH); HPLC tR 0.60 min; 1H-NMR (500 MHz, CD3OD) delta 8.25 (s, 1H, Purine-H), 8.20 (s, 1H, Purine-H), 5.95 (d, J = 5.6 Hz, 1H, H-1?), 4.85 (d, J = 5.6 Hz, 1H, H-2?), 4.27 (dd, J = 5.3, 4.1 Hz, 1H, H-3?), 4.16 (dt, J = 7.6, 3.9 Hz, 1H, H-4?), 3.34 - 3.31 (m, 1H, cyclobutyl-CH), 2.92 (dd, J = 12.6, 7.4 Hz, 1H, H-5?a), 2.86 (dd, J = 12.6, 3.8 Hz, 1H, H-5?b), 2.22 (dtd, J = 14.0, 7.0, 2.8 Hz, 2H, cyclobutyl-CH2), 1.85 - 1.77 (m, 2H, cyclobutyl-CH2), 1.76 - 1.68 (m, 2H, cyclobutyl-CH2), NH, OH and NH2 are missing; 13C-NMR (126 MHz, CD3OD) delta 157.40 (Purine-C), 153.75 (Purine-C), 150.56 (Purine-C), 142.11 (Purine-C), 120.94 (Purine-C), 90.86 (C-1?), 84.95 (C-4?), 74.50 (C-2?), 73.39 (C-3?), 54.96 (cyclobutyl-CH), 49.68 (C-5?), 30.96 (cyclobutyl-CH2), 30.88 (cyclobutyl-CH2), 15.51 (cyclobutyl-CH2); HRMS (ESI+) calcd. For C14H21N6O3+ 321.1670, found 321.1660. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With toluene-4-sulfonic acid In ethanol at 160℃; for 0.5h; Sealed tube; Microwave irradiation; | 4.1.2. General procedure for the preparation of pyrroles 49a-n’ General procedure: The proper 1,4-pentanedione 48 (2.28 mmol) and the suitableamine (2.28 mmol) were dissolved in ethanol (2 ml) in a sealedglass tube equipped with a stirring bar in the presence of p-toluenesulfonicacid (30 mg, 0.17 mmol). The tube was heated in thecavity of the microwave reactor for 30 min (150W, internal temperature160 °C, and internal pressure 150 psi). At the end, thereaction mixture was cooled down and concentrated. The crudematerial was purified by chromatography on aluminum oxide(activity II-III, according to Brockmann) with cyclohexane to givethe expected pyrroles 49a-n’ as solids in satisfactory yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; | HATU (3.25 g, 8.54 mmol), cyclobutanamine (0.506 g, 7.12 mmol) and Et3N (1.191 mL, 8.54 mmol) were added to a solution of <strong>[2016-99-1]2,6-dibromoisonicotinic acid</strong> (2 g, 7.12 mmol, commercially available from, for example, Fluorochem) in DCM (20 mL) at rt. The mixture was stirred overnight, then washed with water (2 x 20 mL), dried and evaporated in vacuo to give a brown solid. The product was dissolvedin DCM (10 mL) and loaded onto a 50 g silica column, then eluted with O-5O% EtOAc/cycohexane and the product-containing fractions were evaporated in vacuo to give 2,6-dibromo-N- cyclobutylisonicotinamide (2.10 g, 6.29 mmol, 88 % yield) as a colourless solid.LCMS (2 mm High pH): Rt = 1.10 mi [MH]+ = 335.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | 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 0 - 20℃; for 2h; | 6-Chloro-N-cyclobutylpyrazine-2-carboxamide: To a suspension of <strong>[23688-89-3]<strong>[23688-89-3]6-chloropyrazine-2-carboxylic</strong> acid</strong> (100 mg, 0.631 mmol), HATU (288 mg, 0.757 mmol), and cyclobutanamine (49 mg, 0.69 mmol) in DMF (1.26 mL) at 0 C was added DIEA (220 pi, 1.26 mmol) and the resulting mixture was stirred at rt for 2 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (0 - 100 % EtOAc in hexanes) to give the title compound (84 mg, 63%) as an off-white solid. MS (ES+) C9H,0C1N30 requires: 211, found: 212 [M+Hf?. ?H NMR (600 MI-Tz, Chloroform-d) oe 9.28 (s, 1H), 8.75 (s, 1H), 7.72 (s, 1H), 4.66 - 4.53 (m, 1H), 2.50 - 2.38 (m, 2H), 2.13 - 1.98 (m, 2H), 1.87- 1.73 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 120℃;Microwave irradiation; | General procedure: In a suitable microwave reaction vessel the required