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CAS No. : | 200064-13-7 | MDL No. : | MFCD11656285 |
Formula : | C9H11BrN2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | N/A |
M.W : | 243.10 g/mol | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.44 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 57.66 |
TPSA : | 25.36 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.87 cm/s |
Log Po/w (iLOGP) : | 2.26 |
Log Po/w (XLOGP3) : | 1.29 |
Log Po/w (WLOGP) : | 1.3 |
Log Po/w (MLOGP) : | 0.97 |
Log Po/w (SILICOS-IT) : | 2.12 |
Consensus Log Po/w : | 1.59 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.44 |
Solubility : | 0.892 mg/ml ; 0.00367 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.42 |
Solubility : | 9.19 mg/ml ; 0.0378 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.07 |
Solubility : | 0.207 mg/ml ; 0.000853 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.15 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
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* 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 |
---|---|---|
1: 22% 2: 17% 3: 40% | With sodium amide; sodium t-butanolate In tetrahydrofuran at 40 - 50℃; for 0.75h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium amide; <i>tert</i>-butyl alcohol In tetrahydrofuran at 20℃; for 0.75h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With piperidine; copper(l) iodide at 100℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 115℃; for 18h; Inert atmosphere; | |
65% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; for 4h; Inert atmosphere; Microwave irradiation; | 1 To a solution of 3,5-dibromopyridine (XL) (1.68 g, 7.1 mmol) in dioxane (14 mL) was added morpholine (682 mg, 7.8 mmol), CsCO3 (3.24 g, 9.93 mmol) and xantphos (123 mg, 0.21 mmol). The solution was degassed before adding Pd2(dba)3 (195 mg, 0.21 mmol). The reaction was microwaved at 90° C. for 4 h. The reaction was poured into a mixture of CHCl3/ H2O; the aqueous layer was separated, washed with water, then brine and concentrated under vacuum. The crude product was purified on a silica gel column (100% hexane→1:3 EtOAc:hexane) to give 4-(5-bromopyridin-3-yl)morpholine (XLI) as a yellow solid (1.12 g, 4.6 mmol, 65% yield). ESIMS found C9H11BrN2O m/z 244 (M+H). |
63% | In 1-methyl-pyrrolidin-2-one; toluene at 180℃; for 1.1h; Microwave irradiation; |
55% | With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene for 12h; Heating; | |
38% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; for 5h; Inert atmosphere; | 96.1 Step 7: Preparation of 4-(5-bromopyridin-3-yl)morpholine To a solution of 3,5-dibromopyridine (1.10 g, 4.60 mmol) in dioxane (2 mL) was added morpholine (200 mg, 2.30 mmol), CS2CO3 (1.10 g, 3.20 mmol), XantPhos (39 mg, 0.068 mmol) and Pd2(dba)3 (62 mg, 0.068 mmol). The resulting mixture was degassed and purged with N2 for three times and then stirred at 90 °C for 5 h under N2. A yellow suspension was formed. TLC-Plate 1 (EtO Ac/PE = 1 : 1) showed starting material was consumed and new spots were formed at Rf = 0.22 and 0.82. LCMS showed the starting material was consumed nearly and the purity of the desired product (Rt = 0.439 min; MS Calcd: 242.0; MS Found: 244.7 [M+H]+). H2O (15 mL) and DCM (20 mL) was added to the reaction mixture and then separated. The combined organic layer was washed with brine (10 mL) dried over anhydrous Na2S04 and concentrated. The crude product was purified by combi flash (50% EtOAc in pentane) and concentrated to give 4-(5-bromopyridin-3-yl)morpholine (300 mg, yield: 38%) as a light yellow solid. (1285) NMR (400 MHz, CDCh) d 3.21 (4H, t, J= 5.2 Hz), 3.87 (4H, t, J= 4.8 Hz), 7.30 (1H, t, J = 2.0 Hz), 8.16 (1H, d, .7= 2.0 Hz), 8.21 (1H, d, .7= 2.4 Hz). |
