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CAS No. : | 767-69-1 | MDL No. : | MFCD00022648 |
Formula : | C5H3BrN4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CTGFGRDVWBZYNB-UHFFFAOYSA-N |
M.W : | 199.01 | Pubchem ID : | 5287830 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 39.38 |
TPSA : | 54.46 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.61 cm/s |
Log Po/w (iLOGP) : | 0.84 |
Log Po/w (XLOGP3) : | 1.28 |
Log Po/w (WLOGP) : | 1.12 |
Log Po/w (MLOGP) : | 0.16 |
Log Po/w (SILICOS-IT) : | 1.86 |
Consensus Log Po/w : | 1.05 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.55 |
Solubility : | 0.566 mg/ml ; 0.00284 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.02 |
Solubility : | 1.89 mg/ml ; 0.00948 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.02 |
Solubility : | 0.189 mg/ml ; 0.000948 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.91 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.5 g | With N-ethyl-N,N-diisopropylamine In <i>tert</i>-butyl alcohol at 85 - 90℃; | Example 6:Preparation of 5-fluoro-3-phenyl-2-[(15)-l-(7H-purin-6-ylamino)propyl]- 4(3H)-quinazolinone [idelalisib] A mixture of 2-(l-aminopropyl)-5-fluoro-3-phenyl-3H-quinazolin-4-one (50 g, 0.17 mole) and 6-bromopurine (37.5 g, 0.18 mole) was taken in tert-butanol (500 mL). To this solution, 43.4 g DIPEA [Ν,Ν,-diisopropylethylamine] was added and the reaction mixture was stirred at 85 °C- 90 °C for 20 to 25 hours. After completion of the reaction, the reaction mixture was concentrated by distillation under vacuum and the residue was dissolved in methanol (500 mL). This solution was slowly added to water (5000 mL) and stirred for next 40 to 60 minutes. The solid was filtered then sucked dried. Finally, the solid was dried at 50 °C- 55 °C under vacuum for 4 to 5 hours to get 5-fluoro-3-phenyl-2-[(15)-l-(7H-purin-6-ylamino)propyl]-4(3H)- quinazolinone (idelalisib) (62.5 g, 89percent molar). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 2-methoxy-ethanol; water; at 130℃; for 0.5h; | EXAMPLE 9; 6-[4-(2-Bromo-5-fluorophenoxy)piperidin-l-yll-9H-purine; A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (900 mg, 4.52 mmol), 4-(2- bromophenoxy)piperidine (1488 mg, 5.43 mmol) and triethylamine (0.946 mL, 6.78 mmol) in 2- methoxyethanol (7.236 mL) and water (1.809 mL) was heated at 130 0C. After 0.5 h, the mixture was diluted with IN HCl (10 mL) and filtered. The product was washed with water and then ether to yield the title compound as a white solid. leta NMR (500 MHz, DMSO-d6): delta 13.04 (s, 1 H), 8.21 (s, 1 H), 8.12 (s, 1 H), 7.61 (dd, 1 H),7.25 (dd, 1 H), 6.79 (td, 1 H), 4.88 (t, 1 H), 4.57-4.37 (m, 2 H), 4.11-4.32 (m, 2 H), 2.04-1.97 (m, 2 H), 1.75-1.69 (m, 2 H). MS (+ESI) m/z 392, 394 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; methyl iodide; In acetonitrile; for 18h; | A. A solution of 6-Bromo-9H-purine (2 g, 10 mmol) and potassium carbonate (2.9 g, 22.1 mmol) in acetonitrile (20 mL) was treated with methyl iodide (0.69 mL, 11 mmol). After 18 h solution was filtered. The filtrate was concentrated to give 6-bromo-9-methyl-9H-purine as a 2:1 mixture of regioisomers and was used as is for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; at 85℃; for 96h; | Example 5; Preparation of IC491835: 3-Phenyl-2-ri-(9H-purin-6-ylamino)-ethvH-3H-thienor3,2- dlpyrimidin-4-one; [00157] IC491835: 3-Phenyl-2-[l-(9H-purin-6-ylamino)-ethyl]-3H- thieno[3,2-d]pyrimidin-4-one.; To a solution of 2-(l-Amino-ethyl)-3-phenyl-3H- thieno[3,2-d]pyrimidin-4-one (125 mg, 0.461 mmol) (E6, preparation shown above) in ethanol (10 mL) was added <strong>[767-69-1]6-bromopurine</strong> (292 mg, 1.47 mmol), and diisopropylethylamine (DIEA) (0.361 mL, 2.07 mmol). The resulting solution was then heated to 85C in a sealed tube for 4 d, then cooled to room temperature and concentrated. The crude residue was then purified by HPLC (C- 18 Luna column 250 x 21.20 mm, 10-20% CH3CN/H2O containing 0.05% CF3CO2H) product was obtained as a light yellow solid after lyophilizing: 1H NMR (400 MHz, DMSO-d6) delta 8. 66 (br s, IH), 8.36 (br s, 2 H), 8.23 (d, / = 5.2 Hz, IH), 7.60 (m, 3H), 7.46 (m, 3H), 4.88 (m, IH), 1.46 (d, / = 7.2 Hz, 3H). LC/MS (AP-ESI, CH3CO2H 0.05%) m/z 390 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | A suspension of <strong>[767-69-1]6-bromo-9H-purine</strong> (4.3 g, 22 mmol) in anhydrous DMF (40 mL) was treated with potassium carbonate (9.0 g, 65 mmol) and stirred for 20 min at room temperature (22 0C). The mixture was treated with 4-methoxybenzyl chloride (5.9 mL, 43 mmol) and allowed to stir for 20 h at 45 0C. The solids were removed by suction filtration and the solvent removed in vacuo. The resulting crude oil was partitioned between water and 3:1 CHC13:IPA (100 mL each). The aqueous layer was extracted with 3:1 CHCl3 :EPA (100 mL). The combined organic extract was washed with saturated NaCl (70 mL), dried over Na2SC>4, filtered, and concentrated in vacuo to a viscous oil. The crude product was chromatographed through a Redi-Sep pre-packed silica gel column (330 g), eluting with a gradient of 40% to 70% EtOAc in hexane, to provide 9-(4- methoxybenzyl)-<strong>[767-69-1]6-bromo-9H-purine</strong> (2.7 g, 39% yield) as a white waxy solid; 1H NMR (400 MHz, DMSOd6) D ppm 3.71 (s, 3 H), 5.44 (d, J=4.02 Hz, 2 H), 6.90 (d, J=8.03 Hz, 2 H), 7.34 (d, J=8.53 Hz, 2 H), 8.76 (d, J=22.59 Hz, 1 H), 8.81 (s, 1 H). | |
28% | PREPARATION 696-Bromo-9-(4-methoxybenzyl)-9H-purine1.00 g (5.02 mmol) of <strong>[767-69-1]6-bromo-9H-purine</strong> (purchased from Aldrich; cat. no. 104981 ) was suspended in 10 mL of DMF and potassium carbonate (2.08 g, 15.05 mmol) was added. The mixture was stirred at room temperature for 20 minutes and then 1 - (chloromethyl)-4-methoxybenzene (1 .40 mL, 10.06 mmol) were added. The reaction mixture was stirred at 45 C overnight. Then the mixture was evaporated to dryness and the residue was partitioned between water and dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was removed in vacuum. The product was purified by flash chromatography (0% to 50% hexane/AcOEt) to yield 447 mg (28%) of the title compound.LRMS (m/z): 320 (M+1 )+.1H NMR (400 MHz, DMSO) delta 8.83 (s, 1 H), 8.75 (s, 1 H), 7.35 (d, 2H), 6.90 (d, 2H), 5.44 (s, 2H), 3.71 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Example 95; Synthesis of 5-Hydroxymethyl-3-methyl-2-(6-thiophen-3-yl-purin tetrahydro-furan-3, 4-diol (1); Step 1; Synthesis of 2-(6-Bromo-purin-9-yl .-5-benzoyloxamethyl-3-methyl- tetrahydro-furan-3, 4-oxybenzoyl; 6-Bromo-9H-purine (Aldrich, 342.3mg, 1.72 mmol) was dissolved in anhydrous acetonitrile (6mL). BSA (0.85mL, 3. 44mmol) was added via syringe, and reaction was refluxed at 90C for 45 minutes. The reaction was then allowed to cool to room temperature. 1, 2,3, 5-Tetra-O-benzoyl-2'-C-methyl (3-D-ribofuranose (500mg, 0.861 mmol) was dissolved in anhydrous acetonitrile (6mL) and added to the reaction mixture. TMSOTf (0.625mL, 3.44 mmol) was then added to the reaction drop wise via syringe. The reaction mixture was then refluxed at 90C for 3.5 hours. The mixture was then diluted with EtOAc (lOOmL) and washed with 100mL saturated bicarbonate solution. The organic layer was extracted 2x with 100mL EtoAc and the combined organic fractions were washed with brine and dried over magnesium sulfate. This mixture was then concentrated in vacuo. The reaction was purified via column chromatography on silica gel (loaded on 5% EtoAc in DCM, eluted with 10% EtoAc in DCM) to yield an off white solid (500mg, 0.76mmol, 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With toluene-4-sulfonic acid; In chloroform; at 0 - 20℃; for 1h; | Step 1. 6-Bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine A solution of <strong>[767-69-1]6-bromo-9H-purine</strong> (5.0 g, 25 mmol) and p-toluenesulfonic acid monohydrate (0.48 g, 2.5 mmol) in chloroform (100 mL) was cooled to 0 C., treated with dihydropyran (3.4 mL, 38 mmol) and stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate, water and brine, dried with MgSO4, filtered, concentrated and purified on silica gel (eluting with 0-50% of ethyl acetate in hexanes) to give the desired product (7.0 g, 98%). |