chloropyrimidine (1 equiv.) was taken up in i-PrOH. To this was added the required amine (1.1 equiv.) and the mixture irradiated under stirring at 120C for 1-2h. Upon completion of the reaction, the mixture was directly purified using FCC to afford the compound. Similarly, any precipitate could be collected under vacuum and washed several time with cold i-PrOH to afford the desired compound.6.2.1.1 100 N-Phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine (9a) (0026) General procedure A. Purification by FCC (eluent, 1:1 EtOAc/PE) afforded 105mg of a white amorphous solid (84%). LCMS (m/z): 281.9 [M+H]+. HPLC: tR 6.244min, >95% purity (214 & 254nm). HRMS (m/z): C16H15N3S requires 282.1071 [M+H]+; found 282.1059. 1H NMR (CDCl3) δ 8.48 (s, 1H), 7.64 (dt, J=8.8, 1.7Hz, 2H), 7.41-7.34 (m, 2H), 7.17-7.10 (m, 2H), 3.06 (dd, J=8.1, 3.9Hz, 2H), 2.85 (dd, J=8.0, 3.9Hz, 2H), 2.03-1.89 (m, 4H). 13C NMR (CDCl3) δ 166.3, 155.0, 152.6, 138.5, 134.7, 129.1, 124.8, 124.0, 121.3, 116.6, 26.5, 25.5, 22.5, 22.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2h; | [1269] Methyl 4-(N-cyclobutylsulfamoyl)-benzoate : To a stirred solution of cyclobutanamine (0.303 g, 4.26 mmol, 1.0 eq) in THF (15 mL) was added triethyl amine (1.78 mL, 12.78 mmol, 3.0 eq) followed by methyl 4-(chlorosulfonyl)benzoate (1.0 g, 4.26 mmol, 1.0 eq) at 0C. The reaction was stirred at room temperature for 2 h. TLC (50% EtOAc in n-Hexane) showed the reaction was completed. After the consumption of starting material, solvent was evaporated under reduced pressure, to get the crude. The crude product was purified by silica gel chromatography (eluting with: Hexane/EtOAc=50:50) to give methyl 4-(N-cyclobutylsulfamoyl)benzoate. LC-MS (m/z)=268.1 [M+H]+. 1H NMR (400 MHz, CDCl3) delta: 1.56-1.67 (m, 2H), 1.71-1.78 (m, 2H), 2.13-2.15 (m, 2H), 3.96 (s, 3H), 3.80-3.88 (m, 1H), 4.65 (d, J=4.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 2H), 8.16 (d, J=7.6 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | General procedure: To a solutionof the corresponding aldehyde (1.2 eq.; unless stated otherwise) in DMF (2 inL per 0.3 mmol of aldehyde; unless stated otherwise) was added the corresponding amine (2.5 eq.; unless stated otherwise) and the resulting solution was stirred at 25 C to form the corresponding inline. Then, the corresponding isocyano(tosyl)methyl)arene reagent (1 eq.; unless stated otherwise) and K2CO3 (1.5 eq.; unless stated otherwise*) were added and the reaction mixture was stirred at 25 C (unless stated otherwise). The reaction was stopped after the time indicated for each particular reaction. The reaction progress was monitored by TLC. (0083) A saturated aqueous solution of NH4CI (10 mL per 1 mmol of aldehyde) was added to the reaction mixture, which was then extracted with EtOAc (2 x 30 mL per 1 mmol of aldehyde). The combined organic extracts were washed with H2O (2 x 25 mL per 1 mmol of aldehyde), dried over MgSCC, filtered, and the solvent was evaporated in vacuo to provide the crude product. The residue obtained after the workup was purified using column chromatography or preparative TLC (unless stated otherwise). (0084) * note: in cases when the amine was used as HC1 salt, 4 eq. of K2CO3 were used |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: cyclobutanone With palladium 10% on activated carbon; benzylamine In toluene at 40℃; for 10h; Autoclave; Stage #2: With hydrogen In toluene at 40 - 80℃; for 24h; Autoclave; | 1-3 