33% | With N,N,N,N-tetraethylammonium tetrafluoroborate In N,N-dimethyl-formamide; acetonitrile at 20℃; for 4.5h; Electrochemical reaction; | |
19.5% | In 1-methyl-pyrrolidin-2-one; toluene at 180℃; for 1h; Microwave irradiation; | 1 Step 1: 4-(5-bromopyridin-3-yl)morpholine To a solution of morpholine (3.67 g, 4.23 mmol), NMP (2 mL) and toluene (4 mL) was added 3,5-dibromopyridine (1.00 g, 4.20 mmol) and the mixture was heated under microwave conditions at 180 °C for 1 h. The solution was partitioned between DCM and water, the organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography eluting with (EtOAc: PE= 1:5). (200 mg, yield 19.5%) MS (ESI+) e/z: 243.0 [M+1]+LCMS. |
With sodium t-butanolate In toluene at 120℃; for 5h; | 80 A mixture of 3,5-dibromopyridine (2.121 g, 8.95 mmol), BINAP (0.279 g, 0.448 mmol), Pd2(dba)3 (0.137 g, 0.149 mmol) and sodium fert-butoxide (1.434 g, 14.92 mmol) in toluene (50 mL) was added morpholine (0.65 mL, 7.46 mmol). The mixture was then heated at 120 °C for ca. 5 h. After cooling to RT, the reaction mixture was filtered through celite and the filtrate was concentrated. The residue was purified by normal phase chromatography, eluting with a gradient of 0-50% ethyl acetate in DCM, to give the title compound (1 .62 g). LCMS (A) m/z: 243/245 [M+1]+, Rt 0.83 min (acidic), | |
1.42 g | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 120℃; Sealed tube; Inert atmosphere; | 57 Synthesis of 6-(5-morpholino-3-pyridyl)-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide (Compound 90, Table 1) In a sealable tube, to a mixture of 3,5-dibromo-pyridine (3.3 g, 13.8 mmol) and NaOtBu (0.051 g, 23 mmol) in toluene (70 mL), is added morpholine (1.0 g, 11.5 mmol). The mixture is bubbled with Argon for 5 min, and then BINAP (428.9 mg, 0.69 mmol) and Pd2(dba)3 (210.2 mg, 0.23 mmol) are added. The reaction mixture is bubbled with Argon for another 5 min. Then the cap is sealed and the reaction mixture is heated at 120° C. overnight and then is cooled to room temperature. The reaction mixture is filtered through diatomaceous earth and washed with DCM. The filtrate is partitioned between water and DCM. The aqueous phase is further extracted with DCM (2×). The combined DCM phases are concentrated. The crude is purified by flash chromatography on a silica gel column (EtOAc/ heptane 0 to 50% gradient, then 50%) to provide 1.42 g of 4-(5-bromo-3-pyridyl)morpholine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 89 percent / piperidine; CuI / Pd(PPh3)2Cl2 / 48 h / 100 °C 2: K2CO3 / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 89 percent / piperidine; CuI / Pd(PPh3)2Cl2 / 48 h / 100 °C 2: K2CO3 / methanol 3: 16 percent / Et3N; CuI / Pd(PPh3)2Cl2 / acetonitrile / 1 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: 3,5-dibromopyridine With TurboGrignard In tetrahydrofuran at 0 - 25℃; for 1.16667h; Inert atmosphere; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #3: lithium morpholide Further stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.9% | With potassium carbonate In N,N-dimethyl-formamide at 120℃; | General procedure: To a solution of 3,5-dibromopyridine (XXXVIII) (2.90 g, 12.24 mmol) in dry DMF (20 mL) was added 1 -methylpiperazine (2.987 mL, 26.93 mmol) and K2C03 (5.58 g, 40.39 mmol). The reaction was heated at 120°C overnight. An additional portion of 1- methylpiperazine (6 mL) was added and heating was continued for another 24 h. The reaction was poured into ice water and filtered. The filtrate was extracted with 66% MeOH/CHCl3. The organic layer was dried over MgS04, filtered and concentrated under vacuum to yield l -(5- bromopyridin-3-yl)-4-methylpiperazine (XL) as a brown viscous oil (2.49 g, 9.76 mmol, 79.8% yield). ESIMS found for Ci0Hi4BrN3 mlz 256 (M+H). |