94% | toluene-4-sulfonic acid; In chloroform; at 0 - 20℃; for 18h; | A solution of <strong>[767-69-1]6-bromo-9H-purine</strong> (2.0 g, 10 mmol) and /?-toluenesulfonic acid monohydrate (190 mg, 1.0 mmol) in chloroform (45 mL) at 0 C was treated with dihydropyran (1.4 mL, 15 mmol) and stirred at 20 C for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with saturated sodium bicarbonate, water and brine, dried with sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0% - 70%) gave the desired product (2.7 g, 94%). LCMS for CiQH^BrNziO (M+H)+: m/z = 283.0, 285.0; Found: 283.0, 285.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (Aldrich, 0.0152 g, 0.07656 mmol), 2-(1-aminopropyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.019 g, 0.064 mmol), and N,N-diisopropylethylamine (0.0134 mL, 0.07666 mmol) in ethanol (0.5 mL) was refluxed under nitrogen overnight. The mixture was cooled and purified on RP-HPLC at pH 10 (XBridge C18 column, eluding with a gradient of acetonitrile/water containing 0.15% NH4OH) to provide the product as the free base. LCMS calculated for C23H22N7O (M+H)+: m/z=412.2; Found: 412.4. 1H NMR (DMSO-d6, 300 MHz) delta 8.07 (2H, m), 7.60 (1H, dd, J=9.0 and 6.9 Hz), 7.39-7.32 (7H, m), 7.00 (1H, m), 6.85 (1H, br d, J=6.9 Hz), 5.13 (1H, m), 2.81 (3H, s), 1.72 (2H, m), 0.65 (3H, t, J=7.2 Hz) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.5% | With N-ethyl-N,N-diisopropylamine; In ethanol;Reflux; Inert atmosphere; | A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (1.65 g, 0.008270 mol), 2-(1-aminopropyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.58 g, 0.00752 mol), and N,N-diisopropylethylamine (1.571 mL, 0.009022 mol) in ethanol (60 mL) was refluxed under nitrogen overnight. The mixture was concentrated and the resulting residue was purified on silica gel, eluding with 0 to 10% methanol in methylene chloride, to provide the desired product (2.86 g, 82.5%). LCMS calculated for C17H17IN7O (M+H)+: m/z=462.1; Found: 462.2. 1H NMR (DMSO-d6, 300 MHz) delta 8.31 (2H, m), 8.19 (1H, s), 8.15 (1H, s), 7.69 (1H, dd, J=8.7 and 6.9 Hz), 7.44 (1H, d, J=8.7 Hz), 6.99 (1H, d, J=6.9 Hz), 5.69 (1H, m), 2.89 (3H, s), 1.91 (2H, m), 0.95 (3H, t, J=7.2 Hz) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (0.064 g, 0.32 mmol), 7-(1-aminoethyl)-3-methyl-6-pyridin-4-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.046 g, 0.16 mmol), and N,N-diisopropylethylamine (0.056 mL, 0.32 mmol) in ethanol (0.5 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the product as the free base. LCMS calculated for C19H17N8OS (M+H)+: m/z=405.1; Found: 405.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.037 g, 0.12 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.048 g, 0.24 mmol), and N,N-diisopropylethylamine (0.042 mL, 0.24 mmol) in ethanol (0.5 mL) was heated at 110 C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H14F2N7OS (M+H)+: m/z=426.1; Found: 426.0. 1H NMR (DMSO-d6, 400 MHz) delta 7.99 (1H, d, J=4.8 Hz), 7.63 (1H, s), 7.53 (1H, d, J=4.8 Hz), 7.24 (1H, m), 7.16 (2H, m), 6.88 (1H, br s), 5.41 (2H, br s), 5.05 (1H, m), 1.27 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) delta -111 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 7-(1-aminoethyl)-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.025 g, 0.086 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.031 g, 0.16 mmol), and N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) in ethanol (0.5 mL) was heated at 110 C. overnight. The mixture was filtered and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H15FN7OS (M+H)+: m/z=408.1; Found: 408.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 7-(1-aminoethyl)-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.025 g, 0.092 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.033 g, 0.16 mmol), and N,N-diisopropylethylamine (0.029 mL, 0.16 mmol) in ethanol (0.5 mL) was heated at 110 C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C19H16N7OS (M+H)+: m/z=390.1; Found: 390.1. 1H NMR (DMSO-d6, 400 MHz) delta 8.08 (1H, s), 8.06 (1H, s), 7.97 (1H, d, J=4.8 Hz), 7.51 (1H, d, J=4.8 Hz), 7.44~7.33 (6H, m), 5.15 (1H, m), 1.29 (3H, d, J=7.2 Hz) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | With chloro-trimethyl-silane; tin(IV) chloride; 1,1,1,3,3,3-hexamethyl-disilazane; In dichloromethane; for 0.0833333h;Microwave irradiation; Inert atmosphere; | A suspension of 25 or 26 and the corresponding purine base in anhydrous acetonitrile (5 mL/mmol) was prepared under argon atmosphere and cooled to 0 C. At this temperature, TMSCl, HMDS and a 1.0 M solution of SnCl4 in CH2Cl2 were added subsequently. The temperature was allowed to rise to 10 C before microwave irradiating at 140 C or 160 C for 5 min. The reactions were quenched by cooling (ice/water bath) and by addition of distilled water. The pH was fixed to 7-8 with a saturated NaHCO3 solution and the aqueous phase extracted with CH2Cl2 and EtOAc. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residues were purified by flash chromatography under gradient elution using mixtures of hexane/ethyl acetate (4/1 ? 1/1) or CH2Cl2/MeOH (100/1 ? 100/5) to afford 14-17. Compounds 27 and 28 were also isolated in the reactions. Compound 23 was isolated in the synthesis of 14. Traces of the N-7 regioisomer analogue was detected in the synthesis of 15.Three different conditions were investigated; method a): purine (2.5 equiv), TMSCl (4.0 equiv), HMDS (4.0 equiv), SnCl4 (1 M solution in CH2Cl2, 4.0 equiv), 160 C, microwave, 5 min; method b): purine (2.5 equiv), TMSCl (4.0 equiv), HMDS (4.0 equiv), SnCl4 (1 M solution in CH2Cl2, 4.0 equiv), 140 C, microwave, 5 min; method c): purine (1.5 equiv), TMSCl (1.5 equiv), HMDS (1.5 equiv), SnCl4 (1 M solution in CH2Cl2, 1.5 equiv), 140 C, microwave, 5 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | With chloro-trimethyl-silane; tin(IV) chloride; 1,1,1,3,3,3-hexamethyl-disilazane; In dichloromethane; for 0.0833333h;Microwave irradiation; Inert atmosphere; | A suspension of 25 or 26 and the corresponding purine base in anhydrous acetonitrile (5 mL/mmol) was prepared under argon atmosphere and cooled to 0 C. At this temperature, TMSCl, HMDS and a 1.0 M solution of SnCl4 in CH2Cl2 were added subsequently. The temperature was allowed to rise to 10 C before microwave irradiating at 140 C or 160 C for 5 min. The reactions were quenched by cooling (ice/water bath) and by addition of distilled water. The pH was fixed to 7-8 with a saturated NaHCO3 solution and the aqueous phase extracted with CH2Cl2 and EtOAc. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residues were purified by flash chromatography under gradient elution using mixtures of hexane/ethyl acetate (4/1 ? 1/1) or CH2Cl2/MeOH (100/1 ? 