Example 3 In a 100 ml autoclave, 10 g of cyclobutanone, 20 g of benzylamine,20 grams of toluene and 0.2 grams of palladium on carbon, heated to 40 ° C for 10 hours;Introduce hydrogen into the autoclave, and keep the pressure of hydrogen at 30atm.Continue to raise the temperature to 80 ° C and react for 24 hours. The gas chromatograph monitors the disappearance of cyclobutanone.The reaction was completed, the palladium carbon was removed by filtration, and the filtrate was rectified to collect the fraction having a boiling point of 85-86 ° C.7.2 g of cyclobutylamine were obtained with a yield of 72% and a purity of 98.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With acetic acid In acetonitrile at 120℃; for 24h; Microwave irradiation; | 3.A Step A: 6-(4-Cyclobutyl-4//-l,2,4-triazol-3-yl)pyridin-2-amine To a mixture of (E)-A/'-(6-(2-((E)-(dimcthylamino)mcthylcnc)hydrazinc- l - carbonyl)pyridin-2-yl)-/V,/V-di methyl formimidamidc (263 mg, 1.0 mmol) and cyclobutanamine (0.17 mL, 2.0 mmol) in a microwave reaction vessel equipped with a magnetic stirring bar was added acetonitrile (3 mL), followed by acetic acid (1 mL). The mixture was heated in a hot plate at 120 °C for 24 h. After this time the reaction was cooled to rt and partitioned between EtOAc and NaHC03 (saturated aqueous solution). The separated aqueous layer was extracted with EtOAc and the combined organic extracts were dried over MgS04, filtered and concentrated. The residue was purified by normal phase column eluting with 100% EtOAc to give the title compound (188 mg, 87%). 1H NMR (400 MHz, CD3OD) d ppm 8.79 (s, 1H), 7.55 (dd, 7=8.28, 7.53 Hz, 1H), 7.17 (d, 7=7.28 Hz, 1H), 6.64 (d, 7=8.28 Hz, 1H), 5.38 - 5.59 (m, 1H), 2.48 - 2.67 (m, 2H), 2.39 (quind, 7=9.57, 9.57, 9.57, 9.57, 2.64 Hz, 2H), 1.79 - 1.99 (m, 2H). MS (ESI): 216.0 [M + H]+. |
87% | With acetic acid In acetonitrile at 120℃; for 24h; Microwave irradiation; | 17.A Step A To a mixture of (E)-N'-(6-(2-((E)-(dimethylamino)methylene)hydrazine-1- carbonyl)pyridin-2-yl)-N,N-dimethylformimidamide (263 mg, 1.00 mmol) and (0397) cyclobutanamine (171 µL, 2.00 mmol) in a microwave tube was added MeCN (3 mL), followed by acetic acid (1 mL). The mixture was heated in a hot plate at 120 °C for 24 h. After this time, the reaction was partitioned between EtOAc and satd. NaHCO3. The aqueous layer was extracted by EtOAc and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The product was purified by normal phase column chromatography eluting with 100% EtOAc to give the title compound (188 mg, 87%).1H NMR (400 MHz, MeOD) d ppm 8.79 (s, 1H), 7.55 (dd, J=8.28, 7.53 Hz, 1H), 7.17 (d, J=7.28 Hz, 1H), 6.64 (d, J=8.28 Hz, 1H), 5.38 - 5.59 (m, 1H), 2.48 - 2.67 (m, 2H), 2.39 (quind, J=9.57, 9.57, 9.57, 9.57, 2.64 Hz, 2H), 1.79 - 1.99 (m, 2H). MS (ESI): 216.0 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.82 g | A mixture of <strong>[74733-27-0]methyl 4-(bromomethyl)-2-methoxybenzoate</strong> 5 (1 g, 3.86 mmol) and cyclobutanamine 5a (0.659 mL, 7.72 mmol) in DMF (2 mL) was heated at 70 C. over 30 min at which point LCMS showed the formation of an amine product. The excess base was evaporated and Hunig's Base (1.348 mL, 7.72 mmol) was added, followed by addition of Boc-anhydride (0.896 mL, 3.86 mmol). LCMS showed the completion of reaction. The solvent was evaporated and the crude product was purified by COMBIFLASH apparatus using EtOAc/hexanes to provide 0.82 g desired product 6 as a colorless oil. LCMS ESI: calculated for C19H27NO5=350.42 (M+H+), found 350.