40% | ||
40% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: diethylamine; n-hexylmagnesium chloride / tetrahydrofuran / -78 °C 1.2: -40 - 0 °C 2.1: cesium fluoride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride Overall yield = 64 %; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane 2.1: N,N,N,N,-tetramethylethylenediamine; t-butyldimethylsiyl triflate / tetrahydrofuran; diethyl ether / -78 - 23 °C 2.2: -78 °C 2.3: -78 °C 3.1: diethylamine; n-hexylmagnesium chloride / tetrahydrofuran / -78 °C 3.2: -40 - 0 °C 4.1: cesium fluoride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: N,N,N,N,-tetramethylethylenediamine; t-butyldimethylsiyl triflate / tetrahydrofuran; diethyl ether / -78 - 23 °C 1.2: -78 °C 1.3: -78 °C 2.1: diethylamine; n-hexylmagnesium chloride / tetrahydrofuran / -78 °C 2.2: -40 - 0 °C 3.1: cesium fluoride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate In 1,4-dioxane at 100℃; for 5h; | 81 A mixture of 4-(5-bromo-3-pyridinyl)morpholine (Description 80) (360 mg, 1.481 mmol), bis(pinacolato)diboron (564 mg, 2.221 mmol), PdCI2(dppf).DCM adduct (121 mg, 0.148 mmol) and potassium acetate (436 mg, 4.44 mmol) in 1 ,4-dioxane (6 mL) was heated at 100 °C for ca. 5 h. The mixture was concentrated and then diluted with DCM (50 mL) and washed with water (30 mL x 3). The organic layer was dried and concentrated, to give what was thought to be the title compound (430 mg) which was used in the next step (Suzuki coupling) without further purification. LCMS (A) m/z: 209 [M+1 ]+, Rt 0.42 min (acidic) [corresponding to the boronic acid]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium acetate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 5 h / 100 °C 2: potassium carbonate; water / tetrakis(triphenylphosphine) palladium(0); bis-triphenylphosphine-palladium(II) chloride / N,N-dimethyl-formamide; 1,4-dioxane / 0.25 h / 120 °C / microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.3% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In 1,4-dioxane at 120℃; for 1h; Microwave irradiation; | 2 Step 2: l-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)-4-(5- morpholinopyridin-3-yl)piperazin-2-one A solution of 4-(5-bromopyridin-3-yl)morpholine (100 mg, 0.413 mmol), l-(3- (3,4-dihydroisoquinolin-2(lH)-yl)-2-hydroxypropyl)piperazin-2-one (119 mg, 0.413 mmol), X-phos (20 mg, 0.042 mmol), Pd(dba)2 (10 mg, 0.017 mmol) and NaOiBu (59.0 mg, 0.615 mmol) in dioxane (5 mL) was heated at 120 °C 1 h under microwave conditions. The crude reaction mixture was filtered, concentrated, and purified by preprative HPLC purification. (6.10 mg, yield 3.3%) 1H NMR (MeOD, 400 MHz), δ ppm: 7.76 (d, J=2.3 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.17 - 7.07 (m, 3H), 7.07 - 7.01 (m, 1H), 6.89 - 6.80 (m, 1H), 4.28 - 4.18 (m, 1H), 3.93 (s, 2H), 3.89 - 3.82 (m, 4H), 3.82 - 3.72 (m, 4H), 3.71 - 3.63 (m, 1H), 3.59 (t, J=1.0 Hz, 2H), 3.32 - 3.28 (m, 1H), 3.27 - 3.16 (m, 4H), 2.99 - 2.90 (m, 2H), 2.90 - 2.81 (m, 2H), 2.68 - 2.58 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,4-dioxane; water at 90℃; for 1h; Sealed tube; Inert atmosphere; | 57 Synthesis of 6-(5-morpholino-3-pyridyl)-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide (Compound 90, Table 1) In a sealed tube which contains the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (generated according to the procedure for Step 3 of Example 16 in 5 ml 1,4-dioxane, 0.78 mmol) is added 