100/5) to afford 14-17. Compounds 27 and 28 were also isolated in the reactions. Compound 23 was isolated in the synthesis of 14. Traces of the N-7 regioisomer analogue was detected in the synthesis of 15.Three different conditions were investigated; method a): purine (2.5 equiv), TMSCl (4.0 equiv), HMDS (4.0 equiv), SnCl4 (1 M solution in CH2Cl2, 4.0 equiv), 160 C, microwave, 5 min; method b): purine (2.5 equiv), TMSCl (4.0 equiv), HMDS (4.0 equiv), SnCl4 (1 M solution in CH2Cl2, 4.0 equiv), 140 C, microwave, 5 min; method c): purine (1.5 equiv), TMSCl (1.5 equiv), HMDS (1.5 equiv), SnCl4 (1 M solution in CH2Cl2, 1.5 equiv), 140 C, microwave, 5 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (0.01504 g, 0.0076 mmol), 7-(1-aminoethyl)-3-methyl-6-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.018 g, 0.063 mmol), and N,N-diisopropylethylamine (0.013 mL, 0.0076 mol) in ethanol (0.5 mL) was refluxed under nitrogen overnight. The mixture was concentrated under reduced pressure and the residue was purified on RP-HPLC at pH 2 to provide the product as a TFA salt. LCMS calculated for free base C20H18N7OS (M+H)+: m/z=404.1; Found: 404.3. 1H NMR (DMSO-d6, 300 MHz) for a TFA salt: delta 8.54 (2H, m), 8.41 (2H, m), 7.44-7.36 (5H, m), 7.08 (1H, d, J=1.2 Hz), 5.21 (1H, m), 2.64 (3H, s), 1.38 (3H, d, J=6.6 Hz) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (0.01258 g, 0.006320 mmol), 7-(1-aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.016 g, 0.053 mmol), and N,N-diisopropylethylamine (0.011 mL, 0.006329 mmol) in ethanol (0.4 mL) was refluxed under nitrogen overnight. The mixture was evaporated and the resulting residue was purified on RP-HPLC at pH 2 to provide the product as a TFA salt. LCMS calculated for C20H17FN7OS (M+H)+: m/z=422.1; Found: 422.3. 1H NMR (DMSO-d6, 300 MHz) for TFA salt: delta 8.55 (2H, m), 8.40 (2H, m), 7.48 (1H, m), 7.25-7.22 (3H, m), 7.09 (1H, s), 5.19 (1H, m), 2.64 (3H, d, J=0.9 Hz), 1.40 (3H, d, J=6.6 Hz) ppm. 19F NMR (DMSO-d6, 282 MHz) for TFA salt: delta -74.2, -114.0 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (0.01258 g, 0.006320 mmol), 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.017 g, 0.053 mmol), and N,N-diisopropylethylamine (0.011 mL, 0.006329 mmol) in ethanol (0.4 mL) was refluxed under nitrogen overnight. The mixture was concentrated under reduced pressure and the resultant residue was purified on RP-HPLC at pH 2 to provide the product as a TFA salt. LCMS calculated for C20H16F2N7OS (M+H)+: m/z=440.1; Found: 440.3. NMR (DMSO-d6, 300 MHz) for TFA salt: delta 8.55 (1H, m), 8.39 (2H, m), 7.29 (1H, m), 7.15-7.11 (3H, m), 5.17 (1H, m), 2.64 (3H, d, J=1.2 Hz), 1.42 (3H, d, J=6.9 Hz) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (9.300 mg, 0.004673 mmol), 7-(1-aminoethyl)-3-methyl-6-pyridin-2-yl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (11 mg, 0.039 mmol), and N,N-diisopropylethylamine (8.152 muL, 0.004680 mmol) in ethanol (0.3 mL) was refluxed under nitrogen overnight. The mixture was concentrated under reduced pressure and the residue was purified on RP-HPLC (eluding with a gradient of methanol/water containing 1% TFA) to provide the product as a TFA salt. LCMS calculated for C19H17N8OS (M+H)+: m/z=405.1; Found: 405.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.8% | (S)-7-(1-Aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (2.30 g, 7.58 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (2.716 g, 13.65 mmol), N,N-diisopropylethylamine (6.60 mL, 37.9 mmol) were dissolved in ethanol (15 mL) and the resultant mixture was heated at reflux under a nitrogen atmosphere for 17 h. HPLC indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel using gradient elution starting at 100% DCM with increasing polarity to 25% of a mixture of DCM/MeOH/aq.NH4OH (100:5:0.5, v/v/v) in DCM. After the silica chromatography, 2.1 g of crude product was obtained. This crude product was further purified by preparative reversed phase HPLC using 0.1% TFA in water and acetonitrile as mobile phases at a flow rate of 60 mL/min. on a SunFire C18, 5 muM, 30×100 mm column. Pure (S)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one trifluoroacetic acid salt (trifluoroacetic acid salt) (1.86 g, 3.47 mmol, 45.8% yield) was obtained as a white solid after lyophilization. LCMS calculated for C20H17FN7OS (M+H)+ for the free base: m/z 422.1; Found: 422.0). 1H NMR (500 MHz, DMSO-d6) delta 9.03 (br s, 1H), 8.53 (s, 1H), 8.51 (s, 1H), 7.47 (m, 1H), 7.21 (m, 3H), 7.09 (s, 1H), 5.23 (m, 1H), 2.65 (d, J=1.3 Hz, 3H), 1.43 (d, J=7.0 Hz, 3H). 13C NMR (125 MHz, DMSO-d6) delta 164.0, 162.1 (JCF=244.9 Hz), 160.5, 160.3, 150.9, 147.6, 147.5, 144.4, 135.9, 135.9, 130.2 (JCF=8.3 Hz), 126.9, 117.4 (JCF=22.6 Hz), 116.1, 114.8 (JCF=21.5 Hz), 111.1, 107.8, 48.5, 19.6, 18.0. Reversed phase analytical HPLC showed purity at 99.8 area %. Chiral HPLC analysis was performed on Chiralcel OJ-H, 4.6×250 mm, 5 micron column using 60% ethanol/40% hexanes as eluent at a flow rate of 0.5 mL/min. The peak for the desired enantiomer (5)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one was observed at a retention time of 21.171 min. (99.1 area %). The minor peak for the undesired enantiomer (R)-7-(1-(9H-purin-6-ylamino)ethyl)-6-(3-fluorophenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one was observed at a retention time of 13.358 min (0.9 area %). The enantiomeric excess of the desired enantiomer was 98.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (0.038 g, 0.19 mmol), 7-(1-aminoethyl)-3-methyl-6-(1,3-thiazol-2-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.028 g, 0.096 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.19 mmol) in ethanol (0.3 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.05% trifluoroacetic acid (TFA)) to give the product as a TFA salt. LCMS calculated for C17H15N8OS2 (M+H)+: m/z=411.1; Found: 411.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (0.038 g, 0.19 mmol), 7-(1-aminoethyl)-3-methyl-6-(1,3-thiazol-4-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.028 g, 0.096 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.19 mmol) in ethanol (0.3 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.05% TFA) to give the product as a TFA salt. LCMS calculated for C17H15H8OS2 (M+H)+: m/z=411.1; Found: 411.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (0.076 g, 0.38 mmol), 7-(1-aminoethyl)-6-(4-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.058 g, 0.19 mmol), and N,N-diisopropylethylamine (0.066 mL, 0.38 mmol) in ethanol (0.6 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated, and the resultant residue was purified on RP-HPLC (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.05% TFA) to give the product as a TFA salt. LCMS calculated for C20H17FN7OS (M+H)+: m/z=422.1; Found: 422.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 7-(1-aminoethyl)-3-methyl-6-(4-methylphenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.040 g, 0.13 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.040 g, 0.20 mmol), and N,N-diisopropylethylamine (0.046 mL, 0.27 mmol) in ethanol (0.3 mL) was heated at 110 C. overnight. The mixture was filtered and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.05% TFA), to give the desired product as a TFA salt. LCMS calculated for C21H20N7OS (M+H)+: m/z=418.1; Found: 418.1. 1H NMR (DMSO-d6, 400 MHz) delta 8.57 (1H, br s), 8.39 (1H, s), 8.38 (1H, s), 7.19 (4H, s), 7.02 (1H, d, J=1.2 Hz), 5.17 (1H, m), 2.59 (3H, s), 2.30 (3H, s), 1.32 (3H, d, J=6.8 Hz) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 7-(1-aminoethyl)-6-(3-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.045 g, 0.14 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.056 g, 0.28 mmol), and N,N-diisopropylethylamine (0.049 mL, 0.28 mmol) in ethanol (0.5 mL) was heated at 110 C. overnight. The mixture was filtered and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.05% TFA), to give the desired product as a TFA salt. LCMS calculated for C20H17ClN7OS (M+H)+: m/z=438.1; Found: 438.0. 