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; | To a stirred mixture of <strong>[723280-98-6]7-bromo-4-chloro-3-nitroquinoline</strong> (2 g, 6.96 mmol, 1 equiv) and TEA (1.06 g, 10.43 mmol, 1.5 equiv) in DCM (80 mL) was added cyclobutanamine (0.59 g, 8.35 mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred for overnight at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 7-bromo-N-cyclobutyl-3- nitroquinolin-4-amine (1.8 g, 80.32%) as a yellow crude solid. LC-MS: (ES, m/z): [M+H]+ =322.0. | |
With triethylamine; In dichloromethane; at 20℃; | To a stirred mixture of <strong>[723280-98-6]7-bromo-4-chloro-3-nitroquinoline</strong> (2 g, 6.96 mmol, 1 equiv) and TEA (1.06 g, 10.44 mmol, 1.5 equiv) in DCM (80 mL) was added cyclobutanamine (0.59 g, 8.35 mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 7-bromo-N-cyclobutyl-3-nitroquinolin-4-amine (1.8 g, 80.32%) as a yellow crude solid. LC-MS: (ES, m/z): [M+H]+ =322.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; tetrabutylammoniun azide In acetonitrile at 25 - 26℃; for 20h; Sealed tube; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.51 g | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; tetrabutylammoniun azide In acetonitrile at 25 - 26℃; for 20h; Irradiation; | 4.2 General Procedure 1 for α-C-H alkylation of primary amines 8 with diethyl vinylphosphonate 9 General procedure: A 20-mL scintillation vial equipped with a stirrer bar was transferred to a nitrogen-filled purge box. In the case of solid or viscous oil amine substrates, the requisite amine 8 (0.45 mmol, 1.0 equiv) was then weighed into the empty vial at this point, and the stirrer bar replaced. The vial was then charged with stock solutions of the 4CzIPN (2.28 mM in MeCN, 1.97 mL, 4.5 μmol, 1 mol%) and tetrabutylammonium azide (70.3 mM in MeCN, 640 μL, 45 μmol, 10 mol%), and made up to a total volume of 3.0 mL by addition of MeCN. For liquid amines, the requisite amine (0.45 mmol, 1.0 equiv) was then transferred into the vial by microlitre syringe at this point. Finally, diethyl vinylphosphonate 9 (70 μL, 74 mg, 0.45 mmol, 1.0 equiv) was added, and the vial was sealed using a B24 rubber septa. It was then removed from the purge box and transferred to a photoreactor, and irradiated (with stirring) for 20 h at 425 nm. Fan cooling was used to maintain an external temperature of 25-26 °C. Following irradiation, the reaction mixture was concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.86% | With triethylamine In ethanol at 80℃; for 3.5h; | 6-chloro-N-cyclobutylpyrimidin-4-amine. 4,6-Dichloropyrimidine (50 g, 335.62 mmol), TEA (50.94 g, 503.43 mmol, 70.17 mL) were dissolved in EtOH (500 mL) and cyclobutanamine (26.26 g, 369.18 mmol, 31.52 mL) was added. The mixture was stirred for 30 min (spontaneous heating was observed) and then for 3 hr at 80 °C. The reaction mixture was cooled to r.t. and evaporated in vacuo at 50 °C. The residue was triturated with H2O (0.5 L). The precipitate was filtered, washed with H2O (3*300 mL) and dried at 40 °C to give 6-chloro-/V-cyclobutyl-pyrimidin-4- amine (56 g, 304.95 mmol, 90.86% yield). 1H NMR (400 MHz, DMSO-r/e) d (ppm) 1.68 (m, 2H), 1.89 (m, 2H), 2.25 (m, 2H), 4.40 (m, 1H), 6.43 (s, 1H), 7.98 (bds, 1H), 8.23 (s, 1H). LCMS (ESI): [M+H]+ m/z: calc’d 183.6; found 184.2; Rt = 1.161 min. |