4-(5-bromo-pyridin-3-yl)-morpholine (228 mg, 0.94 mmol), Na2CO3 (166 mg, 1.56 mmol) and water (1.0 ml). The mixture is bubbled with Argon for 5 min. Then PdCl2(DPPF) DCM complex (64 mg, 0.078 mmol) is added. The mixture is then bubbled with Argon for 5 min. The cap is sealed and the mixture is heated at 90° C. in oil bath for 1 h. The reaction mixture is cooled to room temperature. The reaction mixture is filtered through diatomaceous earth and washed with DCM. The filtrate is partitioned between water and DCM. The aqueous phase is extracted with DCM. The combined DCM phases are concentrated. The crude is purified by flash silica gel column (MeOH/ DCM 0 to 4% gradient, then 4%). The fractions which contain the desired product are combined, concentrated and further purified by C-18 prep HPLC (MeCN with 0.1% TFA/Water with 0.1% TFA, 20 ml/min, 0 to 45% gradient over 10 min run). The desired fractions are combined and basified by 1N Na2CO3 to pH=10, and are extracted by DCM. The DCM phases are combined and concentrated under vacuum to obtain 60 mg of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34 mg | With ammonium hydroxide; copper(II) oxide In 1-methyl-pyrrolidin-2-one; dichloromethane at 120℃; for 1h; Microwave irradiation; | 0090-1 0090-1 0090-1 A 25% ammonia aqueous solution (2 mL) was added to a mixture of 4-(5-bromopyridin-3-yl)morpholine (447 mg) and copper(I) oxide (130 mg) in N-methylpyrrolidone (2 mL), followed by stirring at 120° C. for 60 minutes using a microwave reaction apparatus. Dichloromethane and water were added to the reaction mixture. The organic layer was collected by separation, and dried over anhydrous sodium sulfate. The obtained solution was purified by silica gel column chromatography (methanol-ethyl acetate), thereby obtaining 5-morpholinopyridine-3-amine (34 mg). MS m/z (M+H): 180. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With tris-(dibenzylideneacetone)dipalladium(0); dicyclohexyl[3,6-dimethoxy-2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]phosphine; caesium carbonate In 1,4-dioxane at 100℃; for 18h; Inert atmosphere; | 96.2 Step 2: Preparation of l-(5-methyl-3-((5-morpholinopyridin-3-yl)amino)-5H-chromeno[4,3- c]pyridin-8-yl)pynOlidin-2-one To a mixture of Pd2(dba)3 (15 mg, 0.017 mmol) in dioxane (1 mL) was added BrettPhos (18 mg, 0.034 mmol). The resulting mixture was degassed and purged with N2 and then stirred at 50 °C for 10 min. The reaction mixture was cooled to 20 °C and l-(3-amino-5- methyl-5H-chromeno[4,3-c]pyridin-8-yl)pynOlidin-2-one (50 mg, 0.17 mmol), 4-(5- bromopyridin-3-yl)morpholine (54 mg, 0.22 mmol) and CS2CO3 (165 mg, 0.500 mmol) were added and then stirring at 100 °C for 18 h under N2. A black suspension was formed. LCMS showed the starting material was consumed completely and the purity of the desired product (Rt = 0.701 min; MS Calcd: 457.1; MS Found: 458.2 [M+H]+). The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by prep-HPLC (0.05%NH3·H2q as an additive) and lyophilized to give l-(5-methyl-3-((5-morpholinopyridin- 3-yl)amino)-5H-chromeno[4,3-c]pyridin-8-yl)pynOlidin-2-one (27.7 mg, yield: 35%) as an off-white solid. (1289) NMR (400 MHz, DMSO-rie) d 1.52 (3H, d, J= 6.8 Hz), 2.01-2.09 (2H, m), 2.50 (2H, overlap with DMSO), 3.15 (4H, t, J= 4.8Hz), 3.77 (4H, t, J= 4.8 Hz), 3.83 (2H, t , J= 7.6 Hz), 5.26 (1H, q, J= 6.4 Hz), 6.72 (1H, s), 7.30 (1H, dd, J= 8.4, 2.4 Hz), 7.38 (1H, d , J= 2.4 Hz), 7.87 (3H, dd, J= 8.8 Hz, 2.0 Hz), 8.28 (1H, d, J= 2.0 Hz), 8.66 (1H, s), 9.32 (1H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In 1,4-dioxane; water Inert atmosphere; Heating; |
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