1H NMR (DMSO-d6, 400 MHz) delta 8.29 (1H, s), 7.46 (3H, m), 7.37 (1H, m), 7.08 (1H, s), 5.14 (1H, m), 2.64 (3H, s), 1.37 (3H, d, J=6.8 Hz) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 7-(1-aminoethyl)-6-(2-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.040 g, 0.13 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.052 g, 0.26 mmol), and N,N-diisopropylethylamine (0.046 mL, 0.26 mmol) in ethanol (0.5 mL, 8 mmol) was heated at 110 C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.05% TFA) to give the desired product as a diasteroisomeric mixture (TFA salt). LCMS calculated for C20H17FN7OS (M+H)+: m/z=422.1; Found: 422.1. 1H NMR (DMSO-d6, 400 MHz) delta 8.50 (1H, br s), 8.40 (1H, s), 8.38 (1H, s), 7.50 (1H, m), 7.36~7.25 (3H, m), 7.10 (1H, s), 5.14 (1H, m), 2.64 (3H, s), 1.48 (1.5H, d, J=6.8 Hz), 1.34 (1.5H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) delta -112, -114 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 7-(1-aminoethyl)-6-(2,3-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.038 g, 0.12 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.047 g, 0.24 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.24 mmol) in ethanol (0.5 mL) was heated at 110 C. overnight. The mixture was filtered, and the filtrate was purified on prep-LCMS (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.05% TFA), to give the desired product as a mixture of two diastereomers (TFA salt). LCMS calculated for C20H16F2N7OS (M+H)+: m/z=440.1; Found: 440.0. 1H NMR (DMSO-d6, 400 MHz) delta 8.38~8.34 (3H, m), 7.49~7.10 (4H, m), 5.12 (1H, m), 2.64 (3H, s), 1.50 (1.5H, d, J=6.8 Hz), 1.36 (1.5H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) delta -137.8, -139.8, -140.0 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 7-(1-aminoethyl)-6-(3-chloro-5-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.035 g, 0.10 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.041 g, 0.21 mmol), and N,N-diisopropylethylamine (0.036 mL, 0.21 mmol) in ethanol (0.5 mL) was heated at 110 C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.05% TFA) to give the desired product as a TFA salt. LCMS calculated for C20H16ClFN7OS (M+H)+: m/z=456.1; Found: 456.0. 1H NMR (DMSO-d6, 400 MHz) delta 8.52 (1H, br s), 8.39 (1H, s), 8.36 (1H, s), 7.43 (1H, d, J=8.0 Hz), 7.33-7.27 (3H, m), 7.10 (1H, s), 5.15 (1H, m), 2.64 (3H, s), 1.41 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) delta -112 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 7-(1-aminoethyl)-6-(5-fluoropyridin-3-yl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (9 mg, 0.03 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (8.8 mg, 0.044 mmol), and N,N-diisopropylethylamine (0.010 mL, 0.059 mmol) in ethanol (0.3 mL) was heated at 110 C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.05% TFA), to give the desired product as a TFA salt. LCMS calculated for C19H16FN8OS (M+H)+: m/z=423.1; Found: 423.1. 1H NMR (DMSO-d6, 400 MHz) delta 8.60 (1H, d, J=2.8 Hz), 8.47 (1H, s), 8.35 (1H, s), 8.33 (1H, s), 7.82 (1H, d, J=9.6 Hz), 7.12 (1H, s), 5.09 (1H, m), 2.64 (3H, s), 1.43 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) delta -128 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 7-(1-aminoethyl)-6-(2-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.028 g, 0.088 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.035 g, 0.18 mmol), and N,N-diisopropylethylamine (0.030 mL, 0.18 mmol) in ethanol (0.4 mL) was heated at 110 C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.05% TFA), to give two diastereomers as a TFA salts. On an analytic HPLC (Waters SunFire C18, 2.1×50 mm, 5 muM; injection volume 2 muL; flow rate 3 mL/min; at gradient from 2% to 80% acetonitrile in water containing 0.15% NH4OH in 3 min): First peak has retention time 1.421 min; LCMS calculated for C20H17ClN7OS (M+H)+: m/z=438.1; Found: 438.0. Second peak has retention time 1.516 min; LCMS calculated for C20H17ClN7OS (M+H)+: m/z=438.1; Found: 438.0. 1H NMR (DMSO-d6, 400 MHz) delta 8.36 (1H, s), 8.32 (1H, s), 7.57 (2H, m), 7.44 (2H, m), 7.11 (1H, s), 5.04 (1H, m), 2.64 (1H, s), 1.34 (3H, d, J=6.8 Hz) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 7-(1-aminoethyl)-6-(2,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.045 g, 0.14 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.042 g, 0.21 mmol), and N,N-diisopropylethylamine (0.049 mL, 0.28 mmol) in ethanol (0.3 mL) was heated at 110 C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.05% TFA), to give the desired product as a mixture of two diastereomers (TFA salts). LCMS calculated for C20H16F2N7OS (M+H)+: m/z=440.1; Found: 440.1. 1H NMR (DMSO-d6, 400 MHz) delta 8.64 (1H, br s), 8.38 (1H, s), 8.36 (1H, s), 7.34~7.19 (3H, m), 7.08 (1H, m), 5.06 (1H, m), 2.60 (3H, s), 1.46 (1.5H, d, J=6.8 Hz), 1.33 (1.5H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) delta -117.8, -119.4, -119.8, -119.9 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 2-(1-azido ethyl)-6-methyl-3-phenyl-4H-pyrido pyrimidin-4-one (31 mg, 0.10 mmol) in tetrahydrofuran (1 mL) and water (0.2 mL) was treated with 1 M of trimethylphosphine in tetrahydrofuran (0.20 mL, 0.20 mmol) and stirred at 20 C. for 1 hour. The reaction mixture was diluted with brine (2 mL) and extracted with dichloromethane (3*15 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated to a crude residue. This intermediate amine was used without further purification. A solution of the amine in ethanol (1 mL) was treated with <strong>[767-69-1]6-bromo-9H-purine</strong> (31 mg, 0.16 mmol) and N,N-diisopropylethylamine (24 mL, 0.14 mmol) and then heated at 90 C. for 18 hours. The reaction mixture was purified by RP-HPLC (XBridge C18 column, eluding with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min). LCMS for C22H20N7O (M+H)+: m/z=398.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | A mixture of 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.105 g, 0.327 mmol) (1st peak from Example 23, step 1 chiral separation), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.117 g, 0.588 mmol), and N,N-diisopropylethylamine (0.114 mL, 0.654 mmol) in ethanol (1.5 mL) was heated at 110 C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product (0.073 g, 51%). LCMS calculated for C20H16F2N7OS (M+H)+: m/z=440.1; Found: 440.0. 1H NMR (DMSO-d6, 500 MHz) delta 8.05 (2H, s), 7.34 (1H, br s), 7.18 (1H, m), 7.12 (2H, m), 6.84 (1H, s), 7.01 (1H, s), 5.07 (1H, m), 2.43 (3H, s), 1.31 (3H, d, J=7.0 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) delta -111 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | A mixture of single enantiomer 7-(1-aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.125 g, 0.412 mmol) made from above, <strong>[767-69-1]6-bromo-9H-purine</strong> (0.148 g, 0.742 mmol), and N,N-diisopropylethylamine (0.144 mL, 0.824 mmol) in ethanol (1.5 mL) was heated at 110 C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluding with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product (0.076 g, 44%). LCMS calculated for C20H17FN7OS (M+H)+: m/z=422.1; Found: 422.0. 1H NMR (DMSO-d6, 500 MHz) delta 8.05 (2H, s), 7.43 (1H, m), 7.24~7.14 (5H, m), 6.99 (1H, s), 5.08 (1H, m), 2.59 (3H, s), 1.29 (3H, d, J=6.5 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) delta -114 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | In tert-butyl alcohol; for 24h;Reflux; | Example 24 (S)-2-(1-(9H-purin-6-ylamino)ethyl)-6-bromo-3-phenyl-4H-chromen-4-one To a solution of intermediate 17 (0.20 g, 0.581 mmoles) in tert-butanol (6 ml), N,N-diisopropylethyl amine (0.2 ml, 1.162 mmoles) and <strong>[767-69-1]6-bromopurine</strong> (0.087 g, 0.435 mmoles) were added and refluxed for 24 h. The reaction mixture was concentrated, diluted with water, extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:ethyl acetate to afford the title compound as yellow solid (0.065 g, 24% yield). MP: 151-154 C. 1H-NMR (delta ppm, DMSO-D6, 400 MHz): delta 12.94 (s, 1H), 8.09 (br s, 3H), 7.94 (d, J=7.9 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.42 (m, 6H), 5.22 (br t, 1H), 1.82 (d, J=6.4 Hz, 3H). Mass: 463.99 (M+1). |