90.86% | With triethylamine In ethanol at 80℃; for 3.5h; | 6-(cyclobutylamino)pyrimidine-4-carboxylic acid 6-chloro-N-cyclobutylpyrimidin-4-amine. 4,6-Dichloropyrimidine (50 g, 335.62 mmol), TEA (50.94 g, 503.43 mmol, 70.17 mL) were dissolved in EtOH (500 mL) and cyclobutanamine (26.26 g, 369.18 mmol, 31.52 mL) was added. The mixture was stirred for 30 min (spontaneous heating was observed) and then for 3 hr at 80° C.. The reaction mixture was cooled to r.t. and evaporated in vacuo at 50° C. The residue was triturated with H2O (0.5 L). The precipitate was filtered, washed with H2O (3*300 mL) and dried at 40° C. to give 6-chloro-N-cyclobutyl-pyrimidin-4-amine (56 g, 304.95 mmol, 90.86% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 1.68 (m, 2H), 1.89 (m, 2H), 2.25 (m, 2H), 4.40 (m, 1H), 6.43 (s, 1H), 7.98 (bds, 1H), 8.23 (s, 1H). LCMS(ESI): [M+H]+ m/z: calcd 183.6; found 184.2; Rt=1.161 min. |
40.3% | With potassium carbonate In propan-2-one at 20℃; for 16h; | 75.1 Step 1: Preparation of 6-chloro-N-cyclobutylpyrimidin-4-amine: Cyclobutylamine (200mg, 2.81mmol, 1.0eq) was dissolved in acetone (5mL), 4,6-dichloropyrimidine (420mg, 2.81mmol, 1.0eq) and potassium carbonate (580mg, 4.21mmol, 2.0eq) were added . Stir overnight (16h) at room temperature. The compound was filtered and the filtrate was concentrated. The system was added with 20 mL of water, extracted three times with 5 mL of ethyl acetate, the ethyl acetate phases were combined, washed once with 10 mL of water, once with 10 mL of saturated brine, dried over anhydrous sodium sulfate for 10 minutes, filtered, concentrated, and the crude product was separated by chromatography Purification (PE:EA=0-20%) gave 6-chloro-N-cyclobutylpyrimidin-4-amine (208 mg, 40.3% yield) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In toluene at 90℃; for 72h; Inert atmosphere; | tert-butyl 3-(cyclobutylamino)benzoate. To a solution of tert- butyl 3-bromobenzoate (5 g, 19.45 mmol), cyclobutanamine (5.53 g, 77.78 mmol, 6.64 mL) and sodium tert- butoxide (5.61 g, 58.34 mmol) in toluene (150 mL), 4.5-6/.v(di phenyl phosphino)-9.9- dimethylxanthene (562.59 mg, 972.30 μmol ) and/ra(dibenzylideneacetone)di palladium (0) (445.17 mg, 486.15 μmol ) were added under Ar atmosphere. The resulting mixture was heated at 90 °C for 72 hr and evaporated to dryness to obtain tert- butyl 3-(cyclobutylamino)benzoate (10 g, crude), which was used for the next step without purification. 1H NMR (500 MHz, DMSO- de) d (ppm) 1.15 (s, 9H), 1.50 (m, 1H), 1.69 (m, 3H), 1.80 (m, 2H), 3.81 (m, 1H),6.47 (d, 1H), 6.96 (t, 1H), 7.14 (m, 2H), 7.23 (m, 1H). LCMS (ESI): [M-u]+ m/z: calc’d 191.2; found 192.2; Rt = 1.129 min | |
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In toluene at 90℃; for 72h; | 3-(cyclobutylamino)benzoic acid tert-butyl 3-(cyclobutylamino)benzoate. To a solution of tert-butyl 3-bromobenzoate (5 g, 19.45 mmol), cyclobutanamine (5.53 g, 77.78 mmol, 6.64 mL) and sodium tert-butoxide (5.61 g, 58.34 mmol) in toluene (150 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (562.59 mg, 972.30 umol) and tris(dibenzylideneacetone)dipalladium (0) (445.17 mg, 486.15 umol) were added under Ar atmosphere. The resulting mixture was heated at 90° C. for 72 hr and evaporated to dryness to obtain tert-butyl 3-(cyclobutylamino)benzoate (10 g, crude), which was used for the next step without purification. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 1.15 (s, 9H), 1.50 (m, 1H), 1.69 (m, 3H), 1.80 (m, 2H), 3.81 (m, 1H), 6.47 (d, 1H), 6.96 (t, 1H), 7.14 (m, 2H), 7.23 (m, 1H). LCMS(ESI): [M-tBu]+ m/z: calcd 191.2; found 192.2; Rt=1.129 min. 3-(cyclobutylamino)benzoic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran at 20℃; for 15h; | General procedure for the synthesis of compounds 1, 2, 6-16and 18-39. General procedure: 1-10- Carbonyl diimidazole 43 (0.97 mmol; 1.5 eq) wasadded to a solution of 2-amino- 6-fluoro benzoic acid (0.65 mmol;1.0 eq) in tetrahydrofuran (7 ml) in a round-bottom flask equippedwith a stirring bar in dry conditions. The obtained mixture wasstirred for 24 h at room temperature and then the appropriatehydroxylamine 45a,b, amine 46a-k or hydrazine 47a-t was added(1.30 mmol; 2.0 eq) and the reaction mixture was stirred at roomtemperature for 16 h. At the end the mixture was quenched withsaturated aqueous sodium bicarbonate and the organic solutionwas extracted with ethyl acetate, washed with brine and dried overNa2SO4.After filtration and concentration, the crude material was purifiedby column chromatography on silica gel with a mixture ofdichloromethane/ethyl acetate in the opportune volumes to givethe expected products 1, 2, 6e16 and 18e37.Hydrochloride salts 38 and 39 were prepared by reacting a solutionof the hydrazides 20 or 21 (0.08 mmol, 1 eq) in ethanol(0.5 ml) with aqueous HCl 37% added dropwise. The mixture wasstirred for 30 min at room temperature and then the white precipitatewasseparated by filtration andwashed with cold ethanol toobtain the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With dmap; 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 24h; | 2.1.1. General procedure for the preparation of benzylamide derivatives3-7, 9, 10, 20-25, and 28 General procedure: A solution of XCC (1, 8-[4-[carboxymethyloxy]phenyl]-1,3-di-(npropyl)xanthine (1 eq) [25], the desired amine compound (1 eq),EDAC (1-ethyl-3-(2-dimethylaminoethyl)carbodiimide, 2 eq.) andDMAP (4-[N,N-(dimethylamino)]pyridine, 2.2 eq) in 2 mL of anhydrous dimethylformamide was stirred at room temperature for 24 h. The reactionmixture was evaporated to dryness under a stream of nitrogen,and the residue was purified by preparative silica gel thin layer chromatography(chloroform:methanol = 20:1) and crystallization inmethanol/ethyl ether to afford the desired compounds. |
95% | With dmap; 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 24h; | 2.1.1. General procedure for the preparation of benzylamide derivatives3-7, 9, 10, 20-25, and 28 General procedure: A solution of XCC (1, 8-[4-[carboxymethyloxy]phenyl]-1,3-di-(npropyl)xanthine (1 eq) [25], the desired amine compound (1 eq),EDAC (1-ethyl-3-(2-dimethylaminoethyl)carbodiimide, 2 eq.) andDMAP (4-[N,N-(dimethylamino)]pyridine, 2.2 eq) in 2 mL of anhydrous dimethylformamide was stirred at room temperature for 24 h. The reactionmixture was evaporated to dryness under a stream of nitrogen,and the residue was purified by preparative silica gel thin layer chromatography(chloroform:methanol = 20:1) and crystallization inmethanol/ethyl ether to afford the desired compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With phenolated sodium In acetonitrile at 20℃; for 14h; | 5.3. General procedure for the N-(rhodamine 6G)-lactam-amines General procedure: To a 10.0 mL bottle with a magnetic stirring bar was added Rh-6G (1, 0.1 mmol), amines (2, 0.15 mmol), PhONa (0.2 mmol,23.2 mg), and general acetonitrile (2.0 mL) under air atmosphere.The reaction mixture was vigorously stirred at room temperaturefor 14 h. Afterward the