With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; for 24h;Reflux; | This example is also described in Example 24 of WO 2011/055215. To a solution of (S)-2-(1-aminoethyl)-6-bromo-3-phenyl-4H-chromen-4-one (0.20 g, 0.581 mmoles) in tert-butanol (6 ml), N,N-diisopropylethyl amine (0.2 ml, 1.162 mmoles) and <strong>[767-69-1]6-bromopurine</strong> (0.087 g, 0.435 mmoles) are added and refluxed for 24 h. The reaction mixture is concentrated, diluted with water, extracted with ethyl acetate. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product is purified by column chromatography with methanol:ethyl acetate to afford the title compound as yellow solid. MP: 151-154 C. 1H-NMR (delta ppm, DMSO-D6, 400 MHz): delta 12.94 (s, 1H), 8.09 (br s, 3H), 7.94 (d, J=7.9 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.42 (m, 6H), 5.22 (br t, 1H), 1.82 (d, J=6.4 Hz, 3H). Mass: 463.99 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; for 24h;Reflux; | Example 25 2-((9H-purin-6-ylamino)methyl)-6-bromo-3-phenyl-4H-chromen-4-one To a solution of intermediate 19 (0.20 g, 0.605 mmoles) in tert-butanol (4 ml), N,N-diisopropylethylamine (0.2 ml, 1.211 mmoles) and <strong>[767-69-1]6-bromopurine</strong> (0.096 g, 0.484 mmoles) were added and refluxed for 24 h. The reaction mixture was concentrated, diluted with water, extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:ethyl acetate to afford the title compound as yellow solid (0.065 g, 24% yield). MP: 151-154 C. 1H-NMR (delta ppm, DMSO-D6, 400 MHz): delta 12.90 (s, 1H), 8.20 (ms, 4H), 7.91 (dd, J=9.0, 2.5 Hz, 1H), 7.49-7.35 (m, 6H), 4.64 (br s, 2H). Mass: 448.17 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; for 24h;Reflux; | Example 45 2-((9H-purin-6-ylamino)methyl)-3-(2-fluorophenyl)-4H-chromen-4-one To a solution of intermediate 64 (0.330 g, 1.22 mmoles) in tert-butanol (4 ml), N,N-diisopropylethylamine (0.42 ml, 2.45 mmoles) and <strong>[767-69-1]6-bromopurine</strong> (0.195 g, 0.980 mmoles) were added and refluxed for 24 h. The reaction mixture was concentrated, diluted with water, extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:ethyl acetate to afford the title compound as yellow solid (0.040 g, 8% yield). MP: 143-147 C. 1H-NMR (delta ppm, DMSO-D6, 400 MHz): delta 12.90 (s, 1H), 8.20 (br s, 1H), 8.10 (s, 1H), 8.09 (s, 1H), 8.05 (dd, J=7.9, 1.4 Hz, 1H), 7.79 (dt, J=8.6, 1.5 Hz, 1H), 7.51-7.41 (m, 4H), 7.28 (m, 2H), 4.64 (br s, 2H). Mass: 387.90 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; for 24h;Reflux; | Example 46 2-((9H-purin-6-ylamino)methyl)-3-(3-fluorophenyl)-4H-chromen-4-one To a solution of intermediate 65 (1.50 g, 6.51 mmoles) in dichloromethane (15 ml), triethylamine (2.7 ml, 19.54 mmoles) was added followed by N-Boc-Glycine (1.3 g, 7.81 mmoles). To this mixture HATU (4.9 g, 13.03 mmoles) was added and stirred at RT for 12 h. The reaction mixture was quenched by the addition of water and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the isoflavone intermediate (0.80 g). To a solution of this intermediate (0.80 g) in dichloromethane (10 ml), trifluoroacetic acid (1.5 ml) was added and stirred at RT for 2 h. The reaction mixture was concentrated, basified with sodium bicarbonate solution, extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the amine intermediate (0.471 g). To a solution of this amine intermediate (0.30 g, 1.14 mmoles) in tert-butanol (6 ml), N,N-diisopropylethylamine (0.5 ml, 2.94 mmoles) and <strong>[767-69-1]6-bromopurine</strong> (0.177 g, 0.891 mmoles) were added and refluxed for 24 h. The reaction mixture was concentrated, diluted with water, extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:ethyl acetate to afford the title compound as brown solid (0.235 g, 55% yield). MP: 211-214 C. 1H-NMR (delta ppm, DMSO-D6, 400 MHz): delta 12.97 (s, 1H), 8.20 (br s, 1H), 8.14 (s, 1H), 8.11 (s, 1H), 8.06 (dd, J=7.9, 1.4 Hz, 1H), 7.78 (dt J=8.4, 1.3 Hz, 1H), 7.49 (m, 3H), 7.27-7.17 (m, 3H), 4.10 (q, J=5.3 Hz, 1H), 3.16 (d, J=5.0 Hz, 2H). Mass: 387.90 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; for 24h;Reflux; | Example 47 (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one To a solution of intermediate 65 (2.0 g, 8.68 mmoles) in dichloromethane (20 ml), triethylamine (3.6 ml, 26.06 mmoles) was added followed by N-Boc-Alanine (1.97 g, 10.42 mmoles). To this mixture HATU (6.6 g, 17.37 mmoles) was added and stirred at RT for 12 h. The reaction mixture was quenched by the addition of water and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the isoflavone intermediate (1.70 g). To a solution of this intermediate (1.7 g) in dichloromethane (20 ml), trifluoroacetic acid (3 ml) was added and stirred at RT for 2 h. The reaction mixture was concentrated, basified with sodium bicarbonate solution, extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the amine intermediate (0.641 g). To a solution of this amine intermediate (0.30 g, 1.05 mmoles) in tert-butanol (6 ml), N,N-diisopropylethylamine (0.36 ml, 2.17 mmoles) and <strong>[767-69-1]6-bromopurine</strong> (0.168 g, 0.847 mmoles) were added and refluxed for 24 h. The reaction mixture was concentrated, diluted with water, extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:ethyl acetate to afford the title compound as off-white solid (0.041 g, 10% yield). MP: 135-138 C. 1H-NMR (delta ppm, DMSO-D6, 400 MHz): delta 12.95 (s, 1H), 8.15 (t, J=6.8 Hz, 1H), 8.11 (s, 1H), 8.08 (s, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.81 (t, J=7.3 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.49 (t, J=7.3 Hz, 2H), 7.25 (m, 3H), 5.19 (br m, 1H), 1.56 (d, J=6.9 Hz, 3H). Mass: 402.18 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; for 24h;Reflux; | Example 56 (R)-2-(1-(9H-purin-6-ylamino)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one To a solution of intermediate 65 (1.00 g, 4.34 mmoles) in dichloromethane (15 ml), triethylamine (1.8 ml, 13.02 mmoles) was added followed by N-Boc-D-Alanine (0.986 g, 5.21 mmoles). To this mixture HATU (3.3 g, 8.68 mmoles) was added and stirred at RT for 12 h. The reaction mixture was quenched by the addition of water and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the isoflavone intermediate (1.70 g). To a solution of this intermediate (0.8 g) in dichloromethane (10 ml), trifluoroacetic acid (3 ml) was added and stirred at RT for 2 h. The reaction mixture was concentrated, basified with sodium bicarbonate solution, extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the amine intermediate (0.410 g). To a solution of this amine intermediate (0.41 g, 1.52 mmoles) in tert-butanol (7 ml), N,N-diisopropylethylamine (0.53 ml, 3.04 mmoles) and <strong>[767-69-1]6-bromopurine</strong> (0.242 g, 1.21 mmoles) were added and refluxed for 24 h. The reaction mixture was concentrated, diluted with water, extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:ethyl acetate to afford the title compound as off-white solid (0.130 g, 21% yield). MP: 274-276 C. 1H-NMR (delta ppm, DMSO-D6, 400 MHz): delta 12.96 (s, 1H), 8.14-8.01 (m, 4H), 8.11 (s, 1H), 7.81 (dt, J=8.5, 1.5 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.49 (m, 2H), 7.25-7.19 (m, 3H), 5.18 (br m, 1H), 1.56 (d, J=7.0 Hz, 3H). Mass: 402.04 (M++1). | |
With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; for 24h;Reflux; | This example is also described in Example 56 of WO 2011/055215. To a solution of (R)-2-(1-Amino-ethyl)-3-(3-fluoro-phenyl)-chromen-4-one (0.41 g, 1.52 mmoles) in tert-butanol (7 ml), N,N-diisopropylethylamine (0.53 ml, 3.04 mmoles) and <strong>[767-69-1]6-bromopurine</strong> (0.242 g, 1.21 mmoles) are added and refluxed for 24 h. The reaction mixture is concentrated, diluted with water, and extracted with ethyl acetate. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product is purified by column chromatography with methanol:ethyl acetate to afford the title compound as an off-white solid. MP: 274-276 C. 1H-NMR (delta ppm, DMSO-D6, 400 MHz): delta 12.96 (s, 1H), 8.14-8.01 (m, 4H), 8.11 (s, 1H), 7.81 (dt, J=8.5, 1.5 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.49 (m, 2H), 7.25-7.19 (m, 3H), 5.18 (br m, 1H), 1.56 (d, J=7.0 Hz, 3H). Mass: 402.04 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; for 24h;Reflux; | Example 73 (S)-2-(1-(9H-purin-6-ylamino)ethyl)-3-phenyl-4H-chromen-4-one To a solution of intermediate 59 (2.0 g, 9.42 mmoles) in dichloromethane (20 ml), triethylamine (3.9 ml, 28.26 mmoles) was added followed by N-Boc-Alanine (1.90 g, 10.42 mmoles). To this mixture HATU (6.6 g, 17.37 mmoles) was added and stirred at RT for 12 h. The reaction mixture was quenched by the addition of water and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the isoflavone intermediate (1.70 g). To a solution of this intermediate (1.7 g) in dichloromethane (20 ml), trifluoroacetic acid (3 ml) was added and stirred at RT for 2 h. The reaction mixture was concentrated, basified with sodium bicarbonate solution, extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the amine intermediate (0.641 g). To a solution of this amine intermediate (0.30 g, 1.05 mmoles) in tert-butanol (6 ml), N,N-diisopropylethylamine (0.36 ml, 2.17 mmoles) and <strong>[767-69-1]6-bromopurine</strong> (0.168 g, 0.847 mmoles) were added and refluxed for 24 h. The reaction mixture was concentrated, diluted with water, extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:ethyl acetate to afford the title compound as off-white solid (0.041 g, 10% yield). MP: 135-138 C. 1H-NMR (delta ppm, DMSO-D6, 400 MHz): delta 12.95 (s, 1H), 8.15 (t, J=6.8 Hz, 1H), 8.11 (s, 1H), 8.08 (s, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.81 (t, J=7.3 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.49 (t, J=7.3 Hz, 2H), 7.25 (m, 3H), 5.19 (br m, 1H), 1.56 (d, J=6.9 Hz, 3H). Mass: 384.12 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With N-ethyl-N,N-diisopropylamine; In ethanol; at 110℃; for 16h; | 1 - [3 -(3 ,5 -Difluorophenyl)pyrazolo [ 1 ,5 -a]pyridin-2-yl] ethanamine trifluoroacetate (16 mg, 0.07 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (13 mg, 0.07 mmol, Aldrich 104981) and N,N- diisopropylethylamine (12 mL, 0.07 mmol) were stirred in ethanol (0.47 mL) and heated to 110 C for 16 hours. Purification by preparative LCMS (H20 with 0.1 % TFA (pH 2), 5%acetonitrile to 24% acetonitrile over 1 minute, 24% to 48% acetonitrile over 12 minutes, Waters Sunfire C18, 5 muMu particle size, 30 x 100 mm, RT = 8.75 min.) gave the desired compound (4.0 mg, 12%). LCMS for C20H17F2N7 (M+H)+: m/z = 392.0. 1H NMR (300 MHz, DMSO-<¾): delta 8.75 (m, 1 H), 8.39 (m, 1 H), 8.28 (m, 1 H), 7.64 (m, 1 H), 7.31 (m, 1 H), 7.23 (m, 2 H), 7.17 (m, 1 H), 6.98 (m, 1 H), 5.84 (m, 1 H), 1.62 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With N-ethyl-N,N-diisopropylamine; In ethanol; at 90℃; for 18h; | A solution of l-[3-(3,5-difluorophenyl)-5-methylimidazo[l,2-a]pyridin-2-yl]ethanamine (40 mg, 0.14 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> [Aldrich, 104981] (33 mg, 0.17 mmol), and N,N- diisopropylethylamine (29 mu, 0.17 mmol) in ethanol (1.6 mL) was heated at 90 C for 18 h. The reaction mixture was diluted with methanol and purified by preparative LCMS to give the desired product (33 mg, 58%) as a white solid. LCMS for C2iH18F2N7 (M+H)+: m/z = 406.1 .H NMR (400 MHz, CD3OD): delta 8.12 (s, 1 H), 8.03 (br s, 1 H), 7.49 (d, J= 9.0 Hz, 1 H), 7.25(dd, J= 9.0, 6.8 Hz, 1 H), 7.21 - 7.18 (m, 1 H), 7.00 - 6.94 (m, 2 H), 6.66 (d, J= 6.8 Hz, 1 H), 5.44 (br s, 1 H), 2.15 (s, 3 H), 1.69 (d, J= 7.0 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (0.0274 g, 0.138 mmol), l-{5-chloro-8-[4-(2- methoxyethyl)piperazin-l-yl]quinolin-7-yl}ethanamine (0.024 g, 0.069 mmol), and N,N- diisopropylethylamine (0.02396 mL, 0.1376 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the desired product as a tris-TFA salt. LCMS calculated for C23H28C1N80(M+H)+: m/z = 467.2; found: 467.1. 1H NMR (DMSO-<¾, 400 MHz) delta 9.70 (1H, br s), 8.98 (1H, s), 8.50 (1H, d, J= 8.0 Hz), 8.21 (2H, m), 8.02 (1H, s), 7.66 (1H, dd, J= 8.4 and 4.4 Hz), 6.41 (1H, m), 4.42-3.02 (12H, m), 3.33 (3H, s), 1.55 (3H, d, J= 6.4 Hz) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (0.0274 g, 0.138 mmol), l-{5-chloro-8-[4-(2- methoxyethyl)piperazin-l-yl]quinolin-7-yl}ethanamine (0.024 g, 0.069 mmol), and N,N- diisopropylethylamine (0.02396 mL, 0.1376 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the desired product as a tris-TFA salt. LCMS calculated for C23H28C1N80(M+H)+: m/z = 467.2; found: 467.1. 1H NMR (DMSO-<¾, 400 MHz) delta 9.70 (1H, br s), 8.98 (1H, s), 8.50 (1H, d, J= 8.0 Hz), 8.21 (2H, m), 8.02 (1H, s), 7.66 (1H, dd, J= 8.4 and 4.4 Hz), 6.41 (1H, m), 4.42-3.02 (12H, m), 3.33 (3H, s), 1.55 (3H, d, J= 6.4 Hz) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (0.0203 g, 0.102 mmol), N-{(3S)-l-[7-(l-aminoethyl)- 5-chloroquinolin-8-yl]pyrrolidin-3-yl}acetamide (0.017 g, 0.051 mmol), and N,N- diisopropylethylamine (0.01779 mL, 0.1022 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the products as a mixture of diastereoisomers (bis- TFA salts). LCMS calculated for C22H24C1N80(M+H)+: m/z = 451.2; found: 451.1. 1H NMR (OMSO-d6, 400 MHz) delta 8.99 (1H, dd, J= 4.0 and 1.2 Hz), 8.88 (1H, br s), 8.53 (1H, dd, J= 8.4 and 1.2 Hz), 8.31 (2H, m), 7.96 (1H, s), 7.66 (1H, dd, J= 8.8 and 4.0 Hz), 6.29 (1H, m), 4.54 (1H, m), 3.78 (3H, m), 3.63 (1H, m), 3.42 (1H, m), 2.31 (1H, m), 1.98 (1H, m), 1.86 and 1.84 (3H, 2 singlet in ratio 1 :2), 1.58 (3H, d, J= 6.8 Hz) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (0.0174 g, 0.0876 mmol), l-{5-chloro-8-[(2R)-2-(methoxymethyl)pyrrolidin-l-yl]quinolin-7-yl}ethanamine (0.014 g, 0.044 mmol), and N,N- diisopropylethylamine (0.01525 mL, 0.0876 mmol) in ethanol (0.1 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the product as a mixture of diastereoisomers (bis- TFA salts). LCMS calculated for C22H25C1N70(M+H)+: m/z = 438.2; found: 438.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (0.0688 g, 0.346 mmol), l-[5-chloro-8-(3- fluorophenyl)quinolin-7-yl]ethanamine (0.052 g, 0.17 mmol), and N,N-diisopropylethylamine (0.0602 mL, 0.346 mmol) in ethanol (0.6 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C 18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the desired product as bis-TFA salt. LCMS calculated forC22Hi7ClFN6(M+H)+: m/z = 419.1; found: 419.0. 