solvents were removed under reducedpressure, and the crude mixture was purified by chromatographyon silica gel (petroleum ether/ethyl acetate 10/1 as eluent) toobtain the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.2% | With triethylamine In 1,4-dioxane at 20℃; for 12h; | 4.1.3 General procedure for the preparation of 2-24 and 26-30 General procedure: A suspension of 50mg (0.14mmol) of 1 in 1mL of 1,4-dioxane was added to different amines (1.1 equiv) and 50μL of triethylamine. The mixture was stirred for 12h at room temperature and then detected by TLC. The solvent was removed in vacuo, and the crude material was purified via column chromatography to obtain compounds 2-24 and 26-30. |
91.2% | With triethylamine In 1,4-dioxane at 20℃; for 12h; | 4.1.3 General procedure for the preparation of 2-24 and 26-30 General procedure: A suspension of 50mg (0.14mmol) of 1 in 1mL of 1,4-dioxane was added to different amines (1.1 equiv) and 50μL of triethylamine. The mixture was stirred for 12h at room temperature and then detected by TLC. The solvent was removed in vacuo, and the crude material was purified via column chromatography to obtain compounds 2-24 and 26-30. |
Tags: 2516-34-9 synthesis path| 2516-34-9 SDS| 2516-34-9 COA| 2516-34-9 purity| 2516-34-9 application| 2516-34-9 NMR| 2516-34-9 COA| 2516-34-9 structure
[ 1523571-17-6 ]
trans-Cyclobutane-1,3-diamine dihydrochloride
Similarity: 0.86
[ 1523571-90-5 ]
cis-Cyclobutane-1,3-diamine dihydrochloride
Similarity: 0.86
[ 1523571-17-6 ]
trans-Cyclobutane-1,3-diamine dihydrochloride
Similarity: 0.86
[ 1523571-90-5 ]
cis-Cyclobutane-1,3-diamine dihydrochloride
Similarity: 0.86
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Code | Phrase |
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Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
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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. |
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P240 | Ground/bond container and receiving equipment. |
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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. |
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P282 | Wear cold insulating gloves/face shield/eye protection. |
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Response | |
Code | Phrase |
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P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
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P321 | |
P322 | |
P330 | Rinse mouth. |
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P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
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P350 | Gently wash with plenty of soap and water. |
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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. |
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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. |
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P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
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P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
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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 |
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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 |
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