1H NMR (DMSO-<¾, 400 MHz) delta 9.04 (1H, br s), 8.88 (1H, dd, J= 4.0 and 1.6 Hz), 8.54 (1H, dd, J= 8.4 and 1.6 Hz), 8.40 (1H, m), 8.32 (1H, m), 8.06 (1H, d, J= 7.6 Hz), 7.66 (1H, dd, J= 8.4 Hz and 4.0 Hz), 7.50 (1H, m), 7.42 (1H, m), 7.25 (1H, m), 7.15 (1H, m), 5.30 (1H, m), 1.50 (3H, d, J= 6.8 Hz) ppm. 19F NMR (DMSO-<¾, 376.28 MHz) delta -75.0 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[767-69-1]6-bromo-9H-purine</strong> (0.02696 g, 0.1355 mmol), l-[l-(3-fluorophenyl)-2- naphthyl] ethanamine (0.030 g, 0.1 1 mmol), and N,N-diisopropylethylamine (0.024 mL, 0.14 mmol) in ethanol (0.9 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the product as a TFA salt. LCMS calculated for C23Hi9FN5(M+H)+: m/z = 384.2; found: 384.3. 1H NMR (DMSO-d6, 400 MHz) delta 8.92 (1H, br s), 8.30 (2H, m), 7.97 (1H, d, J= 9.2 Hz), 7.90 (1H, d, J= 7.6 Hz), 7.79 (1H, m), 7.57 (1H, m), 7.47 (1H, m), 7.40 (2H, m), 7.31 (1H, m), 7.19 (2H, m), 5.23 (1H, m), 1.49 (3H, m) ppm. 19F NMR (DMSO-d6, 376.28 MHz) delta -74.6 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-[5-ethyl-8-(3-fluorophenyl)quinolin-7-yl]ethanamine (7.3 mg, 0.025 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (9.9 mg, 0.050 mmol) and N, N-diisopropylethylamine (0.013 mL, 0.074 mmol) in ethanol (0.2 mL) was heated at 1 10 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. LCMS calculated for C24H22FN6 (M+H)+: m/z = 413.2; Found: 413.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-{5-chloro-8-[(35)-3-fluoropyrrolidin-l-yl]quinolin-7-yl} ethanamine (5.2 mg, 0.018 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (5.6 mg, 0.028 mmol) and N,N-diisopropylethylamine (0.0093 mL, 0.053 mmol) in ethanol (0.5 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge C 18 column, eluting with a gradient of acetonitrile in water with 0.05% trifiuoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a mixture of diastereoisomers. LCMS calculated for C20H20CIFN7 (M+H)+: m/z = 412.1; Found: 412.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 2-{4-[7-(l-aminoethyl)-5-chloroquinolin-8-yl]piperazin-l-yl} ethanol (0.016 g, 0.048 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.019 g, 0.096 mmol) md N,N- diisopropylethylamine (0.025 mL, 0.14 mmol) in ethanol (0.5 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. LCMS calculated for C22H26C1N80 (M+H)+: m/z = 453.2; Found: 453.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-[7-(l-aminoethyl)-5-chloroquinolin-8-yl]piperidine- 4-carbonitrile (5.4 mg, 0.017 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (6.8 mg, 0.034 mmol) and N,N-diisopropylethylamine (0.0090 mL, 0.051 mmol) in ethanol (0.5 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. LCMS calculated for C22H22CIN8 (M+H)+: m/z = 433.2; Found: 433.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-[7-(l-aminoethyl)-5-chloroquinolin-8-yl]pyrrolidine- 3-carbonitrile (0.017 g, 0.056 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.022 g, 0.1 1 mmol) and N,N-diisopropylethylamine (0.030 mL, 0.17 mmol) in ethanol (0.5 mL) was heated at 1 10 C overnight. The mixture was purified on a preparative LCMS (XBridge C 18 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a mixture of diastereoisomers. LCMS calculated for C21H20CIN8 (M+H) : m/z = 419.1 ; Found: 419.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 1 -[5-chloro-8-(3-fluoropiperidin- 1 -yl)quinolin-7-yl]ethanamine (0.026 g,0.084 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.034 g, 0.17 mmol) and N,N-diisopropylethylamine (0.044 mL, 0.25 mmol) in ethanol (0.5 mL) was heated at 1 10 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. LCMS calculated for C2iH22ClFN7 (M+H)+: m/z = 426.2; Found: 426.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-[5-chloro-8-(4-fluoropiperidin-l-yl)quinolin-7-yl]ethanamine (0.040 g, 0.13 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.052 g, 0.26 mmol) and N,N-diisopropylethylamine (0.068 mL, 0.39 mmol) in ethanol (0.5 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. LCMS calculated for C21H22CIFN7 (M+H)+: m/z = 426.2; Found: 426.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of {l-[7-(l-aminoethyl)-5-chloroquinolin-8-yl]piperidin-3-yl} methanol (0.025 g, 0.078 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.031 g, 0.16 mmol) and N, N- diisopropylethylamine (0.041 mL, 0.23 mmol) in ethanol (0.5 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. First peak retention time 1.536 minutes, LCMS calculated for C22H25CIN7O (M+H)+: m/z = 438.2; Found: 438.0. Second peak retention time 1.677 minutes, LCMS calculated for C22H25C1N70 (M+H)+: m z = 438.2; Found: 438.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of {l-[7-(l-aminoethyl)-5-chloroquinolin-8-yl]piperidin-4-yl} methanol (0.026 g, 0.081 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.032 g, 0.16 mmol) and N, N- diisopropylethylamine (0.042 mL, 0.24 mmol) in ethanol (0.5 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. LCMS calculated for C22H25CIN7O (M+H)+: m/z = 438.2; Found: 438.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-[5-chloro-8-(4-cyclohexylpiperazin-l-yl)quinolin-7-yl] ethanamine (0.097 g, 0.26 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.10 g, 0.52 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.78 mmol) in ethanol (1 mL) was heated at 1 10 C overnight. The mixture was purified on a preparative LCMS (XBridge C 18 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. LCMS calculated for C26H32C1N8 (M+H)+: m/z = 491.2; Found: 491.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-[5-chloro-8-(4-cyclopropylpiperazin-l-yl)quinolin-7-yl]ethanone (0.0611 g, 0.185 mmol) and ammonium acetate (0.143 g, 1.85 mmol) in methanol (0.8 mL) and acetonitrile (0.8 mL) was heated at 65 C in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride intetrahydrofuran (0.46 mL, 0.46 mmol). The reaction was heated at 65 C overnight. The mixture was cooled to room temperature, quenched with sat. NaHC03 solution and extracted with dichloromethane. The combined organic layers were dried over MgSC^ and concentrated to give the desired product. LCMS calculated for C18H24CIN4 (M+H)+: m/z = 331.2; Found: 331.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-[5-chloro-8-(3-methoxypiperidin-l-yl)quinolin-7-yl]ethanamine (0.033 g, 0.10 mmol) (10033-24), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.041 g, 0.21 mmol) and N,N- diisopropylethylamine (0.054 mL, 0.31 mmol) in ethanol (0.5 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. First peak retention time 1.668 minutes, LCMS calculated for C22H25CIN7O (M+H)+: m/z = 438.2; Found: 438.0. Second peak retention time 1.708 minutes, LCMS calculated for C22H25C1N70 (M+H)+: m z = 438.2; Found: 438.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-[5-chloro-8-(3-methoxypyrrolidin-l-yl)quinolin-7-yl]ethanamine (0.0345 g, 0.113 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.0449 g, 0.226 mmol) and N, N-diisopropylethylamine (0.0590 mL, 0.338 mmol) in ethanol (0.5 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge C 18 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. First peak retention time 1.521 minutes, LCMS calculated for C21H23CIN7O (M+H) : m/z = 424.2; Found: 424.0. Second peak retention time 1.546 minutes, LCMS calculated for C21H23CIN7O (M+H)+: m/z = 424.2; Found: 424.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-[5-chloro-8-(4-cyclobutylpiperazin-l-yl)quinolin-7-yl] ethanamine (0.063 g, 0.18 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.074 g, 0.37 mmol) and N, N-diisopropylethylamine (0.095 mL, 0.55 mmol) in ethanol (0.6 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge C 18 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. LCMS calculated for C^FLsClNs (M+H)+: m/z = 463.2; Found: 463.2. 1H NMR (DMSC ¾, 300 MHz) delta 9.88 (1H, br s), 8.97 (1H, dd, J= 3.9 and 1.5 Hz), 8.51 (1H, dd, J= 8.4 and 1.5 Hz), 8.42 (1H, s), 8.32 (1H, s), 7.98 (1H, s), 7.67 (1H, dd, J= 8.4 and 4.2 Hz), 6.44 (1H, m), 4.38 (1H, m), 4.15 (1H, m), 3.82 (1H, m), 3.56-3.45 (3H, m), 3.20-3.04 (3H, m), 2.25 (4H, m), 1.81-1.69 (3H, m), 1.57 (3H, d, J= 6.9 Hz) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-[8-(l,4'-bipiperidin- -yl)-5-chloroquinolin-7-yl]ethanamine (0.015 g, 0.040 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.016 g, 0.080 mmol) and N, N-diisopropylethylamine (0.021 mL, 0.12 mmol) in ethanol (0.3 mL) was heated at 110 C overnight. The resulting mixture was purified on a preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. LCMS calculated for C26H32CIN8 (M+H)+: m/z = 491.2; Found: 491.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-[5-chloro-8-(4-methoxypiperidin-l-yl)quinolin-7-yl]ethanamine (0.023 g, 0.072 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.029 g, 0.14 mmol) and N, N-diisopropylethylamine (0.038 mL, 0.22 mmol) in ethanol (0.5 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. LCMS calculated for C22H25CIN7O (M+H)+: m/z = 438.2; Found: 438.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-[5-chloro-8-(4-phenylpiperidin-l-yl)quinolin-7-yl]ethanamine (0.026 g, 0.071 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.028 g, 0.14 mmol) and N, N-diisopropylethylamine (0.037 mL, 0.21 mmol) in ethanol (0.5 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. LCMS calculated for C27H27C1N7 (M+H)+: m/z = 484.2; Found: 484.2. 1H NMR (DMSO-< 5, 300 MHz) delta 9.02 (1H, dd, J= 3.9 and 1.5 Hz), 8.50 (1H, dd, J= 8.4 and 1.5 Hz), 8.36 (2H, m), 7.93 (1H, s), 7.65 (1H, dd, J= 9.0 and 4.2 Hz), 7.31 (4H, m), 7.19 (1H, m), 6.43 (1H, br s), 4.16 (1H, m), 3.97 (1H, m), 3.35 (1H, m), 2.94 (1H, m), 2.78 (1H, m), 2.42 (1H, m), 1.86 (4H, m), 1.63 (3H, d, J= 7.2 Hz) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 2-{l-[7-(l-aminoethyl)-5-chloroquinolin-8-yl]piperidin-4-yl} ethanol (0.109 g, 0.326 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.130 g, 0.654 mmol) and N, N- diisopropylethylamine (0.171 mL, 0.979 mmol) in ethanol (2 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. LCMS calculated for C23H27CIN7O (M+H)+: m/z = 452.2; Found: 452.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-{5-chloro-8-[4-(pyridin-4-ylmethyl)piperazin-l-yl]quinolin-7-yl} ethanamine (0.021 g, 0.055 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.022 g, 0.11 mmol) and N, N- diisopropylethylamine (0.029 mL, 0.16 mmol) in ethanol (0.5 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. LCMS calculated for C26H27CIN9 (M+H)+: m/z = 500.2; Found: 500.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-[5-chloro-8-(4-phenoxypiperidin-l-yl)quinolin-7-yl]ethanamine (0.023 g, 0.060 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.024 g, 0.12 mmol) and N, N-diisopropylethylamine (0.031 mL, 0.18 mmol) in ethanol (0.5 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. LCMS calculated for C27H27CIN7O (M+H)+: m/z = 500.2; Found: 500.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of l-[5-chloro-8-(3-phenylpyrrolidin-l-yl)quinolin-7-yl]ethanamine (0.024 g, 0.068 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.027 g, 0.14 mmol) and N, N-diisopropylethylamine (0.036 mL, 0.20 mmol) in ethanol (0.5 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. First peak retention time 2.273 minutes, LCMS calculated for C26H25CIN7 (M+H)+: m/z = 470.2; Found: 470.2. Second peak retention time 2.345 minutes, LCMS calculated for C26H25C1N7 (M+H)+: m/z = 470.2; Found: 470.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of N-{(3S)-l-[7-(l-aminoethyl)-5-chloroquinolin-8-yl]pyrrolidin-3-yl} propanamide (0.010 g, 0.029 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.011 g, 0.058 mmol) and N, N- diisopropylethylamine (0.015 mL, 0.086 mmol) in ethanol (0.3 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired poduct as a TFA salt. First peak retention time 1.715 minutes, LCMS calculated for C23H26C1N80 (M+H)+: m/z = 465.2; Found: 465.1. Second peak retention time 1.750 minutes, LCMS calculated for C23H26C1N80 (M+H)+: m/z = 465.2; Found: 465.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of N-{(35)-l-[7-(l-aminoethyl)-5-chloroquinolin-8-yl]pyrrolidin-3-yl} -2- methylpropanamide (0.023 g, 0.064 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.025 g, 0.13 mmol) and N, N- diisopropylethylamine (0.033 mL, 0.19 mmol) in ethanol (0.5 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired roduct as a TFA salt. First peak retention time 1.912 minutes, LCMS calculated for C24H28C1N80 (M+H)+: m/z = 479.2; Found: 479.1. Second peak retention time 1.943 minutes, LCMS calculated for C24H28C1N80 (M+H)+: m/z = 479.2; Found: 479.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of methyl {(3S)-l-[7-(l-aminoethyl)-5-chloroquinolin-8-yl] pyrrolidin-3- yl}carbamate (0.042 g, 0.12 mmol), <strong>[767-69-1]6-bromo-9H-purine</strong> (0.048 g, 0.24 mmol) and N, N- diisopropylethylamine (0.063 mL, 0.36 mmol) in ethanol (0.6 mL) was heated at 110 C overnight. The mixture was purified on a preparative LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at a flow rate of 30 mL/min) to give the desired product as a TFA salt. First peak retention time 1.923 minutes, LCMS calculated for C22H24CIN8O2 (M+H)+: m/z = 467.2; Found: 467.1. Second peak retention time 1.935 minutes, LCMS calculated for C22H24CIN8O2 (M+H)+: m z = 467.2; Found: 467.1. |
Tags: 767-69-1 synthesis path| 767-69-1 SDS| 767-69-1 COA| 767-69-1 purity| 767-69-1 application| 767-69-1 NMR| 767-69-1 COA| 767-69-1 structure
[ 28279-49-4 ]
6-Bromo-4H-imidazo[4,5-b]pyridine
Similarity: 0.61
[ 90993-26-3 ]
7-Bromo-1H-imidazo[4,5-c]pyridine
Similarity: 0.58
[ 28279-41-6 ]
6-Bromo-5-methyl-1H-imidazo[4,5-b]pyridine
Similarity: 0.56
[ 6055-72-7 ]
7H-Purin-6-amine hydrochloride hydrate (2:2:1)
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Code | Phrase |
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P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
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P306 | IF ON CLOTHING: |
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P314 | Get medical advice/attention if you feel unwell. |
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P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
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P381 | Eliminate all ignition sources if safe to do so. |
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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. |
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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. |
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P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
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P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
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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 |
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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 |
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H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
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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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